Neural Experience of Conscious Time

“Pure perception and pure memory constantly intermingle” Henri Bergson, 1908. One can consider that “Time” and “memory” are related experiential facets of mentality. Without memory, there is no Time. To clarify, we distinguish between the physisist’s objective time (pTime), which has no emotive quality or memory component, and the subjective conscious time (cTime), which engages both emotions and memory. Our tripartite mechanism of a neural memory involves neurons interacting with their surrounding extracellular matrix (nECM). Incoming perceptions are chemically encoded in the nECM as metal-centered cognitive units of information (cuinfo), wherein NTs serve as molecular encoders of emotive states In the context of the tripartite mechanism (Marx & Gilon, 2012-2020), we consider two possible modes whereby the temporal sequence of events (i.e. cTime) could be recalled by the sensing neural net. Chemical (allosteric) sensing of cuinfo in the nECM by neural receptors (i.e. GPCR, integrins, etc.) which establish fleeting contact with the nECM as they diffuse along the neural membrane. Effectively, this is a lateral decoding process. Electrodynamic sensing of cuinfo vertically displaced from the neural surface. New nECM components and cuinfo are constantly being formed, like coral growths, extending from the neural surface. The individual neuron senses and decodes the distal cuinfo in the surrounding nECM (like long-distance radar detection). Neural sensing is consolidated and transformed by the net into comprehensive memory. These speculations suggest experimental tests to measure the interactions of the tripartite components, to examine the electro-chemical aspects of neural encoding of memory perceived as cTime.

Biomechanical Properties of Cancer Cells

Since the crucial role of the microenvironment has been highlighted, many studies have been focused on the role of biomechanics in cancer cell growth and the invasion of the surrounding environment. Despite the search in recent years for molecular biomarkers to try to classify and stratify cancers, much effort needs to be made to take account of morphological and nanomechanical parameters that could provide supplementary information concerning tissue complexity adaptation during cancer development. The biomechanical properties of cancer cells and their surrounding extracellular matrix have actually been proposed as promising biomarkers for cancer diagnosis and prognosis. The present review first describes the main methods used to study the mechanical properties of cancer cells. Then, we address the nanomechanical description of cultured cancer cells and the crucial role of the cytoskeleton for biomechanics linked with cell morphology. Finally, we depict how studying interaction of tumor cells with their surrounding microenvironment is crucial to integrating biomechanical properties in our understanding of tumor growth and local invasion.

Transient mechanical interactions between cells and viscoelastic extracellular matrix

During various physiological processes, such as wound healing and cell migration, cells continuously interact mechanically with a surrounding extracellular matrix (ECM). Contractile forces generated by the actin cytoskeleton are transmitted...

Tripartite Mechanism of Neural Memory: Proof-of-Concept with Neuromimetic Impedence Electrodes

The idea that neural signaling is the basis of mental processes has a long history. We graphically summarize salient developments in the neurobiology of signaling, as a Timeline. In particular, we review the “tripartite mechanism” of neural memory, which centers on the interactions between a neuron with its surrounding extracellular matrix (nECM) doped with metals and neurotransmitters (NTs). Essentially, the neuron employs the nECM as its “memory material”, wherein it uses dopants to encode cognitive units of information (termed “cuinfo”). The NTs, which elicit bodily reactions (feelings), also encode past feelings as emotions, which “color” mental states in real-time and in memory. In the interest of developing experimental tests of the tripartite mechanism, impedance glass electrodes were covalently coated with an exemplar NT (oxytocin) or a sulfated tetra-saccharide analog of the nECM, were constructed and tested. The two types of coated, neuro-mimetic electrodes, termed “neulectrodes”, were capable of detecting metals, such as Hg+2, Pb+2, Cd+2, Cu+2, and Zn+2 with very high selectivity and sensitivity. The “neulectrodes” demonstrated that the chemodynamic interactions of metal cations with NTs or nECM-saccharide analogues can translate into electrodynamic signals. They experimentally validate the concept of the tripartite mechanism that underlies the chemo-electric encoding of neural memory.

Memory, Emotions, Language & Mind

Is “mind” universal to all neural creatures or is it unique to homo sapien, whose talent for language greatly enlarges his/ her ability to recall and enunciate past experience. Philosophers have wrestled with the concept of “mind” but have not delineated whether it emanates from body or spirit. Physicists have called on quantum mechanics to provide an explanatory rationale for mental states. Unfortunately, one cannot employ the metrics of physics to formulate emotions. Computer scientists aspire to emulate the workings of the brain with binary coded algorithms. Though capable of programing a memory function in robots, they too have been hampered by an inability to encode emotions. Upon consideration, “emotions” and “memory” must be integral to the cognitive process implied by “mind”. We biochemists review two proposed processes for the formation and recall of memory. The popular neurological concept is based on “synaptic plasticity”, the ability of neurons to scupt their shape and thereby modulate their signaling functions. It suggests that morphologic and functional modifications of the synapse follow a learning experience, recalled as memory. An alternate biochemical tripartite mechanism is based on interactions of neurons with their surrounding extracellular matrix (nECM) and dopants (metal cations and neurotransmitters (NTs)). Such a chemodynamic process seems physiologically credible in that it involves materials available to the neuron. It invokes a chemical code comprising metalcentered complexes representing cognitive units of information (cuinfo); with emotive states elicited and encoded by neurotransmitters (NTs). The neural chemical code, which evolved from primitive signaling modes of bacteria and slime mold, retained the identical signaling molecules, though augmented with additional neuropeptides. The evolved neurons became organized into ever more complex neural nets instigated a new dimension (phase) of metabolic energy, a mental state characterized by emotive memory, manifest in homo sapien as language and “mind”.

Memory, Emotions, Language & Mind

Is “mind” universal to all neural creatures or is it unique to homo sapien, whose talent for language greatly enlarges his/her ability to recall and enunciate past experience. Philosophers have wrestled with the concept of “mind” but have not delineated whether it emanates from body or spirit. Physicists have called on quantum mechanics to provide an explanatory rationale for mental states. Unfortunately, one cannot employ the metrics of physics to formulate emotions. Computer scientists aspire to emulate the workings of the brain with binary coded algorithms. Though capable of programing a memory function in robots, they too have been hampered by an inability to encode emotions. Upon consideration, “emotions” and “memory” must be integral to the cognitive process implied by “mind”. We biochemists review two proposed processes for the formation and recall of memory. The popular neurological concept is based on “synaptic plasticity”, the ability of neurons to scupt their shape and thereby modulate their signaling functions. It suggests that morphologic and functional modifications of the synapse follow a learning experience, recalled as memory. An alternate biochemical tripartite mechanism is based on interactions of neurons with their surrounding extracellular matrix (nECM) and dopants (metal cations and neurotransmitters (NTs)). Such a chemodynamic process seems physiologically credible in that it involves materials available to the neuron. It invokes a chemical code comprising metal-centered complexes representing cognitive units of information (cuinfo); with emotive states elicited and encoded by neurotransmitters (NTs). The neural chemical code, which evolved from primitive signaling modes of bacteria and slime mold, retained the identical signaling molecules, though augmented with additional neuropeptides. The evolved neurons became organized into ever more complex neural nets instigated a new dimension (phase) of metabolic energy, a mental state characterized by emotive memory, manifest in homo sapien as language and “mind”.

Myosin-X FERM domain modulates integrin activity at filopodia tips

Filopodia assemble unique integrin-adhesion complexes as they sense and attach to the surrounding extracellular matrix. Integrin activation is essential for filopodia stability; however, the regulation of integrin activity within filopodia is poorly defined. Using structured illumination and scanning electron microscopy, we observed that active integrin is spatially confined to filopodia tips and inactive integrin localises throughout the filopodia shaft. RNAi depletion of integrin regulators validated FERM domain containing talin and MYO10 as critical regulators of filopodia function. Importantly, deletion of MYO10-FERM ablates the active pool of integrin from filopodia, indicating that MYO10 FERM domain is required for integrin activation but not for integrin transport to filopodia tips. Yet, remarkably, the MYO10-FERM domain binds both and β integrin tails restricting integrin activation. Swapping MYO10-FERM with talin-FERM leads to an over-activation of integrin receptors in filopodia. Our observations demonstrate a complex regulation of integrin activity, at filopodia tips, via MYO10-FERM domain and challenge the concept of MYO10-dependent integrin transport in filopodia.

Mechanophenotyping of 3D multicellular clusters using displacement arrays of rendered tractions

Epithelial tissues mechanically deform the surrounding extracellular matrix during embryonic development, wound repair, and tumor invasion. Ex vivo measurements of such multicellular tractions within three-dimensional (3D) biomaterials could elucidate collective dissemination during disease progression and enable preclinical testing of targeted antimigration therapies. However, past 3D traction measurements have been low throughput due to the challenges of imaging and analyzing information-rich 3D material deformations. Here, we demonstrate a method to profile multicellular clusters in a 96-well-plate format based on spatially heterogeneous contractile, protrusive, and circumferential tractions. As a case study, we profile multicellular clusters across varying states of the epithelial–mesenchymal transition, revealing a successive loss of protrusive and circumferential tractions, as well as the formation of localized contractile tractions with elongated cluster morphologies. These cluster phenotypes were biochemically perturbed by using drugs, biasing toward traction signatures of different epithelial or mesenchymal states. This higher-throughput analysis is promising to systematically interrogate and perturb aberrant mechanobiology, which could be utilized with human-patient samples to guide personalized therapies.

The Osteocyte: New Insights

Osteocytes are an ancient cell, appearing in fossilized skeletal remains of early fish and dinosaurs. Despite its relative high abundance, even in the context of nonskeletal cells, the osteocyte is perhaps among the least studied cells in all of vertebrate biology. Osteocytes are cells embedded in bone, able to modify their surrounding extracellular matrix via specialized molecular remodeling mechanisms that are independent of the bone forming osteoblasts and bone-resorbing osteoclasts. Osteocytes communicate with osteoclasts and osteoblasts via distinct signaling molecules that include the RankL/OPG axis and the Sost/Dkk1/Wnt axis, among others. Osteocytes also extend their influence beyond the local bone environment by functioning as an endocrine cell that controls phosphate reabsorption in the kidney, insulin secretion in the pancreas, and skeletal muscle function. These cells are also finely tuned sensors of mechanical stimulation to coordinate with effector cells to adjust bone mass, size, and shape to conform to mechanical demands.

Actin polymerization downstream of integrins: signaling pathways and mechanotransduction

A cell constantly adapts to its environment. Cell decisions to survive, to proliferate or to migrate are dictated not only by soluble growth factors, but also through the direct interaction of the cell with the surrounding extracellular matrix (ECM). Integrins and their connections to the actin cytoskeleton are crucial for monitoring cell attachment and the physical properties of the substratum. Cell adhesion dynamics are modulated in complex ways by the polymerization of branched and linear actin arrays, which in turn reinforce ECM-cytoskeleton connection. This review describes the major actin regulators, Ena/VASP proteins, formins and Arp2/3 complexes, in the context of signaling pathways downstream of integrins. We focus on the specific signaling pathways that transduce the rigidity of the substrate and which control durotaxis, i.e. directed migration of cells towards increased ECM rigidity. By doing so, we highlight several recent findings on mechanotransduction and put them into a broad integrative perspective that is the result of decades of intense research on the actin cytoskeleton and its regulation.