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The developmental principles that establish the columnar edifice of the cerebral cortex underlie its evolution and dictate its physiological operations and cognitive capacity. This article contrasts the initial discoveries made by Ramón y Cajal and his contemporaries, based on the ingenious interpretation of neuronal shapes and their relationships using the Golgi method, with new insights based on the application of the most advanced methods of molecular biology and genetics. We can now propose a realistic model of how the sequence of gene expression, cascade of multiple molecular pathways and cell-cell interactions establish the number of neurons, guide their migration and allocation into proper regions and determine their differentiation into specific phenotypes that establish specific synaptic connections. The findings obtained from different levels of analyses sustain the radial unit hypothesis as a useful framework for understanding the mechanisms of cortical development and its evolution as an organ of thought.
Human civilization has advanced for centuries without understanding the organ that made it possible. It was only at the turn of the 19th/20th century that the application of the silver impregnation method ("la reazione nera"), developed by Camillo Golgi, allowed Santiago Ramón y Cajal Ramón y Cajal to expose, until then, a hidden universe of unbelievable complexity and beauty formed by the black silhouettes of nerve cells and their intricate connections. These discoveries were rewarded by a Nobel Prize in1906, for which we now celebrate its Centennial. Many consider this particular prize to be among the most significant because it acknowledged that understanding the biological basis of our mental abilities is a realistic possibility. Thus, it is paradoxical that a rich harvest made by Ramón y Cajal and his contemporaries was followed by about 70 years of relatively slow progress in this field. It was again the introduction of new methods in the second half of the 20th century that opened the door for new advances in understanding our organ of thought.
In this essay, I shall contrast the seminal discoveries revealed by the silver impregnation method with the concepts and insights into molecular and cellular mechanisms of cortical development obtained through modern technology. As this short overview could not possibly give justice to the exquisite drawings and documentation by the old masters, I urge readers to look for the originals in the libraries that are in the era of internet becoming museums. Instead, I will use the power of internet to provide two animated movies on the website to illustrate the dynamic nature of neuronal migration and cortical formation (Supplementary Movies #1: http://rakiclab.med.yale.edu/MigratingCorticalNeuron.html and #2 http://rakiclab.med.yale.edu/RadialMigration.html).
The subject of this present essay is focused on the issue of what we have learned regarding the mechanisms of the development of the cerebral cortex, the organ that subserves complex cognitive tasks including human thought and creativity, how it emerges from the embryonic stem cells during individual development, and how it has expanded during evolution It is not intended to be a comprehensive critical review of this burgeoning research field. Furthermore, since this is the major research theme in my laboratory, I will take advantage of the essay format to reflect on my personal experience in investigating this intellectually appealing subject. Due to the page limitations I can not possibly give credit to all of those who contributed to the understanding of this fascinating and complex subject.
The cerebral cortex, in all species including human, is characterized by two distinct features: it is a sheet of neurons in organized (horizontal) layers intersected by (vertical or radial) columns. Although the laminar arrangement is more obvious, the radial deployment of neurons was already depicted in Ramón y Cajal 's and Rafael Lorente de Nó's rendering of cortical circuits impregnated with the Golgi method (e.g., Ramón y Cajal, 1881, Ramón y Cajal 1891, Ramón y Cajal, Lorente de Nó, 1938). Subsequent research showed that the cortical columns consist of an array of iterative neuronal groups (also called modules) that extend radially (perpendicular to the pial surface) across cellular layers VI to II with layer I at the top (e.g., Mountcastle, 1997; Szentágothai, 1978; Goldman-Rakic, 1987). The neurons within a given column are stereotypically interconnected in the vertical dimension, share extrinsic connectivity and, hence, act as basic units subserving a set of common static and dynamic cortical operations (Eccles, 1984). This concept, inspired by the discoveries of functional columns subserving various attributes of somatic sensations (Mountcastle et al., 1957) and vision (Hubel and Wiesel, 1969), gained in significance by the finding that even in the so called "thinking" or association cortex, neurons with categorically specific responses reside in the same columns (Goldman-Rakic, 1988; Goldman-Rakic, 1995). The evidence for this concept came from a multiple electrode recording in the primate prefrontal cortex during a working memory performance displaying features analogous to the orientation preferences of the primary visual neurons (e.g., Funahashi et al., 1989; Wilson et al., 1993). Collectively, these data showed that neurons positioned adjacent to each other across the tangential axis of the cortex, which spans multiple columns, represents the memory of targets situated in adjacent locations in the visual field. Further, as predicted by the columnar hypothesis, neurons occupying the same column or location share the same tuning properties.
The evidence for the radial organization of neurons and neuronal processes in the association cortex not only provides an infrastructure for representing information symbolically, but also supports the idea that mental content is localizable and that combinatorial principles operate to arrive at a coherent structure of thought and language, just as they appear to do in vision and other sensory processes (Goldman-Rakic, 1987). Recent methodological advances in fMRI imaging are beginning to reveal changes in blood flow on the scale of millimeters; and, thus, will be able to reveal functional columns or modules in the living human brain and to test the validity of the columnar organization (e.g., McKinstry et al., 2002). We still do not have a full understanding of how and why columnar organization may be necessary for cortical operations from a functional point of view (e.g., Mountcastle, 1995). However, as reviewed bellow, we have already learned a great deal about cellular and molecular mechanisms that makes its neuronal organization possible.
If the assembling of cortical neurons into a crystalline–like array of layers and columns is not enough to provoke admiration, then the discovery that none of them are generated within the cortex itself should. In no other organ of the body is such a radical and precisely preprogrammed rearrangement of cell positions observed. Today, the fact that none of the myriad of cortical neurons are generated locally, and that they all acquire their proper areal and laminar positions through long-distance migration is common knowledge, so it is often forgotten how remarkable and unique in biology this phenomenon is. The initial concept was based on a simple histological observation in the human brain, that mitotic figures (which signify cell division) are situated along the lumen of the cerebral ventricles (at the time, called "germinal layer or matrix") and are virtually absent in the developing cortex that is forming below the pial surface (His, 1874; 1904). Based on this finding, as well as on the observation of radially oriented bipolar cells in the middle of the cerebral wall, Swiss embryologist Wilhelm His concluded that after the last mitotic division near the ventricular surface, neurons probably migrate to the overlying cortex. With this revolutionary discovery and his other achievements, he would have been a serious candidate to co-share the Nobel Prize along with Cajal and Golgi, had he not died two years earlier, in 1904, the year when his monumental book on embryonic human brain development was published in Leipzig.
I became aware of the concept of directed neuronal migration during a histology course at the Medical School in Belgrade in the late 1960's. I noticed that in all the other organs of our body, cells are generated locally, or if they do migrate, like during the formation of gonads, their destination is not position-specific. Only in the brain specific cell classes are generated in one place and than subsequently migrate to the very precisely designated final position. This is particularly evident in the cerebral cortex where postmitotioc cells migrate long distance and bypass each other before settling in the final position within specific layer within a given radial column. This extraordinary phenomenon has fascinated and inspired me to extent that I eventually interrupted the prospect of a career in neurosurgery to pursue the question of how and why this occurs. I was young and enthusiastic and thought that how the organ that mediates our humanity evolved is the most fundamental and important question that can be addressed. There are, of course, other great questions, such as origin of universe, but exploring how cerebral cortex develops actually could be accomplished and I was determined to participate in the search.
To begin to find some answers, as part of the work on my doctoral dissertation, I had incubated slices of fresh (postmortem) human fetal cerebral for 24 hours in a tissue culture medium containing 3H-thymidine (Rakic, 1968). Today, the use of slice preparations is commonplace; but, to my knowledge, this was the first use of slices in developmental neurobiology. Furthermore, at the time, marking replication of DNA during cell division with 3H-thymidine was also relatively new. Combining these two approaches, in forebrain slices from an 18 week old fetus, I found that dividing cells continue to synthesize DNA predominantly near the ventricular surface, even at this late stage of cortical neurogenesis when the cerebral wall is relatively thick and convolutions are becoming prominent (Rakic, 1968; Rakic and Sidman, 1968). More specifically, the cell nuclei become heavily radioactive, in the two transient proliferative layers (or zones) near the surface of the lateral cerebral ventricle: the narrow ventricular zone (VZ) at the surface, and the broader zone above, which I termed the SVZ or subventricular zone somewhat inappropriately, since the proliferative cells were situated above (supra) rather than below (sub) the VZ. I draw the schema of model of cortical development including transient embryonic layers using India ink, which gave me an opportunity to express my natural inclination and love for the visual art (as a medical student I was publishing cartoons for the Yugoslavian newspapers). I was also aware that Cajal used India ink to only to describe images that he has observed on the microscope, but also to convey the dynamism and meaning of cellular evens as they occur in time. This particular drawing had been presented by Richard Sidman to the Boulder Committee in Colorado, which published together with it with recommended suggested nomenclature (Boulder Committee, 1970). The important scientific point for the main subject of the present essay is that, apart from the occasional radioactive nucleus in the intermediate zone and marginal zone (prospective layer I), the cortical plate in the slices was devoid of radioactive labeling. I was impressed by this finding and decided to spend my professional life investigating why and how this occurs.
The study of supravital DNA synthesis in the embryonic human and mouse brain (Rakic and Sidman, 1968) was probably among the factors contributing to the offer I have received to join faculty of the Harvard Medical School faculty in 1969. After establishing my laboratory in Boston, I initiated a comprehensive 3H-thymidine autoradiographic study of neurons in vivo in non-human primates to determine the time of origin and routes of their migration (e.g., Rakic, 1974; reviewed in Rakic, 2002). This method is particularly effective in the brain because neurons, unlike most other cells of the body, do not divide after the final division (birthday), leaving a trace of their trajectories and settling behavior. I selected the macaque monkey, because as an Old World Primate it was the species with the most similar cortical and visual system organization to that of human. Pregnancy in this species lasts six and half months (165 days as determined by the time of conception at the middle of the 28-day menstrual cycle). Since injected 3H-thymidine is quickly eliminated from the bloodstream, the heavily labeled cells are only those that were in the last cell division and have not divided again (Nowakowski and Rakic, 1974). Over 120 animals, housed in the New England Regional Primate Research Center (Southborough, MA), were injected with 3H-thymidine and sacrificed at various time periods, ranging from one day to six months and even several years. This research was supported by my first grant, on "Neurogenesis Processes in the Primate Brain" that is now in its 35th year. It was by necessity larger than the average grant, and the criticism that "for that money could be funded three average size grants " was deflected by my statement that "we still would not know what happens in primates".
The results revealed that corticogenesis in the macaque monkey begins almost simultaneously, between E38–E40, in all cortical areas examined (Rakic, 1974, Reviewed in Rakic, 2002). However, the time of cessation of neurogenesis was more variable and has ranged between E70 in the limbic cortex to E102 in the visual cortex. This project provided the normative data for the model in the Supplementary Movie #1: http://rakiclab.med.yale.edu/RadialMigration.html). The typical inside-out gradient of neurogenesis, known from initial studies in rodents (e.g., Angevine and Sidman, 1961) was even more pronounced in the primates; and, the cohorts of isochronously generated neurons eventually occupy a relatively narrow strata within the cortex (Rakic, 1974). The sole exception to the inside-out sequence of neurogenesis in primates was encountered in layer I, where, contrary to rodents, neurogenesis continues throughout the entire period of corticogenesis (Zecevic and Rakic, 2001; Rakic and Zecevic, 2003). Since post-mitotic neurons at later stages of development require more than two weeks to settle into their final positions, we estimated that about one month before birth (between E125 and 135), all cortical neurons in the macaque are settled in their final laminar and radial positions see the Supplementary Movie #1 in: http://rakiclab.med.yale.edu/RadialMigration.html). The biological significance for the inside-to-outside sequence of neurogenesis and settling of neurons in the cerebral cortex is not clear. One hypothesis is that it enables later generated neurons to interact and communicate with the neurons generated earlier when they pass by each other (Rakic, 1990). Teleological reasons are always hard to prove, but this one, actually, makes sense since it is generally agreed that the deeper lying neurons and their connections are phylogenetically older, while the more superficial neurons, which form the bulk of the corticocortical connections, are evolutionarily younger. Furthermore, the disturbance of this sequence by either genetic or environmental factors leads to functional deficits (Reviewed in Caviness and Rakic, 1978; Rakic, 1988b; Ross and Walsh, 2001; Hatten and Mason, 19900; Hatten, 2002).
One unexpected and curious observation from this material was that, except for the granule cells in the cerebellum and hippocampus, we did not observe any labeled neurons in the animals exposed to 3H-thymidine postnatally (Rakic, 2002). It should be emphasized that neuronal cells in the mature primate neocortex can be easily identified in autoradiograms and that non-neuronal cells such as astrocytes, oligodendrocytes and endothelial cells as well as the cells in other organs of the body have been labeled (Rakic, 1985). This observation prompted me to suggest that early completion of neurogenesis in the primate cerebral cortex, without addition or turnover throughout life, may be a critical step in the evolution that allows of mental prowess in Homo sapiens. The basic idea was that a permanent population of cortical neurons may be more valuable for survival of primates, than the replacement of neurons that involves introduction of "naive" neurons that have not been exposed to previous experience and would cause a loss of acquired knowledge (Rakic, 1985). At the occasion of celebrating Cajal's contribution, I would like to emphasize that he came to the conclusion that the neurons that subserve the most precious human mental functions are under normal conditions irreplaceable, based on a much cruder histological method. The observation that cortical neurogenesis in primates is indeed completed before the time of birth and that the number of cortical neurons remain stable during adulthood, has been conclusively proven in the human cerebral by the most advanced and sophisticated methodology of 14C-carbon dating (Bhardwaj et al., 2006).
The early genetic determination of the species-specific number of neurons and radial units and the participating neurons in the adult cortex does not negate the existence of a considerable degree of plasticity during the critical periods of postnatal maturation. Studies in human and non-human primates show that both neurons and their axons are overproduced in the cerebral cortex during well-delineated stages of development. For example, there are about 40% more synapses in the macaque monkey visual cortex during development than in the adult (Bourgeois and Rakic, 1993; Rakic et al., 1986). Furthermore, the newborn monkey has almost four times the callosal axons than in the adult, which are lost at a rate of about 8 million per day or 50 per second during the first three weeks after birth; and, thereafter, 5 per second until the adult value is reached (LaMantia and Rakic, 1990). Other interhemispheric connections, including those between columns, display a similar phase of overproduction and loss of axons, dendrites and synapses (e.g., Lund, 2002; Lund et al., 1977). The functional significance of the loss of axons and synapses is not fully understood, but the prevailing hypothesis has been that activity dependent stabilization plays a critical role (Rakic, 1986; Shatz, 1996).
The next question was how neurons find their way from the ventricular surface in the large and increasingly distant and convoluted human cortex? The application of combined histological, electron microscopic and anatomical methods that became available in the late 1960 and early 1970's, on the embryonic monkey forebrain, provided the next step in understanding the possible mechanism of directed neuronal migration by showing that post mitotic neurons find their way to the appropriate radial position within the cortex by following the elongated shafts of glial cells that span the full thickness of the fetal cerebral wall (Rakic, 1972). The reconstruction of the relationship of the glial shaft, ultra-structurally clearly distinct from the migrating neurons, initially based on the serial EM reconstructions (Rakic et al., 1974) was animated (Supplementary Movie #2: http://rakiclab.med.yale.edu/MigratingCorticalNeuron.html). My studies in monkey renewed interests to these cells that were initially discovered in the human fetal brain by Golgi, Ramón y Cajal and their contemporaries using the silver impregnation method (Golgi, 1885; Ramón y Cajal, 1899; Magini, 1888; Retzius, 1893; Kölliker, 187–9). The classification of cells in the mammalian embryonic cerebral wall by the use of the Golgi method alone was difficult even to the masters of this approach. Thus, for example, Cajal had changed his mind twice as what is the nature of some of these cells, until he came to the realization that the initial bipolar neuroepithelial cells (now often called neural stem cells) transform first into a fetal (radial) glial phenotype and eventually into an astrocyte. It was not until the introduction of electron microscopy and immunohistochemistry that their glial nature as a specialized form of astrocytes had been established based on ultra-structuralultra-structural and molecular characteristics (Rakic, 1972; Levitt and Rakic, 1980). Although there are substantial species-specific differences in the timing of the transformation of the neuroepithelial cells into more differentiated radial glial cells (RGSs), their classification into the glial phenotype has been accepted by the researchers in this field irrespective of the species (reviewed in Rakic, 2003; see also, articles in the Special Issues of Cerebral Cortex: Rubenstein and Rakic, 1999; Kriegstein and Parnavelas, 2003; 2006).
It is not surprising that the initial discoveries of the RGCs as well as their classification into glial phenotype and significance as scaffolding have been made in the primates, because, unlike in rodents, in which these cells become GFAP positive only after birth, in both monkey and human the large, elongated GFAP positive RGCs dominate the scenery of the fetal cerebral wall in mid gestation (Rakic, 1972; Sidman and Rakic, 1973; Sidman and Rakic, 1982; Gadisseux et al., 1985; Choi, 1986; Kadhim et al, 1988; deAzevedo, 2003; Zecevic, 2004; Rakic, 2003). At that stage RGCs in the human cerebrum are truly remarkable in their size reaching a length of up to 4,000 microns in the fetal frontal lobes. Furthermore, the RGCs in primates have distinct ultra-structural and biochemical properties from the much earlier stage than in rodents (Rakic, 1972; Levitt and Rakic, 1980). While some basal processes of the RGCs freely arborize in the intermediate zone and cortical plate or are attached to blood vessels, a subset of RGCs has their basal end feet firmly embedded in the outer cerebral surface that is called the "glia limitans" (Rakic, 1972; Schmechel and Rakic, 1979a). It is this subset of RGCs that in the fetal primate telencephalon does not divide for several months (Schmechel and Rakic, 1979b). We and the others so far could not detect equivalent population of RGCs in the mouse, which in the corresponding three months not only get born but already begin their reproductive cycle.
A substantial difference between RGCs in the rodent and primate cerebral cortex described above should not be very surprising, but I found that even sophisticated neuroscientists who easily accept that lateral geniculate nucleus of the thalamus, which has no laminae in rodents, has distinct layers in the primates, do not accept that a substantial difference occurs during evolution of the cerebral cortex where one should expect the largest advance. By looking only at the common properties we cam miss the most important components - the differences- where the secrets of the human advent may lie. I speculated that maintenance of a stable, non-dividing population of RGCs that provides connections between the ventricular and pial surfaces in the large, rapidly expanding and increasingly convoluted primate cerebrumhas evolved to allow immature bipolar neurons to migrate to the overlying cortical plate. Thus, in primates, RGCs may have evolved to mature early in order to provide a stable scaffolding for the formation of the convoluted cortex (Rakic, 1978; 2003). The generation of radial units in the developing cortex is provided in the animated form (Supplementary Movie #1: http://rakiclab.med.yale.edu/RadialMigration.html). The dynamic model illustrates how relative cell positions in the protomap of the proliferative VZ are preserved during their radial migration to the cortical plate even in the gyrencephalic primate cerebrum which shifts during formation of convolutions (For details see Rakic, 1988a; Rakic, 1988b; Rakic 1995).
At the first glance it may appear paradoxical that non-neuronal (epithelial) cells play such a pivotal role as the scaffolding for placing cortical nerve cells into their proper locations. However, it should be recognized that the vertebrate central nervous system is a derivative and elaboration of the skin of the dorsal surface of the embryo that consists of the epithelial cells with organelles such as cilia that are characteristics of the tissues exposed to the outside environments. After neuronal tube closure the dorsal surface of the embryo becomes the inner lining of the ventricular cavity. During this period cells transform into pseudo-stratified neuroepitehlium that form the neural tube and budding cerebral vesicles, retaining some of the features of skin cells including cilia which can be found in virtually every neuron that derives from the VZ (Breuniug J. and Rakic, P. unpublished observation). However, as outlined below they serve several important developmental functions before disappearing and/or transforming into different cell types.
Apart from its remarkable size and unusual shape, RGC has been recognized as a maverick among brain cells that has a pivotal role in development and evolution of the cerebral cortex. Although it has been known for some time that the primary or conventional RGC phenotype derives from the neuroepithelial form (now called neural stem cells) that can generate neurons (e.g., Cameron and Rakic, 1991), increasing numbers of in vivo and in vitro studies indicated that these can generate not only neuronal progenitors but also directly, post mitotic neurons (Chanas-Sacre et al., 2000; Hartfuss et al. 2001; Noctor et al., 2001; Tamamaki et al., 2001; Gaiano and Fishell, 2002; Heins et al., 2002; Fishell and Kriegstein, 2003; Malatesta et al., 2003; Tramontin et al., 2003; Gal et al., 2006; Rasin et al., 2007). More recent observations confirmed the existence of dedicated neuronal progenitors in the VZ/SVZ that are derived from the parent RGCs and do not inherit the basal fiber that terminates at the pial surface (Rakic, 2003; Noctor et al, 2004; Gal et al., 2006, reviewed in Martinez-Cerdeño et al., 2006). Use of the retroviral gene transfer method, which enables to trace cell lineages in the developing mammalian telencephalon, including primates, also shows a divergence of basic cell types (Luskin et al., 1988; Parnavelas et al., 1991; Kornack and Rakic, 1995).
Classification of cells using the silver impregnation method, which depends on subtle distinctions between cell size and shapes, has suggested, but could not prove or even expose, the full spectrum of cellular heterogeneity of the embryonic cerebral wall. More recently, the use of specific cellular markers, combined with computer-assisted serial EM cell reconstruction, in utero electroporation and time-lapse multiphoton imaging revealed that the embryonic cerebral wall contains multiple cell classes, including dividing, post-mitotic, radially and tangentially migrating and the stationary neuronal and glial cells that are organized into transient layers (Fig. 1 and Gal., et al., 2006).
Apart from the RGCs that span the entire neocortical cerebral wall there are precursors which retract their basal processes during mitotic division (Levitt and Rakic, 1980, Levitt et al., 1983; Gal et al., 2006). In primates, the relative number of GFAP+ and GFAP-precursors changes systematically over the course of cortical neurogenesis (Levitt et al., 1983). However, neural stem cells can be isolated from both the rodent and human cerebrum VZ/SVZ and their properties analyzed in vitro (e.g., Laywell et al., 2000; Carpenter et al., 2001; Kirschenbaum et al., 1994). They can be tagged by the retroviral gene transfer method, their phenotype and migratory pattern followed in slice preparations of mouse and human fetal tissue (Letinic et al., 2002; Gal et al., 2006). Furthermore, the neuron-restricted stem cells produce different classes of projections and local circuit neurons (Parnavelas et al., 1991; Tan et al., 1998). Eventually fetal RGCs transform into ependymal cells, astrocytes and/or glioblasts (Fig. 1) Thus, RGCs give rise to both neuron and astrocytic progenitors that each can produce several generations of dedicated progenitors before their terminal differentiation. The next challenge is to isolate and propagate various subclasses of neuronal stem cells to better understand cortical development, but also to devise a rational strategy for replacement therapy.
While classical methods enabled observations and discoveries of the major principles that were not suited for deciphering molecular mechanisms, recent intense research on neuronal migration in vivo, using spontaneous and induced mutations, and in vitro, as well as dissociated cultures and slice preparations, has revealed that multiple mechanisms and a variety of molecules are involved in this event. The process of neuronal migration itself can be dissociated into several distinct steps: mechanisms that control the mode of cell division in the VZ; those which determine cell polarity and its detachment from the ventricular surface; the extension of the leading process and its selection of migratory pathway; the attachment migrating neuron to the surface of RG fibers; the control of nuclear translocation and rate of migration ending by derailment of the neuron from the RG and cessation of migration at the final destination. Each step possesses complex molecular machinery and only hints of what is actually involved. Progress being made in this field is provided below.
During and shortly after their exit from the asymmetric cell division in the VZ/SVZ, post mitotic daughter neurons become polarized with the leading process directed toward the cortical plate aligned along the RGC shafts (Rakic, 1972, Sidman and Rakic, 1973; reviewed in Fishell and Kriegstein, 2003; Rakic, 2003). The apical processes are interconnected via Cadherin-based adherens junctions (Fishell and Kriegstein, 2003; Gotz and Huttner, 2005; Rasin et al., 2007), so that the interkinetic (up and down), nuclear movement remains restricted to the VZ within the apical processes and their end-feet, as evident by classical in vivo and in vitro approaches (Misson et al., 1991; Temple, 2001) and confirmed with in vivo imaging (e.g., Noctor et al., 2004; Haydar et al., 2003; Gal et al., 2006). Neurons originated in the VZ/SVZ begin migration to the overlying cortex only after completing the last cell division and establishing their polarity. As a first step, Numb (an inhibitor of Notch) segregates at the basolateral side of dividing cells and becomes enriched during interphase along the apical-most end at the adherens junctions associated with Cadherins (Rasin et al., 2007). Thus, this molecular pathway appears to be important for the determination of symmetric/asymmetric divisions as well as the detachment of post-mitotic cells from the ventricular lining and the establishment of apical basal polarity of ventricular cells.
After detaching from the ventricular surface, bipolar migrating neurons extend their leading process towards the cortex. The initial EM-observation of a close neuronglial relationship in the fetal macaque cerebral wall (Rakic, 1972) has indicated the presence of a differential binding affinity and suggests the existence of a "gliophilic" mode of migration that may be mediated by heterotypic adhesion molecules present on apposing neuronal and glial cell surfaces (Rakic, 1991; Rakic et al., 1994). In contrast, the post-mitotic cells, which move tangentially along pre-existing axonal tracts (e.g., bipolar cells in Figs. 2 and 4), were considered "neurophilic" (Rakic, 1991).
In the past three decades, radial glial-guided migration has been observed in a variety of mammalian species, but it is particularly evident in primates where the pathways are long and curvilinear, RGCs differentiate both morphologically and biochemically within the first trimester and many do not divide during the second and third trimesters (Rakic, 1976; Schmechel and Rakic, 1979a, b; Kadhim et al., 1988; Zecevic, 2004). During the late period of corticoneurogenesis (or cortical neurogenesis) in the human brain, as many as 30 migrating GFAP negative neurons have been observed migrating along a single GFAP positive radial glial fascicle (Rakic, 2003). Multiple classes of putative recognition and adhesion molecules are involved in recognition, adhesion and cessation of neuronal cell migration (Rakic, 1981, Rakic et al., 1994; Hatten 2002; Hatten and Mason, 1990). These molecules are selectively and transiently expressed in the leading process of post-mitotic neurons at the surface adjacent to the radial glial fibers. Furthermore, they are involved in a cascade of multiple molecular interactions that eventually affect cytoskeletal remodeling which is essential for nuclear translocation (see below). Glial membrane proteins between migrating neurons and adjacent radial glial fibers are involved in the attachment of neurons to the radial glial shafts (Cameron and Rakic, 1994; Anton et al., 1996).
Our recent study, using a series of genetic, molecular and cell biological studies, shows that proper radial and laminar positioning of cortical neurons during neuronal migration to the cerebral cortex critically depends on the activity of the Notch intracellular domain, which is directly stabilized by Reelin signaling (Hashimoto-Torii et al., 2007). Numerous additional molecular species have been associated with neuronal migration that indicate the complexity of this process (e.g., Schachner et al., 1985; Hatten and Mason, 1990; Fishell and Hatten, 1991; Cameron and Rakic, 1994; Rio et al., 1997; Anton et al., 1996; Anton et al., 1997; Anton et al, 1999; Wu et al., 1999; Wynshaw-Boris and Gambello, 2001; Gongidi et al., 2004; Xie et al., 2006) and their number is growing almost daily. Although most molecules probably have specific tasks and are engaged in an interactive cooperation between neurons and glia, it is premature to assess their relative contribution and relationship to each other; however, we are witnessing big strides in this area of research.
Neuronal migration to the cerebral cortex, similarly as in other laminated structures of the CNS, begins with extension of the leading process to a variable length that is followed by the displacement of the nucleus within the leading process, for which I used the term "nuclear and/or somal translocation" (Rakic, 1971; Rakic 1972; reviewed in Rakic, 1981; 1991). The " four dimensional " figure showing morphogenetic transformation of cereballar granule cells as it develop the descending leading process within which nucleus and surrounding translocate to its final position has been, reproduced and/or quoted over 1000 times as a unique cellular event that explains formation of cerebellar cortical architecture. Although electron microscopic methods have not been suitable for studying the dynamic molecular mechanisms underlying movement on the nucleus, the ultra-structural findings indicated that a transformation of the cytoskeleton must play a role in initiation and cessation of nuclear movement (e.g., Rakic et al., 1996). The extension of the leading process and nuclear translocation are inseparable cellular events. Initially, while the cerebral wall is relatively thin, the tip of the leading process can reach the cortical plate and the nucleus needs to move only a short distance in both the small rodent cerebrum as well as in the human at comparably early embryonic stages (Sidman and Rakic, 1973; Nadarajah et al., 2003). However, when the total length of the migratory pathway increases and the leading processes of many migrating neurons do not span the entire width of the cerebral wall, the nucleus and surrounding cytoplasm are nevertheless being intermittently translocated to reach new distances (reviewed in Sidman and Rakic, 1982; Rakic, 1988a; Rakic, 1991). Time lapse movies of dissociated cells in cultures or in organotypic slices, where the conditions are similar to the environment in vivo, indicate that the leading process first extends slowly, and, after a pause, the nucleus begins to move at a faster rate, consistent with the rapid dissolution of cytoplasmic microtubules (e.g., Rakic et al., 1996; Feng et al., 2004; Schaar and McConnell, 2005; Bellion et al., 2005).
Neuronal migration can be considered as a highly specialized form of cell polarity. Analysis of the polarity of microtubule assemblies (Tubulin polymerization) within the leading and trailing processes reveals that the positive ends of the newly assembled microtubules situated in the leading process are facing the growing tip, while their disintegrating negative ends face the nucleus (Rakic et al., 1996). In the trailing process, by contrast, microtubule arrays are of mixed polarity. Thus, the extension of the leading process and translocation of the soma (nucleus and surrounding cytoplasm) within the membrane envelope may be orchestrated by a synchronized polymerization and disintegration of the microtubule that creates a rearrangement of the cytoskeletal scaffolding (Rivas and Hatten, 1995; Rakic et al., 1996; Feng et al., 2004; Schaar and McConnell, 2005; Xie et al., 2006) that is regulated by Calcium fluxes through the activity of various receptor/channel complexes (e.g., Komuro and Rakic, 1993; Behar et al., 1999; Hirai et al., 1999; Haydar et al., 2000, Owen and Kriegstein, 2002). Synergistic action of other molecular pathways may be involved in cytoskeletal rearrangement, such as Doublecortin and MEKK 4, which is important for mobilization of another cytoskeletal protein, Filamin (Sarkisian et al., 2006).
After passing between previously generated neurons, already settled in the deeper strata of the CP, the leading process enters the MZ, but the movement of the nucleus abruptly stops at the CP/MZ interface. When migrating cells are prevented from detaching from the RGC's fibers at the CP/MZ interface, subsequently arriving neurons cannot bypass their predecessors and accumulate beneath the previously generated neurons, forming an outside-to-inside gradient of neurogenesis (Anton et al., 1996; Anton and Rakic, 2002; Gongidi et al., 2004). A similar event has been observed in the cortex of the neurological mutant Reeler mouse (Caviness and Rakic, 1978).
The above reviewed observations are all consistent with the radial unit hypothesis of cortical development (Rakic, 1988a). According to this hypothesis, the two-dimensional positional information of the proliferative units in the ventricular zone is transformed into a three-dimensional cortical architecture: the X and Y axis of cells is provided by the site of cell origin in the VZ, whereas the Z-axis is provided from the time of their origin (Rakic, 1988). This hypothesis postulates that the radial edifice of the cerebral cortex forms by a migration of vertically oriented cohorts of neurons generated at the same site in the proliferative ventricular zone (VZ) of the cerebral vesicle (Rakic, 1978). As presented in animated form (see Supplementary movie #1: http://rakiclab.med.yale.edu/RadialMigration.html) each radial unit consists of neurons that share their birthplace and migrate radially to the cortex following transient scaffolding made of glial fascicles spanning the cerebral wall (Rakic, 1988). After arriving to the cortical plate, later generated neurons bypass earlier generated ones and settle in an inside-out gradient of neurogenesis, even in the large convoluted primate brain (Angevine and Sidman, 1961; Rakic, 1974). The radial unit hypothesis proposed three decades ago (Rakic, 1978, 1988) has acquired the status of a universal conceptual principle for understanding the complex cellular events underlying formation of the cerebral cortex (e.g., Mountcastle, 1997; Buxhoeveden and Casanova, 2002; Hatten, 2002; Chenn and Walsh, 2003; Tan and Breen, 1993; Kriegstein and Noctor, 2004; Zecevic, 2004).
One of the postulates of the radial unit hypothesis is that cells in a given radial column are clonally related. This was tested experimentally using the retroviral gene transfer method which allowed an analysis of cell lineages in the mammalian brain in vivo (Luskin et al., 1988). The use of the retroviral gene transfer method in the embryonic primate brain showed that even in the large and highly convoluted cerebrum, radial deployment of neuronal clones is remarkably preserved (Kornack and Rakic, 1995; Rakic, 1995a). Use of the same method in slice preparation of the human fetal cerebrum indicates that the same holds true for the human cortex (Letinic et al., 2002).
In addition to the radially deployed clones, there are a number of migrating cells that initially do not obey radial constraints but nevertheless contribute to the columnar edifice of the cerebral cortex. It has been shown that the interneurons, which originate from the ganglionic eminence (GE), migrate tangentially to the dorsal telencephalon before assuming their final place in the appropriate layers within the cortex. (e.g., deCarlos et al., 1996; Anderson et al., 1997, 1999; Tamamaki et al., 2001; Lavdas et al., 1999; Polleux et al., 2002; Tanaka et al., 2003; Wichterle et al., 2001; Ang, et al., 2002; Letinic et al., 2002). While in rodents, the majority of cortical interneurons originate in the GE (Rev. in Marin and Rubenstein, 2001) in the developing human cerebrum, more than 65% of GABAergic cells originate from the SVZ (Letinic et al., 2002). It should be emphasized that even cells that initially migrate tangentially in the fetal cerebrum eventually take a radial route along glial shafts (Fig. 1 and O'Rourke et al., 1992; Ware and Walsh, 1999, Ang et all, 2002; Letinic et al., 2002). Thus, radial migration is the dominant mode of cell translocation, which is particularly evident in the human fetal cerebrum (Rakic, 2003). Despite these and many other species –specific differences, the cerebral cortex, in all species examined, including human, is characterized by two prototypical and common features: it is a sheet of isochronously generated neurons that forms horizontal layers intersected by radial (vertical) columns of neurons that share a common origin in the VZ (Rakic, 1988).
Neither Cajal nor Golgi have paid much attention to the cytoarchitectonic subdivision of the cortex, though they were aware of it and did appreciate its significance. The most prominent students of the histological heterogeneity of the cortical mantle were German neurologists Constantin von Economo and Korbinian Brodmann whose major cytoarchitectonic atlas appeared in 2005 (Brodmann, 1905), one year before the announcement of the Nobel Prize for brain organization. This field was tainted with Joseph Gall's pseudo science, but the Brodmann's map has been included in virtually every book of Neurology and/or neuroscience, and is considered as seminal (Swanson, 2003).
Research on the development of cytoarchitectonic heterogeneity has been dormant until the introduction of new experimental methods. Apparent morphological uniformity of the neuroepithelium lining the cerebral ventricle gave birth to the concept, known popularly as "tabula rasa" which suggests that the ventricular zone produces equipotent cells destined for the cortical plate and that only selective input from the thalamus determines a species-specific pattern of cytoarchitectonic areas. It was an attractive idea that delegates the induction of areas to the periphery, and was well formulated and advocated by Otto Creutzfeldt three decades ago (Creutzfeldt, 1977). However, more recent experimental manipulations of cortical input indicated that cells of the embryonic cerebral vesicle may not all be created equal and have some intrinsic programs for the development of basic species-specific cortical regionalization as formulated in the protomap hypothesis (Rakic, 1988a). The initial evidence of the existence of heterogeneity of the cerebral wall before the arrival of input was initially based on the experimental reduction of size of thalamic input to the developing cortex (e.g. Rakic, 1988a; Rakic 1991). According to this concept known as the "protomap hypothesis", some region-specific cytoarchitectonic features can emerge before and at least initially, independently of the input. This is an important distinction as it opens the possibility that the species-specific changes in the cortex itself may be a direct target of evolution, rather than an indirect consequence of the changes in sensory systems at the periphery (Rakic, 1995). However, the word "proto" in the term "protomap" has been introduced to emphasize the malleable feature of this primordial map in which intrinsic cues, generated within cortical neurons, attract appropriate input that then cooperatively create a final area-specific, three-dimensional organization of each cytoarchitectonic field (Rakic, 1988a). Thus, although we found that input from the thalamus does not initiate regionalization of the cortex, we recognized that it is essential for its proper development and maturation (e.g. Rakic, 1988a, Rakic et al, 1991).
The evidence supporting intrinsic specification of cortical maps (or protomap) has over the years accumulated in numerous reports showing that a selective families of genes and morphoregulatory molecules are expressed in discrete gradients and cortical regions before or independently of the incoming input (Ferri and Levitt, 1993; Nakatsuji et al., 1991; Arimatsu et al., 1992; Simeone, et al., 1992; Gitton et al, 1999; Miyashita–Lin, et al, 1999; Bishop et al., 2000; Sestan et al., 2001; Grove and Fukuchi-Shimogori, 2003; O'Leary and Borngasser, 2006; Cholfin and Rubenstein, 2007; rev in Rubenstein and Rakic 1999). Furthermore, a number of studies in chimeric and transgenic mice have provided direct evidence that the majority of post-mitotic, clonally-related neurons move and remain radially distributed within the intermediate zone and enter only restricted superjacent areas of the cortex (Nakatsuji et al., 1991; Tan and Breen, 1993; Parnavelas et al., 1991; Soriano et al., 1995; Tan et al., 1998; reviewed in Rakic, 1995a). As a consequence many cortical malformations in human such as polymicrogyria have a propensity to develop only in specific regions of the cerebral cortex (e.g. Berkovich et al., 2000; Piao et al., 2004; revewed in Rakic, 2004) The protomap hypothesis has also gained support from evidence that abolition of thalamic input by genetic manipulation does not prevent cortical parcellation (Miyashita-Lin et al., 1999; Mallamaci, et al., 2000; Bishop, et al., 2000; Cholfin and Rubenstein, 2007). Finally, recent studies using genetic approaches have provided firm evidence that layer specificity of the cortical neurons that was indicated by early studies in Reeler mouse (Caviness and Rakic, 1978) and heterologous transplantations (McConnell, 1988) is determined already at the final cell division in the proliferative zones (Chen et al., 2005; Chen et al., 2005; Molyneoux et al., 2005). These studies collectively exemplify the capacity of the modern methods to rearrange and create at will new cortical connections and maps using genetic tools that Ramón y Cajal and his contemporaries could not even predicted. Now we can predict with considerable confidence that some additional genes and morphoregulatory molecules may be involved in cortical specification which then could be tested in rodents and possibly primate models of cortical dysgenesis.
Although, the clonally relationship of labeled cells using this approach was originally based on the law of probability, cell distribution strongly suggested that most progenitors originating in the same site at the ventricular surface remain radially deployed during migration and settle in a columnar fashion in the cortex (Luskin et al., 1988; Kornack and Rakic, 1995; Rakic, 1995a). Thus, radial migration directed by the radial glial scaffolding translates positional information (protomap) from the VZ to the overlying cortical plate (Rakic, 1988a).
Ramón y Cajal recognized that evolution provides nature's experiment and that comparative embryological and anatomical studies are very useful approaches. Cajal also recognized that the cerebral cortex is an organ that makes the most important distinction between human and any other organism. It is a paradox of our time that, seduced by the similarities, we often neglect the importance of distinctions. Indeed it should be expected that millions of years of evolution which selected enhanced mental capacity for survival would leave a significant mark on the organization of cerebral cortex. Although Cajal has often commented on the differences in cortical organization, particularly in terms of cell types (e.g. Ramón y Cajal, 1881,1890,1899), he did not think in terms of the genetic and cellular mechanisms of evolution, nor could he at that time.
Modern methods of molecular and developmental biology now provide the unprecedented opportunity to get a glimpse of what and how our cortex may have evolved. When one thinks about how to approach this question, there is an inescapable conclusion that analysis of the molecular and cellular events occurring at the early stages of embryonic development maybe the only way to learn what might have happened millions of years ago. This is not a resurrection of the discredited Haeckel's law that ontogeny "recapitulates phylogeny", based on morphological similarities, but a realization that genetic mutations that occurred in our ancestors have left imprints on our present phenotype and can be traced back. For example, the fact that the human, mouse or macaque telencephalic primordium is different in size even before the first cortical neuron has been generated, indicated to me that the mutation of the gene(s) that control the size of the neural stem cell pool must be the first step in the expansion of the human cortex. The particular aspect of cortical development that there is an expansion in cortical surface without expansion of cortical width, as predicted by Radial Unit Hypothesis.
The mechanisms underlying the expansion of the cerebral cortex is central to understanding both the potential and limits of our mental capacity including human-specific traits, such as language and abstract thinking. The human cerebral cortex is physically distinguished from other species not only by its larger size, but also by differential expansion and the addition of specialized cytoarchitectonic areas which are associated with an increase in the number of functional columns. Although the exact relationship between the functional columns in the adult cortex and embryonic columns has not been precisely determined, it is clear that the larger the cortex in a given species, the larger the number of participating columnar units (Bugbee and Goldman-Rakic, 1984; Rakic, 1988; Rakic, 1995b).
The evolutionary novelties in the cortex, as in other organs, are likely to be an outcome of relatively small genetic differences effecting the timing, sequence and level of gene expression that are introduced during the early embryonic stages. In this respect, it is important to recognize that the human forebrain is much bigger than in either the mouse or monkey, even at embryonic stages before the onset of neurogenesis of the local VZ (Sidman and Rakic, 1973; Sidman and Rakic 1982; Bystron et al., 2006). During the formation of the layer VI, its surface area enlarges another ten times. Thus, as predicted by the Radial Unit Hypothesis, the increase in cortical surface during evolution is associated with an initial increase in size of the VZ that generates mainly projection neurons. The idea of the Radial Unit Hypothesis of evolution has emerged from our concomitant, comparative analysis of ontogenetic development of the cerebral cortex in the mouse, monkey and human which shows a large and systematic increase in the number of radial columns during evolution without a comparable increase in the height of the columns (Rakic, 1995a).
According to the radial unit hypothesis, an increase in cell production at early stages (before the onset of neurogenesis) would result in an increase in the number of founder cells that give rise to radial columns, while an increase in production at later stages increases in number the neurons within each column. More specifically, a minor increase in the length of cell cycles or the number of cell divisions in the macaque monkey VZ before E40 can result in a large increase in the number of founder cells that form proliferative units (Rakic, 1988a). Since the initial proliferation in the VZ proceeds exponentially by the prevalence of symmetrical divisions, an additional round of mitotic cycles during this phase doubles the number of proliferative units and, consequently, the number of radial columns (Rakic, 1995b). According to this model, about three extra rounds of cell divisions can account for the 8 to 10-fold difference in size of the cortical surface between monkeys and human. In contrast, the 1000-fold difference between the size of the cerebral cortex in mouse and human can be achieved by less than 7 extra symmetrical divisions in the ventricular zone before the onset of corticogenesis (Rakic and Kornack, 2001). After the number of founder cells that will form individual radial units is set and corticogenesis has begun, many progenitor cells start to divide asymmetrically (Rakic, 1988a). Therefore, during this phase of development, an extra round of cell divisions would have a negligible effect on the thickness of the cortex (Rakic, 1995a; 2006). According to this model, one can predict that an approximate additional two weeks of corticogenesis in human compared to the duration in the macaque should enlarge the cortical thickness by only 10% to 20%, which is actually observed (Rakic, 1995b).
Can radial unit hypothesis of evolution be tested experimentally? I think that at least the cellular mechanisms of how it could have happened can be falsified. Based on our experience in studying the developing cortex in mouse, monkey and human, I proposed that a mutation in only one or a few genes can account for the dramatic increase in cortical surface, without a substantial increase in its thickness, provided that the gene(s) act early and that post-mitotic neurons follow the same rules and pattern of migration (Rakic, 1995b). Both excessive proliferation, as well as diminished programmed cell death (apoptosis) could affect the radial columns. An example of the later category is the development of the cerebral cortex in the transgenic mouse deficient in caspase 3 and 9 protease, that are essential for the normal process of programmed cell death (apoptosis). In mice lacking both copies of these genes, the magnitude of apoptosis is reduced in the proliferative VZ at early stages, during production of the founder progenitor cells (Kuida et al., 1996, 1998). Thus, the affected mice have a larger number founder cells and RGCs and as a consequence larger cortical surface that begin to form convolutions (Haydar et al., 1999). A similar, though less dramatic effect on the programmed death of neuronal progenitors can be obtained by modulation of the ephrin-A/EphA signaling pathway (Depaepe et al., 2006; Rakic, 2006).
There are also examples in which an increase in cell proliferation, rather than decrease in cell death in the VZ/SVZ enlarges the surface of the cerebral cortex. Thus, the embryonic mouse brain over expressing β-catenin produces a larger number of neuronal progenitors and eventually more neurons by acting directly on the decision of progenitors to exit the cell cycle in the proliferative zones (Chenn and Walsh, 2005). The increase in the number founder cells lead to larger number of radial columns and the formation of elaborate cerebral convolutions in the mouse that normally has a smooth (lissencephalic) hemispheric surface (Chenn and Walsh, 2005). In contrast, over-expression of cyclin-dependent kinase (cdk) inhibitor p27, increases the production of neurons that form radial columns, thus increasing the thickness of the superficial layers of the cortex, without increasing its surface area (Tarui et al., 2005). Often the picture may be obscured because supernumerary progeny causes additional brain malformations. Nevertheless, genetic and cellular mechanisms by which the neocortex expands are realistic goals of modern developmental neurobiology and a number of candidate genes that control cell proliferation are expected to increase.
During evolution functionally and structurally new cortical areas are introduced and the existing areas do not expand in register with the overall surface expansion. Some of the recent experimental studies in mice can inspire ideas on how the expanded cortex may have acquired additional cytoarchitectonic areas during evolution. For example it is significant that ectopic barrel fields, created de novo by perturbations of the site and expression level of a family member of the fibroblast growth factor (Fgf8) have a reverse (mirror image) representation of the whiskers, as has occurred when an area becomes duplicated during evolution (Fukuchi-Shimogori and Grove, 2001). The recent finding that even subdivisions of the frontal lobes can be distinguished and their size regulated at by extression of Fgf17 at early embryonic is a stag evidence of the role of genes in cortical regionalization (Cholfin and Rubenstein, 2007). The fact that it is now possible to enlarge and/or duplicate at will the sensory cortical representation of the periphery and create a new functional cytoarchitectonic area in the cerebral cortex presents an unprecedented opportunity to find out how these maps develop in individual as well as how they may been introduced during evolution (Rakic, 2001). I was amused that my statement how new cortical area can be created quickly in an individual embryo by manipulation of FGH8, that I made in my Commentary article in Science (Rakic, 2001) has been quoted by the creationalists as a scientific evidence that human cortex can be created in a single day!
It is obvious that the increase in the number of neurons organized into a larger number of radial columns and areas is not sufficient to explain the evolutionary advances made in the cerebral cortex over millions of years of evolution that also involves elaboration of neuronal connections. However, since neurons have to be generated before they form connections, an increase in their number is an essential first step, without which the next steps cannot be achieved. The experiments in which the number of radial units is increased is only an example, which in the context of the radial unit hypothesis explains how a larger-than-normal number of founder cells can create a cortex with an increased surface area and the formation of convolutions. By a single gene mutation, a lissencephalic (smooth) mouse cortex can be transformed into a gyrencephalic (convoluted) cerebrum! These are the kind of experiments that Cajal and Golgi could not do, or even perhaps could not imagine that could ever be accomplished. These experiments illustrate the remarkable power of molecular and developmental neurobiology: how by application of the genes identified initially in invertebrates can be applied to test the principles that were discovered in the human cerebral cortex. We can, for example, use a cell death gene, identified in a roundworm, to help us understand how changes in the regulation of cell death during cortical neurogenesis may have lead to cortical expansion during primate evolution. This type of reseach gives us confidence that human advent in universe, achieved through expansion and elaboration of cerebral cortex, can and will be eventually explained.
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View Album
So it goes.
The Magnificent Futaleufu!
My "international" vacation really begins at the L.A. airport where I embrace every language under the sun. It's here where I finally realize I'm going. This is it. No more wintertime for me--the south, and the Fu await me.
I can now relax and wait for Lan Airlines flight to whisk me away to all of the beauty that awaits me.

subset: commoncrawl


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November 13, 2012 | Filed under: Awards
Search Results by tag: Haiti
Wade Davis was awarded the £20,000 Samuel Johnson Prize for Non-Fiction for his book Into the Silence: The Great War, Mallory and the Conquest of Everest (Vintage Canada) at an award ceremony in London, U.K., last ... Read More »
In the January/February issue, Q&Q looks ahead at the spring season's new books. FICTION Two prolific American literary novelists are set to publish new titles this spring. Nobel Prize and Pulitzer Prize winner Toni Morrison ... Read More »
Although it was released just last month, Cornered: Hijinks, Highlights, Late Nights and Insights (HarperCollins Canada) by Ron MacLean with Kirstie McLellan Day has quickly become one of Canada's top sports titles of 2011. Booksellers ... Read More »
November 11, 2011 | Filed under: Book news, Books of the Year
In the July/August issue, Q&Q looks ahead at the fall season's biggest books. NOVELS One of the most anticipated releases of the fall season is surely the new novel from internationally acclaimed author Michael Ondaatje, ... Read More »
There are several ways to pen a story concerning young girls and criminal acts. One method: treat it lightly, à la Alan Bradley's Flavia de Luce mysteries, playing the crime as an old-fashioned puzzler. Another ... Read More »
June 9, 2010 | Filed under: Children and YA Non-fiction, Fiction: Novels
Here is today's crop of literary links: Vancouver poet laureate Brad Cran (who also happens to be an accountant) is offering a money-handling workshop for writers and freelancers The National Post profiles Andrew Kaufman, whose ... Read More »
February 23, 2010 | Filed under: Book news
Two of the latest victims of the tragic earthquake in Port-au-Prince are Quebec author Georges Anglade and his wife, Mireille. The two were there on a family holiday, and Anglade was meant to take part ... Read More »
January 14, 2010 | Filed under: Book news
Montreal author (and recent Q&Q cover star) Dany Laferrière is on a roll lately. After winning the $10,000 Blue Metropolis Literary Grand Prix last week, he has now been named recipient of France's illustrious Prix ... Read More »
November 4, 2009 | Filed under: Awards
The cover star of the September issue of Q&Q is the Haitian-born, Montreal-based author Dany Laferrière, who came to national attention in the 1980s with his first novel, How to Make Love to a Negro ... Read More »
September 4, 2009 | Filed under: Opinion
"Most know that Tropicana Pure Premium is not from concentrate. Few know what it is." That's what Toronto-based author Alissa Hamilton says in Squeezed, her examination of the evolution of Florida's orange juice industry. For ... Read More »
August 11, 2009 | Filed under: Politics & Current Affairs


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Jamie-Lynn Sigler Shows Off Her Post Baby Body! (Photos)Joanna Mazewski
Hollywood actress Jamie-Lynn Sigler was spotted showing off her amazing post-baby body as she was dining out with her fiance, Cutter Dykstra, while in Los Angeles, Calif. on Friday afternoon. Jamie-Lynn gave birth to her son, Beau Kylie, not even one month ago.
I don't know how Jamie-Lynn did it in record time, but she looks absolutely fantastic! But then again, she looked pretty good while she was pregnant, too.
Check out our photo gallery below and tell us, what do you think of Jamie-Lynn's new mom style here?
Jamie-Lynn Sigler 1 of 5
Jamie-Lynn Sigler enjoys a date night with fiance, Cutter Dykstra, after the birth of her son, Beau Kyle, in Los Angeles.
Post-Baby 2 of 5
Wow, Jamie-Lynn bounced back pretty quickly!
Cutter 3 of 5
Cutter doesn't look too bad himself!
All Smiles 4 of 5
That smile must mean that everything is all good!
Tell Us Your Thoughts 5 of 5
What do you think of Jamie-Lynn's new mom style?
Photos via PacificCoastNews.com
Want more of Joanna's pop culture ramblings? Follow her on Twitter!


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1st Annual Pet Industry Leadership Conference a Success
Over 250 pet industry leaders representing manufacturing, distribution and retail convened at the Loews Ventana Canyon Resort in Tucson, Arizona, for the 1st Annual Pet Industry Leadership Conference. The energy of this new format was felt throughout the week packed with programming and networking events. Attendees seized the opportunity to reconnect with industry colleagues, make new contacts and mingle with companies not normally accessible in day to day operations ...read more.
PIDA Members Endorse New Credit Exchange
PIDA has partnered with Inet Credit Exchange (ICE) to create an industry exchange that will help our members make faster and more accurate decisions when extending credit to independent pet stores. ICE has a track record of reducing bad debt within an industry ... read more.
Pet Business Names Pet Industry Distributors Association (PIDA) President Steve King as its 2016 Pet Industry Executive of the Year
During his more than a quarter century as the president of the Pet Industry Distributors Association, Steve King has been able to use diplomacy and a broad vision of what is best for the pet trade to benefit the entire industry ... (read more)
Dates announced for the 2016 Sales Professional Training Camps with Don Buttrey.
Through PIDA's partnership with the Association Education Alliance (AEA), members can attend the Four Pillars of the Sales Profession training course at a discounted rate. Dates are March 1-3, May 24-26 and August 9-11 in Dayton, Ohio. This program features two and a half days of practical skills, tools and fundamental disciplines that are essential for sales professionals. LEARN MORE AND REGISTER
Global Pet Expo Reports Record-Setting Year
Global Pet Expo 2016 experienced record setting attendance and new product launches during the three-day show. Now in its twelfth year, Trade Show Executive Magazine's (TSE) "Greatest Show on Earth," Global Pet Expo, presented by APPA and the Pet Industry Distributors Association (PIDA), featured more than 320,000 net square feet of exhibit space (nearly 10,000 feet larger than 2015), to accommodate the growing numbers in booths and attendees.
In 2016, Global Pet Expo experienced an impressive spike in domestic buyers at 4,679, an 8.4% increase over last year, with a total of 6,170 buyers in attendance ... read more.
Pet Ownership Saves $11.7 Billion in Health Care Costs . The Human Animal Bond Research Initiative (HABRI) Foundation today announced the findings of a new economic study on the healthcare cost savings associated with pet ownership. The economic analysis, conducted by two researchers from George Mason University, calculated an $11.7 billion savings in U.S. healthcare costs as a result of pet ownership ... read more.
Pet Industry Spending Makes History, Surpasses $60 Billion
Bob Vetere, president and CEO of the American Pet Products Association (APPA), announced at Global Pet Expo, an annual trade show presented by APPA and the Pet Industry Distributors Association (PIDA), that overall spending in the pet industry for 2015 came in at a record $60.28 billion. The spending figures are part of APPA's annual comprehensive report that covers pet spending in the market categories of: food, supplies/over-the-counter (OTC) medications, veterinary care, live animal purchases and other services.
"The pet humanization trend is alive and well and continues to drive growth at the premium end of the market," said Vetere. "As millennials prepare to take the reins from the baby boomer generation as the primary demographic of pet owners, they stand to further develop this trend." ... read more.


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Hello -
I saw another rider on a commute recently who was donning (sp?) a pair of safety glasses while riding. Really, if I didn't have woodshop experience and know what styles safety glasses could come in, I wouldn't have known... they look like sunglasses, nearly.
From what I figure, the benefits are pretty good:
ANSI safe (shouldn't your glasses protect you from crap flying into your eye anyway?)
the "UV protection" coating is actually monitored by safety councils, so it's guaranteed as opposed to just an un-reliable sticker incentive
comes in dark shades, yellows or oranges (two colours which increase contrast and can help bring out road conditions.... in addition to brightening your day ;-) )
they're still safety glasses, NOT designed by a cycling company
Just wondering if anyone else here has used safety glasses for riding or can offer some insight...?
Here's the pair the person was wearing...
http://www.petesdepot.com/335878.html (yeah, it's the only link I could find that wasn't horrendous in length)
the company x-factor makes other pairs of safety glasses that look "sporty"... froogle "safety glasses x factor"


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High School: Lettered four years at Crescenta Valley High School ... Led the Falcons to three league titles and four CIF playoff appearances ... Two-time first-team All-Pacific League selection ... Also garnered all-area honors three times ... Scored five goals and had two assists as a defensive midfielder in 2012-13.
Club: Played five years for the Camarillo Eagles ... Helped her squad to the U16 Elite Clubs National League title in 2011 ... Also won the Surf Cup, advanced to the finals of the So Cal Summer Showcase and reached the semifinals of the National Cup ... Invited to participate in the Premier Division of the Coast Soccer League for the 2011-12 season.
Personal: Cousin, Kyle, was a quarterback in the NFL for nine seasons ... Played for the Baltimore Ravens, St. Louis Rams and Oakland Raiders ... Was also a three-year starter at Cal ... Cousin, Candice, played volleyball at Loyola Marymount ... Majoring in nursing.
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Long Beach State forward Ashley Gonzales was named to Soccer America's All-Freshman Second Team...
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Long Beach State women's soccer had four players named to the 2014 NSCAA/Continental Tire NCAA...
Long Beach State Puts up Tremendous Fight in 2-...11/09/2014 - W. Soccer
The third-seeded Long Beach State women's soccer team left everything on the field but ultimately...
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Beach Tops Cal Poly in Penalty Kicks, Advances ...11/06/2014 - W. Soccer
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Long Beach State Dominates All-Big West Women's...11/05/2014 - W. Soccer
The Long Beach State women's soccer team claimed four of the six individual All-Big West awards...


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21st Century Witch by Poch4NWatch
©2013-2016 Poch4N
"WHO NEEDS THE BUS??! I'LL JUST FLY TO SCHOOL! Hope nobody sees my panties though..."
Jojojo Niceee...good line man...xD
your style is sooo amazing and unique, it's so crazy
Where's her Samsung Universe?
y-yes....just fly to school....
Did you say that in a 'I wish I could do that too' or a 'go ahead so I can take a peek' kind of way? xD
this is amazing ;A; absolutely awesome work!
It's amazing as always. When is the manga coming out?
great, love your inking style
....i wish i know how to ink as good as you (-_\\)
You make it sound as if it's impossible xD Just keep trying your best and eventually you may even become better than me!
Dude seriously, your art inspires me to draw *A* *place you in the awesome people list*
so freaking coooooool ♥♥♥
you never stop to impress <333
reminds me of the old awesome days of soul eater!!
you never stop to impress <333
reminds me of the old awesome days of soul eater!!
As you might be able to tell, my art is heavily inspired by that manga xD Thanks you once again, for the compliment, nevertheless!
My lines are never that smooth... damn these shaky hands!
Sweet work! continue blowing minds!
Sweet work! continue blowing minds!
Those hands have been quite busaaaaayyyyy.... IfyouknowwhatImean *ahem* Anyways... Thanks! I shall indeed continue to attempt to detonate the cranial matter of many individuals!
Pretty cool.
I give this no less than an A++
Did you see Little Witch Academia?
Did you see Little Witch Academia?
liking the niche of her using the bus sign as a broom gj gj also stop using that FUCKING MOON
this is pretty awesome


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Calling Doctor Laura: A Graphic Memoir
by Nicole Georges
When Nicole Georges was two years old, her family told her that her father was dead. When she was twenty-three, a psychic told her he was alive. Her sister, saddled with guilt, admits that the psychic is right and that the whole family has conspired to keep him a secret. Sent into a tailspin about her identity, Nicole turns to radio talk-show host Dr. Laura Schlessinger for advice.
There's a certain power here to Nicole's emotional exploration and resolution. The bravery is hard to deny and it's powerful from someone I've known for over a decade; to see her work through the issues her mom saddled her with and watch her develop the tools to navigate it and ultimately realize her own methods of coming to peace with her life. It doesn't hurt that it's beautifully-drawn and contains many parallels and hints to solving the inner-family drama of any reader likely to touch it. We applaud Nicole for the bravery to publicly display this journey.
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Traffic violation leads to marijuana discovery
Published: Thursday, August 14, 2014 at 3:38 p.m.
Last Modified: Thursday, August 14, 2014 at 3:38 p.m.
A motorist driving left of center Wednesday led to Davidson County sheriff's deputies arresting a man and finding two pounds of marijuana in the bed of his truck, said Davidson County Sheriff's Office Sgt. Jerry Soles.
Joey Early Brinkley, 61, of 1153 Craver Road, was charged Thursday with felony possession with intent to sell and deliver marijuana, felony possession of cocaine, carrying a concealed weapon and possession of drug paraphernalia. He was placed in the Davidson County Detention Center under a $10,000 secured bond.
Deputies made a traffic stop for driving left of center on Brinkley's 2009 Chevrolet Silverado on Nat Conrad Road at Holly Grove Road, Soles said. Deputies utilized a K-9 to search for drugs and found two pounds of marijuana in a large drill case in the bed of the truck. Soles said deputies were informed that Brinkley had a small amount of marijuana in his toolbox.
They also alleged they found a small amount of cocaine wrapped up in a dollar bill in a pants pocket, the sergeant said. Soles added that Brinkley was carrying a loaded pistol in his center console.
Soles said deputies previously received information on Brinkley's participation in the involvement of illegal drugs in Davidson County. The sergeant called the two pounds a "substantial amount of marijuana." Soles said the seizure prevents the marijuana being sold back into the Davidson County area.
Brinkley has an Aug. 28 court date in Lexington District Court.
Darrick Ignasiak can be reached at 249-3981, ext. 217, or firstname.lastname@example.com. Follow Darrick on Twitter: @DispatchDarrick
Reader comments posted to this article may be published in our print edition. All rights reserved. This copyrighted material may not be re-published without permission. Links are encouraged.


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A free update to Adobe Captivate 8 is now available!
We've just released a free update for Adobe Captivate 8 with some great new enhancements and bug fixes.
To get the new update, open Adobe Captivate 8, and click Help > Updates and install the new update. You can also directly download and install the update from here.
Once the update is installed, your new Captivate version will be 18.104.22.168
Let me take you through some of my favorite Captivate 8.0.1 features and enhancements: Continue reading…


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Tobacco may actually have a health benefit towards fighting cancer.
Researchers at Stanford used tobacco plants to create personalized cancer vaccines. 16 patients with a specific type of Lymphoma participated in the study. Cells from their tumors were injected to special tobacco leaves, then the plant cells grew and created antibodies against the tumor. Researchers then ground up the leaves and created a vaccine.
This study was only looking at vaccine safety and researchers report none of the participants experienced major side effects. 70 percent of the patients had an immune response to the vaccine.


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You can't really separate Bollywood from Bombay. I mean, it is the home of Bollywood. Travel around Bombay and you will see billboards advertising the latest Bollywood blockbuster. The posters, and the poster-makers, are a part of the ancillary Bollywood industry. Today, most of these posters are digitally printed but given the ongoing fascination with Indian kitsch, vintage Bollywood posters are in fair demand these days. Of course, there are some people who have been collecting Bollywood posters for some time now and as some recent articles have pointed out, they are now sitting on a pile of cash.
But being an old collector is not the only way to lay your hands on these vintage beauties. If you are in the mood for some hustlin' and bustlin', you should head to Chor Bazaar. The Mansoori family runs three stores on Mutton Street in Chor Bazaar: Bollywood Bazaar, Mini Market and Super Sale. The prices of the posters go up to Rs. 5000 (c.US$100). Besides posters, you will also find various Bollywood memorabilia at these stores. You can call them at: +91-22-23472427. These are some of the posters that I picked up from the store.
Loose Ends at Bandra (Shop. No.1, A.N. House, 31st Road, lane opp. Shoppers' Stop, off Linking Road, Bandra (W), Ph: +91-22-65224725) also occasionally carries old movie posters and other Bollywood inspired merchandise.
If you would rather sit in the comfort of your own house and just order these things off the internet, you could check out http://bollywoodfilmposter.com/ and http://www.cafedreams.com/.
Bonus option:
If you want some cool, personalised Bollywood posters, you can visit Indian Hippy at www.hippy.in. They have artists who can create portraits for you, Bollywood style!
Super bonus option:
If you are one of those persons who likes the movies but would run the other way from the techni-coloured posters, I got just the thing for you. You should check out Akshar Pathak's work at Minimal Bollywood Posters. He offers reinterpretations of various movie posters (old and new) and in my opinion, they are loaded with awesomeness, creativity and that cool factor. I have already ordered some for myself and I am sharing a few of his works.
Go on, own your piece of Bollywood!
Oh and if you want to know, my fascination with Bollywood posters was sparked off by this episode of The Dewarists, featuring Zeb & Haniya, Swanand Kirkire and Shantanu Moitra. The show had an interesting concept and I would recommend that you watch the entire episode but if you are the impatient kinds, the actual song starts off at 31:47. The song is a soulful beauty. 37:59 is the exact moment that started my fascination with the posters!


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Wearing the Olukai Women's Kui Sandals is like having your own tiny little beach to walk on every where you go. Super-soft construction babies your feet so you feel like you're walking on soft sand. Bold hardware (Kui is Hawaiian for nail) visually grabs the eye and adds a bit of refinement to these supremely comfortable flip-flops.
- Anatomically molded EVA cradles your feet and absorbs impact
- Leather-wrapped latex footbed gives you extra cushioning
- Reviews
What do you think about this product?
Have questions about this product?
- Familiarity: I've put it through the wringer
These are absolutely beautiful sandals. (Obviously a bit spendy for flip flops, but worth the investment, I think!). The construction is flawless, and the leather is gorgeous, I opted for the "Dark Java" color which is wonderful for most any outfit. I like these so much because they are casual but can also be used to dress up your style a bit. The comfort is phenomenal, Olukai calls this the "wet sand principle" your feet actually sink down into the cushioning on these puppies. WOW. You can't really explain it, you just have to try it!
The only con I have to report is that the bottoms of these shoes don't offer great traction. I would opt for something else if you plan to do any scrambling.


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Columbia Men's Coolhead Ball Cap III
Product Information:
When you keep your head cool with the Columbia® Coolhead Ball Cap III, your temperature starts to drop. Featuring an Omni-Freeze ZERO™ sweatband and Omni-Freeze™ in the fabric, it's guaranteed to cool you down in intense conditions. A simple hook and loop back adjustments easily provides the perfect fit, while built-in sunscreen shields you from harmful rays. Don't head outdoors without the Coolhead III performance cap.
- Omni-Freeze ZERO™ sweat-activated super cooling sweatband
- Omni-Freeze™ sweat-activated cooling
- Omni-Shade™ UPF 50 sun protection
- Hook and loop adjustment
- One size fits all
- Fabric: 91% Polyester/9% elastane Freezer Ice jersey
- Style: CM9484
- Columbia
Country of Origin: TaiwanWeb ID: 13220052
Customer Reviews:
Rated 4.2 out of 5�by 20 reviewers.
Rated 1 out of 5�by Db1441 No thank you. I sent it back as soon as I saw it in person.Some might like it. I hated it. January 16, 2016
Rated 5 out of 5�by Dano Great hat This is a great hat. It is cool and airy and keeps the sun off. My favorite hat. September 15, 2015
Rated 4 out of 5�by Soccer Keeping cool I am a soccer referee and bought this hat for service as a visor and to help keep the sweat out of my eyes. It works on both of those needs. I question that it keeps me cooler than being hat-free, but it sure keeps my brow from dripping into my eyes. September 8, 2015
Rated 3 out of 5�by BF48 Running hat Good or just Ok The description of the item discussed it's cooling properties. The hat fits well and is comfortable, however I have not noticed it is any cooler than any other of the running hats I have worn. It is a good running hat, just not the ultimate answer to keep your head cooler as I had hoped it would be. August 26, 2015
Rated 5 out of 5�by Telly Well Worth the Money Wore this hat at the beach and my head stayed cool. Fabric is light and fits comfortably. August 2, 2015
Rated 5 out of 5�by Debo Columbia Men's cookhead ball cap iii Bought for my son and he loves it. It is much cooler to wear fishing. June 30, 2015
Rated 5 out of 5�by micaforest comfort Its a great hat and very comfortable, well worth the money May 27, 2015
Rated 5 out of 5�by jeni my dad loved it the material is light and smooth. easily managed and keeps you cool May 19, 2015
Rated 5 out of 5�by Amy Love it Mine is black and looks very sporty. I really like the hat. It breathes well and I love the material. March 4, 2015
Rated 5 out of 5�by Steve39 The overall best ballcap for any use or conditions I have ever owned. This is the second one I have and I bought it to keep in my vehicle in case I forget to take the first one. I have used it from Key West Florida to Alaska. It somehow knows the temp, dries quickly and can be used in almost any condition! Wash it, hang to line dry for 30 minutes and it is ready to go, you can't hurt it! High quality but lightweight. The new Grill Gray color seems to go with everything. March 4, 2015


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May 31, 2016
If a patient develops a breast lump or other breast change, it may be necessary to have a biopsy. That's a procedure that removes a sample of cells or tissue from the breast to be tested.
There are two different types of biopsies. One is the needle biopsy. The other type is the open surgical biopsy.
"We do it here. The biopsy is done through a small skin nick. A stitch isn't even needed," said interventional radiologist, Dr. John Blackwell of Riley Hospital. "We just put a bandage over the incision. But that isn't the right thing to do for all patients though. Some patients need a surgical biopsy, where a surgeon will make a large incision, go in and actually incise the tissue."
However just because an abnormality is found and a biopsy is ordered, that doesn't mean the patient has breast cancer.
"The vast number of biopsies we perform come back negative, benign. It's part of normal aging of the breast," Blackwell said.
One thing Blackwell reminds the public about is how important the self breast exam is to the early detection of breast cancer.
To receive a monthly self breast exam reminder and a newsletter full of helpful information about breast cancer, click on the link below to reach the sign up page.
And please remind your friends and family to conduct their self breast exam each month.
Click Here to access the online Public Inspection File
Viewers with disabilities can get assistance accessing this station's FCC Public Inspection File by contacting the station with the information listed below. Questions or concerns relating to the accessibility of the FCC's online public file system should be directed to the FCC at 888-225-5322, 888-835-5322 (TTY), or email@example.com.


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Its appears that EK has agreed with CVS the RSS agreement til December 2016 under the Kodak nameplate.
This is one valuable piece that is up sale. For instance if Fujifilm were to acquire this, this would give them a large portion of the market.
Any guesses how much this would sale for?
Judge Gropper approved on Friday a deal between EK & CVS Pharmacy extending the agreement for 4 more years.
Laura Quatela, President of Kodak & Personal Imaging is marketing this similar to an IPO. The buyer of this division will have no liability of Kodak going forward.
This is a very attractive IPO considering the following:
* operates 7,400 CVS Stores
105 Kodak Picture Kiosks
* $1.3 Billion in Sales 2011
$1.1 Billion in Sales Estimate 2012
* Completion of Sale of division First Half 2013
* Consist of RSS/Paper & Output Systems/Event Imaging
* The sale could probably include Kodak name for a time period
This really looks good for Private Equity to acquire and bring public 2-3 years from now. Or this could fit into a high tech company who could exploit what is already there.
Doesn't it seems strange that stakeholders have not heard any info regarding the sale of the CVS RSS unit after the agreement with CVS was finalized.
The POR is in the 1st qtr of 2013. My guess is that this would sell for more than $500M and should be up for bidding like the patents or the EBP Utility.
Its look like Assets Disposition is next of the agenda for EK. The latest Linklaters LLP statement shows much time spend discussing disposition of assets.
The Trustee now permits the viewing of Monthly Statement of Counsels without the names associated with the clients. From the Statement you get what the Counsels were working on to get their compensation.
The CVS Replacement Agreements comes next in Judge Gropper's Court on Friday December 7, 2012.
11/19/2012 PR Newswire
New KODAK Kiosk Connect App allows consumers to create photo gifts wirelessly and on-the-go using their smartphone photos
Just in time for the holidays, creating prints and photo gifts from a smartphone is now easier than ever before. Starting today, consumers can wirelessly transfer images directly from their ANDROID and APPLE Smartphones using the KODAK Kiosk Connect App at KODAK Picture Kiosks in CVS/pharmacy and Bartell Drug stores throughout and U.S.
Valuation of RSS is moving higher especially +7,000 locations
The possibilities are ALL here. EK is going to sell its brand name, film processing, & most important its kiosks(+ 7000 locations inside CVS).
All the buyer needs is $$$$$$ and a game plan.
Shorts, ever come to you why CVS gave EK a lease till December 2016? CVS would need assurances that the potential buyer had clout. I don't think CVS would want to go through an ugly divorce if things did not work out well.
Maybe PRO was right.
"This is one valuable piece that is up sale."
Do you think that it is enough to satisfy the Creditors?
The other sales apparently won't be.
What would satisfy the Creditors? 100%? Maybe. 100% plus interest?
" 'These are not easy decisions,' Perez said, adding that selling the businesses was motivated in part by the need to satisfy creditors of the bankrupt company."
Lets see, Kodak has to pay administration fees,trustee, invoices, satisfy the creditors,cough up $635 million for Retirees and $40 million for ATCL(sp) then work through all of the other classes of unsecured claims above commons share holders and it is preparing to sell off 2 of its 3 sectors plus 1100 patents to satisfy Creditors. Yeah, I'm pretty sure that AP's worries over common share holders keep him awake at night.
This is Alix Partners take:
"The Debtors and their advisors have reached out to numerous potentially interest parties and provided additional information on the business and sale process to the significant number of parties that executed non-disclosure agreements with Kodak. The Debtors have already received a first round bids, commenced management meetings with a number of potential buyers and are providing a number of additional information to support the diligence efforts."
The cost that EK negotiated with the Retirees & ATLC has already taken into account when EK are soliciting bids from the interested parties.
Whats interesting is CVS has over 7,000 stores with this concept. If a major player wanted to taken this space and could deal with CVS on their new direction from now on, the arrangement has very good potential going forward.
CVS don't really have too much tech things in their stores but this could change.
"Any guesses how much this would sale for?"
Take AP's estimate and divide by 5.
"Eastman Kodak exiting still photography business
By Matthew Daneman, USA TODAY Updated 8/24/2012 2:24 PM
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ROCHESTER, N.Y. – After decades of churning out untold millions of little yellow boxes of camera film, Eastman Kodak is saying goodbye to the still photography business.
Annette Lein, Rochester Democrat and Chronicle
Kodak headquarters in Rochester, N.Y.
Annette Lein, Rochester Democrat and Chronicle
Kodak headquarters in Rochester, N.Y.
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The company synonymous with photography said Thursday it is putting a batch of businesses up for sale, including more than 100,000 photo kiosks installed at retailers around the globe and its professional and consumer still camera film operation.
"These are attractive, market-leading businesses with great teams of employees and products," CEO Antonio M. Perez said in a phone briefing with reporters. "We believe they have good long-term prospects."
Perez's decision to sell the still film and photo kiosk businesses marks a 180-degree turn from just a few weeks ago. When Kodak gave creditors a rough sketch of its post-bankruptcy business plan, it included the personalized imaging unit, of which the still film and kiosk businesses are parts. Kodak estimated at the time that the personalized imaging business would generate $1.1 billion in revenue this year.
"These are not easy decisions," Perez said, adding that selling the businesses was motivated in part by the need to satisfy creditors of the bankrupt company.
Kodak's fortunes for much of its history revolved around camera film, with the company in 1885 rolling out Eastman American Film, the first transparent film negative. And the sale follows Kodak's announcement in February that it was shuttering its digital camera business. That unit is to close by Sept. 30.
The latest sales add to the growing list of operations the Rochester icon has unloaded in the past year. In the months leading up to the Chapter 11 bankruptcy filing in January, Kodak sold its CMOS and CCD sensor businesses and its microfilm business. Since the filing, it has sold the Cinesite special effects business and Kodak Gallery.
Also up for sale are Kodak's document imaging business, which is primarily document scanners; its silver halide paper business; and its specialty imaging business, which primarily does souvenir photos at events and theme parks.
The sale of these businesses doesn't automatically mean the end of such manufacturing work being done locally. Indeed, the Rochester economy is increasingly peppered with Kodak spinoffs, from medical imaging company Carestream Health to CCD image sensor firm Truesense Imaging.
Perez said Kodak, through its investment banker and financial adviser Lazard, is marketing the businesses now and hoping to have them sold off in the first half of 2013. He declined to say how much Kodak is counting on from the sale.
In the conference call, Perez repeatedly circled back to the idea that these sales were part of Kodak's goal to focus in the future on a set of core businesses — commercial printing, packaging printing and various printing services.
Kodak made a point of saying that businesses, such as consumer inkjet printing, motion picture and television film, and specialty chemicals, are outside of the core. Ken Luskin, president of California wealth management firm Intrinsic Value Asset Management, said the company seems to be indicating that it will also sell those businesses.
Kodak spokesman Christopher Veronda, when asked if Kodak has plans to sell the consumer inkjet line, said that it is "one of the other businesses that we continue to own and operate."
"Our consumer inkjet printers have built a strong market niche," Veronda said. "We continue to sell and support printers and ink, including through partnerships."
The sales announced Thursday should lead to a Kodak that fits together better and could give investors more confidence, Luskin said.
"Here's a nice cohesive company that makes sense and has a mid-cap niche, something that Wall Street with a new CEO in there would say, 'Hey, this is a new Kodak.' This is the right thing to do and it keeps their creditors at bay."
During the 15-minute briefing, Perez provided few details about the status of Kodak's ongoing auction of 1,100 digital imaging patents for potentially billions of dollars. The auction began Aug. 8 and the company had initially planned on wrapping it up by Aug. 13. Kodak has said, and reiterated Thursday, that it is still in discussions with unnamed parties regarding the potential sale and that it might opt ultimately to not sell them at all.
Perez declined to elaborate. "There are a lot of companies that are interested," he said. "There are all sorts of issues to deal with."
Daneman also reports for The Rochester (N.Y.)Democrat and Chronicle"
If you haven't learn buy now its way too late! Don't believe ANYTHING Kodak says in a news release.


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