söndag 6 mars 2011

Neural communication outside synapses I. The mystery and magic of glia.

Synapses are 'degraded' more. Synapses are not the only way brain can 'talk' on. The tripartite synapse bought in the communication from glia cells and connective tissue (meridians). Now also extracellular space signaling is found. Proteins and peptides are responsible for 80% of the signaling, said Candace Pert in 'Molecules of Emotion'. Emotions = peptides = control? Emotions exist both as energy and matter, in the vibrating receptors on every cell in the body. The body sings or screams?

Neurons are only about 10 percent of all the cells in the brain. The other 90 percent, so-called glial cells, have talents of their own. Knowing what glial cells do, and how they do it, could help explain brain disorders and how to cure them. But getting neuron-centric brain scientists to accept this is another matter entirely. Glial cells’ activities are subtler. Unlike their flashier electronic cousins, glia speak in chemical whispers.

Video: Visualizing the brain as a Universe of synapses. Only mammals have the brain structure called the cerebral cortex. Scientists believe this six-cell-thick layer coating the brain's surface is largely responsible for our species' intellectual prowess. One single healthy adult's cerebral cortex contains more than 125 trillion - trillion! - synapses. "That's more than the number of stars in 1,500 Milky Way galaxies," says Smith. They come in a variety of types with differing signaling properties - they're more like microprocessors than mere on/off switches. Even the most sophisticated machines we can think of are ridiculously simple in comparison to the human brain, maybe the most complex entity in the known Universe. Smith and his team have figured out how to not only accurately and quickly count but also, effectively, color-code synapses by type. And they've translated all that data into a virtual video "fly-through" - in this case, of a mouse's cerebral cortex. Neurons green, synapses multicolored dots. Can the color code be seen as a quantum charachter? Synapses are turned on/off by gla/GABA, then modulated to 'sing'? But this is surely too simplistic. A single neuron may interconnect with as many as tens of thousands of others, forging circuits of a complexity that leaves computer scientists gasping.

The brain has evolved ways of scaling the absolute strengths of all these synapses so that relative differences in the strength of one versus another are maintained, while the total neuron’s overall metabolic requirement remains within reasonable bounds. Competition is an essential trait for the brain; supply resources are limited.

Synaptic plasticity: rapid, long-lasting tweaks in synaptic strengths believed to mediate the changes that living imposes on our brains. Changing the strengths of a neuron’s thousands of synapses can result in big changes in total metabolic demands on a neuron, Malenka says. Imagine that in response to an experience, 8,000 of a single neuron’s 10,000 synaptic connections to other neurons are strengthened, 1,000 weakened and 1,000 left the same. This could be exhausting to the neuron, or could put it into overdrive.

In physically active test animals, calcium signals, or flares, propagate from astrocyte to astrocyte over relatively huge distances in the animals’ cerebellum (a brain region associated with physical movement). Nearby blood vessels enlarged almost immediately after the flares. When the animals were awake but at rest, neither the flares nor subsequent blood-vessel dilation occurred. This supports the notion that astrocytes monitor neurons’ electrical activity levels and respond by generating calcium flares that, by yet unknown means, lead local blood vessels to supply more nutrients to the active site. Axel Nimmerjahn. Video.

Calciumwaves are behind most of treatments with drugs too.

Most neurobiologists know that neurons, although talented, are slobs. And they’ve known for a couple of decades that astrocytes clean up after them. Astrocytes take care of housekeeping functions such as feeding the neurons (supplying nutrients, energy-rich molecules and neurotransmitter precursors) or mopping up after them (for example, speedily slurping up spent neurotransmitter molecules from the synapses so that the next signal will be a clean one). Also astrocytes play a major role in controlling where and when our brain’s all-important synapses will form (Barres 2005) . Publications list here.

Without the glial cells — astrocytes, microglia and oligodendrocytes — there would be no show at all. Astrocytes are known to send out numerous projections that contact both neurons and the tiny blood vessels that pervade the brain. This would put astrocytes in the catbird seat if one of their objectives were to alter blood flow in response to neuronal activity.

Oligodendrocytes account for 40 percent of the cells in the human brain, extrude a flagship fatty product, myelin, which insulates neuronal surfaces.

Ben Barres and his team have since shown that adding a single protein (thrombospondin) secreted by astrocytes to the medium in which these purified neurons were growing boosted their synapse construction immensely. Astrocytes produce the protein during brain development, “at a time and place synapses are sprouting all over.” When brain maturation is complete, thrombospondin expression shuts down everywhere in the brain — except in the hippocampus, the part of the brain where new memories are formed, and one of the few places in the brain where constant, large-scale synapse formation is known to take place. “But when the brain is injured, the neighborhood astrocytes go into a completely altered state. They take on totally new properties. One of those is that they turn back on thrombospondin expression.”

Could those astrocytes be playing a part in inducing and repairing synapses in the injured brain?

Virtually all of an organism’s cells have the same genes, but in one cell type only some genes work, while in a second type a different set are functional. Likewise, a healthy cell may turn on one set of genes, a sick cell another set. By extracting genetic material from purified cultures of single cell types and pouring the material over a “gene chip” — a device that can quickly quantify the extent to which genes are turned on within cells — Barres and his colleagues have learned which genes are active in each cell type, and at what levels. Gene-profiling comparisons show that the three major glial-cell types are as different from one another as each is from a neuron, Barres says. That is, the genes these cell types turn on vary drastically. This has allowed the Barres group to harvest extremely specific markers for major brain-cell types. Astrocytes envelop neurons’ synapses. One such astrocyte can envelop thousands at a time. A key feature in healthy, young brains — the very ones in which it’s so critical for synapses to form — is, ironically, synapse death. That’s because the developing brain generates far more synapses than it needs. Astrocytes marks (protein q1q) the cell surface for destruction. C1q-mediated synapse loss may turn out to be an important feature of such neurodegenerative disorders as Alzheimer’s. The cardinal feature of all neurodegenerative disease is synapse loss. Also epilepsy with enhanced connectivity?
  • Astrocyte heterogeneity: an underappreciated topic in neurobiology. Zhang Y, Barres BA. Curr Opin Neurobiol. 2010; 20 (5): 588-94

Astrocytes, one of the most numerous types of cells in the central nervous system, are crucial for potassium homeostasis, neurotransmitter uptake, synapse formation, regulation of blood-brain-barrier, and the development of the nervous system. Historically, astrocytes have been studied as a homogeneous group of cells. However, evidence has accumulated that suggests heterogeneity of astrocytes across brain regions as well as within the same brain regions. Astrocytes differ in their morphology, developmental origin, gene expression profile, physiological properties, function, and response to injury and disease. A better understanding of the heterogeneity of astrocytes will greatly aid investigation of the function of astrocytes in normal brain as well as the roles of astrocytes in neurological disorders.
As one ascends the scale of evolutionary complexity, an increasing proportion of the brain’s cells are glial. In the simple nematode worm, they’re sparse; in a fruit fly, they’re up to 25 percent; in a mouse, about 65 percent. In a human brain, behind every great neuron stand nine great glial cells. In an elephant, it’s 97 percent - “Doesn’t that tell us something?” An elephant never forgets.
In certain parts of the brain astrocytes outnumber neurons 10 to 1, resulting in a network engaged in information processing ten times the size of the neuronal network in terms of the number of nodes and several orders of magnitude greater in the number of links or functional connections between nodes. In fact, in some parts of the brain one astrocyte usually connects to six neurons but forms between 100,000 to 140,000 synaptic connections with those neurons. As one moves up the phylogenetic tree, species have more and more astrocytes in their brains as a function of brain complexity culminating with humans, which have the greatest number. Indeed, anecdotally several decades ago neuroscientists made the observation that Albert Einstein's brain had a larger number of astrocytes than an average brain after parts of Einstein's brain were sectioned and histologically stained following his death. More empirically, recent work published earlier this year has shown that human astrocytes are quite different than rodent astrocytes: they are structurally more complex and display more complex signaling. Astrocytes might not just be participating in information processing in the brain, they might actually be making us smarter.
Interesting literature:
  • M Buibas and GA Silva (in press) A framework for simulating and estimating the state and functional topology of complex dynamic geometric networks. Neural Computation. [ArXiv 0908.3934) PDF]
  • BP Sprouse, CL MacDonald, and GA Silva (2010) Computational efficiency of fractional diffusion using adaptive time step memory. ArXiv 1004.5128 PDF
Can diffuse extrasynaptic signaling form a guiding template? asked Semyanov 2008.
Brain functions such as information processing, learning and memory are commonly associated with changes in synaptic strength, the synaptic plasticity. Extrasynaptic diffusion of transmitters thought to mediate only a modulatory effect. Here I suggest a hypothesis that concentration profile of signaling molecules in the extracellular space can form a "diffuse guiding template" for signal propagation through neuronal network. Such template can be potentially involved in information processing and storage.
Regular neurotransmitters are not that important? In Perts model they were responsible only for 20% of the signaling. Synapses are responsible for only about 10 % of the brain communication? (Can Libets finding, the readiness potential, be about entanglement at a distance, by calciumwaves produced by glias?) What are their functional role in the signaling system? We must basically reconsider this?
The term 'tripartite synapse' refers to a concept in synaptic physiology based on the demonstration of the existence of bidirectional communication between astrocytes and neurons. Consistent with this concept, in addition to the classic 'bipartite' information flow between the pre- and postsynaptic neurons, astrocytes exchange information with the synaptic neuronal elements, responding to synaptic activity and, in turn, regulating synaptic transmission. Because recent evidence has demonstrated that astrocytes integrate and process synaptic information and control synaptic transmission and plasticity, astrocytes, being active partners in synaptic function, are cellular elements involved in the processing, transfer and storage of information by the nervous system. Consequently, in contrast to the classically accepted paradigm that brain function results exclusively from neuronal activity, there is an emerging view, which we review herein, in which brain function actually arises from the coordinated activity of a network comprising both neurons and glia.
Astrocytes have been revealed as integral elements involved in the synaptic physiology here.
The meridians are not structural paths but functional piezoelectric ones in the connective tissue, near both blood vessels and nerves. Meridians goes in glia cells in the brain, and are thus regulating the nerves?
Synaptic plasticity consists in a change in synaptic strength that is believed to be the basis of learning and memory. Synaptic plasticity has been for a very long period of time a hallmark of neurons. Recent advances in physiology of glial cells indicate that astrocyte and microglia possess all the features to participate and modulate the various form of synaptic plasticity. Indeed beside their respective supportive and immune functions an increasing number of study demonstrate that astrocytes and microglia express receptors for most neurotransmitters and release neuroactive substances that have been shown to modulate neuronal activity and synaptic plasticity. Because glial cells are all around synapses and release a wide variety of neuroactive molecule during physiological and pathological conditions, glial cells have been reported to modulate synaptic plasticity in many different ways. From change in synaptic coverage, to release of chemokines and cytokines up to dedicated "glio" transmitters release, glia were reported to affect synaptic scaling, homeostatic plasticity, metaplasticity, long-term potentiation and long-term depression.
By forming close contacts with synapses, astrocytes secrete neuroactive substances and remove neurotransmitters, thus influencing the processing of information by the nervous system. Here, we review recent work on astrocytes and their roles in regulating neuronal function and synaptic plasticity. Astrocytes are organized as networks and communicate with each other, thereby affecting larger neural circuits. They also provide a link between neurons and the vasculature, potentially changing the cerebral microcirculation.
...suggests that nervous system function actually arises from the activity of neuron-glia networks. Most of our knowledge of the properties and physiological consequences of the bidirectional communication between astrocytes and neurons resides at cellular and molecular levels. In contrast, much less is known at higher level of complexity, i.e. networks of cells, and the actual impact of astrocytes in the neuronal network function remains largely unexplored.
Another question is what are the proteins in the signaling process good for? Control? Inhibition? Creating of a brain'Hum'?
... gliotransmitters, that can directly influence synaptic transmission. During periods of synaptogenesis, astrocyte processes are highly mobile and may contribute to the stabilization of new synapses. As our understanding of the extent of their influence at the synapse unfolds, it is clear that astrocytes are well poised to modulate multiple aspects of synaptic plasticity.
Many, but likely most, neurons in the central nervous system have a nonmotile "primary" cilium extending like an antenna or finger from one of the pair of centrioles in the cell's centrosome into the extracellular space. Since their discovery over 100 years ago, these organelles have been either dismissed as functionless relicts of a bygone era or more often simply ignored. However, it has long been known that the photoreceptor-bearing outer segments of retinal rods and cones are modified primary cilia and it has recently been found that kidney cells' primary cilia are sensitive flowmeters the disabling of which causes polycystic kidney disease. It has also been recently shown that somatostatin sst3 receptors and serotonin 5-HT(6) receptors are selectively sited on neurons in various parts of the rat brain. It seems likely that these selectively receptored neuronal primary cilia will turn out to be the forerunners of a family of cell-signaling devices that help drive various brain functions by sending signals into their own cells and into adjacent cells through gap junctions and via conventional chemical synapses.

The synapse and cilias, fibrils.

Ah, something ignored? Cilias? In Alzheimers are also cilias making troubles. There are even links between Alzheimer’s and the curious tendency of brain cells under stress to double their genetic material. Damage: Chemicals that carry messages between nerve cells go MIA, brain cells’ birthrates plummet, cells’ energy output goes haywire, cell waste begins to pile up and harmful reactive chemicals get produced. Ominous deposits of the A-beta protein (along with tangles of another protein, called tau, that has also garnered a fair share of investigation) were what caught the eye of German physician Alois Alzheimer when he first described the disease a little over a century ago. Now the protein itself is less and less suspected, but reasons behind the amyloid (kind of prion), found in nearly every cell in perfectly healthy brains, but unknown function.

Gabriel Silva: In a dish of astrocytes, a droplet of the A-beta protein sparked a signal that can silence chatter between nerve cells, the brain’s main communicators. The signal traveled as a wave of calcium atoms that washed across cells, kicking off a series of damaging events that could end with disrupted nerve cell communication, and probably has a more direct path to harming synapses.

Data from Caleb Finch’s group, and work by other researchers, have made the case that the oligomers are the most damaging form of A-beta. “We are convinced that the oligomeric forms, small assemblies of three to 10, are more toxic than the long fibrils,” Finch says. Smaller particles are more effective in controlling? The “exploded drugstore” in the brain confounds the math, Finch says. Chemicals and salts floating around in the brain may influence the conversion rate of A-beta oligomers into plaques. “You can do beautiful model assemblies in a test tube … but how relevant that is to the mess of small molecules in the brain is imponderable”?

Literature:

So small molecules are more efficient? Then massless 'molecules' (particles) must be most efficient?

Clinical symptoms are only seen when the neurons are dead. We know that people aren’t symptomatic until they lose 60 to 70 percent of the neurons in key brain regions. The “inflammation hypothesis” has been proposed as one cause. First comes an injury, which may be related to some sort of vascular event such as a microstroke or mild head trauma suffered during a fall. This minor event then kicks off an inflammatory response in the brain. But it may be a consequence.

Karl Herrup says that the idea of Alzheimer’s without A-beta must be considered. Herrup points to patients who exhibit all of the cognitive impairments that follow Alzheimer’s disease, yet for whom subsequent imaging experiments or postmortem tests find no plaques in the brain. Also presence of A-beta plaques in cognitively healthy people raises doubts about A-beta as the bad actor it was once assumed to be. Lowering A-beta levels in human brains hasn’t improved brainpower.
While most textbooks describe the typical CNS neuron as “permanently postmitotic,” we have been exploring the ways in which the textbook needs to be re-written. We are particularly interested in the ways in which cell cycle dysregulation is linked to cell death – in normal situations and in human diseases such as Alzheimer’s disease.
Herrup’s hunch is that this switch might be related to a curious fact about neurons: When they’re under stress, they duplicate their genetic material. Usually, when most cells in the body do this, it’s in preparation for replication of the whole cell, and the new copy of the cell gets the extra set of DNA. But instead of dividing, neurons under duress just chug along with double the amount of DNA. Once the DNA is doubled, there’s no way for a brain cell to get rid of it, short of dividing. And neurons don’t divide. The link between extra DNA and neurons fated for destruction, though intriguing, is preliminary.
Most neurons undergo their last cell division within the first 1 to 2% of the lifespan of an organism. This has been interpreted to mean that adult neurons are permanently postmitotic, but Alzheimer's disease (AD) is an example of a late-onset neurodegenerative disease that challenges this concept. In AD, neurons in populations at risk for death reactivate their cell cycle and replicate their genome - but rather than complete the cycle with mitosis and cytokinesis, the neurons die. While opening new perspectives on the etiology of AD dementia, the simple linear model suggested by this description gains in complexity with the maturation of the adult brain. This complexity makes the full understanding of the relationship between cell division and cell death more difficult to achieve. The quest for understanding is worthwhile, however, as fresh avenues for therapeutic intervention are the prizes for success.
Modern medicine’s approach to treating heart disease isn’t to withhold therapies until after the heart fails - which unfortunately so often though is seen.
Barres believes opportunities for putting this insight to practical use abound. “There’ve been a thousand failed clinical trials for stroke, all of them focused on keeping the neurons alive. But we know that the astrocytes make the chemical signals that keep the neurons alive. I keep hammering on this. If you’re gonna keep one cell alive in the stroke treatment, focus on the astrocytes!”

And glias are connective tissue, our meridians?

Neural communication dependent on chromosomes? The findings of Montagnier and his team could mean a revolution comparable to that sparked by the Origin of Species, said Matti Pitkänen. TGD based model for the findings of Montagnier's team see the article DNA Waves and Water.

The immunological synapse.
Microtubulis are essential parts of a functioning membrane and synapse, membrane trafficking.

Cells of the immune system communicate both by direct interactions via membrane-bound receptors and via secreted mediators from one cell to another. Although the membrane-bound antigen receptors specifically recognize their target cells, this is not necessarily true for secreted proteins such as cytokines. The problem of specificity on secreted proteins seems to have been overcome by the formation of what has become known as the immunological synapse.
Conclusions: "The parallels between the cilium, the immune synapse, trichocyst secretion, and cytokinesis are intriguing. They suggest that the centrosome may play a role in identifying a specialized area of membrane for focal endocytosis and exocytosis. Precisely which signals direct the centrosome to a given point on the membrane in each system are yet to be discovered. This mechanism seems to have been adopted successfully by several specialized cell types, not least of all lymphocytes, when communicating via the immunological synapse."

This centrosome identification would explain 'the patchy membrane' and the creation of 'flux tubes' inTGD?

Vibrational effects. In scent this has been prooved to be vibrational, electromagnetic, not molecular, see Turin. Video here. There is also a Wikipedia article about Vibration Theory of Olfaction. Flies can smell the difference between normal hydrogen and deuterium. This is not in accordance with the standard theory of olfaction which says that olfaction relies on the shape of the molecule.
  • Franco, M. I., Turin, L., Mershin, A. & Skoulakis, E. M. C. Proc. Natl Acad. Sci. USA doi:10.1073/pnas.1012293108 (2011)
  • Olfaction of insects is analogous to seeing at IR frequencies. Callahan, P. S. (1977). Moth and Candle: the Candle Flame as a Sexual Mimic of the Coded Infrared Wavelengths from a Moth Sex Scent. Applied Optics. 16(12) 3089-3097.
In TGD inspired theory of qualia one must distinguish between the sensory input inducing the quale and its secondary representation in terms of Josephson and cyclotron frequencies.

****
There are many different cells in the immune system. To mount an effective immune response, they need to communicate with each other. One way in which this is done is by the formation of immunological synapses between cells. Recent developments show that the immune synapse serves as a focal point for exocytosis and endocytosis, directed by centrosomal docking at the plasma membrane. In this respect, formation of the immunological synapse bears striking similarities to cilia formation and cytokinesis. These intriguing observations suggest that the centrosome may play a conserved role in designating a specialized area of membrane for localized endocytosis and exocytosis.


The immunological synapse. Cartoon summary of the organization of receptors showing the relative positions of the cSMAC, pSMAC, dSMAC, centrioles, actin and microtubule cytoskeletons, and secretory lysosomes at the immunological synapse in cross section and across the area of cell contact.

The mother centriole, membrane protrusions formed during ciliogenesis, and microtubules linking the centriole to the membrane. An area of tight contact between the flagella pocket and flagella and a flat compartment close to the flagella pocket.

A common theme in the architecture of diverse cellular structures. Cartoon illustrating comparison of the organization of the immune synapse (A), primary cilium (B), flagella pocket (C), point of trichocyst secretion in paramecia (D), and site of cytokinesis in dividing cells (E), indicating that the site of centrosome polarization is a focal point for exocytosis and endocytosis in different cellular systems. Similarities between some or all of these examples include (1) polarization of the centrosome (pink) to the plasma membrane; (2) formation of membrane protrusions (brown) opposite the point of centrosome docking; polarized movement of (3) the microtubule cytoskeleton and (4) the Golgi complex (green) and endocytic recycling compartments (mauve) away from the nucleus (gray) toward the site of centrosome docking at the plasma membrane; (5) redirection of the biosynthetic (green), endocytic (blue), and recycling (purple) pathways to the plasma membrane; (6) focused polarization of regulated secretory organelles (e.g., trichocysts [crimson] in paramecia and secretory lysosomes [claret] with secretory cores [crimson] in CTLs) to specialized secretory domains at the plasma membrane (orange) by minus end–directed transport along microtubules; and (7) formation of specialized enclosed (e.g., secretory clefts [CTLs] and flagella pockets) or semienclosed (cilia and trichocyst) extracellular spaces to which endocytosis and exocytosis are focused.

To be continued.

2 kommentarer:

  1. http://brainblogger.com/2010/07/12/mind-your-immune-system/
    Mind your Immune System
    a “hair pulling” disorder, very similar to its human counterpart trichotillomania.
    the basis of this psychological aberration was a reduced population of microglia, which are the immune system cells in the brain. The genetic mutation responsible was pinpointed to the Hox8 gene, which belongs to a family of genes that determine body plan and architecture in all vertebrates, apart from regulating development and growth of organs. The brain microglia cells are thought to originate from the bone marrow, and are the only brain cells that express this gene — thus they are thought to play a key role in the brain’s development.
    if bone marrow containing Hox8 expressed stem cells (early forms which give rise to microglia) were transplanted to affected mice, their hair pulling disorder was cured within four months. By contrast when bone marrow from affected mice was transplanted into normal ones, the disorder appeared in normal ones.

    Apart from the fact that this is the world’s first reported behavior transplant, this finding is an important landmark in our understanding of the genetic basis of behavior. To what extent are our behaviors pre-determined by our immune system and our mind interconnected? To what extent does a malfunction of one lead to problems with the other?

    Chen SK, Tvrdik P, Peden E, Cho S, Wu S, Spangrude G, & Capecchi MR (2010). Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell, 141 (5), 775-85 PMID: 20510925

    SvaraRadera
  2. http://www.dana.org/news/features/detail.aspx?id=30798
    Brain's Use of 'Alternative Energy' May Be Related to Alzheimer's

    Energy-deficit?

    the regions where A-beta deposits are seen in the brains of people with Alzheimer’s closely match the regions that normally rely heavily on less-efficient but faster processes of energy production in cells. The studies’ authors propose that A-beta in its disease-driving forms might impair these processes, and thus might principally harm the brain regions that most depend on them.

    Adult cells usually make ATP in a multi-step process that includes the simple sugar glucose and oxygen and leaves water and carbon dioxide as byproducts. But there are faster, less-efficient ways of turning glucose into ATP, and some cellular processes in the brain depend on them. These faster processes, which don’t require oxygen, account for only 10–15 percent the adult brain’s use of glucose and are used more extensively by fetal cells and cancer cells, and by muscle cells during intense exercise.

    These non-oxygen-consuming uses of glucose in the brain increase temporarily when brain activity increases. these alternative uses of glucose seemed to vary considerably from region to region in ordinary brains. Also piquing his interest was the observation that the regions that relied the most on these alternate energy processes appeared to be the ones that make up the “default mode network,” a set of brain regions that are relatively active when a person is not engaged in any specific task. the regions that make up the network are also the ones that gather the most A-beta deposits.

    More reduction? Bigger systems? More coherence?

    One possible explanation for the finding is that these alternate glucose uses are especially vulnerable to disruption by A-beta.

    Raichle points out that glucose-fuelled processes are used by helper cells known as astrocytes to keep concentrations of the neurotransmitter glutamate below toxic levels in the synapses of cortical neurons. In principle, disruption of these processes by A-beta could lead to the deaths of the neurons. A-beta in its disease-causing forms does alter the metabolism of astrocytes, apparently putting them under stress and ultimately weakening the neurons they are meant to protect. “One of the things that astrocytes do is to remove A-beta from the extracellular space,

    evidence of a similar abnormality in glycolysis in Huntington’s disease, suggests testing to see whether glucose use affects A-beta deposition rather than vice-versa.

    SvaraRadera