Spatial aspects of Ca2+ signalling

Spatial aspects of Ca²⁺ signalling

a, Elementary events (red) result from the entry of external Ca²⁺ across the plasma membrane or release from internal stores in the endoplasmic or sarcoplasmic reticulum (ER/SR). They generate localized concentrations of Ca²⁺ that can activate many processes, including export of cellular material (1), opening of K⁺ channels (2) and metabolism in the mitochondria (3). The Ca²⁺ signals can also enter the nucleus (4). All of these processes respond to the very high concentrations of Ca²⁺ that build up within the sub-domain of the elementary events. b, Global Ca²⁺ signals are produced by coordinating the activity of elementary events to produce a Ca²⁺ wave that spreads throughout the cell. c, The activity of neighbouring cells within a tissue can be coordinated by an intercellular wave that spreads from one cell to the next.

Gut microbiota in health and disease

Gut microbiota in health and disease

The human gastrointestinal (GI) tract contains complex consortia of trillions of microorganisms (approximately 1 × 10¹³ to 1 × 10¹⁴, biomass > 1 kg), thousands of bacterial phylotypes, as well as hydrogen-consuming methanogenic archaea with a collective genome (also termed microbiome), the majority of which resides in the colon  As a whole, the microbiome represents more than 100 times the human genome. Thus, the human ‘metagenome’ consists of a mixture of genes embedded in the human genome (Homo sapiens) and in the genomes of our microbial partners. The microbiota and its microbiome provide us humans with additional gene products, we lack, and these serve many functions pertinent to the maintenance of our homeostasis. The human gut microbiota system may be regarded as a ‘microbial organ’ within the gut, which contributes to multiple host processes including the defense against pathogens at the gut level, immunity (mediated through a number of signal molecules and metabolites), the development of the intestinal microvilli, and the synthesis of several vitamins. Accumulating evidence indicates that the gut microbiota has a crucial role in conditions including obesity, diabetes, non-alcoholic fatty liver disease, inflammatory bowel disease (IBD) and even cancer. Gut microbial composition among healthy humans is influenced by host genotype, diet, age and sex, and it appears that organic disease and drugs can modulate microbiome composition and activities. At birth, the gut is sterile and is colonized immediately, ultimately developing into a stable community, although there are marked variations in microbial composition between individuals. Within an individual the composition is remarkably stable at different anatomical locations along the gut, but absolute number vary greatly, ranging from 10¹¹ cells g⁻¹ content in the ascending colon to 10^{7–8 in the distal ileum and 10−2–3 in the proximal ileum and jejunum.}

Gut Microbiota Host Health

Gut Microbiota Host Health

The intestinal microbiota is a complicated ecosystem that influences many aspects of host physiology (i.e. diet, disease development, drug metabolism, and regulation of the immune system). It also exhibits spatial patterning and temporal dynamics.

As the microbiota is recognized as an entirely separate organ (and containing a diversity of genes that is at least 100 times greater than the other organs

The microbiota plays important roles exerting functions essential to the maintenance of human health and well being, such as stimulation of immune system, antagonistic effects against pathogens, detoxification of carcinogenic compounds, fermentation of nondigestible food ingredients and release of a variety of metabolites involved in the crosstalk between the microbiota and the host. More than 80% of the species of the dominant intestinal microbiota cannot be cultivated by the methods available.

The catalog contains 3.3 million non-redundant genes, 150-fold more than the human genome equivalent and includes a large majority of the gut metagenomic sequences determined across three continents,

Gut microbiota epithelial function and derangements in obesity

Gut microbiota epithelial function and derangements in obesity

The gut epithelium is a barrier between the ‘outside' and ‘inside' world. The major function of the epithelium is to absorb nutrients, ions and water, yet it must balance these functions with that of protecting the ‘inside' world from potentially harmful toxins, irritants, bacteria and other pathogens that also exist in the gut lumen. The health of an individual depends upon the efficient digestion and absorption of all required nutrients from the diet. This requires sensing of meal components by gut enteroendocrine cells, activation of neural and humoral pathways to regulate gastrointestinal motor, secretory and absorptive functions, and also to regulate food intake and plasma levels of glucose. In this way, there is a balance between the delivery of food and the digestive and absorptive capacity of the intestine. Maintenance of the mucosal barrier likewise requires sensory detection of pathogens, toxins and irritants; breakdown of the epithelial barrier is associated with gut inflammation and may ultimately lead to inflammatory bowel disease. However, disruption of the barrier alone is not sufficient to cause frank inflammatory bowel disease. Several recent studies have provided compelling new evidence to suggest that changes in epithelial barrier function and inflammation are associated with and may even lead to altered regulation of body weight and glucose homeostasis. This article provides a brief review of some recent evidence to support the hypothesis that changes in the gut microbiota and alteration of gut epithelial function will perturb the homeostatic humoral and neural pathways controlling food intake and body weight.

GUT MICROBIOTA AND HOMEOSTASIS

GUT MICROBIOTA AND HOMEOSTASIS

The gastro-intestinal microbiota is a highly diverse bacterial community that performs an important digestive function and, at the same time, provides resistance against colonization by entero-pathogenic bacteria. Commensal bacteria resist pathogens thanks to resources competition, growth inhibition due to short-chain fatty acid production, killing with bacteriocins, and immune responses stimulation, external challenges such as antibiotic therapies can harm the microbiota stability and make the host susceptible to pathogen colonization

The human microbiome plays a key role in a wide range of host-related processes and has a profound effect on human health.

The human body is a complex ecosystem where microbes compete, and cooperate. These interactions can support health or promote disease, e.g. in dental plaque formation.

In nature, organisms rarely live in isolation, but instead coexist in complex ecologies with various symbiotic relationships. As defined in macroecology, observed relationships between organisms span a wide range including win-win (mutualism), win-zero (commensalism), win-lose (parasitism, predation), zero-lose (amensalism), and lose-lose (competition) situations

These interactions are also widespread in microbial communities, where microbes can exchange or compete for nutrients, signaling molecules, or immune evasion mechanisms

Gut microbiota and homeostasis and health

Gut microbiota and homeostasis and health

The gut microbiota has profound effects on the health and wellness of the host.

The human intestine is lined by epithelial cells that process nutrients and provide the first line of defense against food antigens and pathogens. Approximately one-sixth of intestinal epithelial cells are shed (exfoliated) daily.

This corresponds to the daily exfoliation of 10⁸ to 10¹⁰ cells.

 

Gut Brain Interaction in Sepsis

Gut Brain Interaction in Sepsis

The Enteric Nervous System: The Brain in the Gut

The gut has a mind of its own, the "enteric nervous system". Just like the larger brain in the head, researchers say, this system sends and receives impulses, records experiences and respond to emotions. Its nerve cells are bathed and influenced by the same neurotransmitters. The gut can upset the brain just as the brain can upset the gut.

 

The gut's brain or the "enteric nervous system" is located in the sheaths of tissue lining the esophagus, stomach, small intestine and colon. Considered a single entity, it is a network of neurons, neurotransmitters and proteins that zap messages between neurons, support cells like those found in the brain proper and a complex circuitry that enables it to act independently, learn, remember and, as the saying goes, produce gut feelings.

 

The gut's brain is reported to play a major role in human happiness and misery. Many gastrointestinal disorders like colitis and irritable bowel syndrome originate from problems within the gut's brain. Also, it is now known that most ulcers are caused by a bacterium not by hidden anger at one's mother.

 

‘Giant’ bacteria and giant virus

‘Giant’ bacteria and giant virus

It is commonly accepted that c. 80% of the bacterial species found by molecular tools in the human gut are uncultured or even unculturable

The typical diameter of the isolated bacteria ranged from 0.5 to 1.5 μm

the largest isolated bacterium, Microvirga massiliensis, reached 2.28 μm according to transmission electron microscopy, and was also shown to possess the largest genome (9.35 Mb) of any bacterium previously obtained from a human sample

The giant (194 nm in diameter) Senegalvirus isolated by amoebal co-culture is the first giant virus ever isolated from the human gut.

From prokaryotes to eukaryotes

From prokaryotes to eukaryotes

The appearance of eukaryotic cells ~2 billion years ago has been linked to the introduction of oxygen in the atmosphere and therefore aerobic metabolism. The increased presence of oxygen produces a more efficient energy source in the form of aerobic metabolism, producing 16–18 times more adenosine triphosphate (ATP) per hexose sugar than anaerobic metabolism. Since aerobic metabolism generates more energy, approximately 1000 more reactions can occur than under anaerobic metabolism.

This allowed the generation of new metabolites, for example, steroids, alkaloids and isoflavonoids

Steroids and polyunsaturated fatty acids are important elements of membranes; thus, they must have been involved in promoting organelle formation and cell compartmentalisation.

As some of the metabolites produced from respiration are involved in processes that target nuclear receptors, it has been hypothesized that higher ambient oxygen promoted these nuclear signalling systems within cells. Nuclear factors have conserved volumes and are highly hydrophobic, since they must pass through cell membranes. Experiments comparing the volume and hydrophobicity of both aerobic and anaerobic metabolites to those known for nuclear ligands indicate that aerobic metabolites are more hydrophobic and more closely match the required volumes of appropriate molecules for nuclear factors compared to the anaerobic molecules.

Since these appear important in superior eukaryotes, it has been hypothesized that such events influenced by increased oxygen levels have influenced biological evolution.

approximately 68% of transmembrane proteins in humans are high-oxygen content, whereas in most bacteria, such as E. coli, only 36% are oxygen rich. The size of the extracellular domains of transmembrane proteins increased as ambient oxygen concentration increased.

The size of the extracellular domains of transmembrane proteins increased as ambient oxygen concentration increased.

Larger and higher oxygen-containing proteins are more energy demanding than those lacking oxygen in their side chains. However, the primary hypothesis suggests that the presence of large and oxygen-rich amino acids as side chains would have resulted in weak protein structures during anoxic eras

Eukaryotes assign more communication roles to proteins than prokaryotes, allowing for more complex and variable signalling pathways. In order to achieve this, various changes in protein structure and function had to occur during evolution. The secondary structures of transmembrane proteins are more hydrophobic, and oxygen as well as nitrogen is important during the formation of hydrophilic structures. Acquisti et al. studied the oxygen content and the topology of transmembrane proteins of different organisms. The ratio of receptors to channels was higher, with a greater amount of oxygen-rich proteins, in more highly developed and ‘recent’ organisms. For example, approximately 68% of transmembrane proteins in humans are high-oxygen content, whereas in most bacteria, such as E. coli, only 36% are oxygen rich. The size of the extracellular domains of transmembrane proteins increased as ambient oxygen concentration increased. Larger and higher oxygen-containing proteins are more energy demanding than those lacking oxygen in their side chains. However, the primary hypothesis suggests that the presence of large and oxygen-rich amino acids as side chains would have resulted in weak protein structures during anoxic eras. Eukaryotes have an abundance of oxygen in the plasma membrane, as oxygen is utilized in the mitochondria. This compartmentalisation may have evolved as a mechanism to protect the transmembrane proteins, which are rich in oxygen. Through the development of complex compartmentalisation of cells, multiple processes including signalling and oxygen levels could also be controlled in different parts of the cell. In addition, there has been the emergence of multiple cell types within the same ‘greater’ organism, with over 200 different cell types in the adult human body. Multicellular organisms may have required both the accumulation of oxygen-rich amino acids in their transmembrane proteins and the allocation of respiration to specific intracellular compartments, that is, mitochondria.

Five Things Your Microbiome Can Tell You

Five Things Your Microbiome Can Tell You

1. Obesity. Ley et al (2006) and others have identified gut microbes associated with obesity, such as Eubacterium rectale. In addition, Upadhyay et al (2012) did experiments with mouse models and suggested the possibility that the microbiome could be manipulated for weight control in the near future

2. Dietary composition. Wu et al (2011) found that gut enterotypes were strongly associated with long-term diets, particularly protein and animal fat (Bacteroides) versus carbohydrates (Prevotella).

3. Antibiotics. If you have recently taken antibiotics, your gut microflora may not yet have been replenished. Dethlefsen et al (2008) found that ciprofloxacin treatment influenced the abundance of about a third of the bacterial taxa in the gut. Similarly, Jernberg et al (2007) found that long after the selection pressure from a short antibiotic exposure has been removed, there are persistent long term impacts on the human intestinal microbiota that remain for up to two years post-treatment.

4. Allergies. Is your nasal microbiome associated with the profile of chronic sinusitis? Abreu et al (2012) found that multiple, phylogenetically distinct lactic acid bacteria were depleted concomitant with an increase in the relative abundance of a single species, Corynebacterium tuberculostearicum, in patients suffering from chronic sinusitis.

5. Bacterial vaginosis. If you have a penis, your microbiome may be correlated with bacterial vaginosis in women. Price et al (2010) found that two families found in certain penis microbiomes — Clostridiales Family XI and Prevotellaceae — have been previously associated with bacterial vaginosis. This may correspond to frequent infections in your partner.

 

Features of the gut brain axis

Features of the gut brain axis

The brain and the gut are intimately connected via the gut–brain axis, which is a bidirectional communication system involving neural and humoral mechanisms. Neural connections involve the central, autonomic and enteric nervous systems. The enteric nervous system receives modulatory input from the brain and provides information to the brain via ascending neural circuits; it can also operate independently of the brain.

The effector limb of the enteric nervous system integrates physiological responses (including gut motility and secretion) and also modulates immune activity, as most immune cells possess receptors for neurotransmitters. The afferent limb comprises sensory nerves that contribute to gut reflexes and convey information to the brain. This information includes signals about noxious stimuli such as gut distension, as well as potentially dangerous signals, including the presence of bacterial endotoxins or pro-inflammatory cytokines. This information is conveyed to the brain and might result in pain, discomfort, or compensatory responses that are aimed at restoring homeostasis; these responses might involve changes in the gut physiology or immune function (for example, cytokine secretion).

The autonomic nervous system links the gut and the brain and consists of sympathetic and parasympathetic nerves. The vagus nerve is a major pathway for signals originating from the foregut and the proximal colon, whereas sacral parasympathetic nerves innervate the distal colon. The sympathetic system primarily exerts an inhibitory influence on the gut, decreasing intestinal motor function and secretion via the release of neurotransmitters such as noradrenaline. Responses to stress are conveyed via the sympathetic system and the hypothalamic–pituitary–adrenal axis.

The autonomic input from the gut is connected to the limbic system of the brain, the most important components of which are the hippocampus, the amygdala and the limbic cortex. The limbic system is responsible for a range of brain processes: the amygdala integrates responses to fear and arousal, whereas the hippocampus is responsible for memory and spatial navigation, and the limbic cortex regulates olfaction and integrates sensory and motor functions. The limbic system receives input from other brain regions that are responsible for a range of behaviours; these regions include the prefrontal cortex, the anterior cingulated gyrus, the temporal lobe and basal ganglia. Communication between the limbic and autonomic systems provides the neural circuitry underlying the strong link between behaviour and gut function in health (such as stomach 'butterflies') and disease (such as irritable bowel syndrome).

The humoral components of the gut–brain axis consist of the hypothalamic–pituitary–adrenal axis, the enteroendocrine system and the mucosal immune system. The hypothalamic–pituitary–adrenal axis is responsible for stress responses, resulting in the release of corticosterone, adrenaline and noradrenaline. Enteroendocrine cells produce hormones such as cholecystokinin and ghrelin, both of which regulate appetite, and 5-hydroxytryptamine, which has a broad range of effects on gut and brain functions.

Nature Reviews Microbiology 10, 735-742 (November 2012)

 

Features of the gut brain axis

Features of the gut brain axis

The brain and the gut are intimately connected via the gut–brain axis, which is a bidirectional communication system involving neural and humoral mechanisms. Neural connections involve the central, autonomic and enteric nervous systems. The enteric nervous system receives modulatory input from the brain and provides information to the brain via ascending neural circuits; it can also operate independently of the brain.

The effector limb of the enteric nervous system integrates physiological responses (including gut motility and secretion) and also modulates immune activity, as most immune cells possess receptors for neurotransmitters. The afferent limb comprises sensory nerves that contribute to gut reflexes and convey information to the brain. This information includes signals about noxious stimuli such as gut distension, as well as potentially dangerous signals, including the presence of bacterial endotoxins or pro-inflammatory cytokines. This information is conveyed to the brain and might result in pain, discomfort, or compensatory responses that are aimed at restoring homeostasis; these responses might involve changes in the gut physiology or immune function (for example, cytokine secretion).

The autonomic nervous system links the gut and the brain and consists of sympathetic and parasympathetic nerves. The vagus nerve is a major pathway for signals originating from the foregut and the proximal colon, whereas sacral parasympathetic nerves innervate the distal colon. The sympathetic system primarily exerts an inhibitory influence on the gut, decreasing intestinal motor function and secretion via the release of neurotransmitters such as noradrenaline. Responses to stress are conveyed via the sympathetic system and the hypothalamic–pituitary–adrenal axis.

The autonomic input from the gut is connected to the limbic system of the brain, the most important components of which are the hippocampus, the amygdala and the limbic cortex. The limbic system is responsible for a range of brain processes: the amygdala integrates responses to fear and arousal, whereas the hippocampus is responsible for memory and spatial navigation, and the limbic cortex regulates olfaction and integrates sensory and motor functions. The limbic system receives input from other brain regions that are responsible for a range of behaviours; these regions include the prefrontal cortex, the anterior cingulated gyrus, the temporal lobe and basal ganglia. Communication between the limbic and autonomic systems provides the neural circuitry underlying the strong link between behaviour and gut function in health (such as stomach 'butterflies') and disease (such as irritable bowel syndrome).

The humoral components of the gut–brain axis consist of the hypothalamic–pituitary–adrenal axis, the enteroendocrine system and the mucosal immune system. The hypothalamic–pituitary–adrenal axis is responsible for stress responses, resulting in the release of corticosterone, adrenaline and noradrenaline. Enteroendocrine cells produce hormones such as cholecystokinin and ghrelin, both of which regulate appetite, and 5-hydroxytryptamine, which has a broad range of effects on gut and brain functions.

 

Features of the gut brain axis

Features of the gut brain axis

The interplay between the intestinal microbiota and the brain

Nature Reviews Microbiology 10, 735-742 (November 2012)

The brain and the gut are intimately connected via the gut–brain axis, which is a bidirectional communication system involving neural and humoral mechanisms. Neural connections involve the central, autonomic and enteric nervous systems. The enteric nervous system receives modulatory input from the brain and provides information to the brain via ascending neural circuits; it can also operate independently of the brain.

The effector limb of the enteric nervous system integrates physiological responses (including gut motility and secretion) and also modulates immune activity, as most immune cells possess receptors for neurotransmitters. The afferent limb comprises sensory nerves that contribute to gut reflexes and convey information to the brain. This information includes signals about noxious stimuli such as gut distension, as well as potentially dangerous signals, including the presence of bacterial endotoxins or pro-inflammatory cytokines. This information is conveyed to the brain and might result in pain, discomfort, or compensatory responses that are aimed at restoring homeostasis; these responses might involve changes in the gut physiology or immune function (for example, cytokine secretion).

The autonomic nervous system links the gut and the brain and consists of sympathetic and parasympathetic nerves. The vagus nerve is a major pathway for signals originating from the foregut and the proximal colon, whereas sacral parasympathetic nerves innervate the distal colon. The sympathetic system primarily exerts an inhibitory influence on the gut, decreasing intestinal motor function and secretion via the release of neurotransmitters such as noradrenaline. Responses to stress are conveyed via the sympathetic system and the hypothalamic–pituitary–adrenal axis.

The autonomic input from the gut is connected to the limbic system of the brain, the most important components of which are the hippocampus, the amygdala and the limbic cortex. The limbic system is responsible for a range of brain processes: the amygdala integrates responses to fear and arousal, whereas the hippocampus is responsible for memory and spatial navigation, and the limbic cortex regulates olfaction and integrates sensory and motor functions. The limbic system receives input from other brain regions that are responsible for a range of behaviours; these regions include the prefrontal cortex, the anterior cingulated gyrus, the temporal lobe and basal ganglia. Communication between the limbic and autonomic systems provides the neural circuitry underlying the strong link between behaviour and gut function in health (such as stomach 'butterflies') and disease (such as irritable bowel syndrome).

The humoral components of the gut–brain axis consist of the hypothalamic–pituitary–adrenal axis, the enteroendocrine system and the mucosal immune system. The hypothalamic–pituitary–adrenal axis is responsible for stress responses, resulting in the release of corticosterone, adrenaline and noradrenaline. Enteroendocrine cells produce hormones such as cholecystokinin and ghrelin, both of which regulate appetite, and 5-hydroxytryptamine, which has a broad range of effects on gut and brain functions.

 

Factors at the commensal-host interface associated with health and disease

Factors at the commensal-host interface associated with health and disease

Factors at the commensal-host interface associated with health and disease. Environmental and host factors (which are under genetic control) determine the composition and functional consequences of the components within the lumenal milieu. The lumenal milieu consists of commensal microbiota and their products and secreted factors of the host (blue). These lumenal states are metastable at any given point in time and likely age-dependent. Health is associated with symbiosis of the commensal microbiota and host responses (lumenal, epithelial, and subepithelial), which are a reflection of homeostasis. Disease on the other hand is characterized by dysbiosis of the commensal microbiota and the corollary host responses. Whether symbiosis or dysbiosis is a primary or secondary factor in disease development remains an open question. The ultimate development of disease at any given set point in this model is dependent on many factors, which determine tissue tolerance and include genetic susceptibility among others. GPCR43, G protein–coupled receptor 43; PSA, polysaccharide antigen A; Treg, T regulatory cell; ER, endoplasmic reticulum; wt, wild-type allele; mut, mutant allele; TMA, trimethylamine; Th, T helper; IL, interleukin; TGFβ, transforming growth factor–β; IFNγ, interferon-γ; iNKT, invariant natural killer T.

Factors at the commensal host interface associated with health and disease.

Factors at the commensal host interface associated with health and disease.

Environmental and host factors (which are under genetic control) determine the composition and functional consequences of the components within the lumenal milieu. The lumenal milieu consists of commensal microbiota and their products and secreted factors of the host (blue). These lumenal states are metastable at any given point in time and likely age-dependent. Health is associated with symbiosis of the commensal microbiota and host responses (lumenal, epithelial, and subepithelial), which are a reflection of homeostasis. Disease on the other hand is characterized by dysbiosis of the commensal microbiota and the corollary host responses. Whether symbiosis or dysbiosis is a primary or secondary factor in disease development remains an open question. The ultimate development of disease at any given set point in this model is dependent on many factors, which determine tissue tolerance and include genetic susceptibility among others. GPCR43, G protein–coupled receptor 43; PSA, polysaccharide antigen A; Treg, T regulatory cell; ER, endoplasmic reticulum; wt, wild-type allele; mut, mutant allele; TMA, trimethylamine; Th, T helper; IL, interleukin; TGFβ, transforming growth factor–β; IFNγ, interferon-γ; iNKT, invariant natural killer T.

Exposure to a Social Stressor Alters the Structure of the Intestinal Microbiota: Implications for Stressor-Induced Immunomodulation

Exposure to a Social Stressor Alters the Structure of the Intestinal Microbiota: Implications for Stressor-Induced Immunomodulation

The external surfaces of the body are colonized by vast arrays of microbes that outnumber cells of the body by a factor of 10 (i.e., 10¹⁴ bacterial cells to 10¹³ human cells). This means that 90% of the cells of our body are our commensal microbiome. The vast majority of these microbes reside in the intestines as part of the intestinal microbiota, with microbiota levels ranging from < 10⁵ bacteria per gram of digesta in the upper parts of the small intestine, to > 10¹² bacteria per gram of digesta in the large intestine

Many of these bacteria are simple opportunistic colonizers, while the majority are true symbiotic organisms in the sense that they have beneficial interactions with each other and the host. For example, many metabolic activities in the intestines are derived from the microbiota, such as the synthesis of vitamin K and vitamin B complex and the metabolism of carcinogens

Exponential Thinking

it becomes apparent that thinking about the future is truly a brain teaser. Because we are products of billions of years of evolution, we are tuned to think linearly - but the fact is, these are exponential times - and our minds are lost in translation

ER stress-induced inflammation: does it aid or impede disease progression

ER stress-induced inflammation: does it aid or impede disease progression

Schematic representation of IRE1a-mediated, ATF6-mediated, and PERK-mediated inflammatory transcriptional program. Following ER stress, PERK activates NF-kB via translational attenuation. The activated PERK-eIF2a arm causes translational arrest, which leads to decreased levels of IkB protein and a consequent increase in the ratio of NF-kB to IkB. This change in the ratio causes the release of NF-kB protein, which then carries out its proinflammatory transcriptional role in the nucleus. Similarly, the PERK-eIF2a arm also carries out immunomodulation via CHOP, which activates transcription of the gene for IL-23, a proinflammatory cytokine. PERK-eIF2a causes CHOP production via ATF4, whose mRNA is transcribed only under conditions of translational attenuation. Interestingly, it was recently observed that ER stress-induced CHOP activation can also negatively regulate the inflammatory responses by modulating NF-kB as well as JNK (leading to modulation of downstream AP-1 activity). By contrast, ER stress can also cause the activation of IRE1a, which can then bind the tumor-necrosis factor (TNF)-a-receptor-associated factor 2 (TRAF2). Importantly, this IRE1a–TRAF2 complex can activate IkB kinase (IKK). Activated IKK then causes IkB degradation, thereby freeing NF-kB to transcribe the proinflammatory gene program. Similarly, the IRE1a–TRAF2 complex has also been shown to activate the JNK protein, which consequently phosphorylates and activates AP-1 (which in turn transcribes its own inflammatory gene program) [99]. Finally, under conditions of ER stress, ATF6 can leave the ER and reach the Golgi complex, where it can undergo ‘regulated intramembrane proteolysis’ (RIP). During RIP, ATF6 is cleaved by local site 1 and site 2 proteases (S1P and S2P) [6,100]. The activated ATF6 fragments form homodimers and transcribe acute-phase response (APR)-associated genes, such as those encoding acute-phase proteins (APPs) [6,101].

ER stress-induced inflammation in health and disease. Crosstalk between inflammation and ER stress can either aid or impede the pathogenesis and/or progression of certain diseases. For instance, ER stress-induced inflammation and even ER stress on its own, can affect pancreatic b cells as well as adipocytes and macrophages, thereby aiding the progression of type 2 diabetes and obesity, respectively. Obesity-associated inflammation can further aid type 2 diabetes progression by suppressing insulin receptor signaling. Similarly, ER stress-induced inflammation can affect intestinal epithelial cells, Paneth cells, and goblet cells, possibly aiding the progression of inflammatory bowel diseases (IBDs) such as Crohn’s disease and ulcerative colitis. Furthermore, ER stress-induced inflammation has been implicated in aiding the progression of cystic fibrosis and cigarette smoke-induced chronic obstructive pulmonary disease, both of which are chronic inflammatory airway diseases. However, the link between ER stress-induced inflammation and cancer is not as simple, although ER stress-induced inflammation has been shown to aid tumorigenesis, it has also been shown to impede tumorigenesis by inducing immunogenic cell death-based antitumor immunity.

Endothelium is the largest organ in the body strategically located between the wall of blood vessels and the blood stream.

Endothelium is the largest organ in the body strategically located between the wall of blood vessels and the blood stream.

The human body contains approximately 10¹³ endothelial cells weighing approximately 1 kg, and covering a surface area of 4000 to 7000 m² equivalent to the soccer playground.

Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders

Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders

The endothelial cell (EC) surface in an adult human is composed of approximately 1 to 6 × 10¹³ cells, weighs approximately 1 kg, and covers a surface area of approximately 1 to 7 m². ECs line vessels in every organ system and regulate the flow of nutrient substances, diverse biologically active molecules, and the blood cells themselves.

Prokaryotic and Eukaryotic Diversity of the Human Gut

 

Drug and the dynamic microbiome

Drug and the dynamic microbiome

Xenobiotics Shape the Physiologyand Gene Expression of the Active Human Gut Microbiome

The gut microbiome is highly active, similar to nutrient-rich productive systems ► Firmicutes dominate the active and damaged subsets of the gut microbiome ► Both antibiotics and host-targeted drugs rapidly alter the active gut microbiome ► Xenobiotics induce genes for drug metabolism, drug resistance, and stress response

The human gut contains trillions of microorganisms that influence our health by metabolizing xenobiotics, including host-targeted drugs and antibiotics. Recent efforts have characterized the diversity of this host-associated community, but it remains unclear which microorganisms are active and what perturbations influence this activity. Here, we combine flow cytometry, 16S rRNA gene sequencing, and metatranscriptomics to demonstrate that the gut contains a distinctive set of active microorganisms, primarily Firmicutes. Short-term exposure to a panel of xenobiotics significantly affected the physiology, structure, and gene expression of this active gut microbiome. Xenobiotic-responsive genes were found across multiple bacterial phyla, encoding antibiotic resistance, drug metabolism, and stress response pathways. These results demonstrate the power of moving beyond surveys of microbial diversity to better understand metabolic activity, highlight the unintended consequences of xenobiotics, and suggest that attempts at personalized medicine should consider interindividual variations in the active human gut microbiome.

Drive towards complexity

Drive towards complexity

It is of interest to compare anoxygenic light harvesting mechanisms to oxygenic ones. Purple bacteria, which perform anoxygenic photosynthesis, feature the oldest known light harvesting apparatus, while the oxygenic cyanobacteria, plants and green algea are evolutionarily more recent. In a purple bacterial photosynthetic unit pigments form highly symmetric ring-like structures (see figure). In contrast, the pigment network of photosystem I from oxygenic species forms a rather random looking array with a higher packing density of chlorophyll per unit mass. In fact, photosystem I and its associated complexes display a greater complexity in plants as compared to cyanobacteria as discussed in the tale of two photosystems.

DNA

DNA

In bacteria and other simple or prokaryotic cell organisms, DNA is distributed more or less throughout the cell. In the complex or eukaryotic cells that make up plants, animals and in other multi-celled organisms, most of the DNA resides in the cell nucleus. The energy-generating organelles known as chloroplasts and mitochondria also carry DNA, as do many viruses.

Dendritic spines are small actin-rich protrusions on the surface of dendrites whose morphological and molecular plasticity play key roles in learning and memory. Both the form and function of spines are critically dependent on the actin cytoskeleton.

Dendritic spines are small actin-rich protrusions on the surface of dendrites whose morphological and molecular plasticity play key roles in learning and memory. Both the form and function of spines are critically dependent on the actin cytoskeleton.

Dendritic spines are small actin-rich protrusions that form the postsynaptic part of most excitatory synapses. They play critical roles in synaptic function and exhibit a striking degree of structural plasticity, which is closely linked to changes in strength of synaptic connections.Dynamic microtubules and the proteins that specifically associate with the growing microtubule plus-ends recently emerged as temporal and spatial regulators of actin organization, which controls dynamic changes in structure and function of dendritic spines.

Dendritic spines are the major sites of excitatory synaptic input, and their morphological changes have been linked to learning and memory processes.

Defibrillation Plus CPR: A Critical Combination

Defibrillation Plus CPR: A Critical Combination

Early defibrillation is critical to survival from sudden cardiac arrest (SCA) for several reasons

the most frequent initial rhythm in out-of-hospital witnessed SCA is ventricular fibrillation (VF),

the treatment for ventricular fibrillation is defibrillation,

the probability of successful defibrillation diminishes rapidly over time,

and VF tends to deteriorate to asystole over time.

For every minute that passes between collapse and defibrillation, survival rates from witnessed VF SCA decrease 7% to 10% if no CPR is provided.

When bystander CPR is provided, the decrease in survival rates is more gradual and averages 3% to 4% per minute from collapse to defibrillation.

CPR can double or triple survival from witnessed SCA at most intervals to defibrillation.

If bystanders provide immediate CPR, many adults in VF can survive with intact neurologic function, especially if defibrillation is performed within 5 to 10 minutes after SCA.

defibrillation (shock success) is typically defined as termination of VF for at least 5 seconds following the shock.

VF frequently recurs after successful shocks, but this recurrence should not be equated with shock failure.

Shock success using the typical definition of defibrillation should not be confused with resuscitation outcomes such as restoration of a perfusing rhythm (ROSC), survival to hospital admission, or survival to hospital discharge.

Cycles of equilibrium and imbalance at the commensal host interface.

Cycles of equilibrium and imbalance at the commensal host interface.

Homeostasis is associated with symbiotic commensalism and colonization resistance together with epithelial and immune balance. Perturbations, such as enteropathogenic invasions, disrupt this balance by inducing inflammation, resulting not only in tissue destruction but also breakdown in the state of commensalism and, consequently, dysbiosis. Dysbiosis can be associated with the evolution of pathobionts that function as inflammatory allies (for example, Proteobacteria), which are able to flourish in the inflammatory milieu and further promote inflammation induced by the invading pathogen. Some types of perturbations, such as antibiotics, can lead directly to breakdown in commensalism and subsequent colonization by pathobionts and pathogens that are able to take advantage of the niche (for example, C. difficile). Under normal circumstances, the host can restore a metastable state of commensalism associated with control of pathobionts and pathogens, reestablishment of colonization resistance, and tissue repair. Individuals who are unable to accomplish this develop chronic disease. Factors that affect each of these hypothetical parts of this health-disease cycle include genetics, age, and environmental experiences among others. NADPH, reduced form of nicotinamide adenine dinucleotide phosphate; AIEC, adherent-invasive E. coli.

CONVERGENCE TECHNOLOGY

CONVERGENCE TECHNOLOGY

NBICS (NANO-BIO-INFO-COGNO-SOCIO) CONVERGENCE TO IMPROVE HUMAN PERFORMANCE: OPPORTUNITIES AND CHALLENGES

A deep repor from National Science Foundation (USA) about the technologycal convergence (Nano-Bio-Info-Cogno) that is empowering the human perfomance.

 

Nsf Human Perfomance

Peter Ulrich VanDer Kracken

Converging Technologies for Improving Human Performance: Nanotechnology, Biotechnology, Information Technology and the Cognitive Science

Roco, M. C. and W. S. Bainbridge. (eds.). 2002. Converging Technologies for Improving Human Performance: Nanotechnology, Biotechnology, Information Technology and the Cognitive Science, Arlington, VA: National Science Foundation.

CONSCIOUSNESS, BRAIN, AND CAUSALITY

CONSCIOUSNESS, BRAIN, AND CAUSALITY

Consciousness involves awareness, phenomenal experience(composed of what philosophers term“qualia”), sense of self, feelings, apparent choice and control of actions,memory,a model of the world,thought,language,and,e.g.,when we close our eyes, or meditate,internally-generated images and geometri cpatterns. But what consciousness sactually is remains unknown. Most scientists and philosophers view consciousness as an emergent property of complex computation among networks of the brain’s 100 billion“integrate-and-fire”neurons.

Indigital computers, discrete voltage levels represent information units

concept about how a failing kidney and the intestinal microbiota affect each other

concept about how a failing kidney and the intestinal microbiota affect each other

Under physiological conditions, the predominance of symbiotic bacteria, an intact intestinal barrier, defensins production, mucus integrity, and immunoglobulin A (IgA) secretion support the symbiosis between the host and its gut microbiota. An intramural innate immunity controls pathobiont overgrowth inside the lumen of the intestinal tract. (Right part) The metabolic changes that are associated with the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD) change the balance of symbionts and pathobionts in a way that favors pathobiont overgrowth, that is dysbiosis. Pathobiont overgrowth induces inflammation and loss of barrier function that in turn promotes increased translocation of bacterial components and even living bacteria into the host’s internal environment. This process will activate innate immunity characterized by production of proinflammatory cytokines that define a state of systemic inflammation. This process potentially modulates a number of clinically relevant processes in CKD such as the progression of CKD, accelerated atherogenesis, and protein wasting.

‘Endotoxin tolerance’ or transient versus persistent activation of innate immunity

Transient activation of, for example, Toll-like receptors (TLRs) stimulates nuclear factor (NF)-κB-dependent secretion of proinflammatory cytokines that triggers systemic inflammation. Repeated or persistent TLR stimulation of monocytes and macrophages induces ‘tolerance’ or ‘compensatory anti-inflammatory syndrome’ that defines a refractory status of the innate immune system. It appears that in chronic kidney disease/end-stage renal disease (CKD/ESRD), both elements of innate immune activation and acquired immunosuppression coexist because some leukocytes are massively activated whereas others remain deactivated. This results in the clinical syndrome of persistent inflammation accompanied by an immunosuppressive state. IL, interleukin; TGF-β, transforming growth factor-β.