Establishing appropriate area patterning in the neocortex is a critical developmental event, and transcription factors whose expression is graded across the developing neural axes have been ...implicated in this process. While previous reports suggested that the transcription factor Emx1 does not contribute to neocortical area patterning, those studies were performed at perinatal ages prior to the emergence of primary areas. We therefore examined two different Emx1 deletion mouse lines once primary areas possess mature features. Following the deletion of Emx1, the frontal and motor areas were expanded while the primary visual area was reduced, and overall the areas shifted posterio-medially. This patterning phenotype was consistent between the two Emx1 deletion strategies. The present study demonstrates that Emx1 is an area patterning transcription factor and is required for the specification of the primary visual area.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The disproportional enlargement of the neocortex through evolution has been instrumental in the success of vertebrates, in particular mammals. The neocortex is a multilayered sheet of neurons ...generated from a simple proliferative neuroepithelium through a myriad of mechanisms with substantial evolutionary conservation. This developing neuroepithelium is populated by progenitors that can generate additional progenitors as well as post-mitotic neurons. Subtle alterations in the production of progenitors vs. differentiated cells during development can result in dramatic differences in neocortical size. This review article will examine how cadherin adhesion proteins, in particular α-catenin and N-cadherin, function in regulating the neural progenitor microenvironment, cell proliferation, and differentiation in cortical development.
It is well established that cadherin protein levels impact canonical Wnt signaling through binding and sequestering β-catenin (β-cat) from T-cell factor family transcription factors. Whether changes ...in intercellular adhesion can affect β-cat signaling and the mechanism through which this occurs has remained unresolved. We show that axin, APC2, GSK-3β and N-terminally phosphorylated forms of β-cat can localize to cell-cell contacts in a complex that is molecularly distinct from the cadherin-catenin adhesive complex. Nonetheless, cadherins can promote the N-terminal phosphorylation of β-cat, and cell-cell adhesion increases the turnover of cytosolic β-cat. Together, these data suggest that cadherin-based cell-cell adhesion limits Wnt signals by promoting the activity of a junction-localized β-cat phosphodestruction complex, which may be relevant to tissue morphogenesis and cell fate decisions during development.
Categorization is an important cognitive process. However, the correct categorization of a stimulus is often challenging because categories can have overlapping boundaries. Whereas perceptual ...categorization has been extensively studied in vision, the analogous phenomenon in audition has yet to be systematically explored. Here, we test whether and how human subjects learn to use category distributions and prior probabilities, as well as whether subjects employ an optimal decision strategy when making auditory-category decisions. We asked subjects to classify the frequency of a tone burst into one of two overlapping, uniform categories according to the perceived tone frequency. We systematically varied the prior probability of presenting a tone burst with a frequency originating from one versus the other category. Most subjects learned these changes in prior probabilities early in testing and used this information to influence categorization. We also measured each subject's frequency-discrimination thresholds (i.e., their sensory uncertainty levels). We tested each subject's average behavior against variations of a Bayesian model that either led to optimal or sub-optimal decision behavior (i.e. probability matching). In both predicting and fitting each subject's average behavior, we found that probability matching provided a better account of human decision behavior. The model fits confirmed that subjects were able to learn category prior probabilities and approximate forms of the category distributions. Finally, we systematically explored the potential ways that additional noise sources could influence categorization behavior. We found that an optimal decision strategy can produce probability-matching behavior if it utilized non-stationary category distributions and prior probabilities formed over a short stimulus history. Our work extends previous findings into the auditory domain and reformulates the issue of categorization in a manner that can help to interpret the results of previous research within a generative framework.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE:Although bleeding frequently occurs in critical illness, no published definition to date describes the severity of bleeding accurately in critically ill children. We sought to develop ...diagnostic criteria for bleeding severity in critically ill children.
DESIGN:Delphi consensus process of multidisciplinary experts in bleeding/hemostasis in critically ill children, followed by prospective cohort study to test internal validity.
SETTING:PICU.
PATIENTS:Children at risk of bleeding in PICUs.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:Twenty-four physicians worldwide (10 on a steering committee and 14 on an expert committee) from disciplines related to bleeding participated in development of a definition for clinically relevant bleeding. A provisional definition was created from 35 descriptors of bleeding. Using a modified online Delphi process and conference calls, the final definition resulted after seven rounds of voting. The Bleeding Assessment Scale in Critically Ill Children definition categorizes bleeding into severe, moderate, and minimal, using organ dysfunction, proportional changes in vital signs, anemia, and quantifiable bleeding. The criteria do not include treatments such as red cell transfusion or surgical interventions performed in response to the bleed. The definition was prospectively applied to 40 critically ill children with 46 distinct bleeding episodes. The kappa statistic between the two observers was 0.74 (95% CI, 0.57–0.91) representing substantial inter-rater reliability.
CONCLUSIONS:The Bleeding Assessment Scale in Critically Ill Children definition of clinically relevant bleeding severity is the first physician-driven definition applicable for bleeding in critically ill children derived via international expert consensus. The Bleeding Assessment Scale in Critically Ill Children definition includes clear criteria for bleeding severity in critically ill children. We anticipate that it will facilitate clinical communication among pediatric intensivists pertaining to bleeding and serve in the design of future epidemiologic studies if it is validated with patient outcomes.
Little is known about the architecture of cellular microenvironments that support stem and precursor cells during tissue development. Although adult stem cell niches are organized by specialized ...supporting cells, in the developing cerebral cortex, neural stem/precursor cells reside in a neurogenic niche lacking distinct supporting cells. Here, we find that neural precursors themselves comprise the niche and regulate their own development. Precursor-precursor contact regulates β-catenin signaling and cell fate. In vivo knockdown of N-cadherin reduces β-catenin signaling, migration from the niche, and neuronal differentiation in vivo. N-cadherin engagement activates β-catenin signaling via Akt, suggesting a mechanism through which cells in tissues can regulate their development. These results suggest that neural precursor cell interactions can generate a self-supportive niche to regulate their own number.
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► Cortical ventricular zone neural precursors exhibit β-catenin signaling ► N-cadherin maintains β-catenin signaling in cortical precursors ► N-cadherin regulates neuronal differentiation and cell cycle exit via β-catenin ► N-cadherin signals through Akt and phosphor-Ser552 of β-catenin
Cerebral cortical precursor cells reside in a neuroepithelial cell layer that regulates their proliferation and differentiation. Global disruptions in epithelial architecture induced by loss of the ...adherens junction component αE-catenin lead to hyperproliferation. Here we show that cell autonomous reduction of αE-catenin in the background of normal precursors in vivo causes cells to prematurely exit the cell cycle, differentiate into neurons, and migrate to the cortical plate, while normal neighboring precursors are unaffected. Mechanistically, αE-catenin likely regulates cortical precursor differentiation by maintaining β-catenin signaling, as reduction of αE-catenin leads to reduction of β-catenin signaling in vivo. These results demonstrate that, at the cellular level, αE-catenin serves to maintain precursors in the proliferative ventricular zone, and suggest an unexpected function for αE-catenin in preserving β-catenin signaling during cortical development.
In mammals, the neocortical layout consists of few modality-specific primary sensory areas and a multitude of higher order ones. Abnormal layout of cortical areas may disrupt sensory function and ...behavior. Developmental genetic mechanisms specify primary areas, but mechanisms influencing higher order area properties are unknown. By exploiting gain-of and loss-of function mouse models of the transcription factor Emx2, we have generated bi-directional changes in primary visual cortex size in vivo and have used it as a model to show a novel and prominent function for genetic mechanisms regulating primary visual area size and also proportionally dictating the sizes of surrounding higher order visual areas. This finding redefines the role for intrinsic genetic mechanisms to concomitantly specify and scale primary and related higher order sensory areas in a linear fashion.
Alpha (α) catenin proteins can regulate both cell adhesion and cell proliferation. Here, we characterize the expression of two forms of α-catenin, αE-catenin and αN-catenin, in the developing ...cerebral cortex and primary cortical cultures. In situ hybridization and immunofluorescence studies reveal that αE-catenin is highly expressed in neuroepithelial precursor cells in the developing cortical ventricular zone, with markedly reduced expression in the cortical plate; in contrast, αN-catenin expression is low in the ventricular zone and high in the developing cortical plate. In the ventricular zone, immunoreactivity for both αE-catenin and αN-catenin is enriched in rings at the lumenal surface, reflecting localization at adherens junctions together with β-catenin. Expression of αE-catenin in primary cortical precursor cultures is initially robust, but declines as neural precursors differentiate into neurons. Reflecting its expression pattern in vivo, αN-catenin is expressed in both neural precursors as well in neurons differentiated in culture. These differential expression patterns of αE-catenin and αN-catenin suggest both distinct and overlapping functions during cortical development.
Crayfish, bearing dangerous weapons in the form of chelae, resolve intraspecific conflicts using stereotyped behaviors and structured, escalated encounters. According to predictions of game theory ...models, any decision to resort to unrestrained combat without prior careful behavioral assessment of the opponent’s fighting abilities carries great risks. The present study examines the significance of internal hunger states and the presence of chemical food cues in this decision process using a 2 × 2 factorial design. Hungry crayfish escalated more rapidly, and thus took greater risks, during agonistic encounters, while the presence of a food source reduced the rate at which fights increased in intensity. However, there were no significant differences in fighting behavior as a result of the interaction between these two variables. We then address the complex trade‐offs that individuals face in fighting with respect to increased risks of injury, appetitive states, and opportunities for resource access.
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