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Purpose While Millennials are the most educated generation to date, the unique contributions of higher education as a source of vocational anticipatory socialization (VAS) for organizational success remains unknown. Thus, this paper aims to establish a formative understanding from the student perspective of how faculty help ready the youngest of the Millennial generation for industry. This also allows for a comparison to their older counterparts. Design/methodology/approach Data were collected via an online mixed-methods survey with nearly 400 Millennials (n = 353). Findings Two prominent themes emerged including the professor as a socialization agent, where Millennials report learning from faculty as they are “managers of the classroom.” Additionally, the data indicate that many Millennials doubt the strength of the connection between higher education and career socialization, though a smaller cohort reported using the university environment, and more specifically, their interactions with faculty to practice and refine future workplace behaviors. In contrast to parents and peers, faculty nearly always ranked as the lowest source of VAS information. Research limitations/implications Some Millennials demonstrate a keen awareness of the importance of relational communication, boding especially well for their relationships with future managers and for their leadership skills as they transition into positions of management. Practical implications Faculty should consider how to address three concerns: a potential lack of perceived relevance, workplace inferences based on college experiences and leveraging interactions to strengthen student practice of professional communication. Managers would be well served to anticipate how to address newcomers’ expectations that stem from interpreting communicative experiences in the college classroom as analogous to workplace interactions. Originality/value The data indicate that traditional ideas about the impact of vocational anticipatory socialization sources and messaging need to be rethought, and instead, it appears some of the most fruitful socialization experiences faculty can provide is in giving students space and opportunity to practice and refine future workplace behaviors.

"Gaze following"—when one individual witnesses another shift its orientation, and then re-orients in the same direction—has been observed in a wide range of species. Related work with dolphins has to date focused on human–dolphin interactions. In this conspecific study, we examined a group of dolphins orienting, in passing, to gateways between their pools, as opportunities for witnesses to demonstrate "gaze following". Seven bottlenose dolphins were synchronously videotaped on six underwater cameras, for 21 h over three days, and the recordings analyzed by trained observers. The identities of all animals present, their partner state, and whether and to what degree they had altered their access to the gate (e.g., from Monocular to Binocular, or Binocular toVisio-Echoic) was recorded. Compared to animals that did not witness such a change, witnesses of an increase in access by another dolphin were significantly more likely to also act to increase their own access. We observed 460 such cases of "gaze following" in these animals. Dolphins who were partnered (showed sustained swimming within 1 body length) were significantly more likely, than non-partnered animals, to "gaze follow". Dolphins also showed a significant tendency toward matching the kind of access they observed. No significant difference was found in the presence of animals in the back pools, during changes in orientation that were followed, versus in those that were not. These findings support adding bottlenose dolphins to the growing list of species that display conspecific "gaze following".

Systems for detecting and tracking social marine mammals, including dolphins, can provide data to help explain their social dynamics, predict their behavior, and measure the impact of human interference. Data collected from video surveillance methods can be consistently and systematically sampled for studies of behavior, and frame-by-frame analyses can uncover insights impossible to observe from real-time, freely occurring natural behavior. Advances in boat-based, aerial, and underwater recording platforms provide opportunities to document the behavior of marine mammals and create massive datasets. The use of human experts to detect, track, identify individuals, and recognize activity in video demands significant time and financial investment. This paper examines automated methods designed to analyze large video corpora containing marine mammals. While research is converging on best solutions for some automated tasks, particularly detection and classification, many research domains are ripe for exploration.

Infants are biologically prepared to learn complex behaviors by interacting in dynamic, responsive social environments. Although the importance of interactive social experiences has long been recognized, current methods for studying complex multimodal interactions are lagging. This paper outlines a systems approach for characterizing fine-grained temporal dynamics of developing social interaction. We provide best practices for capturing, coding, and analyzing interaction activity on multiple-temporal scales, from fractions of seconds (e.g., gaze shifts), to minutes (e.g., coordinated play episodes), to weeks or months (e.g., developmental change). © 2013 IEEE.

Go is a fascinating game that has yet to be played well by a computer program due to its large board size and exponential time complexity. This paper presents a GPU implementation of PV-Split, a parallel implementation of a widely used game tree search algorithm for two-player zero-sum games. With many game trees, it often takes too much time to traverse the entire tree, but theoretically, the deeper the tree is traversed, the more accurate the best move found will be. By parallelizing the Go game tree search, we have successfully reduced the computation time, enabling deeper levels of the tree to be reached in smaller amounts of time. Results for the sequential and GPU implementations were compared, and the highest speedup achieved with the parallel algorithm was approximately 72x at 6 levels deep in the game tree. Although there has been related work with respect to game tree searches on the GPU, no exact best move search algorithms have been presented for Go, which uses significantly more memory due to its large board size. This paper also presents a technique for reducing the amount of required memory from previous game tree traversal methods while still allowing each processing element to play out games independently.

© 2016 The Society for Research in Child Development, Inc. Previous developmental accounts of joint object activity identify a qualitative "shift" around 9-12 months. In a longitudinal study of 26 dyads, videos of joint object interactions at 4, 6, 9, and 12 months were coded for all targets of gaze and manual activity (at 10 Hz). At 12 months, infants distribute their sensorimotor modalities between objects handled by the parent and others controlled by the infant. Analyses reveal novel trajectories in distributed joint object activity across the 1st year. At 4 months, infants predominantly look at and manipulate a single object, typically held by their mothers. Between 6 and 9 months, infants increasingly decouple their visual and haptic modalities and distribute their attention between objects held by their mothers and by themselves. These previously unreported developments in the distribution of multimodal object activity might "bridge the gap" to coordinated joint activity between 6 and 12 months.

The Virtual Watershed Client, built using the Unity game engine, provides a tool that allows researchers, students, and others to observe and analyze geospatial datasets and theoretical model data acquired from the Virtual Watershed Platform. The Virtual Watershed Platform is used as a service to acquire data that is used by the Virtual Watershed Client to create terrain, satellite imagery, shapes, and model data. A detailed design and the current implementation of this Virtual Watershed Client will be discussed in this paper.

Social attention involves attention directed toward other individuals, as well as the coordination of attention among individuals. This topic has been the focus of much recent research with nonhuman primates. In this review, we focus on the behavior of the participants in this research—both the animals and the humans—rather than on its cognitive implications. After briefly reviewing theoretical issues and the sensorimotor constraints on primate attention, we describe the ethological and experimental work that has been done. The former, involving observational studies in field and captive settings, focuses on the functions of social attention and on differences in traditional and contemporary micro-ethological techniques. The experimental work is organized in terms of the types of social relationships—solicitous, competitive, collaborative—that the various paradigms establish between subjects or between subject and experimenter. These include co-orientation (gazefollowing) tasks, food-sharing tasks (such as conditional begging, donor choice, and object choice tasks), conspecific competition (such as occluder and informed leader tasks), and collaborative cue production (where subjects must cue an ignorant experimenter). In all of these tasks, we report the relative effectiveness of various attentional cues, including use of the hands (e.g., touching, pointing) and orientation of the body, head, and eyes. In our final discussion, we consider differences in focus in the observational vs experimental approaches (on negotiating social relationships vs access to food, respectively) and suggest ways in which the methods in these two arenas might be successfully integrated. We also discuss the advantages of considering the “ecology” of the laboratory setting and how recognizing the social and perceptual configurations established by different protocols can aid in their interpretation and design. Finally, we discuss the prevalence of individual differences in this research and how this underscores the importance of rearing history and other contextual factors in primate social attention.

This study extends earlier reports regarding the in vitro and in vivo efficacies of the nitroimidazopyran PA-824 against Mycobacterium tuberculosis . PA-824 was tested in vitro against a broad panel of multidrug-resistant clinical isolates and was found to be highly active against all isolates (MIC < 1 μg/ml). The activity of PA-824 against M. tuberculosis was also assessed grown under conditions of oxygen depletion. PA-824 showed significant activity at 2, 10, and 50 μg/ml, similar to that of metronidazole, in a dose-dependent manner. In a short-course mouse infection model, the efficacy of PA-824 at 50, 100, and 300 mg/kg of body weight formulated in methylcellulose or cyclodextrin/lecithin after nine oral treatments was compared with those of isoniazid, rifampin, and moxifloxacin. PA-824 at 100 mg/kg in cyclodextrin/lecithin was as active as moxifloxacin at 100 mg/kg and isoniazid at 25 mg/kg and was slightly more active than rifampin at 20 mg/kg. Long-term treatment with PA-824 at 100 mg/kg in cyclodextrin/lecithin reduced the bacterial load below 500 CFU in the lungs and spleen. No significant differences in activity between PA-824 and the other single drug treatments tested (isoniazid at 25 mg/kg, rifampin at 10 mg/kg, gatifloxacin at 100 mg/kg, and moxifloxacin at 100 mg/kg) could be observed. In summary, its good activity in in vivo models, as well as its activity against multidrug-resistant M. tuberculosis and against M. tuberculosis isolates in a potentially latent state, makes PA-824 an attractive drug candidate for the therapy of tuberculosis. These data indicate that there is significant potential for effective oral delivery of PA-824 for the treatment of tuberculosis.

Reliable housekeeping gene controls are critical for measuring and comparing gene expression at the transcription level by Northern blot and RT-PCR. In order to develop such controls for studying cytokine mRNA expression in dogs, DNA sequence encoding a full-length canine HPRT protein has been obtained. Numerous primer pairs derived from the canine HPRT sequence have been tested on canine genomic DNA as well as cDNA. The data from the present study suggest that there may be processed HPRT pseudogenes in dogs. Three pairs of canine HPRT primers designed and tested in the present study were able to differentiate between cDNA and genomic DNA under specific PCR conditions. These primers would be useful controls for measurement of mRNA expression by RT-PCR in the dog.

Detecting and tracking social marine mammals, including bottlenose dolphins, can help to explain their social dynamics, predict their behavior, and measure the impact of human interference. Multi-camera setups provide an opportunity to record the behavior of captive dolphins and create a massive dataset from which long term statistics can be extracted, but the use of human experts to track dolphin positions over time demands a high time and financial investment cost. In this paper, we examine automated methods to analyze large video corpora. We use background subtraction to detect dolphins over time in the video data and to visualize the paths by which dolphins regularly traverse their environment. We demonstrate the use of these background subtraction methods as a way to initialize a preexisting real-time compressive tracking algorithm, which previously required human interaction. Detecting when dolphins transfer between pools both supplements 3D tracking efforts, helping identify moments when dolphins move between cameras, and augments human performance, providing a way for researchers to manually annotate dolphin pool positions 14 times as fast.

Two decades of attempts to model the emergence of language as a collective cognitive activity have demonstrated a number of principles that might have been part of the historical process that led to language. Several models have demonstrated the emergence of structure in a symbolic medium, but none has demonstrated the emergence of the capacity for symbolic representation. The current shift in cognitive science toward theoretical frameworks based on embodiment is already furnishing computational models with additional mechanisms relevant to the emergence of symbolic language. An analysis of embodied interaction among captive, but not human-enculturated, bonobo chimpanzees reveals a number of additional features of embodiment that are relevant to the emergence of symbolic language, but that have not yet been explored in computational simulation models; for example, complementarity of action in addition to imitation, iconic in addition to indexical gesture, coordination among multiple sensory and perceptual modalities, and the orchestration of intra- and inter-individual motor coordination. The bonobos provide an evolutionarily plausible intermediate stage in the development of symbolic expression that can inform efforts to model the emergence of symbolic language.

Anticipating the location of a temporarily obscured target—what Piaget (the construction of reality in the child. Basic Books, New York, 1954) called ‘‘objectpermanence’’—is a critical skill, especially in hunters of mobile prey. Previous research with bottlenose dolphins found they could predict the location of a target that had been visibly displaced into an opaque container, but not one that was first placed in an opaque container and then invisibly displaced to another container. We tested whether, by altering the task to involve occlusion rather than containment, these animals could show more advanced object permanence skills. We projected dynamic visual displays at an underwater-viewing window and videotaped the animals’ head moves while observing these displays. In Experiment 1, the animals observed a small black disk moving behind occluders that shifted in size, ultimately forming one large occluder. Nine out of ten subjects ‘‘tracked’’ the presumed movement of the disk behind this occluder on their first trial—and in a statistically significant number of subsequent trials—confirming their visible displacement abilities. In Experiment 2, we tested their invisible displacement abilities. The disk first disappeared behind a pair of moving occluders, which then moved behind a stationary occluder. The moving occluders then reappeared and separated, revealing that the disk was no longer behind them. The subjects subsequently looked to the correct stationary occluder on eight of their ten first trials, and in a statistically significant number of subsequent trials. Thus, by altering the stimuli to be more ecologically valid, we were able to show that the dolphins could indeed succeed at an invisible displacement task.

We compared carbon and nutrient concentrations and stocks in aboveground vegetation and soils between secondary forests (10-, 20-, and 40-year-old stands subject to repeated cycles of slash-and-burn agriculture) and a primary forest fragment in the Bragantina region of Para, Brazil. We hypothesized that repeated agricultural use would result in lower nutrient concentrations and/or stocks in the plant tissue and soils of the secondary forest stands relative to the primary forest fragment. Yet there were no significant differences in median foliar tissue concentrations of C, N, P, K, Ca, or Mg between the secondary forests and the primary forest. In woody tissue, the primary forest had a lower median Mg concentration (205 μg g−1) than all secondary forest plots (356–620 μg g−1) and a higher median N concentration (0.3%) than the 40-year-old secondary forest (0.2%). Foliar nutrient stocks were higher in the secondary forests than in the primary forest due to higher foliar biomass estimates for those plots. Aboveground woody nutrient stocks were greatest in the primary forest with the exception of Mg. Soil concentrations of exchangeable Ca decreased with increasing stand age; soil concentrations of exchangeable Mg were higher in all secondary plot soils than in the primary plot soil. Labile P stocks were greater in the primary forest soil than in all secondary forest soils. Soil labile P stocks were larger than aboveground P stocks in the 10- and 20-year-old secondary plots and the primary plot and approximately equal to aboveground stocks in the 40-year-old plot. Relative to other tropical and temperate locations, nutrient capital at these sites is low in both the vegetation and the soil, but a century of shifting cultivation does not yet appear to have introduced soil nutrient limitations to forest regrowth.

A model of "distributed cognition" is contrasted with the "mental representation" model exemplified by Tomasello and Call's Primate Cognition. Rather than using behavior as a basis for inferences to invisible mental events such as intentions, the distributed approach treats communicative interactions as, themselves, directly observable cognitive events. Similar to a Vygotskian approach, this model characterizes cognition as "co-constructed" by the participants. This approach is thus particularly suitable for studying primates (including humans), whose reliance on multiparty negotiations can undermine the researcher's ability to extrapolate from observable outcomes back to individual intentions. Detailed (e.g., frame-by-frame) analyses of such interactions reveal cross-species differences in the relevant media of information flow (e.g., behavioral coordination, relative gaze) as well as in the flexibility and complexity of the trajectories observed. Plus, with its focus on dynamics, the distributed approach is especially useful for modeling developmental and evolutionary processes. In discussing enculturation and the ontogeny of imitation, its emphasis is on changes in how expert and novice participate in such events, rather than how either may represent them. Primate cognitive evolution is seen as involving changes in context sensitivity, multi-tasking, and the coordination of social attention. Humans in particular – in, especially, the context of teaching – are seen as having specialized in linking co-perception with the refined sensory-motor coordination that enables them to translate observed behavior into strategically similar action. Highlighting the continuity between human and nonhuman development, this promising, complementary model enables us to tap the richness of micro-ethology as a cognitive science.

To examine rates of aboveground biomass accumulation (ABA) in global secondary forests following stand-clearing disturbances, we compiled aboveground biomass data from 283 known-age plots drawn from chronosequence and long-term studies. We focused on three likely influences on ABA for which data are readily available: climate, soil texture, and forest type. Growing-season degree-years (GSDY, stand age × growing-season length × growing-season temperature) generally predicted ABA better than stand age alone. Using regression analyses and slope homogeneity tests, we determined that broadleaf forest plots on sandy textured soils exhibited slower GSDY-adjusted ABA than those on nonsandy soils. On nonsandy soils, the GSDY-adjusted ABAs of tropical and nontropical plots were indistinguishable; tropical forest post-disturbance ABA was not particularly slow. Compared to broadleaf forests, needle-leaf forest, GSDY-adjusted ABA was less sensitive to soil texture and was intermediate in rate between sandy and nonsandy broadleaf forest ABA. Foliar nutrient concentration did not significantly influence the GSDY-adjusted ABA of a subset of the nonsandy broadleaf forests for which foliar nutrient data were available. At the global scale, differences in climate (represented by growing-season length and temperature) and moisture-holding capacity (represented by soil texture) are the principal independent factors influencing ABA in most post-disturbance secondary forests.

“Peering”—close-proximity staring at the mouth of another—was observed in ten (three males and seven females) mature (at least 7 years old) bonobos (Pan paniscus) living in three social groups at the San Diego Zoo and Wild Animal Park. Instantaneous scan samples, taken at 2-min intervals, over a three-and-a-half year period, yielded 617 observations of peering (1.4 per observation hour). Food was exchanged in only 15 of these scans. Peering was most often performed by younger animals and was primarily directed toward older females (“matrons”). In a given dyad, the animal more likely to peer at the other was also more like to both peer and be peered at if they frequently groomed and infrequently displayed aggression at a given female. An adolescent male showed the highest frequency of peering when living with two older females, but dropped to adult male levels when later housed with two younger (albeit mature) females. A reversal in which animal was more likely to peer, follow, and groom occurred in one female dyad, after the birth of the younger animal's first infant. After a similar birth in the other group, no such changes were observed. We discuss how these and related findings, in conjunction with what is known of the social structure of this species, suggest that one possible function of peering in bonobos may be as a signal acknowledging female status.

It remains unknown whether the expression of cell-mediated protective immunity and the capacity to mount a delayed-type hypersensitivity (DTH) reaction in tuberculosis infection represent two manifestations of a basic response or are dissociable events. In this study, we present data in favor of the latter hypothesis, by showing that tuberculosis infection in the lungs of mice possessing only a truncated form of intracellular adhesion molecule 1 due to gene disruption was still adequately controlled by the expression of protective immunity in the absence of any sustained influx of macrophages and the lack of formation of appreciable granulomas. These animals also had no detectable DTH response to mycobacterial proteins in the footpad assay, indicating that the accumulation of blood-borne macrophages at sites of mycobacterial infection or antigen deposition is not essential to control of the infection. These data support the hypothesis that the DTH component of the cellular response is not protective but contributes by walling off the sites of infection to prevent dissemination and reactivation disease.

Objective: Use gene disrupted mice to examine the possible role of secretory antibody on resistance to re-exposure to pulmonary tuberculosis. Design: Mice deficient in B cells due to targeted gene disruption were infected by aerosol exposure with Mycobacterium tuberculosis. A further set were identically exposed then given isoniazid to clear the infection and establish a state of memory immunity. Results: Control of the aerosol infection and generation of gamma interferon proceeded in a similar manner in both naive and memory immune mice, regardless of B cell deficiency. Conclusions: The absence of antibody responses did not affect the course of infection, thus confirming the classical literature that antibody plays no significant protective role.

Previous accounts of the development of triadic attention identify a ‘‘curious'' shift around nine to twelve months. We introduce a novel approach inspired by distributed and embodied cognition frameworks. In a longitudinal study of five mother-infant dyads, videos of home play interactions were recorded over the infants' first year. We scrutinized the real-time organization of mother-infant sensorimotor activity, including the targets of hands, gaze, and mouth, as the dyad members attended to one another and to toys. We identified a pervasive developmental pattern: At four months, infants converged all sensory modalities on objects introduced by the mother. From six to twelve months, infants showed increasing decoupling of hands and eyes and increasingly elaborate sequences in multi-object play. Concurrently, dyads engaged in increasingly elaborate social exchanges (e.g., turn-taking) as mothers adapted to infants' sensorimotor skills. We therefore theorize that triadic attention emerges not as a novel form of social cognition but as a continuous product of sensorimotor development, scaffolded by parents' expanding social actions.

Infants rapidly develop the skills to coordinate attention to objects and people. In particular, the period 9–12 months is thought to bring a new ability to coordinate with and to share the objects of another persons' attention—like following the gaze of the mother or playing a ball tossing game together. This has been termed “triadic” or “you-me-it” attention and is thought to be the basis for future learning, including early language (Bruner, 1975; Tomasello & Farrar, 1986).

Global patterns of histone methylation are remodelled during cleavage development. Of the five histone methyltransferases known to mediate methylation of the lysine 9 residue of histone H3 (H3K9), euchromatic histone-lysine N-methyltransferase 2 (EHMT2; also known as G9a) has been shown to be a primary mediator of H3K9 dimethylation; BIX-01294 has been shown to be a specific inhibitor of EHMT2. The objective of the present study was to determine the effect of BIX-01294 treatment on global H3K9 dimethylation in porcine embryos. We hypothesised that inhibition of EHMT2 by BIX-01294 would result in reduced levels of H3K9 dimethylation and compromised embryo development. Our results showed that incubation in 5 µM BIX-01294 markedly reduced global levels of H3K9 dimethylation at the pronuclear, 2-cell and 4-cell stages of development and resulted in developmental arrest before blastocyst formation. Although transient exposure of embryos to BIX-01294 did not alter in vitro development, embryos transiently exposed to BIX-01294 did not establish pregnancy. These data demonstrate that BIX-01294 is a potent inhibitor of H3K9 dimethylation and that transient alterations in global histone modifications can have profound effects on embryo developmental potential.

This project characterizes the development of early social interactions in a longitudinal sample of mothers and their infants. To do this we track the interaction in as a temporal configuration of multimodal, multiparty components, coding a total of 14 dimensions at each frame. Our final goal is to develop methods which we can use to systematically document regularities in the way attention gets organized longitudinally in a large sample of mother-infant dyads. Coding systematically at this scale allows us to ground a developmental account of early social interaction. For this project, we developed 1) ways to reduce the labor intensity of coding frame-by-frame multidimensional data over the entire sample and 2)ways of quantifying complex configural regularities across our sample. © ACM 2010.

Dimethylated H3K9 is a heritable epigenetic mark that is closely linked with transcriptional silencing and known to undergo global remodelling during cleavage development. Five mammalian histone methyltransferases (HMTases), namely Suv39H1, Suv39H2, SetDB1, EHMT1 and EHMT2, have been shown to mediate the methylation of H3K9. The aim of the present study was to determine the developmental requirements of these HMTases during cleavage development in porcine embryos. We hypothesised that knockdown of the abovementioned HMTases would differentially affect porcine cleavage development. To test this hypothesis, IVM and IVF porcine oocytes were divided into one of three treatment groups, including non-injected controls, oocytes injected with a double-stranded interfering RNA molecule specific for one of the HMTases and oocytes injected with a corresponding mutated (control) double-stranded RNA molecule. Nuclei were counted in all embryos 6 days after fertilisation. Although no significant difference in total cell number was detected in embryos injected with EHMT1 and EHMT2 interfering RNAs (compared with their respective control groups), embryos injected with interfering RNAs that targeted Suv39H1, Suv39H2 and SetDB1 had significantly lower cell numbers than their respective control groups (P

Methylation of the lysine 9 residue of histone H3 (H3K9) is linked to transcriptional repression. The observed structure of chromatin in porcine and murine embryos is different with regard to H3K9 dimethylation status, leading to our hypothesis that the intracellular mechanisms responsible for H3K9 methylation would also differ between these two species. The objectives of this study were: (1) to determine the extent that DNA, mRNA, and protein synthesis serve in maintaining the asymmetrical distribution of dimethylated H3K9 in porcine zygotes, (2) determine the extent to which the intracellular localization of individual pronuclei correlated with H3K9 dimethylation status, and (3) to determine the abundance of transcripts encoding the histone methyltransferases, with H3K9 methylation activity, in porcine oocytes and embryos. Our findings are that (1) H3K9 dimethylation status is not affected by DNA replication, transcription, or protein synthesis, (2) the location of a pronucleus does not significantly affect the H3K9 dimethylation status of the chromatin within that pronucleus, and (3) the histone methyltransferases with activity for H3K9 differ in transcript abundance in porcine oocytes and cleavage stage embyros. These results support our hypothesis that there is a difference in intracellular mechanisms affecting dimethylation status of H3K9 between porcine and murine embryos.

A novel subclass of quinolones, 2-pyridones, showed potent activity against Mycobacterium tuberculosis , with KRQ-10018 being an early lead. KRQ-10018 showed better activity in vitro against M. tuberculosis versus moxifloxacin. In vivo efficacy of KRQ-10018 at 300 mg/kg of body weight was similar to that of isoniazid at 25 mg/kg, but showed less activity than moxifloxacin at 300 mg/kg.

The assessment of physiochemical and pharmacological properties at early stages of drug discovery can accelerate the conversion of hits and leads into candidates for further development. A strategy for streamlined evaluation of compounds against Mycobacterium tuberculosis in the early preclinical stage is presented in this report. As a primary assay to rapidly select experimental compounds with sufficient in vitro activity, the growth inhibition microtiter plate assay was devised as an alternative to current methods. This microdilution plate assay is a liquid culture method based on spectrophotometric readings of the bacillary growth. The performance of this method was compared to the performance of two established susceptibility methods using clinical available tuberculosis (TB) drugs. Data generated from all three assays were similar for all of the tested compounds. A second simple bioassay was devised to assess the oral bioavailability of compounds prior to extensive in vivo efficacy testing. The bioassay estimates drug concentrations in collected serum samples by a microdilution MIC plate method using M. tuberculosis . In the same assay, the MIC of the compound is also determined in the presence of 10% mouse serum as an indication of protein binding. The method was validated using different clinically available TB drugs, and results are discussed in this report. With these methodological advances, screening of compounds against tuberculosis in the preclinical phase will be rapid, can be adapted to semi-high-throughput screening, and will add relevant physicochemical and basic pharmacological criteria to the decision process of drug discovery.

We evaluated the efficacy of nanoparticle-encapsulated antituberculosis drugs administered every 10 days versus that of daily nonencapsulated drugs against Mycobacterium tuberculosis aerosol infection in guinea pigs. Both treatments significantly reduced the bacterial count and lung histopathology, suggesting that the nanoparticle drug delivery system has potential in intermitted treatment of tuberculosis.

Besides the long-term effectiveness of a given compound, safety is a very important feature to consider when developing new compounds for chemotherapy against tuberculosis. Reports of fatal and severe liver injury associated with rifampicin-pyrazinamide (RIF-PZA) treatment regimens for latent tuberculosis infections prompted this study to evaluate whether a mouse model has any potential as a tool to assess liver injury following extensive exposure to tuberculosis drugs. Mice were administered high doses of existing drug regimens for latent tuberculosis over a relatively short time period. Alanine aminotransferase (ALT), aspartate aminotransferase and bilirubin levels were determined after 2 weeks and 4 weeks of treatment in serum samples collected from uninfected mice as well as mice infected with Mycobacterium tuberculosis. ALT levels increased significantly after a RIF-PZA treatment regimen for 4 weeks in uninfected mice and after 2 weeks in infected mice. Bilirubin serum levels were also significantly elevated in the M. tuberculosis-infected mice after 4 weeks of RIF-PZA treatment. The data obtained indicate that changes in serum enzyme levels in mice after extensive exposure to tuberculosis drugs could be useful as an initial indicator of drug-related hepatotoxicity.

These studies sought to determine the gene expression and short-term effects of intralesional lipid-complexed immunogene therapy with constructs encoding Staphylococcus aureus enterotoxin A and canine interleukin-2 (L-SEA/cIL-2) in dogs with tumors of various histotypes, and then to assess the safety and efficacy of repeated L-SEA/cIL-2 injections in dogs with spontaneous soft tissue sarcomas (STS). In the first study, pet dogs with a variety of tumors received a single intralesional injection of L-SEA/cIL-2, and surgical excision was performed 48 h later. In the second study, dogs with histologically confirmed STS were treated weekly for a maximum of 12 weeks with escalating doses of L-SEA/cIL-2. Tumors were then surgically excised and assessed histologically and immunohistochemically. Overall, treatments were well tolerated, with no dose-limiting toxicities encountered. At 48 h, in the single injection study, plasmid DNA was detected in 14 of 16 tumor samples, and plasmid-specific mRNA was detected in 3 of 14. In the multiple injection study, the overall response rate in dogs with STS was 25%, consisting of 3 complete responses (CR) and 1 partial response (PR). Diffuse lymphoplasmacytic inflammation was observed in all tumors from patients experiencing CR or PR, whereas these changes were not evident in tumors from nonresponders. The infiltrate was composed primarily of CD3(+) cells at 48 h from the single-injection study, and was composed of both CD3(+) and CD79a(+) cells at 12 weeks in responding dogs from the multiple-injection study. In conclusion, these studies suggests that intralesional L-SEA/cIL-2 immunotherapy is well tolerated, results in detectable transgene expression in canine tumors, and has antitumor activity in dogs with spontaneous STS.

Each of two bottlenose dolphins, Tursiops truncatus, was trained to mimic a set of behaviors on command. They were tested on transfer of the mimic command to a set of familiar behaviors which they had not previously been commanded to mimic. They were similarly tested on two novel behaviors. One dolphin demonstrated complete mimicry of 5 of 11 familiar behaviors; the other dolphin mimicked 1 of 9 behaviors. None of the mimicked behaviors was exhibited to an inappropriate model, suggesting that performance was not due to chance. Neither dolphin imitated the novel behaviors.

Shanker & King's (S&K's) proposal is consistent with a Vygotskian model of development which assumes that cognition is first social and visible, and only later internalized and invisible. Rather than slipping into positing “epistemic operators” like understand or intend as generative of behavior during language learning or theory of mind tasks, this approach profits from keeping its focus on charting the ontogeny of embodied interactions.