Mind the gap: investigating toddlers' sensitivity to contact relations in predictive events

Toddlers readily learn predictive relations between events (e.g., that event A predicts event B). However, they intervene on A to try to cause B only in a few contexts: When a dispositional agent initiates the event or when the event is described with causal language. The current studies look at whether toddlers' failures are due merely to the difficulty of initiating interventions or to more general constraints on the kinds of events they represent as causal. Toddlers saw a block slide towards a base, but an occluder prevented them from seeing whether the block contacted the base; after the block disappeared behind the occluder, a toy connected to the base did or did not activate. We hypothesized that if toddlers construed the events as causal, they would be sensitive to the contact relations between the participants in the predictive event. In Experiment 1, the block either moved spontaneously (no dispositional agent) or emerged already in motion (a dispositional agent was potentially present). Toddlers were sensitive to the contact relations only when a dispositional agent was potentially present. Experiment 2 confirmed that toddlers inferred a hidden agent was present when the block emerged in motion. In Experiment 3, the block moved spontaneously, but the events were described either with non-causal ("here's my block") or causal ("the block can make it go") language. Toddlers were sensitive to the contact relations only when given causal language. These findings suggest that dispositional agency and causal language facilitate toddlers' ability to represent causal relationships.     

Genetic tumor archeology: microdissection and genetic heterogeneity in squamous and basal cell carcinoma

Carcinogenesis is a multi-step series of somatic genetic events. The complexity of this multi-hit process makes it difficult to determine each single event and the definitive outcome of such events. To investigate the genetic alterations in cancer-related genes, sensitive and reliable detection methods are of major importance for generating relevant results. Another critical issue is the quality of starting material which largely affects the outcome of the analysis. Microdissection of cells defined under the microscope ensures a selection of representative material for subsequent genetic analysis. Skin cancer provides an advantageous model for studying the development of cancer. Detectable lesions occur early during tumor progression, facilitating molecular analysis of the cell populations from both preneoplastic and neoplastic lesions. Alterations of the p53 tumor suppressor gene are very common in non-melanoma skin cancer, and dysregulation of p53 pathways appear to be an early event in the tumor development. A high frequency of epidermal p53 clones has been detected in chronically sun-exposed skin. The abundance of clones containing p53 mutated keratinocytes adjacent to basal cell (BCC) and squamous cell carcinoma (SCC) suggests a role in human skin carcinogenesis. Studies using p53 mutations as a clonality marker have suggested a direct link between actinic keratosis, SCC in situ and invasive SCC. Microdissection-based studies have also shown that different parts of individual BCC tumors can share a common p53 mutation yet differ with respect to additional alterations within the p53 gene, consistent with subclonal development within tumors. Here, we present examples of using well-defined cell populations, including single cells, from complex tissue in combination with molecular tools to reveal features involved in skin carcinogenesis.     

Comparison of design strategies for a three‐arm clinical trial with time‐to‐event endpoint: Power,time‐to‐analysis,and operational aspects

To optimize resources, randomized clinical trials with multiple arms can be an attractive option to simultaneously test various treatment regimens in pharmaceutical drug development. The motivation for this work was the successful conduct and positive final outcome of a three‐arm randomized clinical trial primarily assessing whether obinutuzumab plus chlorambucil in patients with chronic lympocytic lymphoma and coexisting conditions is superior to chlorambucil alone based on a time‐to‐event endpoint. The inference strategy of this trial was based on a closed testing procedure. We compare this strategy to three potential alternatives to run a three‐arm clinical trial with a time‐to‐event endpoint. The primary goal is to quantify the differences between these strategies in terms of the time it takes until the first analysis and thus potential approval of a new drug, number of required events, and power. Operational aspects of implementing the various strategies are discussed. In conclusion, using a closed testing procedure results in the shortest time to the first analysis with a minimal loss in power. Therefore, closed testing procedures should be part of the statistician's standard clinical trials toolbox when planning multiarm clinical trials.     

Fusion and fission of genes define a metric between fungal genomes

Gene fusion and fission events are key mechanisms in the evolution of gene architecture, whose effects are visible in protein architecture when they occur in coding sequences. Until now, the detection of fusion and fission events has been performed at the level of protein sequences with a post facto removal of supernumerary links due to paralogy, and often did not include looking for events defined only in single genomes. We propose a method for the detection of these events, defined on groups of paralogs to compensate for the gene redundancy of eukaryotic genomes, and apply it to the proteomes of 12 fungal species. We collected an inventory of 1,680 elementary fusion and fission events. In half the cases, both composite and element genes are found in the same species. Per-species counts of events correlate with the species genome size, suggesting a random mechanism of occurrence. Some biological functions of the genes involved in fusion and fission events are slightly over- or under-represented. As already noted in previous studies, the genes involved in an event tend to belong to the same functional category. We inferred the position of each event in the evolution tree of the 12 fungal species. The event localization counts for all the segments of the tree provide a metric that depicts the “recombinational” phylogeny among fungi. A possible interpretation of this metric as distance in adaptation space is proposed.     

Discrete-time nonparametric estimation for semi-Markov models of chain-of-events data subject to interval censoring and truncation

Chain-of-events data are longitudinal observations on a succession of events that can only occur in a prescribed order. One goal in an analysis of this type of data is to determine the distribution of times between the successive events. This is difficult when individuals are observed periodically rather than continuously because the event times are then interval censored. Chain-of-events data may also be subject to truncation when individuals can only be observed if a certain event in the chain (e.g., the final event) has occurred. We provide a nonparametric approach to estimate the distributions of times between successive events in discrete time for data such as these under the semi-Markov assumption that the times between events are independent. This method uses a self-consistency algorithm that extends Turnbull's algorithm (1976, Journal of the Royal Statistical Society, Series B 38, 290-295). The quantities required to carry out the algorithm can be calculated recursively for improved computational efficiency. Two examples using data from studies involving HIV disease are used to illustrate our methods.     

Pain Now or Later: An Outgrowth Account of Pain-Minimization

The preference for immediate negative events contradicts the minimizing loss principle given that the value of a delayed negative event is discounted by the amount of time it is delayed. However, this preference is understandable if we assume that the value of a future outcome is not restricted to the discounted utility of the outcome per se but is complemented by an anticipated negative utility assigned to an unoffered dimension, which we termed the “outgrowth.” We conducted three studies to establish the existence of the outgrowth and empirically investigated the mechanism underlying the preference for immediate negative outcomes. Study 1 used a content analysis method to examine whether the outgrowth was generated in accompaniment with the delayed negative events. The results revealed that the investigated outgrowth was composed of two elements. The first component is the anticipated negative emotions elicited by the delayed negative event, and the other is the anticipated rumination during the waiting process, in which one cannot stop thinking about the negative event. Study 2 used a follow-up investigation to examine whether people actually experienced the negative emotions they anticipated in a real situation of waiting for a delayed negative event. The results showed that the participants actually experienced a number of negative emotions when waiting for a negative event. Study 3 examined whether the existence of the outgrowth could make the minimizing loss principle work. The results showed that the difference in pain anticipation between the immediate event and the delayed event could significantly predict the timing preference of the negative event. Our findings suggest that people’s preference for experiencing negative events sooner serves to minimize the overall negative utility, which is divided into two parts: the discounted utility of the outcome itself and an anticipated negative utility assigned to the outgrowth.     

Proteolytic conversion of hepatitis B virus e antigen precursor to end product occurs in a postendoplasmic reticulum compartment.

At least two proteolytic events are involved in the biogenesis of hepatitis B virus e antigen. The first proteolytic event removes the signal peptide and results in the translocation of the precursor protein, P22, into the lumen of the endoplasmic reticulum (ER). The second proteolytic event removes the carboxy-terminal arginine-rich sequence of P22 and converts it to the 16-kDa hepatitis B virus e antigen end product. In contrast to the first proteolytic event, the second proteolytic event is suppressed by brefeldin A, a chemical that inhibits the transport of protein from the ER to the Golgi apparatus. In subcellular fractionation experiments, P22 was detected in both the ER and the Golgi fractions, but P16 was detected only in the Golgi fraction. On the basis of these results, we conclude that the conversion of P22 to P16 occurs ina post-ER compartment, mostly likely the Golgi apparatus.     

Toddler formula supplemented with docosahexaenoic acid (DHA) improves DHA status and respiratory health in a randomized,double-blind,controlled trial of US children less than 3 years of age

Studies of docosahexaenoic acid (DHA) intake and status in US toddlers are lacking. One national survey found low DHA intakes. The objectives of this double-blind, randomized study were to (a) determine usual DHA intakes, (b) measure the effect of consuming formulas with DHA on red blood cell (RBC) and plasma DHA and (c) record adverse events in US children between 18 and 36 months of age. Children aged 18–36 months were provided 237-ml formula with 0, 43, or 130 mg DHA per day for 60 days. Blood was obtained at 0 and 60 days and 24-hour dietary recalls at 0, 30 and 60 days. Usual median daily DHA intake was 13.3 mg. RBC DHA increased in a dose-dependent manner with increasing DHA intake (p<0.05). Toddlers consuming the formula with 130 mg DHA per day have fewer adverse events (p=0.007) and a lower incidence of respiratory illness (p=0.024), compared to the formula without DHA. US toddlers have low DHA intake and status. Modest increases in DHA intake in toddlers might improve development, including respiratory health.     

Cholesterol-dependent attachment of human respiratory cells by Bordetella pertussis

Bordetella pertussis is a re-emerging human respiratory pathogen whose infectious process is not fully understood, hampering the design of effective vaccines. The nature of bacterial attachment to host cells is a key event in the outcome of the infection. However, host cell receptors involved in B. pertussis colonization of the respiratory tract are still under investigation. Here, we report that cholesterol-rich domains are involved in B. pertussis adhesion to epithelial cells. Treatment of A549 cells with cholesterol-sequestering drugs such as methyl-β-cyclodextrin, nystatin, or filipin resulted in a significant decrease of B. pertussis attachment. Confocal laser microscopy studies showed B. pertussis associated with cholesterol-rich domains. Accordingly, B. pertussis was found in detergent-resistant membrane domain fractions isolated from bacterial-infected A549 cells. Our results indicate a main role of filamentous hemagglutinin, an environmentally regulated virulence factor, in this interaction, and a specific affinity for cholesterol, one of the major components of traqueal secretions, which might additionally contribute to the effective colonization of the respiratory tract.     

A comparison of lifelong and posttrauma nightmares in a civilian trauma sample: Nightmare characteristics, psychopathology, and treatment outcome.

Nightmares and sleep disturbances are thought to play a key role in the development of posttrauma problems. Research efforts have increased in an attempt to understand this association. The present study examined differences in nightmare characteristics, related psychopathology, treatment outcome, and trauma history among trauma-exposed individuals whose nightmares began before a traumatic event and those whose nightmares began after a traumatic event, while controlling for posttraumatic stress disorder status. Individuals whose nightmares began following a trauma experienced more depression and posttraumatic stress symptoms and poorer sleep quality, reported a higher number of traumatic events, and were more likely to report nightmares replicative of or similar to the trauma than those whose nightmares began before the trauma. No other between-groups differences were found for nightmare characteristics or response to treatment. This study is an important step in understanding the nature of nightmares and their relationship to traumatic events and consequences, but additional research is warranted. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Modeling the effects of a bidirectional latent predictor from multivariate questionnaire data

Researchers often measure stress using questionnaire data on the occurrence of potentially stress-inducing life events and the strength of reaction to these events, characterized as negative or positive and assigned an ordinal ranking. In studying the health effects of stress, one needs to obtain measures of an individual's negative and positive stress levels to be used as predictors. Motivated by data of this type, we propose a latent variable model, which is characterized by event-specific negative and positive reaction scores. If the positive reaction score dominates the negative reaction score for an event, then the individual's reported response to that event will be positive, with an ordinal ranking determined by the value of the score. Measures of overall positive and negative stress can be obtained by summing the reactivity scores across the events that occur for an individual. By incorporating these measures as predictors in a regression model and fitting the stress and outcome models jointly using Bayesian methods, inferences can be conducted without the need to assume known weights for the different events. We propose an MCMC algorithm for posterior computation and apply the approach to study the effects of stress on preterm delivery.     

Analysis of doubly-censored survival data, with application to AIDS

This paper proposes nonparametric and weakly structured parametric methods for analyzing survival data in which both the time origin and the failure event can be right- or interval-censored. Such data arise in clinical investigations of the human immunodeficiency virus (HIV) when the infection and clinical status of patients are observed only at several time points. The proposed methods generalize the self-consistency algorithm proposed by Turnbull (1976, Journal of the Royal Statistical Society, Series B 38, 290-295) for singly-censored univariate data, and are illustrated with the results from a study of hemophiliacs who were infected with HIV by contaminated blood factor.     

Redundant RNA recognition events in bicoid mRNA localization.

A cis-acting signal in the 3' UTR of the Drosophila bicoid mRNA directs both the transport of the mRNA from the nurse cells to the oocyte and its anterior localization within the oocyte. Here we demonstrate that the signal mediates redundant RNA recognition events, A and B, that initiate largely overlapping programs of mRNA localization during oogenesis. Recognition event A requires a region encompassing stem-loops IV/V of the predicted secondary structure, and can be eliminated by a single nucleotide mutation. Localization initiated through event B begins slightly later in oogenesis, and requires sequences that have not been narrowly defined. Using forms of the 3' UTR lacking this RNA recognition redundancy, we reexamine the roles of the swallow, staufen, and exuperantia genes, which are all required for normal bicoid mRNA localization. Our results reveal that exuperantia first becomes essential for localization at a time when well-defined microtubule tracks between the nurse cells and oocyte disappear. Thus, exuperantia may specifically facilitate a form of nurse cell-to-oocyte mRNA transport not dependent on the microtubule tracks.     

Predicting events in clinical trials using two time‐to‐event outcomes

In clinical trials with time‐to‐event outcomes, it is of interest to predict when a prespecified number of events can be reached. Interim analysis is conducted to estimate the underlying survival function. When another correlated time‐to‐event endpoint is available, both outcome variables can be used to improve estimation efficiency. In this paper, we propose to use the convolution of two time‐to‐event variables to estimate the survival function of interest. Propositions and examples are provided based on exponential models that accommodate possible change points. We further propose a new estimation equation about the expected time that exploits the relationship of two endpoints. Simulations and the analysis of real data show that the proposed methods with bivariate information yield significant improvement in prediction over that of the univariate method.     

The Development of Infants’ Sensitivity to Behavioral Intentions when Inferring Others’ Social Preferences

The present study investigated whether infants reason about others’ social preferences based on the intentions of others’ interactive actions. In Experiment 1, 12-month-old infants were familiarized with an event in which an agent either successfully helped a circle to climb up a hill (successful-helping condition) or failed to help the circle to achieve its goal (failed-helping condition). During the test, the infants saw the circle approach either the helper (approach-helper event) or the hinderer (approach-hinderer event). In the successful-helping condition, the 12-month-old infants looked for longer at the approach-hinderer event than at the approach-helper event, but in the failed-helping condition, looking times were about equal for the two test events. These results suggest that 12-month-old infants could not infer the circle’s preference when the helper’s action did not lead to its intended outcome. In Experiment 2, 16-month-olds were tested in the failed-helping condition; they looked longer at the approach-hinderer event than at the approach-helper event, which suggests that they could reason about the third party’s social preferences based on the exhibited intentions. In Experiment 3, 12-month-olds were familiarized with events in which the final outcomes of helping and hindering actions were ambiguous. The results revealed that 12-month-old infants are also sensitive to intentions when inferring other’s social preferences. The results suggest that by 12-months of age, infants expect an agent to prefer and approach another who intends to help the circle to achieve its goal, regardless of the outcome. The current research has implications for moral reasoning and social evaluation in infancy.     

Mechanism of allosuppression: evidence for direct suppression of responding B cells.

The mechanism of allosuppression has been investigated. As previously described, negative allogeneic effects result when T cells recognize MHC-encoded alloantigens on responding lymphocytes, preventing the generation of a secondary anti-PFC response in vitro. Several experiments suggested that this suppression was not due to the generation of cytotoxic effectors. First, effective suppression occurred only when T cells, either unprimed or alloantigen activated, were added during the first 24 hr of the responding culture. Even previously generated cytotoxic effectors were relatively ineffective when added late in the response. Furthermore, no detectable cytotoxic effectors were found in suppressed cultures. The major target of suppression was the responding B cell. Only B cells carrying alloantigens (thus recognized by the T cells) were suppressed; bystander B cells were little affected. Thus allosuppression appears to involve the recognition by T cells of alloantigens on responding B cells and direct suppression of some early event in the development of these B cells into PFC. The responses of primed B cells were found to be preferentially sensitive to the suppressive effects of allo- T cells, whereas the response of unprimed B cells was influenced preferentially by the helper effects of alloantigen-activated T cells. It is possible that the state of differentiation of the B cell may determine the outcome of the interaction with regulatory T cells.     

Comparative studies of vertebrate aldehyde dehydrogenase 3: sequences, structures, phylogeny and evolution. Evidence for a mammalian origin for the ALDH3A1 gene

Mammalian ALDH3 genes (ALDH3A1, ALDH3A2, ALDH3B1 and ALDH3B2) encode enzymes of peroxidic and fatty aldehyde metabolism. ALDH3A1 also plays a major role in anterior eye tissue UV-filtration. BLAT and BLAST analyses were undertaken of several vertebrate genomes using rat, chicken and zebrafish ALDH3-like amino acid sequences. Predicted vertebrate ALDH3 sequences and structures were highly conserved, including residues involved in catalysis, coenzyme binding and enzyme structure as reported by Liu et al. [27] for rat ALDH3A1. Phylogeny studies of human, rat, opossum, platypus, chicken, xenopus and zebrafish ALDH3-like sequences supported three hypotheses: (1) the mammalian ALDH3A1 gene was generated by a tandem duplication event of an ancestral vertebrate ALDH3A2 gene; (2) multiple mammalian and chicken ALDH3B-like genes were generated by tandem duplication events within genomes of related species; and (3) vertebrate ALDH3A and ALDH3B genes were generated prior to the appearance of bony fish more than 500 million years ago.