Normal development of the nervous system is achieved through an elaborate program of guided neuronal migration and axonal growth. In the last few years, a flood of research has dissected the molecular bases of these phenomena, and several cell‐surface and extracellular matrix molecules, which are implicated in neuronal and axonal targeting processes, have been recognized. Taking this knowledge a step further, a recent paper by Tom Curran's group(1) reports the molecular cloning of the gene deleted in the autosomal recessive mouse (...) mutation reeler, affecting cortical neuronal migration. This gene encodes reelin, a novel extracellular matrix protein. (shrink)

JIPs are JNK interacting proteins and bind to JNK cascade kinases. JIP1 and JIP3 were known to be adaptors linking cargo to Kinesin‐I, a major molecular motor for axonal transport. Recent research sheds further light on JIPs' complex roles in axonal transport, namely in activation of Kinesin‐I and in cargo release. In Drosophila, APLIP1/JIP1 allows the Kinesin‐I complex to enable cargo release through activation of JNK signaling.1 In mammalian cell culture, JIP1 is necessary and, together with UNC‐76/FEZ1, sufficient for activating (...) Kinesin‐I.2 I discuss and compare the many roles played by JIP1 and JIP3 through interactions with several distinct players, in retrograde as well as anterograde transport. BioEssays 30:10–14, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

The Classical Theory of function in the nervous system postulates that the nerve impulse is the result of a sequential reversal of the membrane potential due to an increased permeability of the membrane, first to sodium ions, then to potassium ions. The new theory presents a bio-physical model which depicts the nerve impulse as an event involving the motions of electrons and waves, and their interactions with sodium and potassium atoms and ions. The velocity of the nerve impulse (the most (...) important parameter of nerve function) is determined by the product of two constants: c = the speed of light, which is a constant for all nerves; k =a constant for each nerve and is believed to be a specific property of nerve matter related in some way to the atomic process. The theory proposes that the nerve impulse in the axon is dualistic in nature (particles and waves play equally significant roles). The dualistic nature accounts for the three most fundamental characteristics of conduction of the nerve impulse: periodicity (conduction of a nerve impulse over long distances with constant velocity and form); non-summing (two nerve impulses cannot be in the same place at the same time); quantum nature of each nerve impulse — i.e., the unit message of the nerve impulse is an indivisible unit. (shrink)

Neurons have developed elaborate mechanisms for sorting of proteins to their destination in dendrites and axons as well as dynamic local trafficking. Recent evidence suggests that polarized axonal sorting of β‐site converting enzyme 1 (BACE1), a type I transmembrane aspartyl protease involved in Alzheimer's disease (AD) pathogenesis, entails an unusual journey. In hippocampal neurons, BACE1 internalized from dendrites is conveyed in recycling endosomes via unidirectional retrograde transport towards the soma and sorted to axons where BACE1 becomes enriched. In comparison to (...) other transmembrane proteins that undergo transcytosis or elimination in somatodendritic compartment, vectorial transport of internalized BACE1 in dendrites is unique and intriguing. Dysfunction of protein transport contributes to pathogenesis of AD and other neurodegenerative diseases. Therefore, characterization of BACE1 transcytosis is an important addition to the multiple lines of evidence that highlight the crucial role played by endosomal trafficking pathway as well as axonal sorting mechanisms in AD pathogenesis. (shrink)

Thy‐1 is a small glycoprotein of 110 amino acids which, folded in the characteristic structure of an immunoglobulin variable domain1, are anchored to the plasma membrane via a glycophosphatidylinositol (GPI) tail(2,3) (Fig. 1). It is a major component of the surface of various cell types, including neurons, at certain stages of their development (4). These qualities doubtlessly appeal to certain cognoscenti, but it is not clear why they would raise Thy‐1 to the status of a favourite molecule. Indeed, few scientists (...) readily admit to having a favourite. We study individual molecules because science is rooted in specific observations; but we do so in order to discover mechanisms of general importance. A molecule's appeal is dependent on its ability to reveal novel aspects of how nature works.Thy‐1 has been unusual in this respect. It was the first lymphocyte surface antigen shown to be restricted to a functional subset of lymphocytes (T cells in the mouse), a finding crucial to the development of cellular immunology(5); it was one of the first cell surface molecules to be sequenced and indicated the importance of immunoglobulin domains and GPI anchors as structural motifs(1–3); it has been pivotal in studies demonstrating that GPI‐anchored molecules are able to signal across the membrane they do not span(6, 7). Thy‐1 has revealed this much, however, with the charm of an adroit stripper: it has always promised glimpses of things more exciting than that displayed. In particular, the function of this molecule has never emerged.Our current work on Thy‐1 in the nervous system is, we believe, finally prizing this last secret into the open. It suggests that Thy‐1 on the neuronal surface interacts with one of the main glial types of adult brain, the astrocyte, to restrict axonal growth(8). There is no current consensus that astrocytes do regulate such growth, and this is the wider question we are addressing from the perspective of Thy‐1. At issue also is how to progress from knowing the nature of a molecule to defining its function. This task has already been achieved with molecules which were harder to characterise than Thy‐1. The problem is a classic Catch 22 situation: Thy‐1 has been readily characterised because it is small and abundant it is ten times more abundant than any other surface glycoprotein on rat thymocytes(9); but since there is so much of it, whatever it does it must do rather badly (or there would be no need to have so much of it!). Defining a function based on low activity or affinity is not trivial.Here I describe two aspects of work on Thy‐1. One is long completed ‐ the research which led to Thy‐1 being isolated and characterised ‐ and included because it demonstrates features which are still applicable to much research using a antibodies today. The other is our ongoing work on the nervous system, which is at that exciting early stage where hypotheses are formed, but the answers are still coming in. (shrink)

The interaction between syntax and its semantics is one which has been well studied in categorical logic. The results of this particular study are employed to understand how the brain is able to create meanings. To emphasize the toy character of the proposed model, we prefer to speak of the homunculus brain rather than the brain per se. The homunculus brain consists of neurons, each of which is modeled by a category, and axons between neurons, which are modeled by functors (...) between the corresponding neuron-categories. Each neuron has its own program enabling its working, i.e. a theory of this neuron. In analogy to what is known from categorical logic, we postulate the existence of a pair of adjoint functors, called Lang and Syn, from a category, now called BRAIN, of categories, to a category, now called MIND, of theories. Our homunculus is a kind of “mathematical robot”, the neuronal architecture of which is not important. Its only aim is to provide us with the opportunity to study how such a simple brain-like structure could “create meanings” and perform abstraction operations out of its purely syntactic program. The pair of adjoint functors Lang and Syn model the mutual dependencies between the syntactical structure of a given theory of MIND and the internal logic of its semantics given by a category of BRAIN. In this way, a formal language and its meanings are interwoven with each other in a manner corresponding to the adjointness of the functors Lang and Syn. Higher cognitive functions of abstraction and realization of concepts are also modelled by a corresponding pair of adjoint functors. The categories BRAIN and MIND interact with each other with their entire structures and, at the same time, these very structures are shaped by this interaction. (shrink)

Neurofibromatosis type 1 is associated with peripheral and central nervous system tumors. It is noteworthy that the regions in which these tumors frequently arise are the optic pathways and the brainstem. Thus, we decided to trace the procedure of diffusion Magnetic Resonance Imaging alterations along with Short-Wavelength Automated Perimetry examinations of the OPs after surgery and chemotherapy over 1 year, which enabled us to evaluate chemotherapy's efficacy in an NF1 patient with an OP tumor. In this study, a 25-year-old woman (...) with NF1 and left optic radiation glioma underwent surgery to remove the glioma. Immunohistochemistry revealed a Pilocytic Astrocytoma WHO grade I. Post-operation chemotherapy done using nine treatment cycles of administering Temozolomide for 5 days every 4 weeks. Applying the region of interest differential tractography method and SWAP four times every 3 months allowed us to follow the patient's visual acuity alterations longitudinally. The differential deterministic tractography method and statistical analyses enabled us to discover the white matter tracts anisotropy alterations over time. Furthermore, statistical analyses on the SWAP results along time illustrated possible alterations in visual acuity. Then, we could compare and associate the findings with the SWAP examinations and patient symptoms longitudinally. Statistical analyses of SWAP tests revealed a significant improvement in visual fields, and longitudinal differential tractography showed myelination and dense axonal packing in the left OR after 1 year of treatment. In this study, we examined an old hypothesis suggesting that chemotherapy is more effective than radiotherapy for NF1 patients with OP gliomas because of the radiation side effects on the visual field, cognition, and cerebrovascular complications. Our longitudinal clinical case study involving dMRI and SWAP on a single NF1-OPG patient showed that chemotherapy did not suppress the OP myelination over time. However, it should be noted that this is a clinical case study, and, therefore, the generalization of results is limited. Future investigations might focus on genetic-based imaging, particularly in more cases. Further, meta-analyses are recommended for giving a proper Field Of View to researchers as a subtle clue regarding precision medicine. (shrink)

The overarching guiding principle of Alan Turing’s work was directed towards modelling the human mind as a machine. It is extraordinary that Turing introduced, in his early papers, ideas that are only now beginning to be investigated. Throughout his life, he considered conjectures to be of great importance because they suggest useful lines of research. In my own conjecture, I am asking the question: what is the brain’s geometry? Can it ever be unravelled, or does its complexity defy any form (...) of visual representation? Recent research reveals that the detailed workings of the brain take place in a ‘global workspace’, where conscious contents appear to be disseminated globally to a great multitude of networks throughout the brain that are unconscious. During conscious tasks, neurons contributing to the global workspace enter into a coherent activation pattern by being tightly connected through long axons. Is it possible, therefore, that my proposed geometric pattern (an Islamic latticework) can be envisaged as a useful means of interconnecting multiple long axons in a unified global workspace dedicated to conscious thought? I share and communicate my idea through a process that combines visual imagery with musical performance (i.e. visual music). It is a method that can assist in clarifying concepts that might otherwise remain elusive or esoteric. (shrink)

The quest for molecular mechanisms that guide axons or specify synaptic contacts has largely focused on molecules that intuitively relate to the idea of an “instruction.” By contrast, “permissive” factors are traditionally considered background machinery without contribution to the information content of a molecularly executed instruction. In this essay, I recast this dichotomy as a continuum from permissive to instructive actions of single factors that provide relative contributions to a necessarily collaborative effort. Individual molecules or other factors do not constitute (...) absolute instructions by themselves; they provide necessary context for each other, thereby creating a composite that defines the overall instruction. The idea of composite instructions leads to two main conclusions: first, a composite of many seemingly permissive factors can define a specific instruction even in the absence of a single dominant contributor; second, individual factors are not necessarily related intuitively to the overall instruction or phenotypic outcome. (shrink)

In a companion review1 we discussed the data supporting the conclusion that at least two subtypes of spectrin exist in mammalian brain. One form is found in the cell bodies, dendrites, and post‐synaptic terminals of neurons (brain spectrin(240/235E)) and the other subtype is located in the axons and presynaptic terminals (brain spectrin(240/235)). Our recent understanding of brain spectrin subtype localization suggests a possible explanation for a conundrum concerning brain 4.1 localization. Amelin, an immunoreactive analogue of red blood cell (rbc) cytoskeletal (...) protein 4.1, is localized in neuronal cell bodies and dendrites when brain sections are stained with antibody against rbc protein 4.1. However, it has recently been suggested that synapsin I, a neuron‐specific phosphoprotein associated with the cytoplasmic surface of small synaptic vesicles, is related to erythrocyte 4.1. In this review we hypothesize that there are at least two forms of brain 4.1: a cell body/dendritic form (amelin) which is detected with rbc protein 4.1 antibody, and a unique form found exclusively in the presynaptic terminal (synapsin I). The binding of synapsin I to brain spectrin(240/235), and its ability to stimulate the spectrin/F‐actin interaction in a phosphorylation‐dependent manner suggests a model for the regulation of synaptic transmission mediated by the neuronal cytoskeleton. (shrink)

Filosofskoe i publit︠s︡isticheskoe nasledie -- Iz pisem -- Slovo sovremennikov o Chaadaeve -- Slovo potomkov.