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Rethinking biology: What role does physical structure play in the development of cells?

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That’s structuralism, in part. Further to Evelyn Fox Keller’s comment that the landscape of biological thought is being “radically reconfigured,” a cancer geneticist writes to say that a tumor’s physical environment fuels its growth and causes treatment resistance:

The forces of cancer

In vitro experiments showing that cancer cells actively migrate in response to fluid flow have supported the hypothesis that fluid escaping from the boundary of a tumor may guide the invasive migration of cancer cells toward lymphatic or blood vessels, potentially encouraging metastasis. There remains controversy over how the fluid forces induce the migration; the cells may respond to chemical gradients created by the cells and distorted by the flowing fluid,8 or the fluid may activate cell mechanosensors. Because of the potential for new therapeutic interventions, the transduction of mechanical fluid forces into biochemical signals by cell mechanosensors is an active area of investigation. In a more direct manner, the fluid flow can physically carry cancer cells to lymph nodes.

And fluid pressure is just one of the many forces in a tumor that can influence its development and progression. Tumors also develop increased solid pressure, as compared with normal tissue, stemming from the uncontrolled division of cancer cells and from the infiltration and proliferation of stromal and immune cells from the surrounding tissue and circulation. High-molecular-weight polysaccharides known as hydrogels found in the extracellular matrix (ECM) also add pressure on a tumor. The most well-studied of these hydrogels is hyaluronan; when the polysaccharide absorbs water, it swells, pressing on surrounding cells and structural elements of the tissue. More. (The Scientist, April 1, 2016)

and

May the Force be with you

The dissection of how cells sense and propagate physical forces is leading to exciting new tools and discoveries in mechanobiology and mechanomedicine.

Of course, mechanical properties and forces aren’t just important in disease, but in health as well. Almost all living cells and tissues exert and experience physical forces that influence biological function. The magnitudes of those forces vary among different cell and tissue types, as do cells’ sensitivities to changes in magnitudes, frequencies, and durations of the forces. Touch, hearing, proprioception, and certain other senses are well-known examples of specialized force sensors. But force detection and sensing are not limited to these special cases; rather, they are shared by all living cells in all tissues and organs. The underlying mechanisms of force generation and detection are not well understood, however, leaving many open questions about force dynamics; the distance over which a force exerts its impact; and how cells convert mechanical signals into biochemical signals and changes in gene expression (The Scientist, February 1, 2017)More.

We may come to understand evolution better if we see what can and can’t happen in physics terms.

See also: Keller: Landscape of biological thought is being “radically reconfigured”

Comments
[...] the conceptions that view morphogenetic phenomena as processes directed strictly by genes and morphogenes alone must be abandoned, and substituted by a view which also includes the role of mechanical forces.
Demystification of animal symmetry: symmetry is a response to mechanical forces Gábor Holló Biol Direct. 2017; 12: 11. doi: 10.1186/s13062-017-0182-5
Abandon previous conceptions? What guarantees that the newly proposed conception won't have to be abandoned too? This paper seems to beg the question "where's the beef?" It seems to draw pseudoscientific conclusions prematurely. They ain't seen nothin' yet. The most revealing discoveries are still ahead. Complex functionally specified informational complexity.Dionisio
November 12, 2017
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[...] the probability of membrane fusion increases when external tension is applied to one of the participating membranes. It is clear that mechanical tension plays a pivotal role in vesicle trafficking and it will be interesting to see in the future how cells regulate tension to adjust the energy landscape of these processes in order to control their kinetics. [...] at intermediate tension, SNARE-mediated fusion efficiency is indeed increased substantially, which we attribute to facilitation of lipid splaying and assisted fusion pore expansion. [...] membrane tension steers membrane fusion and might therefore be an essential prerequisite for fast fusion as observed for the release of neurotransmitters at the neuronal synapse. [...] local tension needs to be substantial, even close to bilayer lysis to increase fusion efficiency with unstressed vesicles.
Membrane tension increases fusion efficiency of model membranes in the presence of SNAREs Torben-Tobias Kliesch,1 Jörn Dietz,1 Laura Turco,2 Partho Halder,3 Elena Polo,1 Marco Tarantola,2 Reinhard Jahn,3 and Andreas Janshoffcorresponding author1 Sci Rep. 2017; 7: 12070. doi: 10.1038/s41598-017-12348-w
Complex functionally specified informational complexity.Dionisio
November 12, 2017
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The large gap in time scales between membrane fusion occurring in biological systems during neurotransmitter release and fusion observed between model membranes has provoked speculations over a large number of possible factors that might explain this discrepancy. One possible reason is an elevated lateral membrane tension present in the presynaptic membrane. Fusion of small membranous organelles inside a cell and fusion of vesicles with the plasma membrane are the key steps in the secretory pathway for the transport of lipids, proteins and signalling molecules in eukaryotic cells.
Membrane tension increases fusion efficiency of model membranes in the presence of SNAREs Torben-Tobias Kliesch,1 Jörn Dietz,1 Laura Turco,2 Partho Halder,3 Elena Polo,1 Marco Tarantola,2 Reinhard Jahn,3 and Andreas Janshoffcorresponding author1 Sci Rep. 2017; 7: 12070. doi: 10.1038/s41598-017-12348-w
Complex functionally specified informational complexity.Dionisio
November 12, 2017
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Surprisingly, scission of the intercellular bridge after the first mitotic division in C. elegans does not appear to exhibit an absolute requirement for the ESCRT machinery, arguing instead for the existence of a parallel, potentially actin-dependent pathway that supports this process. How membrane removal orchestrated by the ESCRT machinery directly contributes to the timing of abscission and midbody internalization represents an important issue to be addressed in the future.
Membrane remodeling during embryonic abscission in Caenorhabditis elegans. König J1, Frankel EB2, Audhya A3, Müller-Reichert T4. J Cell Biol. 2017 May 1;216(5):1277-1286. doi: 10.1083/jcb.201607030.
Did somebody say 'Surprisingly'? Did somebody say 'orchestrated'? Did somebody say 'timing'? Did somebody say 'machinery'? Work in progress... stay tuned. Complex functionally specified informational complexity.Dionisio
November 12, 2017
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[...] cytokinesis is initiated by signals from the anaphase spindle, triggering the assembly of an actomyosin ring that constricts the plasma membrane to generate a narrow intercellular bridge containing two bundles of antiparallel microtubules that overlap in the central zone called the midbody [...] Our findings highlight conserved mechanisms that contribute to the abscission process but also demonstrate unique features that distinguish cytokinesis in an embryonic system from that observed in mammalian cells in culture.
Membrane remodeling during embryonic abscission in Caenorhabditis elegans. König J1, Frankel EB2, Audhya A3, Müller-Reichert T4. J Cell Biol. 2017 May 1;216(5):1277-1286. doi: 10.1083/jcb.201607030.
Complex functionally specified informational complexity.Dionisio
November 12, 2017
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Abscission is the final step of cytokinesis and results in the physical separation of two daughter cells. [...] membrane scission occurs on both sides of the midbody ring with random order [...] [...] completion of the scission process requires actomyosin-driven membrane remodeling, but not microtubules. Moreover, continuous membrane removal predominates during the late stages of cytokinesis, mediated by both dynamin and the ESCRT (endosomal sorting complex required for transport) machinery. Surprisingly, in the absence of ESCRT function in C. elegans, cytokinetic abscission is delayed but can be completed, suggesting the existence of parallel membrane-reorganizing pathways that cooperatively enable the efficient severing of cytoplasmic connections between dividing daughter cells.
Membrane remodeling during embryonic abscission in Caenorhabditis elegans. König J1, Frankel EB2, Audhya A3, Müller-Reichert T4. J Cell Biol. 2017 May 1;216(5):1277-1286. doi: 10.1083/jcb.201607030.
Did somebody say 'Surprisingly'? Complex functionally specified informational complexity.Dionisio
November 12, 2017
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@3 addendum
In the future, advanced imaging techniques, novel biosensors and use of conditional mutants should further enhance our understanding of cellular contractile responses to stretch within tubular tissues in vivo. Further studies are also required to better understand the assembly and organization of the contractile machinery within in vivo tubes. Basic questions include how actin bundles are aligned within cells and what determines their dominant orientation, which proteins contribute to the development and maintenance of stress fiber-like structures and how forces might contribute to these processes [...] knowledge of the mechanotransduction pathways involved in regulating tubular contractility might suggest novel therapeutic targets.
Stretch-induced actomyosin contraction in epithelial tubes: Mechanotransduction pathways for tubular homeostasis. Sethi K1, Cram EJ2, Zaidel-Bar R3. Semin Cell Dev Biol. 2017 Nov;71:146-152. doi: 10.1016/j.semcdb.2017.05.014.
Work in progress... stay tuned. Complex functionally specified informational complexity.Dionisio
November 12, 2017
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@3 addendum
Tubular structures, such as blood vessels, exocrine glands, and airway passages, are a common feature of the animal body plan. Though each tubular structure in the body is anatomically distinct, they all experience external forces that influence their structure and function. [...] much less is known about regulation of contractile stress fiber-like structures in epithelial tubes. [...] very few studies have addressed the cellular responses to stretching in vivo. [...] multiple mechanical cues influence cells in vivo [...] [...] multiple biochemical path-ways also regulate contractility [...]
Stretch-induced actomyosin contraction in epithelial tubes: Mechanotransduction pathways for tubular homeostasis. Sethi K1, Cram EJ2, Zaidel-Bar R3. Semin Cell Dev Biol. 2017 Nov;71:146-152. doi: 10.1016/j.semcdb.2017.05.014.
Complex functionally specified informational complexity.Dionisio
November 12, 2017
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The mechanisms of extrusion of epithelial cells are now being unraveled though it remains unclear what the determinants are of an individual epithelial cell being shed. There is now also an increasing understanding that epithelial cell shedding can be a protective mechanism against infection through expulsion of invading pathogens. Further studies are likely to reveal therapeutic targets for inflammatory and infective bowel disease.
Deciphering the Complex Signaling Systems That Regulate Intestinal Epithelial Cell Death Processes and Shedding. Patterson AM1,2, Watson AJM1,2. Front Immunol. 2017 Jul 18;8:841. doi: 10.3389/fimmu.2017.00841.
Work in progress… stay tuned. Complex functionally specified informational complexity.Dionisio
November 12, 2017
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Intestinal epithelial cells play a fundamental role in maintaining homeostasis. Shedding of intestinal cells in a controlled manner is critical to maintenance of barrier function. Barrier function is maintained during this shedding process by a redistribution of tight junctional proteins to facilitate closure of the gap left by the shedding cell. However, despite the obvious importance of epithelial cell shedding to gut health, a central question is how the extrusion of epithelial cells is achieved, enabling barrier integrity to be maintained in the healthy gut and restored during inflammation remains largely unanswered.
Deciphering the Complex Signaling Systems That Regulate Intestinal Epithelial Cell Death Processes and Shedding. Patterson AM1,2, Watson AJM1,2. Front Immunol. 2017 Jul 18;8:841. doi: 10.3389/fimmu.2017.00841.
Complex functionally specified informational complexity.Dionisio
November 12, 2017
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[...] the subsequent construction of individual neuronal circuits relies on the concerted action of many different signaling pathways [...] [...] presence of other effectors of the Nodal pathway that contribute to L/R nerve asymmetries independently of MMP processing [...] [...] co-expression of several MMPs acting with partial redundancies with each other [...] [...] MMPs have many different substrates with potentially opposite effects on the same biological process. The MMP substrates that are responsible for asymmetric phrenic nerve patterning remain to be determined [...] [...] the in vivo assessment of these hypotheses will be challenging.
Genetic specification of left-right asymmetry in the diaphragm muscles and their motor innervation. Charoy C1, Dinvaut S1, Chaix Y1, Morlé L1, Sanyas I1, Bozon M1, Kindbeiter K1, Durand B1, Skidmore JM2,3, De Groef L4, Seki M5, Moons L4, Ruhrberg C6, Martin JF7, Martin DM2,3,8, Falk J1, Castellani V1. Elife. 2017 Jun 22;6. pii: e18481. doi: 10.7554/eLife.18481
Work in progress… stay tuned. Complex functionally specified informational complexity.Dionisio
November 12, 2017
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Future work should aim to address how and at which stage phrenic motoneurons are imprinted. The resulting L/R imprints could occur early on during neurogenesis or later on during motoneuron differentiation. [...] a L/R imprint confers specific axon behaviors to the left and right phrenic motoneurons. Further investigations are thus needed to assess with more specific tools Robo protein dynamics and distribution along phrenic axons and in the growth cones. This work will provide a better characterization of the functional outcome determined by the balance of short and long Robo forms in the establishment of phrenic nerve patterns.
Genetic specification of left-right asymmetry in the diaphragm muscles and their motor innervation. Charoy C1, Dinvaut S1, Chaix Y1, Morlé L1, Sanyas I1, Bozon M1, Kindbeiter K1, Durand B1, Skidmore JM2,3, De Groef L4, Seki M5, Moons L4, Ruhrberg C6, Martin JF7, Martin DM2,3,8, Falk J1, Castellani V1. Elife. 2017 Jun 22;6. pii: e18481. doi: 10.7554/eLife.18481
Work in progress... stay tuned. Complex functionally specified informational complexity.Dionisio
November 12, 2017
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The diaphragm is the main respiratory muscle of mammalian organisms, separating the thoracic and abdominal cavities. [...] a genetic program that establishes other differences between the left and right sides of the embryo also gives rise to the differences between the left and right sides of the diaphragm. This program switches on different genes in the left and right phrenic nerves, which activate different molecular pathways in the left and right sides of the diaphragm muscle. [...] the first asymmetry instruction in diaphragm patterning is provided by early Nodal signaling, which sets the L/R axis and visceral asymmetry of the embryo. Beyond this early mechanism, phrenic motoneurons have an intrinsic, genetically encoded L/R asymmetry that manifests itself in the differential activation of molecules that have key roles in axon guidance, including Robo1 and MMP2.
Genetic specification of left-right asymmetry in the diaphragm muscles and their motor innervation. Charoy C1, Dinvaut S1, Chaix Y1, Morlé L1, Sanyas I1, Bozon M1, Kindbeiter K1, Durand B1, Skidmore JM2,3, De Groef L4, Seki M5, Moons L4, Ruhrberg C6, Martin JF7, Martin DM2,3,8, Falk J1, Castellani V1. Elife. 2017 Jun 22;6. pii: e18481. doi: 10.7554/eLife.18481
Did somebody say 'program'? Did somebody say 'instruction'? Complex functionally specified informational complexity.Dionisio
November 12, 2017
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The diaphragm is a dome-shaped muscle that forms the floor of the rib cage, separating the lungs from the abdomen. As we breathe in, the diaphragm contracts. This causes the chest cavity to expand, drawing air into the lungs. A pair of nerves called the phrenic nerves carry signals from the spinal cord to the diaphragm to tell it when to contract. These nerves project from the left and right sides of the spinal cord to the left and right sides of the diaphragm respectively.
Genetic specification of left-right asymmetry in the diaphragm muscles and their motor innervation. Charoy C1, Dinvaut S1, Chaix Y1, Morlé L1, Sanyas I1, Bozon M1, Kindbeiter K1, Durand B1, Skidmore JM2,3, De Groef L4, Seki M5, Moons L4, Ruhrberg C6, Martin JF7, Martin DM2,3,8, Falk J1, Castellani V1. Elife. 2017 Jun 22;6. pii: e18481. doi: 10.7554/eLife.18481
Complex functionally specified informational complexity.Dionisio
November 12, 2017
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The diaphragm muscle is essential for breathing in mammals. Its asymmetric elevation during contraction correlates with morphological features suggestive of inherent left-right (L/R) asymmetry. Whether this asymmetry is due to L versus R differences in the muscle or in the phrenic nerve activity is unknown. [...] both the diaphragm muscle and phrenic nerves have asymmetries, which can be established independently of each other during early embryogenesis in pathway instructed by Nodal, a morphogen that also conveys asymmetry in other organs. [...] phrenic motoneurons receive an early L/R genetic imprint, with L versus R differences both in Slit/Robo signaling and MMP2 activity and in the contribution of both pathways to establish phrenic nerve asymmetry. Our study therefore demonstrates L-R imprinting of spinal motoneurons and describes how L/R modulation of axon guidance signaling helps to match neural circuit formation to organ asymmetry.
Genetic specification of left-right asymmetry in the diaphragm muscles and their motor innervation. Charoy C1, Dinvaut S1, Chaix Y1, Morlé L1, Sanyas I1, Bozon M1, Kindbeiter K1, Durand B1, Skidmore JM2,3, De Groef L4, Seki M5, Moons L4, Ruhrberg C6, Martin JF7, Martin DM2,3,8, Falk J1, Castellani V1. Elife. 2017 Jun 22;6. pii: e18481. doi: 10.7554/eLife.18481
Complex functionally specified informational complexity.Dionisio
November 12, 2017
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Slits are secreted proteins that bind to Roundabout (Robo) receptors. Slit-Robo signaling is best known for mediating axon repulsion in the developing nervous system. However, in recent years the functional repertoire of Slits and Robo has expanded tremendously and Slit-Robo signaling has been linked to roles in neurogenesis, angiogenesis and cancer progression among other processes. Likewise, our mechanistic understanding of Slit-Robo signaling has progressed enormously.
The role of Slit-Robo signaling in the regulation of tissue barriers. Wu MF1,2, Liao CY3, Wang LY3, Chang JT Development. 2016 Sep 1;143(17):3037-44. doi: 10.1242/dev.132829
Complex functionally specified informational complexity.Dionisio
November 12, 2017
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Mechanical, Electronic and Control Systems Engineering Design on exceedingly large doses of steroids? We ain't seen nothin' yet. The most fascinating discoveries are still ahead.Dionisio
November 11, 2017
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Epithelial tissues are defined by polarized epithelial cells that are integrated into tissues and exhibit barrier function in order to regulate what is allowed to pass between cells. Cell-cell junctions must be stable enough to promote barrier function and tissue integrity, yet plastic enough to remodel when necessary. This remarkable ability to dynamically sense and respond to changes in cell shape and tissue tension allows cell-cell junctions to remain functional during events that disrupt epithelial homeostasis including morphogenesis, wound healing, and cell division. In order to achieve this plasticity, both tight junctions and adherens junctions are coupled to the underlying actomyosin cytoskeleton. Together, Rho GTPases, their regulators, and effectors form compartmentalized signaling modules that regulate actomyosin structure and contractility to achieve proper cell-cell adhesion and tissue barriers.
Rho GTPases and actomyosin: Partners in regulating epithelial cell-cell junction structure and function. Arnold TR1, Stephenson RE1, Miller AL2. Exp Cell Res. 2017 Sep 1;358(1):20-30. doi: 10.1016/j.yexcr.2017.03.053
Complex functionally specified informational complexity.Dionisio
November 11, 2017
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[...] it is tempting to speculate that asymmetric distributions of mechanical tension might guide both actin and septin filament systems to self-assemble into polarized networks during cytokinesis. Mechanical forces have has been suggested to shape other actin-based structures [...] [...] the actomyosin ring of vertebrate cells responds to intrinsically generated forces. [...] it will be interesting to further investigate the intricate relationship between contractile forces and actin network organization.
Cytokinesis in vertebrate cells initiates by contraction of an equatorial actomyosin network composed of randomly oriented filaments. Spira F1, Cuylen-Haering S1, Mehta S2, Samwer M1, Reversat A3, Verma A2, Oldenbourg R2, Sixt M3, Gerlich DW1. Elife. 2017 Nov 6;6. pii: e30867. doi: 10.7554/eLife.30867.
Complex functionally specified informational complexity.Dionisio
November 11, 2017
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Animal cells divide by contracting the cell cortex in an equatorial zone between the two poles of the mitotic spindle, resulting in the ingression of a cleavage furrow. This is initiated by activation of the small GTPase RhoA at the equatorial cell cortex, which induces polymerization of unbranched actin filaments and activation of non-muscle myosin II [...]
Cytokinesis in vertebrate cells initiates by contraction of an equatorial actomyosin network composed of randomly oriented filaments. Spira F1, Cuylen-Haering S1, Mehta S2, Samwer M1, Reversat A3, Verma A2, Oldenbourg R2, Sixt M3, Gerlich DW1. Elife. 2017 Nov 6;6. pii: e30867. doi: 10.7554/eLife.30867.
Complex functionally specified informational complexity.Dionisio
November 11, 2017
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The actomyosin ring generates force to ingress the cytokinetic cleavage furrow in animal cells, yet its filament organization and the mechanism of contractility is not well understood. [...] cleavage furrow ingression initiates by contraction of an equatorial actin network with randomly oriented filaments. The network subsequently gradually reoriented actin filaments along the cell equator. This strictly depended on myosin II activity, suggesting local network reorganization by mechanical forces. Cortical laser microsurgery revealed that during cytokinesis progression, mechanical tension increased substantially along the direction of the cell equator, while the network contracted laterally along the pole-to-pole axis without a detectable increase in tension. [...] an asymmetric increase in cortical tension promotes filament reorientation along the cytokinetic cleavage furrow, which might have implications for diverse other biological processes involving actomyosin rings.
Cytokinesis in vertebrate cells initiates by contraction of an equatorial actomyosin network composed of randomly oriented filaments. Spira F1, Cuylen-Haering S1, Mehta S2, Samwer M1, Reversat A3, Verma A2, Oldenbourg R2, Sixt M3, Gerlich DW1. Elife. 2017 Nov 6;6. pii: e30867. doi: 10.7554/eLife.30867.
Complex functionally specified informational complexity.Dionisio
November 11, 2017
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Many tissues in our body have a tubular shape and are constantly exposed to various stresses. Luminal pressure imposes tension on the epithelial and myoepithelial or smooth muscle cells surrounding the lumen of the tubes. Contractile forces generated by actomyosin assemblies within these cells oppose the luminal pressure and must be calibrated to maintain tube diameter homeostasis and tissue integrity. In this review, we discuss mechanotransduction pathways that can lead from sensation of cell stretch to activation of actomyosin contractility, providing rapid mechanochemical feedback for proper tubular tissue function.
Stretch-induced actomyosin contraction in epithelial tubes: Mechanotransduction pathways for tubular homeostasis. Sethi K1, Cram EJ2, Zaidel-Bar R3. Semin Cell Dev Biol. 2017 Nov;71:146-152. doi: 10.1016/j.semcdb.2017.05.014.
Complex functionally specified informational complexity.Dionisio
November 11, 2017
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Interesting topic. Thanks.Dionisio
November 11, 2017
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The nervous system uses a LOT of mechanical engineering. An example I encountered today while building courseware: The outer hair cells in the cochlea serve partly as sensors, mainly as an adaptive automatic gain control to insure that our attention stays focused on new and important info. Some of the AGC is in software and some is purely mechanical. Here's a purely mechanical mechanism: Each hair cell handles one frequency. Each has a long cilium that is yanked back and forth by the acoustic wave in the tectorial membrane. The long cilium pulls its shorter partners with a rope-like link. As the wave at this frequency continues, the rope reels out of a little ratchet in the long cilium, so that the overall impulse from all the cilia grows weaker. When the wave stops, the ratchet winches the rope back to its original tension. imagepolistra
November 10, 2017
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