Differential Response to Mechanical Cues in Uterine Fibroid Versus Paired Myometrial Cells.

Uterine leiomyomas, or fibroids, are common, benign tumors for which hysterectomy is the only definitive treatment. The extracellular matrix of fibroids is disorganized and stiffer than the surrounding myometrial tissue. To understand how stiffness affects fibroid cells, patient-matched fibroid and myometrial cells were cultured on substrates with stiffnesses varying from 0.2 to 150 kPa. Fibroid cells grew more slowly than myometrial cells overall, and only the myometrial cells altered their growth rate in response to stiffness. In both cell types, cell proliferation decreased with inhibition of PI3K and increased with inhibition of IGF-1. The cellular area was greater for the fibroid cells. The only significant effect of stiffness on the cell area was between the 0.2 and 64 kPa substrates, and this was true for both cell types. To investigate intracellular stiffness, intracellular particle tracking microrheology was used. Fibroid cells exhibited a more than 100-fold increase in elastic modulus at a frequency of 1 Hz in response to the addition of external stress, while myometrial cells showed little change in elastic modulus. Overall, the responses of both cells followed similar trends in response to stiffness and inhibitors, although the response was attenuated in the fibroid cells. The changes that were demonstrated by the change in intracellular stiffness with response to compression suggest that other mechanical forces may provide insight into differences in the two cell types.

Expression of QKI proteins and MAP1B identifies actively myelinating oligodendrocytes in adult rat brain.

We have studied developing oligodendrocytes in tissue sections as they initiate myelination and have found that the transition from premyelinating oligodendrocytes into myelin-bearing cells is accompanied by a dramatic upregulation in expression of the RNA binding QKI proteins. We show that in mature oligodendrocytes in culture, the localization of cytoplasmic QKI isoforms requires an intact cytoskeleton. Together with previous observations, this indicates that cytoplasmic QKI proteins facilitate movement of mRNAs to myelin via the cytoskeleton. In the adult rat brain, we found that a subset of oligodendrocytes displays characteristics of actively myelinating cells seen during development, i.e., connections to myelin sheaths and elevated levels of QKI proteins and also MAP1B. These observations suggest that instead of merely maintaining myelin, oligodendrocytes in the normal adult CNS are capable of responding to demands for new myelin sheaths. This has important implications for the prospect of repair of myelin in demyelinating conditions such as multiple sclerosis.

NG2-expressing cells in the central nervous system: are they oligodendroglial progenitors?

Antibodies against the chondroitin sulphate proteoglycan, NG2, are increasingly being used to identify the widespread population of oligodendrocyte progenitor cells in the adult mammalian CNS. However, the specificity of this marker and the role of NG2-expressing cells in CNS function are still open to question. In this review we consider the evidence that NG2(+) cells in the CNS are part of the oligodendrocyte lineage and whether they can give rise to new oligodendrocytes following demyelination. In both the developing and mature rodent CNS, NG2(+) cells express the established oligodendrocyte lineage marker PDGF-alphaR and from P7, the late progenitor antigen O4, which persists in immature oligodendrocytes. They do not express markers of other CNS populations, such as OX42 or GFAP, at any developmental age. NG2(+) cells represent the major cycling cell population in the normal adult rat CNS, suggesting they have stem cell-like properties. NG2 immunoreactivity is upregulated as a result of physical, viral, excitotoxic and inflammatory insults to the CNS. Following demyelination NG2(+) cell number increases in the immediate vicinity of the lesion and rapid remyelination ensues. NG2 expression has also been investigated in human tissue. Multi-process bearing cells, which morphologically resemble those identified with antibodies against O4, persist in chronically demyelinated multiple sclerosis lesions.

Generation of oligodendroglial progenitors in acute inflammatory demyelinating lesions of the rat brain stem is associated with demyelination rather than inflammation.

Remyelination is an extremely efficient process in the adult rodent central nervous system yet the source of new oligodendroglia that appear following primary demyelination is still subject to much debate. Using a reliable marker for oligodendroglial progenitor cells in vivo, the NG2 chondroitin sulphate proteoglycan, we have evaluated the response of endogenous NG2(+) cells in the adult rat brain stem and cerebellum to inflammatory demyelinating lesions in an experimentally induced animal model of multiple sclerosis (MS), antibody augmented experimental allergic encephalomyelitis (ADEAE). We have manipulated T-cell mediated EAE in Lewis rats by injecting in addition, either anti-myelin/oligodendroglial glycoprotein (MOG) antibodies to induce inflammatory demyelination, or non-specific mouse immunoglobulins to induce an inflammatory response without demyelination. We have examined the relationship of NG2(+) progenitor cells to microglia (OX-42(+)), astrocytes (GFAP(+)) and mature oligodendroglia (CNP(+)), in the normal and demyelinated CNS. In the normal CNS NG2-expressing cells are closely intermingled with other glia but represent a distinct cell population. A prominent inflammatory response, identified by the presence of large perivascular and periventricular accumulations of reactive OX42(+) macrophages/microglia, occurred in animals with ADEAE at 7-9 days post injection (DPI), coinciding with severe clinical symptoms. In animals injected with anti-MOG antibodies inflammation was followed by the appearance of large areas of demyelination at 11-14 DPI, at which point the animals had recovered clinically. The response of NG2(+) cells was different depending on whether the inflammation was accompanied by demyelination. In the presence of inflammation, NG2(+) cells responded by an increase in immunoreactivity and an alteration in their morphology, exhibiting enlarged cell bodies and an increased number of intensely stained processes. In areas of demyelination NG2(+) cells had fewer intensely stained processes reminiscent of progenitor cells seen during development. Quantitative analysis revealed a 3-fold increase in the number of NG2(+) cells in demyelinated lesions at 11 DPI, whereas no change was observed in areas of inflammation in the absence of demyelination. Mitotic figures were only seen in NG2(+) cells in areas of demyelination. NG2(+) cell numbers appeared to return to control levels following remyelination. These results suggest that endogenous oligodendroglial progenitors divide and/or migrate, in response to signals triggered by demyelinating rather than inflammatory events, to generate a large progenitor population sufficient to promote the rapid and successful remyelination observed in this model.

The effect of adapting luminance on the latency of visual search.

Computational models of attentional processing typically view the "attentional spotlight" as a winner-take-all network whose focus can be shifted serially about a display if required. As a result, lateral inhibition is assumed in these models to be an important mechanism involved in visual search. On the basis of this assumption, we predicted that changes in adapting luminance would produce specific changes in search latency functions in virtue of affecting visual inhibition. The results of our first two experiments confirmed these predictions: when search was difficult, and produced reaction time results characteristic of serial processing, there was a main effect of adapting luminance and a significant interaction between adapting luminance and the number of display elements. These effects were both reflected in increases in the slopes and the intercepts of average search latency functions when adapting luminance was decreased. When search was easy, and produced pop out effects characteristic of parallel processing, there were no significant effects of adapting luminance on search latency. The third experiment used adapting luminance to further explore the possibility that arrow junctions are detected preattentively. The results suggested that a visual search for such elements involves a substantial serial component, which weighs against the claim that they are detected by low-level vision.

Classification and staging of dementia of the Alzheimer type: a comparison between neural networks and linear discriminant analysis.

OBJECTIVE: To examine the utility of artificial neural networks (ANNs) for differentiating patients with Alzheimer disease from healthy control subjects and for staging the degree of dementia. DESIGN: Comparison of the classification abilities of ANNs with the statistical technique of linear discriminant analysis (LDA) using the results of 11 neuropsychological tests as predictors. PARTICIPANTS: Ninety-two patients with a diagnosis of probable Alzheimer disease (referred from a geriatric clinic) and 43 elderly control subjects (independently solicited). The patients met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable dementia, with clinical ratings of dementia severity derived from the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX). MAIN OUTCOME MEASURES: Classifications between and within groups were determined by using LDA and ANNs, and more detailed comparisons of the 2 methods were performed by using chi2 analyses and unweighted and weighted kappa statistics. RESULTS: Linear discriminant analysis correctly identified 71.9% of cases. Artificial neural networks, trained to classify the subjects using the same data, correctly classified 91.1% of the cases. Subsidiary analyses showed that although both techniques effectively discriminated between the control subjects and patients with dementia, the ANNs were more powerful in discriminating severity levels within the dementia population. The analyses for goodness of fit revealed that the ANN classification produced a better fit to the actual data. A comparison of the weighted proportion of agreement between the criterion and predictor variables also showed that the ANNs clearly outperformed LDA in classification accuracy for the full data set and patients-only data set. CONCLUSION: The results demonstrate the utility of ANNs for group classification of patients with Alzheimer disease and elderly controls and for staging dementia severity using neuropsychological data.

Artificial neural networks that use single-photon emission tomography to identify patients with probable Alzheimer's disease.

Single-photon emission tomographic (SPET) images using technetium-99m labelled hexamethyl-propylene amine oxime were obtained from 97 patients diagnosed as having Alzheimer's disease, as well as from a comparison group of 64 normal subjects. Multiple linear regression was used to predict subject type (Alzheimer's vs comparison) using scintillation counts from 14 different brain regions as predictors. These results were disappointing: the regression equation accounted for only 33.5% of the variance between subjects. However, the same data were also used to train parallel distributed processing (PDP) networks of different sizes to classify subjects. In general, the PDP networks accounted for substantially more (up to 95%) of the variance in the data, and in many instances were able to distinguish perfectly between the two subjects. These results suggest two conclusions. First, SPET images do provide sufficient information to distinguish patients with Alzheimer's disease from a normal comparison group. Second, to access this diagnostic information, it appears that one must take advantage of the ability of PDP networks to detect higher-order nonlinear relationships among the predictor variables.

Polarity matching in the Ternus configuration.

Two experiments were conducted to examine the effect of changes in the sign of element contrast on perceptions of the Ternus apparent motion display. In the first experiment, the contrast polarity of all three elements in the display were alternated from the first frame of view to the second. At short durations, this increased perceptions (relative to a control condition) of simultaneity in the display, decreased perceptions of element motion, and did not significantly affect perceptions of group motion. At long durations, this manipulation did not affect performance. In a second experiment, patterns of element polarity were manipulated to favour perceptions of either element motion or of group motion relative to a control condition in which all elements had identical contrast polarity. At a long duration, this manipulation affected perceptions of the configuration; this manipulation did not affect the appearance of the display at a short duration. Together, these results are inconsistent with the predictions of Grossberg and Rudd's [Psychological Review, 99, 78-121 (1992)] motion oriented contrast filter. However, they are consistent with a model of motion correspondence processing that includes a polarity matching constraint.

Primitive fossil rodent from Inner Mongolia and its implications for mammalian phylogeny.

The evolutionary origin of rodents is obscured by the group's sudden and highly transformed first appearance in the fossil record in the latest Paleocene. We report here the discovery of nearly complete dental remains of an extraordinary new primitive rodent from strata of transitional Paleocene-Eocene age in Inner Mongolia, China. The strikingly conservative morphological features of this taxon, Tribosphenomys minutus, gen. et sp. nov., substantially modify previous ideas about the ancestral rodent morphotype, which in turn has important implications for understanding the origin of rodents and their relationship to other eutherian mammals. This new fossil, in conjunction with recent morphological and molecular evidence confirming rodent monophyly, indicates the need for a reassessment of phylogenetic affinities among gliriform eutherians. Our results indicate a sister-group position of the new taxon to other rodents, and support the alliance of lagomorphs (rabbits) and rodents (cohort Glires). They also suggest that paraphyly of an extinct assemblage, the 'Eurymylidae', and reveal an unexpectedly complex pattern of character evolution near the ancestry of Rodentia.

A diverse new primate fauna from middle Eocene fissure-fillings in southeastern China.

We report the discovery of a fauna of primates from Eocene (approximately 45 Myr) deposits in China having a diversity greater than in European and North American localities of similar antiquity. From the many forms that will illuminate questions of primate phylogeny comes evidence for a basal radiation of primitive simians.

Simultaneity in the Ternus configuration: psychophysical data and a computer model.

The Ternus configuration is an apparent motion display which is typically described as being bistable; subjects usually describe seeing either element motion or group motion, depending upon temporal properties of the display. The results of an experiment are reported in which subjects are also permitted to report seeing four stationary display elements (simultaneity). It was found that simultaneity was produced when both frame durations and interstimulus intervals (ISIs) were brief. A weaker than expected effect of stimulus onset asynchrony (SOA) was revealed because this third type of judgment was obtained. Furthermore, statistical analyses indicated that SOA was not by itself the best predictor of judgment type. The interaction between duration and ISI was also an important predictor. This suggested that a complete account of the Ternus configuration requires two mechanisms: a visible persistence mechanism, governed by an SOA law, and a motion correspondence mechanism, governed by an ISI law. These two mechanisms were added to Dawson's (1991) [Psychological Review, 98, 569-603] autoassociative network for motion correspondence processing. The resulting model could generate each of the three interpretations of the Ternus configuration at appropriate combinations of frame duration and ISI.

Training redundant artificial neural networks: imposing biology on technology.

One biological principle that is often overlooked in the design of artificial neural networks (ANNs) is redundancy. Redundancy is the replication of processes within the brain. This paper examines the effects of redundancy on learning in ANNs when given either a function-approximation task or a pattern-classification task. The function-approximation task simulated a robotic arm reaching toward an object in two-dimensional space, and the pattern-classification task was detecting parity. Results indicated that redundant ANNs learned the pattern-classification problem much faster, and converge on a solution 100% of the time, whereas standard ANNs sometimes failed to learn the problem. Furthermore, when overall network error is considered, redundant ANNs were significantly more accurate than standard ANNs in performing the function-approximation task. These results are discussed in terms of the relevance of redundancy to the performance of ANNs in general, and the relevance of redundancy in biological systems in particular.

The how and why of what went where in apparent motion: modeling solutions to the motion correspondence problem.

A model that is capable of maintaining the identities of individuated elements as they move is described. It solves a particular problem of underdetermination, the motion correspondence problem, by simultaneously applying 3 constraints: the nearest neighbor principle, the relative velocity principle, and the element integrity principle. The model generates the same correspondence solutions as does the human visual system for a variety of displays, and many of its properties are consistent with what is known about the physiological mechanisms underlying human motion perception. The model can also be viewed as a proposal of how the identities of attentional tags are maintained by visual cognition, and thus it can be differentiated from a system that serves merely to detect movement.

Apparent motion and element connectedness.

Two experiments attempted to determine the effect of the topological property of connectedness on the perception of apparent motion. In Experiment I, direction detection points at subjective equality (PSEs) were measured in a motion competition paradigm. Results indicated that apparent motion was not more likely to be seen between topologically identical elements (e.g., two connected figures) than between elements similar in appearance, but which differed with respect to connectedness. This failed to replicate one finding of Chen (1985). Experiment II tested the possibility that connectedness might affect the quality or visibility of apparent motion. Displacement PSEs for the visibility of motion were measured. Apparent motion between identical figures was significantly more visible than apparent motion between figures similar in appearance, but of different connectedness. These results are discussed in terms of a two-stage model of the long-range motion system.

The consistency of element transformations affects the visibility but not the direction of illusory motion.

Two experiments tested whether the consistency of element transformations affected perceptions of long-range apparent motion. Vertical lines were used to generate apparent motion against one of two different backgrounds, control and depth. Consistency was manipulated by changing the size of the vertical lines. In some displays, the size of the vertical lines remained constant during movement. In other displays, the size of the vertical lines changed during movement. Consistent movement occurred when the size manipulation was in agreement with the type of background used. In Experiment I, points of subject equality for the quality of motion relative to a standard display were measured. These PSEs indicated that consistent movement (e.g., line sizes held constant for control background displays) was more visible than inconsistent movement (e.g., line sizes constant for depth background displays). In Experiment II, a motion competition display was used to measure thresholds for perceived direction of motion. The depth background was used to make motion in one direction more consistent than motion in the opposite direction. However, no significant differences were noted between thresholds obtained in this condition and those obtained in a control condition. Thus the consistency of element transformations affected the quality of motion, but did not affect the perceived direction of motion. These results are consistent with Ullman's (The Interpretation of Visual Motion, MIT Press, 1979) two-component theory of apparent motion.

Fission-track dating of haughton astrobleme and included biota, devon island, Canada.

Haughton Astrobleme is a major extraterrestrial impact structure located on Devon Island in the Canadian Arctic Archipelago, Northwest Territories. Apatite grains separated from shocked Precambrian gneiss contained in a polymict breccia from the center of the astrobleme yielded a fission-track date of 22.4 million +/- 1.4 million years before the present or early Miocene (Aquitanian). This provides a date for the impact event and an upper limit on the age of crater-filling lake sediments and a flora and vertebrate fauna occurring in them. A geologically precise date for these fossils provides an important biostratigraphic reference point for interpreting the biotic evolution of the Arctic.

Moving contexts do affect the perceived direction of apparent motion in motion competition displays.

Three experiments were performed to test Ullman's [The Interpretation of Visual Motion. MIT Press, Cambridge, Mass. (1979)] independence hypothesis, used in the minimal mapping theory of motion correspondence. Subjects were required to detect the direction of motion (left vs right) of an element in a motion competition display. In control conditions, threshold interelement distances were obtained for this task in the absence of any moving context. In experimental conditions, context elements that moved either to the left or to the right were added to the display. This resulted in changes in thresholds (relative to the control condition) that indicated that a context moving in one direction increased the probability of seeing the competition element move in the same direction. The magnitude of the context effect was shown to be related to the proximity of the context to the competition display, as well as to the number of elements in the context. These results are in conflict with Ullman's independence hypothesis. An alternative model of the motion correspondence process, which uses information about interdependencies between element movements, is briefly discussed.

Spatio-temporal parameters and the three-dimensionality of apparent motion: evidence for two types of processing.

The minimum ISI required for perceiving apparent motion in depth was measured as a function of the 2D separation of stimuli and the physical separation of stimuli in depth. It was found that temporal thresholds increased as a function of the separation of stimuli in depth. This supports the results of previous research indicating that the perceived three-dimensionality of apparent motion in depth increases with ISI. In addition, the rate of threshold increase was significantly greater in displays with short 2D separations of stimuli than in displays with large 2D separations. This robust functional dissociation of thresholds indicates that the short-range system may be involved in the processing of apparent motion in depth in the former case.