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Understanding of cellular transdifferentiation is limited by the technical inability to track multiple lineages in vivo. To overcome this we developed a new tool to simultaneously fate map two distinct cell types in the kidney, and genetically test whether cells of renin lineage (CoRL) can transdifferentiate to a podocyte fate. Ren1cCreER/tdTomato/Nphs1-FLPo/FRT-EGFP mice (CoRL-PODO mice) were generated by crossing Ren1c-CreER/tdTomato CoRL reporter mice with Nphs1-FLPo/FRT-EGFP podocyte reporter mice. Following tamoxifen administration in these animals, CoRL were labeled with red fluorescence (tdTomato) and co-localized with renin. Podocytes were labeled green (enhanced green fluorescent protein) and co-localized with nephrin. Following podocyte loss by nephrotoxic antibody and subsequent enalapril-enhanced partial replacement, tdTomato-EGFP-labeled CoRL were detected as yellow-colored cells in a subset of glomerular tufts, without the use of antibodies. Co-localization with podocin indicated that these cells are podocytes, derived from CoRL origin. Thus, our novel study shows that two distinct cell types can be simultaneously labeled in the mouse kidney and provide strong genetic evidence in vivo that lost podocytes can be replaced in part by CoRL.

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Advanced age portends a poorer prognosis in FSGS. To understand the impact of age on glomerular podocytes and parietal epithelial cells (PECs), experimental FSGS was induced in 3m-old mice (20-year old human age) and 27m-old mice (78-year old human age) by abruptly depleting podocytes with a cytopathic anti-podocyte antibody. Despite similar binding of the disease-inducing antibody, podocyte density was lower in aged FSGS mice compared to young FSGS mice. Activated PEC density was higher in aged versus young FSGS mice, as was the percentage of total activated PECs. Additionally, the percentage of glomeruli containing PECs with evidence of phosphorylated ERK and EMT was higher in aged FSGS mice. Extracellular matrix, measured by collagen IV and silver staining, was higher in aged FSGS mice along Bowman's capsule. However, collagen IV accumulation in the glomerular tufts alone and in glomeruli with both tuft and Bowman's capsule accumulation were similar in young FSGS and aged FSGS mice. Thus, the major difference in collagen IV staining in FSGS was along Bowman's capsule in aged mice. The significant differences in podocytes, PECs and extracellular matrix accumulation between young mice and old mice with FSGS might explain the differences in outcomes in FSGS based on age.

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The current studies used genetic fate mapping to prove that adult podocytes can be partially replenished following depletion. Inducible NPHS2-rtTA/tetO-Cre/RS-ZsGreen-R reporter mice were generated to permanently label podocytes with the ZsGreen reporter. Experimental focal segmental glomerulosclerosis (FSGS) was induced with a cytotoxic podocyte antibody. On FSGS day 7, immunostaining for the podocyte markers p57, synaptopodin, and podocin were markedly decreased by 44%, and this was accompanied by a decrease in ZsGreen fluorescence. The nuclear stain DAPI was absent in segments of reduced ZsGreen and podocyte marker staining, which is consistent with podocyte depletion. Staining for p57, synaptopodin, podocin, and DAPI increased at FSGS day 28 and was augmented by the ACE inhibitor enalapril, which is consistent with a partial replenishment of podocytes. In contrast, ZsGreen fluorescence did not return and remained significantly low at day 28, indicating replenishment was from a nonpodocyte origin. Despite administration of bromodeoxyuridine (BrdU) thrice weekly throughout the course of disease, BrdU staining was not detected in podocytes, which is consistent with an absence of proliferation. Although ZsGreen reporting was reduced in the tuft at FSGS day 28, labeled podocytes were detected along the Bowman's capsule in a subset of glomeruli, which is consistent with migration from the tuft. Moreover, more than half of the migrated podocytes coexpressed the parietal epithelial cell (PEC) proteins claudin-1, SSeCKS, and PAX8. These results show that although podocytes can be partially replenished following abrupt depletion, a process augmented by ACE inhibition, the source or sources are nonpodocyte in origin and are independent of proliferation. Furthermore, a subset of podocytes migrate to the Bowman's capsule and begin to coexpress PEC markers.

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An apparatus for generating quasi-free-space microwave-driven plasmas has been designed, constructed, and tested. The plasma is driven by a multi-kW, ∼5 GHz microwave beam focused at the center of a vacuum chamber using a Koch-type metal plate lens. Sustained plasma discharges have been generated in argon at pressures ranging from 150 to 200 mTorr, at beam power levels ranging from 5 to 10 kW, and at gas flow rates of approximately 200 SCCM.

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Humans make smooth pursuit eye movements to foveate moving objects of interest. It is known that smooth pursuit alters visual processing, but there is currently no consensus on whether changes in vision are contingent on the direction the eyes are moving. We recently showed that visual crowding can be used as a sensitive measure of changes in visual processing, resulting from involvement of the saccadic eye movement system. The present paper extends these results by examining the effect of smooth pursuit eye movements on the spatial extent of visual crowding-the area over which visual stimuli are integrated. We found systematic changes in crowding that depended on the direction of pursuit and the distance of stimuli from the pursuit target. Relative to when no eye movement was made, the spatial extent of crowding increased for objects located contraversive to the direction of pursuit at an eccentricity of approximately 3°. By contrast, crowding for objects located ipsiversive to the direction of pursuit remained unchanged. There was no change in crowding during smooth pursuit for objects located approximately 7° from the fovea. The increased size of the crowding zone for the contraversive direction may be related to the distance that the fovea lags behind the pursuit target during smooth eye movements. Overall, our results reveal that visual perception is altered dynamically according to the intended destination of oculomotor commands.

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The generation of referring expressions is a central topic in computational linguistics. Natural referring expressions - both definite references like 'the baseball cap' and pronouns like 'it' - are dependent on discourse context. We examine the practical implications of context-dependent referring expression generation for the design of spoken systems. Currently, not all spoken systems have the goal of generating natural referring expressions. Many researchers believe that the context-dependency of natural referring expressions actually makes systems less usable. Using the dual-task paradigm, we demonstrate that generating natural referring expressions that are dependent on discourse context reduces cognitive load. Somewhat surprisingly, we also demonstrate that practice does not improve cognitive load in systems that generate consistent (context-independent) referring expressions. We discuss practical implications for spoken systems as well as other areas of referring expression generation.

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Adults of both genders without dementia consumed a nutriceutical formulation ("NF," consisting of folic acid, B12, Vitamin E, S-adenosylmethionine, N-acetyl cysteine and Acetyl-L-carnitine), previously shown to improve cognitive performance in Alzheimer's disease, or placebo. Participants receiving NF but not placebo improved statistically and clinically in the California Verbal Learning Test II and the Trail-Making Test. Both groups improved further during a 3-month open-label extension. Additional individuals displayed identical improvement during a separate 6-month open-label trial. Performance declined to baseline following withdrawal of NF, and statistically improved when participants resumed taking NF. Additional participants receiving NF but not placebo demonstrated improvement within 2 weeks in Trail-making and Digit-Memory tests; both groups improved in a 2-week open-label extension. An increased percentage of participants > or = 74 years of age did not show improvement with NF, which may relate to age-related difficulties in adsorption and/or basal nutritional deficiencies, or age-related cognitive decline during the course of this study. These findings support the benefit of nutritional supplements for cognitive performance and suggest that additional supplementation may be required for the elderly.

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Hybognathus is a putatively monophyletic group of North American minnows containing seven extant species. Although much is known about the taxonomy, biology, and life history of Hybognathus species, their phylogenetic relations with each other remain unclear. We address this problem with partial sequences of mitochondrial cytochrome-b, 16S rRNA, and ND4 mtDNA genes and nuclear growth hormone (GH) and S7 introns from representatives of all Hybognathus species and four outgroup taxa. Phylogenetic analyses of these data corroborated previous studies on the monophyly of seven recognized species of Hybognathus, and indicated weak support for monophyly of the genus. Topological tests, however, revealed significant (all P<0.001) conflict among molecular data sets. Ad hoc removal of taxa from topologies and subsequent testing indicated that incongruence was localized to two specific ingroup taxa (H. hayi and H. regius) and suggested that the conflict is a function of underlying processes that have generated the observed phylogenetic patterns. Hybridization (ancestral), which is commonplace in cyprinids, may best explain topological disagreements among datasets; however, retention of ancestral polymorphism and natural selection remain as alternative hypotheses. Our results highlight methodological and topological problems associated with estimating interspecific phylogenies from multiple genes.

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A new paradigm was developed to examine prospective memory performance in a visual-spatial task that resembles some aspects of the work of air traffic controllers. Two experiments examined the role of workload (number of aeroplanes that participants directed), delay (between receipt of prospective instructions and execution), and phonological rehearsal. High workload increased prospective memory errors but increasing delay from 1-3 or 5 minutes had no effect. Shadowing aurally presented text reduced prospective memory performance, presumably because it prevented verbal rehearsal of the prospective instructions. However, performance on the foreground task of directing aeroplanes to routine destinations was affected only by workload and not by opportunity for rehearsal. Our results suggest that ability to maintain performance on a routine foreground task while performing a secondary task--perhaps analogous to conversation--does not predict ability to retrieve a prospective intention to deviate from the routine.

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Under certain circumstances, external stimuli will elicit an involuntary shift of spatial attention, referred to as attentional capture. According to the contingent involuntary orienting account (Folk, Remington, & Johnston, 1992), capture is conditioned by top-down factors that set attention to respond involuntarily to stimulus properties relevant to one's behavioral goals. Evidence for this comes from spatial cuing studies showing that a spatial cuing effect is observed only when cues have goal-relevant properties. Here, we examine alternative, decision-level explanations of the spatial cuing effect that attribute evidence of capture to postpresentation delays in the voluntary allocation of attention, rather than to on-line involuntary shifts in direct response to the cue. In three spatial cuing experiments, delayed-allocation accounts were tested by examining whether items at the cued location were preferentially processed. The experiments provide evidence that costs and benefits in spatial cuing experiments do reflect the on-line capture of attention. The implications of these results for models of attentional control are discussed.

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It is widely assumed that the allocatian of spatial attention results in the "selection" of attended objects or regions of space. That is, once a stimulus is attended, all its feature dimensions are processed irrespective of their relevance to behavioral goals. This assumption is based in part on experiments showing significant interference for attended stimuli when the response to an irrelevant dimension conflicts with the response to the relevant dimension (e.g., the Stroop effect). Here we show that such interference is not due to attending per se. In two spatial cuing experiments, we found that it was possible to restrict processing of attended stimuli to task-relevant dimensions. This new evidence supports two novel conclusions: (a) Selection involves more than the focusing of attention per se: and (b) task expectations play a key role in detertnining the depth of processing of the elementary feature dimensions of attended stimuli.

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How do top-down factors (e.g., task expectancy) and bottom-up factors (e.g., task recency) interact to produce an overall level of task readiness? This question was addressed by factorially manipulating task expectancy and task repetition in a task-switching paradigm. The effects of expectancy and repetition on response time tended to interact underadditively, but only because the traditional binary task-repetition variable lumps together all switch trials, ignoring variation in task lag. When the task-recency variable was scaled continuously, all 4 experiments instead showed additivity between expectancy and recency. The results indicated that expectancy and recency influence different stages of mental processing. One specific possibility (the configuration-execution model) is that task expectancy affects the time required to configure upcoming central operations, whereas task recency affects the time required to actually execute those central operations.

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An analysis of activation models of visual word processing suggests that frequency-sensitive forms of lexical processing should proceed normally while unattended. This hypothesis was tested by having participants perform a speeded pitch discrimination task followed by lexical decisions or word naming. As the stimulus onset asynchrony between the tasks was reduced, lexical-decision and naming latencies increased dramatically. Word-frequency effects were additive with the increase, indicating that frequency-sensitive processing was subject to postponement while attention was devoted to the other task. Either (a) the same neural hardware shares responsibility for lexical processing and central stages of choice reaction time task processing and cannot perform both computations simultaneously, or (b) lexical processing is blocked in order to optimize performance on the pitch discrimination task. Either way, word processing is not as automatic as activation models suggest.

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Recent free flight proposals to relax airspace constraints and give greater autonomy to aircraft have raised concerns about their impact on controller performance. Relaxing route and altitude restrictions would reduce the regularity of traffic through individual sectors, possibly impairing controller situation awareness. We examined the impact of this reduced regularity in four visual search experiments that tested controllers' detection of traffic conflicts in the four conditions created by factorial manipulation of fixed routes (present vs. absent) and altitude restrictions (present vs. absent). These four conditions were tested under varying levels of traffic load and conflict geometry (conflict time and conflict angle). Traffic load and conflict geometry showed strong and consistent effects in all experiments. Color coding altitude also substantially improved detection times. In contrast, removing altitude restrictions had only a small negative impact, and removing route restrictions had virtually no negative impact. In some cases conflict detection was actually better without fixed routes. The implications and limitations of these results for the feasibility of free flight are discussed. Actual or potential applications include providing guidance in the selection of free flight operational concepts.

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Previous research suggests that attentional capture by abrupt onsets is contingent on top-down attentional control settings. Four experiments addressed whether similar contingencies hold for capture elicited by the appearance of new perceptual objects. In a modified spatial cuing task, targets defined by abrupt onset or color were paired with distractors consisting of an abrupt brightening of an existing object or the abrupt appearance of a new object. In Experiments 1 and 2, when subjects searched for an onset target, both distractor types produced evidence of capture. When subjects searched for a color target, however, distractors produced no evidence of attentional capture, regardless of whether they consisted of a new perceptual object or not. Experiments 3-5 showed that the lack of distractor effects in the color-target condition cannot be accounted for by rapid recovery from capture. It was concluded that attentional capture by new objects is subject to top-down modulation by attentional control settings.

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Four experiments addressed the degree of top-down control over attentional capture in visual search for featural singletons. In a modified spatial cuing paradigm, the spatial relationship and featural similarity of target and distractor singletons were systematically varied. Contrary to previous studies, all 4 experiments showed that when searching for a singleton target, an irrelevant featural singleton captures spatial attention only when defined by the same feature value as the target. Experiments 2, 3 and 4 provided a potential explanation for the discrepancy with previous studies by showing that irrelevant singletons can produce distraction effects that are dissociable from shifts of spatial attention. The results suggest the existence of 2 distinct forms of attentional capture.

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The product of the bcl-2 oncogene has been shown to play an important role in apoptosis and programmed cell death. In this study, a herpes simplex virus type-1 vector was constructed to carry the human bcl-2 gene. The possible role of bcl-2 in protecting neurons from excitoxicity was investigated by using the viral vector to deliver the gene into neuronal cultures before or after the cells were exposed to glutamate under conditions in which 50-80% of neurons died. Infection with the bcl-2 expressing vector 24 h prior to glutamate treatment effectively prevented the cell death that normally follows this treatment. Moreover, infection with the vector as late as 8 h after the glutamate insult still resulted in substantial neuroprotective effects. These results have potential implications for new therapies in stroke or ischemic neuropathies.

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Color and form are elementary stimulus encoding dimensions that have effects on the representation of visual stimuli at early processing stages. Little is known, however, about their effects on visual long-term memory. In three experiments we investigated whether color is part of the memory representation, whether color and form are bound in the memory representation, and the effect of color context on memory performance. Experimental results suggest that color is part of the memory representation and that color and form can be represented separately in memory and accessed independently. We suggest that the binding of color and form is a deliberate strategic act that requires focal attention, not a natural consequence of processing visual stimuli. We compare our results with the predictions of two computational memory models regarding feature binding. The effect of color context was not straightforward; however, results are consistent with the encoding specificity principle.

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Five spatial cuing experiments tested 2 hypotheses regarding attentional capture: (a) Attentional capture is contingent on endogenous attentional control settings, and (b) attentional control settings are limited to the distinction between dynamic and static discontinuities (C. L. Folk, R. W. Remington, & J. C. Johnston, 1992). In Experiments 1 and 2, apparent-motion precues produced significant costs in performance for targets signaled by motion but not for targets signaled by color or abrupt onset. Experiment 3 established that this pattern is not due to differences in the difficulty of target discrimination. Experiments 4 and 5 revealed asymmetric capture effects between abrupt onset and apparent motion related to stimulus salience. The results support the hypotheses of Folk et al. (1992) and suggest that stimulus salience may also play a role in attentional capture.

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Four experiments tested a new hypothesis that involuntary attention shifts are contingent on the relationship between the properties of the eliciting event and the properties required for task performance. In a variant of the spatial cuing paradigm, the relation between cue property and the property useful in locating the target was systematically manipulated. In Experiment 1, invalid abrupt-onset precues produced costs for targets characterized by an abrupt onset but not for targets characterized by a discontinuity in color. In Experiment 2, invalid color precues produced greater costs for color targets than for abrupt-onset targets. Experiment 3 provided converging evidence for this pattern. Experiment 4 investigated the boundary conditions and time course for attention shifts elicited by color discontinuities. The results of these experiments suggest that attention capture is contingent on attentional control settings induced by task demands.

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