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Jan Kubovy, Tom D Boswell, Guy Vautier, Malcolm M Arnold Department of Gastroenterology, Hawkes Bay Hospital, Hastings, New ZealandAbstract: Endoscopic variceal ligation (EVL) is an important treatment modality in managing complications of portal hypertension. Since its advent 30 years ago, the procedural complications have decreased significantly, especially when compared with variceal sclerotherapy. With the current widespread use of EVL, rare complications are now becoming increasingly recognized. We present a case of complete esophageal obstruction, its management, and clinical course. Our literature review identified only eight reported cases. We compare the varied treatment approaches and outcomes in the cited articles. Keywords: portal hypertension, esophageal varices, endoscopic variceal ligation, esophageal obstruction

Abstract Background Traditional rural housing in hot, humid regions of sub-Saharan Africa usually consists of single-level, poorly ventilated dwellings. Houses are mostly poorly screened against malaria mosquitoes and limited airflow discourages the use of bednets resulting in high indoor transmission. This study aims to determine whether living in a novel design house with elevated bedrooms and permeable screened walls reduces malaria, respiratory tract infections, and diarrhoea among children in rural Tanzania. Methods/study design This is a household-randomized, controlled study in 60 villages in Mtwara, Tanzania. A total of 550 households are randomly selected, 110 of which are allocated a novel design house and 440 households continue to reside in traditional houses. A dynamic cohort of about 1650 children under 13 years will be enrolled and followed for 3 years, approximately 330 living in novel design houses and 1320 in traditional rural houses. The primary endpoint is the incidence of malaria; secondary endpoints are incidences of acute respiratory tract infections and diarrhoea diseases detected by passive and active surveillance. Exposure to malaria vectors will be assessed using light traps in all study houses. Structural, economic, and social science studies will assess the durability, cost-effectiveness, and acceptability of the new houses compared with traditional housing. Environmental data will be collected indoors and outdoors in study homes to assess the differences between house typologies. Discussion This is the first randomized controlled trial to assess the protective efficacy of a new house design targeting malaria in sub-Saharan Africa. The findings of this study could influence the future construction of homes in hot and humid zones of Africa. Trial registration ClinicalTrials.gov NCT04529434 . Registered on August 27, 2020

IntroductionThe population of Africa set to reach 2 billion by 2050. There is therefore great demand for housing across the continent. Research on modified novel designs for housing is a priority to ensure that these homes are not sites of infection for diseases transmission such as malaria. One trial to assess the protection afforded by novel design houses is underway in Mtwara Region, southeastern Tanzania. After constructing 110 of such homes across 60 villages, project staff encountered a certain reticence of the target population to occupy the homes and were faced with accusations of having nefarious intentions. This article explores these accusations, their impacts on home occupancy and lessons for future housing studies.MethodsThis qualitative study drew on in-depth interviews and focus group discussions with ten occupants of the intervention homes, six community leaders and a further 24 community members. Interviews were recorded, transcribed verbatim and translated to English for qualitative content analysis.ResultsIn communities around the Star Homes, during construction and handover, project staff were widely associated with 'Freemasons', a term used to practices, secrecy, and other conspiracy theories in rural Tanzania. These connections were attributed to other community members and explained in terms of knowledge deficit or envy, with others hoping to be allocated the home. The stories were embedded in assumptions of reciprocity and suspicions about study motives, linked to limited experience of research. The relationship between the accusations of freemasonry and reticence to occupy the houses was not straightforward, with project staff or relatives playing a role in decisions. The stakes were high, because the recipients of Star Homes were the poorest families in targeted communities.ConclusionThe results indicate the need for long-term and proactive community engagement, which focuses on building relationships and providing information through recognizable voices and formats. Given the stakes at play in housing interventions, research teams should be prepared for the social upheaval the provision of free new housing can cause.

Malaria is transmitted by many Anopheles species whose proportionate contributions vary across settings. We re-assessed the roles of Anopheles arabiensis and Anopheles funestus, and examined potential benefits of species-specific interventions in an area in south-eastern Tanzania, where malaria transmission persists, four years after mass distribution of long-lasting insecticide-treated nets (LLINs). Monthly mosquito sampling was done in randomly selected households in three villages using CDC light traps and back-pack aspirators, between January-2015 and January-2016, four years after the last mass distribution of LLINs in 2011. Multiplex polymerase chain reaction (PCR) was used to identify members of An. funestus and Anopheles gambiae complexes. Enzyme-linked immunosorbent assay (ELISA) was used to detect Plasmodium sporozoites in mosquito salivary glands, and to identify sources of mosquito blood meals. WHO susceptibility assays were done on wild caught female An. funestus s.l, and physiological ages approximated by examining mosquito ovaries for parity. A total of 20,135 An. arabiensis and 4,759 An. funestus were collected. The An. funestus group consisted of 76.6% An. funestus s.s, 2.9% An. rivulorum, 7.1% An. leesoni, and 13.4% unamplified samples. Of all mosquitoes positive for Plasmodium, 82.6% were An. funestus s.s, 14.0% were An. arabiensis and 3.4% were An. rivulorum. An. funestus and An. arabiensis contributed 86.21% and 13.79% respectively, of annual entomological inoculation rate (EIR). An. arabiensis fed on humans (73.4%), cattle (22.0%), dogs (3.1%) and chicken (1.5%), but An. funestus fed exclusively on humans. The An. funestus populations were 100% susceptible to organophosphates, pirimiphos methyl and malathion, but resistant to permethrin (10.5% mortality), deltamethrin (18.7%), lambda-cyhalothrin (18.7%) and DDT (26.2%), and had reduced susceptibility to bendiocarb (95%) and propoxur (90.1%). Parity rate was higher in An. funestus (65.8%) than An. arabiensis (44.1%). Though An. arabiensis is still the most abundant vector species here, the remaining malaria transmission is predominantly mediated by An. funestus, possibly due to high insecticide resistance and high survival probabilities. Interventions that effectively target An. funestus mosquitoes could therefore significantly improve control of persistent malaria transmission in south-eastern Tanzania.

Skin-to-skin-contact presents the earliest sensory experience of men and animals. Deprivation of age-relevant touch experiences during infancy results in compromised psychosocial and biological development. The 2021 Nobel Prize in Physiology or Medicine has been awarded for the discoveries of receptors for temperature and touch. Clinical studies have demonstrated the benefit of professional salutary touch for prevention and treatment of various illnesses. However, in the present practice of medicine the application of salutary touch does not meet adequate interest. Proposing a new medical discipline "Touch Medicine" we link the findings of modern touch research to clinical medicine. The treatment of depression which we conceive primarily as a disease afflicting the body will serve as an example to demonstrate the usefulness of touch therapy. Controlled studies and systematic reviews have convincingly shown antidepressive, anxiolytic and analgesic effects of salutary touch. The effectiveness and efficacy of touch therapy has also been demonstrated in many areas such as neonatology, pediatrics, oncology, and geriatrics. We discuss the underlying mechanisms on various explanatory levels including interoceptive and oxytocinergic mechanisms as well as the role of C tactile afferent nerve fibers., Competing Interests: BMOE, ME, HN, MG und KUM erklären, dass kein Interessenkonflikt besteht. GMK führt eine Privatpraxis für Körpertherapie und leitet Ausbildungsseminare für die von ihr entwickelte Massagemethode. MMA betreibt eine Privatpraxis für Berührungsmedizin., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Exposure to air pollutants has been previously associated with respiratory viral infections, including influenza, measles, mumps, rhinovirus, and respiratory syncytial virus. Epidemiological studies have also suggested that air pollution exposure is associated with increased cases of SARS-CoV-2 infection and COVID-19-associated mortality, although the molecular mechanisms by which pollutant exposure affects viral infection and pathogenesis of COVID-19 remain unknown. In this review, we suggest potential molecular mechanisms that could account for this association. We have focused on the potential effect of exposure to nitrogen dioxide (NO 2 ), ozone (O 3 ), and particulate matter (PM) since there are studies investigating how exposure to these pollutants affects the life cycle of other viruses. We have concluded that pollutant exposure may affect different stages of the viral life cycle, including inhibition of mucociliary clearance, alteration of viral receptors and proteases required for entry, changes to antiviral interferon production and viral replication, changes in viral assembly mediated by autophagy, prevention of uptake by macrophages, and promotion of viral spread by increasing epithelial permeability. We believe that exposure to pollutants skews adaptive immune responses toward bacterial/allergic immune responses, as opposed to antiviral responses. Exposure to air pollutants could also predispose exposed populations toward developing COIVD-19-associated immunopathology, enhancing virus-induced tissue inflammation and damage., (© 2020 New York Academy of Sciences.)

The clinical picture of depressive disorders is characterized by a plethora of somatic symptoms, psychomotor retardation, and, particularly, anhedonia. The number of patients with residual symptoms or treatment resistance is high. Touch is the basic communication among humans and animals. Its application professionally in the form of, e.g., psychoactive massage therapy, has been shown in the past to reduce the somatic and mental symptoms of depression and anxiety. Here, we investigated the effects of a specially developed affect-regulating massage therapy (ARMT) vs. individual treatment with a standardized relaxation procedure, progressive muscle relaxation (PMR), in 57 outpatients with depression. Patients were given one ARMT or PMR session weekly over 4 weeks. Changes in somatic and cognitive symptoms were assessed by standard psychiatric instruments (Hamilton Depression Scale (HAMD) and the Bech-Rafaelsen-Melancholia-Scale (BRMS)) as well as a visual analogue scale. Furthermore, oral statements from all participants were obtained in semi-structured interviews. The findings show clear and statistically significant superiority of ARMT over PMR. The results might be interpreted within various models. The concept of interoception, as well as the principles of body psychotherapy and phenomenological aspects, offers cues for understanding the mechanisms involved. Within a neurobiological context, the significance of C-tactile afferents activated by special touch techniques and humoral changes such as increased oxytocin levels open additional ways of interpreting our findings.

Objectives: Vascular anatomy of the aortic arch and supra-aortic arteries has been suggested as influencing the risk of carotid artery stenting (CAS). The expert opinion based Delphi anatomical risk (DAR) score was developed to predict difficulty of CAS in relation to procedural stroke risk, and thereby aid patient selection. The aim was to validate the DAR score in the context of a randomised clinical trial., Methods: In this post hoc analysis of the International Carotid Stenting Study (ICSS), only patients treated by CAS with available pre-procedural CT angiography (CTA) were included. Patients with tortuous anatomy unsuitable for stenting were excluded from ICSS. CTA based vascular anatomy was rated by two independent observers. Every possible combination of anatomy resulted in a risk score, divided in four categories of expected risk (low, < 5.0; low-intermediate, 5.0-5.9; high-intermediate, 6.0-6.9; high, ≥ 7.0). Binomial logistic regression was used to assess the relationship between anatomical risk score and procedural risk of any stroke. Differences between predefined age groups were also assessed., Results: A total of 275 patients were included. Interobserver reliability for all anatomical risk factors was high (κ = 0.76-0.84). In total, 16 strokes (6%) occurred in the procedural period. No significant relationship was observed between the DAR score and risk of procedural stroke, with the risk of stroke being 9% in the high risk vs. 4% in the low risk categories (p = .49). A higher mean DAR score was observed in patients ≥70 years compared with younger patients (4.6 ± 1.5 vs. 3.9 ± 1.4, p < .001), which was mainly explained by higher rates of arch atheroma (44% vs. 20%, p < .001). Prolonged intervention duration was significantly associated with increased stroke risk (11% vs. 4%, p < .04), but not with the DAR score., Conclusions: No statistically significant association was found between anatomical difficulty, as defined in the DAR score, and procedural stroke risk. However, the small sample size potentially rendered the study underpowered to detect group differences, and confirmation with a larger sample is essential., (Copyright © 2019 European Society for Vascular Surgery. All rights reserved.)

Biases in the assessment and integration of evidence are likely contributors to anomalistic (e.g., paranormal, extra-terrestrial) beliefs because of the non-evidence based nature of these beliefs. However, little research has examined the relationship between anomalistic beliefs and evidence integration biases. The current study addressed this gap by examining the relationship between anomalistic belief and four such biases; bias against disconfirmatory evidence (BADE), bias against confirmatory evidence (BACE), liberal acceptance bias, and the jumping to conclusions bias (JTC). Standard BADE scenarios were used to measure BADE, BACE, and the liberal acceptance bias: Participants were given three pieces of evidence, one at a time, and required to rate several alternative explanations. The JTC was measured using two draws-to-decisions tasks (beads and emotionally salient), and participants also completed measures of anomalistic belief and delusion-proneness. Results showed that liberal acceptance was the only evidence integration bias that significantly predicted greater overall anomalistic belief. However, this relationship was no longer significant once delusion proneness was controlled for. Additionally, BADE significantly predicted experiential (but not other types of) anomalistic beliefs even after controlling for delusion proneness. We propose that liberal acceptance may lead people to form anomalistic beliefs on the basis of little evidence, and that stronger BADE may make these beliefs highly resistant to change., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose of Review: Rotavirus vaccines were first introduced more than a decade ago and have had a tremendous impact on reducing the number of hospitalizations and deaths due to rotavirus-associated diarrhea. This review will discuss current rotavirus vaccines, post-licensure surveillance, progress in non-replicating vaccine development, and why continued research is important for understanding a virus that remains a globally leading cause of death due to diarrhea., Recent Findings: Research advances have enhanced our understanding of how vaccines induce protection against subsequent severe disease, how the virus replicates and spreads in the face of the host immune system, and basic mechanisms governing the viral life cycle., Summary: Much remains to be learned about how to improve vaccine success, what are the molecular determinants of host range and virulence, and what are the interactions of the virus with the host that drive its replicative success, among many other important questions.

A growing body of research has shown people who hold anomalistic (e.g., paranormal) beliefs may differ from nonbelievers in their propensity to make probabilistic reasoning errors. The current study explored the relationship between these beliefs and performance through the development of a new measure of anomalistic belief, called the Anomalistic Belief Scale (ABS). One key feature of the ABS is that it includes a balance of both experiential and theoretical belief items. Another aim of the study was to use the ABS to investigate the relationship between belief and probabilistic reasoning errors on conjunction fallacy tasks. As expected, results showed there was a relationship between anomalistic belief and propensity to commit the conjunction fallacy. Importantly, regression analyses on the factors that make up the ABS showed that the relationship between anomalistic belief and probabilistic reasoning occurred only for beliefs about having experienced anomalistic phenomena, and not for theoretical anomalistic beliefs., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Unlabelled: The rotavirus nonstructural protein NSP1 acts as an antagonist of the host antiviral response by inducing degradation of key proteins required to activate interferon (IFN) production. Protein degradation induced by NSP1 is dependent on the proteasome, and the presence of a RING domain near the N terminus has led to the hypothesis that NSP1 is an E3 ubiquitin ligase. To examine this hypothesis, pulldown assays were performed, followed by mass spectrometry to identify components of the host ubiquitination machinery that associate with NSP1. Multiple components of cullin RING ligases (CRLs), which are essential multisubunit ubiquitination complexes, were identified in association with NSP1. The mass spectrometry was validated in both transfected and infected cells to show that the NSP1 proteins from different strains of rotavirus associated with key components of CRL complexes, most notably the cullin scaffolding proteins Cul3 and Cul1. In vitro binding assays using purified proteins confirmed that NSP1 specifically interacted with Cul3 and that the N-terminal region of Cul3 was responsible for binding to NSP1. To test if NSP1 used CRL3 to induce degradation of the target protein IRF3 or β-TrCP, Cul3 levels were knocked down using a small interfering RNA (siRNA) approach. Unexpectedly, loss of Cul3 did not rescue IRF3 or β-TrCP from degradation in infected cells. The results indicate that, rather than actively using CRL complexes to induce degradation of target proteins required for IFN production, NSP1 may use cullin-containing complexes to prevent another cellular activity., Importance: The ubiquitin-proteasome pathway plays an important regulatory role in numerous cellular functions, and many viruses have evolved mechanisms to exploit or manipulate this pathway to enhance replication and spread. Rotavirus, a major cause of severe gastroenteritis in young children that causes approximately 420,000 deaths worldwide each year, utilizes the ubiquitin-proteasome system to subvert the host innate immune response by inducing the degradation of key components required for the production of interferon (IFN). Here, we show that NSP1 proteins from different rotavirus strains associate with the scaffolding proteins Cul1 and Cul3 of CRL ubiquitin ligase complexes. Nonetheless, knockdown of Cul1 and Cul3 suggests that NSP1 induces the degradation of some target proteins independently of its association with CRL complexes, stressing a need to further investigate the mechanistic details of how NSP1 subverts the host IFN response., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Rotavirus is a leading cause of death due to diarrhea among young children across the globe. Despite the limited coding capacity that is characteristic of RNA viruses, rotavirus dedicates substantial resources to avoiding the host innate immune response. Among these strategies is use of the interferon antagonist protein NSP1, which targets cellular proteins required for interferon production to be degraded by the proteasome. Although numerous cellular targets have been described, there remain many questions about the mechanism of NSP1 activity and its role in promoting replication in specific host species., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Previous studies have shown that punishing people through a large penalty for volunteering incorrect information typically leads them to withhold more information (metacognitive response bias), but it does not appear to influence their ability to distinguish between their own correct and incorrect answers (metacognitive accuracy discrimination). The goal of the current study was to demonstrate that punishing people for volunteering incorrect information-versus rewarding volunteering correct information-produces more effective metacognitive accuracy discrimination. All participants completed three different general-knowledge tests: a reward test (high points for correct volunteered answers), a baseline test (equal points/penalties for volunteered correct/incorrect answers) and a punishment test (high penalty for incorrect volunteered answers). Participants were significantly better at distinguishing between their own correct and incorrect answers on the punishment than reward test, which has implications for situations requiring effective accuracy monitoring.

A growing body of research has shown that context manipulations can have little or no impact on accuracy performance, yet still significantly influence metacognitive performance. For example, participants in a test-list context paradigm study one list of words with a medium levels-of-processing task and a second word list with either a shallow or deep task: Recognition for medium words does not differ across conditions, however medium words are significantly more likely to be labeled as "remembered" (vs. merely familiar) if they had been studied with a shallow word list (Bodner & Lindsay, 2003). The goal of the current studies was to extend the test-list context paradigm to strategic regulation (report/withhold recognition test), and broaden it to incorporate different types of stimuli (i.e., face stimuli in place of a medium word list). The paradigm also was modified to include separate answer (studied/new) confidence and decision (report/withhold) confidence ratings at test. Results showed that context did not impact recognition accuracy for faces across the context conditions, however participants were more likely to report (i.e., volunteer) their face responses if they had studied the shallow word list. The results also demonstrated a difference between answer confidence and decision confidence, and the pattern of this difference depended on whether responses were reported or withheld (Experiment 1). Overall, the data are presented as support for the functional account of memory, which views memory states as inferential and attributional rather than static categories., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The influence of test context on reports of recollection and familiarity depends on how these subjective recognition experiences are conceptualized and measured. Bodner and Lindsay (2003) found that critical items elicited more remember judgments but fewer know judgments in a less (vs. more) memorable context. In contrast, Tousignant and Bodner (2012) found that independent ratings of recollection and familiarity were both higher in a less memorable context. We replicated the dissociative pattern with judgments using recollect/familiar labels (Experiment 1), and in a novel R/F/B task that added a "both" option to eliminate the mutual exclusivity between the recollect and familiar options (Experiment 2). Adding a "guess" option eliminated these context effects (Experiment 3), however whether allowing guesses "cleans up" or "desensitizes" recollection and familiarity judgments remains unclear. Determining which task variants provide appropriate measures of subjective recognition experiences will require an examination of additional dissociations and triangulation with other measures., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Phasic dopamine transmission is posited to act as a critical teaching signal that updates the stored (or "cached") values assigned to reward-predictive stimuli and actions. It is widely hypothesized that these cached values determine the selection among multiple courses of action, a premise that has provided a foundation for contemporary theories of decision making. In the current work we used fast-scan cyclic voltammetry to probe dopamine-associated cached values from cue-evoked dopamine release in the nucleus accumbens of rats performing cost-benefit decision-making paradigms to evaluate critically the relationship between dopamine-associated cached values and preferences. By manipulating the amount of effort required to obtain rewards of different sizes, we were able to bias rats toward preferring an option yielding a high-value reward in some sessions and toward instead preferring an option yielding a low-value reward in others. Therefore, this approach permitted the investigation of dopamine-associated cached values in a context in which reward magnitude and subjective preference were dissociated. We observed greater cue-evoked mesolimbic dopamine release to options yielding the high-value reward even when rats preferred the option yielding the low-value reward. This result identifies a clear mismatch between the ordinal utility of the available options and the rank ordering of their cached values, thereby providing robust evidence that dopamine-associated cached values cannot be the sole determinant of choices in simple economic decision making.

Tobacco use is the leading cause of preventable death. Although the health risks are well known, cessation rates remain low. Whereas behavioral and neuroanatomical studies on tobacco addiction conventionally use nicotine, there is evidence that other constituents, such as monoamine oxidase inhibitors, may be important factors for modeling smoking. The aims of the present study were therefore to determine whether norharmane, a tobacco constituent and monoamine oxidase inhibitor, is self-administered alone and/or in combination with nicotine, and to evaluate the neural mechanisms underlying acquisition of self-administration of the two drugs. Sprague-Dawley rats were catheterized and allowed to intravenously self-administer either saline, nicotine (7.5 μg/kg/inj), norharmane (0.25 or 2.5 μg/kg/inj), alone or combined together (7.5+2.5 μg/kg/inj) for five days at fixed ratio (FR)1, two days each at FR2 and FR5, and one day at progressive ratio. Animals acquired self-administration of norharmane alone (2.5 μg/kg/inj), and the reinforcing effects of nicotine and norharmane were additive. For neuroanatomical analyses, rats self-administered the same treatments for six days at FR1, then brains were collected and processed by in situ hybridization for cfos mRNA expression. Treatment-specific profiles of regional cfos expression and correlations between cfos mRNA levels and behavioral responding were observed. Thus, not only was norharmane behaviorally reinforcing but, when combined with nicotine, resulted in patterns of neural activation distinct from that of norharmane or nicotine alone. This suggests that non-nicotine constituents can have central activating effects independent of nicotine, further substantiating the need for their inclusion in preclinical investigations of tobacco dependence., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Under formula-scoring rules for multiple-choice exams, a penalty is applied to incorrect responses to reduce noise in the observed score. To avoid the penalty individuals are allowed to "pass," and therefore they must be able to strategically regulate the accuracy of their reporting by deciding which and how many questions to answer. To investigate the effect of bias within this framework, Higham (2007) introduced bias profiles, which show the score obtained under formula scoring (corrected score) as a function of the omission rate. Bias profiles estimate the optimal number of questions that should be answered to maximize the corrected score (i.e., optimal bias). Our initial research showed that individuals tend to be too conservative when setting reporting criteria, "omitting" too many answers. The present three experiments introduced a feedback manipulation whereby participants were informed of the optimal omission rate after completing a test and asked to alter their reporting decisions accordingly. This feedback and concomitant alteration of reporting decisions led to improved corrected scores on true/false (Experiment 1), 2-alternative tests (Experiments 2), and 4-alternative tests (Experiment 3). Importantly, corrected scores at optimal bias also were higher than at forced-report for both true/false and 2-alternative tests. Furthermore, in Experiment 3, feedback based on one test improved scores on a second test, and participants were more likely to perform optimally on a third test without feedback. These effects suggest that optimal-bias feedback may have long-term effects and generalize to new tests., (PsycINFO Database Record (c) 2013 APA, all rights reserved.)

Although there is a great deal of research focused on identification issues related to own-versus other-race faces very few experiments have explored whether metacognitive monitoring contributes to the own-race bias. In the current experiment the typical own-race bias paradigm was modified so that type-2 signal detection measures (e.g. Higham & Arnold, 2007a,b) could be used to directly measure metacognitive monitoring at retrieval. A second goal of the experiment was to explore whether self-reported confidence ratings differed depending on whether they were directed at answer accuracy (e.g., judging a face as "studied") versus at decisions about that answer (e.g., volunteering vs. withholding that answer). Overall the results demonstrated that monitoring does contribute to the own-race bias, in that participants were better at monitoring their memory for own-race faces. Further, there was a significant difference between the two confidence measures, and the pattern of this difference depended on whether responses had been volunteered or withheld., (© 2013.)

Rotavirus nonstructural protein NSP1 can inhibit expression of interferon (IFN) and IFN-stimulated gene products by inducing proteasome-mediated degradation of IFN-regulatory factors (IRFs), including IRF3, IRF5, and IRF7. All IRF proteins share an N-terminal DNA-binding domain (DBD), and IRF3, IRF5, and IRF7 contain a similar C-proximal IRF association domain (IAD) that mediates IRF dimerization. An autoinhibitory domain (ID) at the extreme C terminus interacts with the IAD, burying residues necessary for IRF dimerization. Phosphorylation of serine/threonine residues in the ID induces charge repulsions that unmask the IAD, enabling IRF dimerization and subsequent nuclear translocation. To define the region of IRF proteins targeted for degradation by NSP1, we generated IRF3 and IRF7 truncation mutants and transiently expressed each with simian SA11-4F NSP1. These assays indicated that the IAD represented a necessary and sufficient target for degradation. Because NSP1 did not mediate degradation of truncated forms of the IAD, NSP1 likely requires a structurally intact IAD for recognition and targeting of IRF proteins. IRF9, which contains an IAD-like region that directs interactions with signal inducer and activator of transcription (STAT) proteins, was also targeted for degradation by NSP1, while IRF1, which lacks an IAD, was not. Analysis of mutant forms of IRF3 unable to undergo dimerization or that were constitutively dimeric showed that both were targeted for degradation by NSP1. These results indicate that SA11-4F NSP1 can induce degradation of inactive and activated forms of IAD-containing IRF proteins (IRF3 to IRF9), allowing a multipronged attack on IFN-based pathways that promote antiviral innate and adaptive immune responses.

Even in the absence of external stimuli there is ongoing activity in the cerebral cortex as a result of recurrent connectivity. This paper attempts to characterize one aspect of this ongoing activity by examining how the information content carried by specific neurons varies as a function of brain state. We recorded from rats chronically implanted with tetrodes in the primary visual cortex during awake and sleep periods. Electro-encephalogram and spike trains were recorded during 30-min periods, and 2-4 neuronal spikes were isolated per tetrode off-line. All the activity included in the analysis was spontaneous, being recorded from the visual cortex in the absence of visual stimuli. The brain state was determined through a combination of behavior evaluation, electroencephalogram and electromyogram analysis. Information in the spike trains was determined by using Lempel-Ziv Complexity. Complexity was used to estimate the entropy of neural discharges and thus the information content (Amigóet al. Neural Comput., 2004, 16: 717-736). The information content in spike trains (range 4-70 bits s(-1) ) was evaluated during different brain states and particularly during the transition periods. Transitions toward states of deeper sleep coincided with a decrease of information, while transitions to the awake state resulted in an increase in information. Changes in both directions were of the same magnitude, about 30%. Information in spike trains showed a high temporal correlation between neurons, reinforcing the idea of the impact of the brain state in the information content of spike trains., (© 2012 European Sleep Research Society.)

Viral pathogens must overcome innate antiviral responses to replicate successfully in the host organism. Some of the mechanisms viruses use to interfere with antiviral responses in the infected cell include preventing detection of viral components, perturbing the function of transcription factors that initiate antiviral responses, and inhibiting downstream signal transduction. RNA viruses with small genomes and limited coding space often express multifunctional proteins that modulate several aspects of the normal host response to infection. One such virus, rotavirus, is an important pediatric pathogen that causes severe gastroenteritis, leading to ~450,000 deaths globally each year. In this review, we discuss the nature of the innate antiviral responses triggered by rotavirus infection and the viral mechanisms for inhibiting these responses.

Brain and primary neuron fractions enriched in synaptic terminals are important tools for neuroscientists in biochemical, neuroanatomical and physiological studies. We describe an annotated updated micro-method for preparing synaptoneurosomes (SNs) enriched in presynaptic and postsynaptic elements. An easy to follow, step-by-step, protocol is provided for making SNs from small amounts of mammalian brain tissue. This includes novel applications for material obtained from human neurosurgical procedures and primary rat neuronal cultures. Our updated method for preparing SNs using smaller amounts of tissue provides a valuable new tool and expands the capabilities of neuroscientists., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The rotavirus (RV) non-structural protein NSP3 forms a dimer that has binding domains for the translation initiation factor eIF4G and for a conserved 3'-terminal sequence of viral mRNAs. Through these activities, NSP3 has been proposed to promote viral mRNA translation by directing circularization of viral polysomes. In addition, by disrupting interactions between eIF4G and the poly(A)-binding protein (PABP), NSP3 has been suggested to inhibit translation of host polyadenylated mRNAs and to stimulate relocalization of PABP from the cytoplasm to the nucleus. Herein, we report the isolation and characterization of SA11-4Fg7re, an SA11-4F RV derivative that contains a large sequence duplication initiating within the genome segment (gene 7) encoding NSP3. Our analysis showed that mutant NSP3 (NSP3m) encoded by SA11-4Fg7re is almost twice the size of the wild-type protein and retains the capacity to dimerize. However, in comparison to wild-type NSP3, NSP3m has a decreased capacity to interact with eIF4G and to suppress the translation of polyadenylated mRNAs. In addition, NSP3m fails to induce the nuclear accumulation of PABP in infected cells. Despite the defective activities of NSP3m, the levels of viral protein and progeny virus produced in SA11-4Fg7re- and SA11-4F-infected cells were indistinguishable. Collectively, these data are consistent with a role for NSP3 in suppressing host protein synthesis through antagonism of PABP activity, but also suggest that NSP3 functions may have little or no impact on the efficiency of virus replication in widely used RV-permissive cell lines.

The viral factories of mammalian reovirus (MRV) are cytoplasmic structures that serve as sites of viral genome replication and particle assembly. A 721-aa MRV non-structural protein, µNS, forms the factory matrix and recruits other viral proteins to these structures. In this report, we show that µNS contains a conserved C-proximal sequence (711-LIDFS-715) that is similar to known clathrin-box motifs and is required for recruitment of clathrin to viral factories. Clathrin recruitment by µNS occurs independently of infecting MRV particles or other MRV proteins. Ala substitution for a single Leu residue (mutation L711A) within the putative clathrin-binding motif of µNS inhibits clathrin recruitment, but does not prevent formation or expansion of viral factories. Notably, clathrin-dependent cellular functions, including both endocytosis and secretion, are disrupted in cells infected with MRV expressing wild-type, but not L711A, µNS. These results identify µNS as a novel adaptor-like protein that recruits cellular clathrin to viral factories, disrupting normal functions of clathrin in cellular membrane trafficking. To our knowledge, this is the only viral or bacterial protein yet shown to interfere with clathrin functions in this manner. The results additionally establish a new approach for studies of clathrin functions, based on µNS-mediated sequestration., (© 2011 John Wiley & Sons A/S.)

Our current study aims to evaluate the mechanisms of tranylcypromine (TCP)-mediated enhancement of nicotine self-administration. We replicated our previous findings which demonstrate that 1 h pretreatment with TCP (3 mg/kg, i.p.) enhances nicotine self-administration (7.5 μg/kg/inj, i.v.) when compared with vehicle-treated rodents. We tested whether TCP-mediated enhancement of nicotine self-administration was due to MAO inhibition or off-target effects by (i) extending the TCP pretreatment time from 1 to 20 h, and (ii) evaluating the role of the individual TCP stereoisomers in nicotine self-administration studies. While 20 h and (-)TCP pretreatment induced significant inhibition of MAO (60-90%), animals found nicotine only weakly reinforcing. Furthermore, while both (+) and (±)TCP treatment induced nearly 100% MAO inhibition, (+)TCP pretreated animals took longer to acquire nicotine self-administration compared to (±)TCP pretreated animals. Stable nicotine self-administration in (+)TCP pretreated animals was influenced by nicotinic receptor activation but not nicotine-paired cues. The opposite was found in (±)TCP pretreated animals. Treatment with (-) or (±)TCP increased dopamine and serotonin overflow, while the (+) and (±)TCP treatment enhanced monoamine overflow subsequent to nicotine. Together, our data suggests TCP enhancement of nicotine self-administration are mediated through mechanisms independent of MAO inhibition, including nicotine-paired cues and monoamine uptake inhibition., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Responses to sound in the auditory cortex are influenced by the preceding history of firing. We studied the time course of auditory adaptation in primary auditory cortex (A1) from awake, freely moving rats. Two identical stimuli were delivered with different intervals ranging from 50 ms to 8 s. Single neuron recordings in the awake animal revealed that the response to a sound is influenced by sounds delivered even several seconds earlier, the second one usually yielding a weaker response. To understand the role of neuronal intrinsic properties in this phenomenon, we obtained intracellular recordings from rat A1 neurons in vitro and mimicked the same protocols of adaptation carried out in awake animals by means of depolarizing pulses of identical duration and intervals. The intensity of the pulses was adjusted such that the first pulse would evoke a similar number of spikes as its equivalent in vivo. A1 neurons in vitro adapted with a similar time course but less than in awake animals. At least two potassium currents participated in the in vitro adaptation: a Na(+)-dependent K(+) current and an apamin-sensitive K(+) current. Our results suggest that potassium currents underlie at least part of cortical auditory adaptation during the awake state.

Studies involving limited numbers of rotavirus (RV) strains have shown that the viral gene 5 product, NSP1, can antagonize beta interferon (IFN-β) expression by inducing the degradation of IFN-regulatory factors (IRFs) (IRF3, IRF5, and IRF7) or a component of the E3 ubiquitin ligase complex responsible for activating NF-κB (β-transducin repeat-containing protein [β-TrCP]). To gain a broader perspective of NSP1 activities, we examined various RV strains for the ability to inhibit IFN-β expression in human cells. We found that all strains encoding wild-type NSP1 impeded IFN-β expression but not always through IRF3 degradation. To identify other degradation targets involved in suppressing IFN-β expression, we used transient expression vectors to test the abilities of a diverse collection of NSP1 proteins to target IRF3, IRF5, IRF7, and β-TrCP for degradation. The results indicated that human RVs rely predominantly on the NSP1-induced degradation of IRF5 and IRF7 to suppress IFN signaling, whereas NSP1 proteins of animal RVs tended to target IRF3, IRF5, and IRF7, allowing the animal viruses a broader attack on the IFN-β signaling pathway. The results also suggested that the NSP1-induced degradation of β-TrCP is an uncommon mechanism of subverting IFN-β signaling but is one that can be shared with NSP1 proteins that induce IRF degradation. Our analysis reveals that the activities of NSP1 proteins are diverse, with no obvious correlations between degradations of pairs of target proteins. Thus, RVs have evolved functionally distinct approaches for subverting the host antiviral response, a property consistent with the immense sequence variation noted for NSP1 proteins.

Virally induced structures called viral factories form throughout the cytoplasm of cells infected with mammalian orthoreoviruses (MRV). When expressed alone in cells, MRV nonstructural protein microNS forms factory-like structures very similar in appearance to viral factories, suggesting that it is involved in forming the structural matrix of these structures. microNS also associates with MRV core particles; the core proteins mu2, lambda1, lambda2, lambda3, and sigma2; and the RNA-binding nonstructural protein sigmaNS. These multiple associations result in the recruitment or retention of these viral proteins or particles at factory-like structures. In this study, we identified the regions of microNS necessary and sufficient for these associations and additionally examined the localization of viral RNA synthesis in infected cells. We found that short regions within the amino-terminal 220 residues of microNS are necessary for associations with core particles and necessary and sufficient for associations with the proteins mu2, lambda1, lambda2, sigma2, and sigmaNS. We also found that only the lambda3 protein associates with the carboxyl-terminal one-third of microNS and that viral RNA is synthesized within viral factories. These results suggest that microNS may act as a cytoplasmic scaffolding protein involved in localizing and coordinating viral replication or assembly intermediates for the efficient production of progeny core particles during MRV infection.

Rotavirus is a primary cause of severe dehydrating gastroenteritis in infants and young children. The virus is sensitive to the antiviral effects triggered by the interferon (IFN)-signaling pathway, an important component of the host cell innate immune response. To counteract these effects, rotavirus encodes a nonstructural protein (NSP1) that induces the degradation of proteins involved in regulating IFN expression, such as members of the IFN regulatory factor (IRF) family. In some instances, NSP1 also subverts IFN expression by causing the degradation of a component of the E3 ubiquitin ligase complex responsible for activating NF-κB. By antagonizing multiple components of the IFN-induction pathway, NSP1 aids viral spread and contributes to rotavirus pathogenesis.

People sometimes report recovering long-forgotten memories of childhood sexual abuse. The memory mechanisms that lead to such reports are not well understood, and the authenticity of recovered memories has often been challenged. We identified two subgroups of people reporting recovered memories of childhood sexual abuse. These subgroups differed dramatically in their cognitive profiles: People who recovered memories of abuse through suggestive therapy exhibited a heightened susceptibility to the construction of false memories, but showed no tendency to underestimate their prior remembering. Conversely, people who recovered memories of abuse spontaneously showed a heightened proneness to forget prior incidences of remembering, but exhibited no increased susceptibility to false memories. This double dissociation points to mechanisms that underlie recovered-memory experiences and indicates that recovered memories may at times be fictitious and may at other times be authentic.

Genome replication of mammalian orthoreovirus (MRV) occurs in cytoplasmic inclusion bodies called viral factories. Nonstructural protein microNS, encoded by genome segment M3, is a major constituent of these structures. When expressed without other viral proteins, microNS forms cytoplasmic inclusions morphologically similar to factories, suggesting a role for microNS as the factory framework or matrix. In addition, most other MRV proteins, including all five core proteins (lambda1, lambda2, lambda3, micro2, and sigma2) and nonstructural protein sigmaNS, can associate with microNS in these structures. In the current study, small interfering RNA targeting M3 was transfected in association with MRV infection and shown to cause a substantial reduction in microNS expression as well as, among other effects, a reduction in infectious yields by as much as 4 log(10) values. By also transfecting in vitro-transcribed M3 plus-strand RNA containing silent mutations that render it resistant to the small interfering RNA, we were able to complement microNS expression and to rescue infectious yields by ~100-fold. We next used microNS mutants specifically defective at forming factory-matrix structures to show that this function of microNS is important for MRV growth; point mutations in a C-proximal, putative zinc-hook motif as well as small deletions at the extreme C terminus of microNS prevented rescue of viral growth while causing microNS to be diffusely distributed in cells. We furthermore confirmed that an N-terminally truncated form of microNS, designed to represent microNSC and still able to form factory-matrix structures, is unable to rescue MRV growth, localizing one or more other important functions to an N-terminal region of microNS known to be involved in both micro2 and sigmaNS association. Thus, factory-matrix formation is an important, though not a sufficient function of microNS during MRV infection; microNS is multifunctional in the course of viral growth.

The knew-it-all-along (KIA) effect occurs when individuals report that they previously knew something that they learned only recently. People often err when reporting the level of knowledge they had prior to feedback, but there is no research exploring the subjective experience of this effect. We incorporated a remember/just know/ guess judgment into a traditional (Experiment 1A: rating scale) and a modified-traditional (Experiment 1B: two-alternative forced choice) KIA procedure. Experiments 2A, 2B, and 3 were similar in format to Experiments 1A and 1B, but the trivia stimuli were replaced with word puzzles, which were expected to be better suited to inducing a feeling of having known it all along, because answers to trivia questions typically seem arbitrary, whereas word puzzles often give rise to ah-ha experiences. A KIA effect was observed in all the experiments, but an accompanying subjective feeling of having known it all along arose only with word puzzles.

Pulmonary drug delivery of controlled release formulations may provide an effective adjunct approach to orally delivered antibiotics for clearing persistent lung infections. Dry powder formulations for this indication should possess characteristics including; effective deposition to infected lung compartments, persistence at the infection site, and steady release of antibiotic. Large porous particles ( approximately 10-15 microm) have demonstrated effective lung deposition and enhanced lung residence as a result of their large diameter and reduced clearance by macrophages in comparison to small microparticles ( approximately 1-5 microm). In this report, Precision Particle Fabrication technology was used to create monodisperse large porous particles of poly(d,l-lactic-co-glycolic acid) (PLGA) utilizing oils as extractable porogens. After extraction, the resulting large porous PLGA particles exhibited a low density and a web-like or hollow interior depending on porogen concentration and type, respectively. Ciprofloxacin nanoparticles (nanoCipro) created by homogenization in dichloromethane, possessed a polymorph with a decreased melting temperature. Encapsulating nanoCipro in large porous PLGA particles resulted in a steady release of ciprofloxacin that was extended for larger particle diameters and for the solid particle morphology in comparison to large porous particles. The encapsulation efficiency of nanoCipro was quite low and factors impacting the entrapment of nanoparticles during particle formation were elucidated. A dry powder formulation with the potential to control particle deposition and sustain release to the lung was developed and insight to improve nanoparticle encapsulation is discussed.

A low-copy component of mammalian reovirus particles is mu2, an 83-kDa protein encoded by the M1 viral genome segment and packaged within the viral core. Previous studies have identified mu2 as a nucleoside triphosphate phosphohydrolase (NTPase) as well as an RNA 5'-triphosphate phosphohydrolase (RTPase), putatively involved in reovirus RNA synthesis and/or 5'-capping. Other studies have identified mu2 as a microtubule-binding protein, which also associates with the viral factory matrix protein muNS and thereby anchors the factories to cellular microtubules during infections by most reovirus strains. To extend studies of mu2 functions during infection, we tested a small interfering RNA (siRNA) directed against the M1 plus-strand RNAs of reovirus strains Type 1 Lang (T1L) and Type 3 Dearing (T3D). The siRNA strongly suppressed mu2 expression by either strain and reduced infectious yields in a strain-dependent manner. This first strain difference was genetically mapped to the M1 genome segment and tentatively assigned to a single mu2 sequence polymorphism, Pro/Ser208, which also determines a T1L-T3D strain difference in microtubule association. The siRNA-based defect in mu2 expression was rescued by plasmids, containing silent mutations in the siRNA-targeted sequence, which encoded either T1L or T3D mu2, but the growth defect was rescued only by T1L mu2. This second strain difference was also mapped to Pro/Ser208, in that swapping this one residue between T1L and T3D mu2 reversed the rescue phenotypes. Thus, the T1L-T3D strain difference in mu2-microtubule association was correlated not only with the extent of reduction in infectious yields by the siRNA but also with the extent of rescue by plasmid-derived mu2. In addition, the rescue capacity of T1L mu2 was abrogated by nocodazole treatment, providing independent evidence for the importance of mu2-microtubule association in plasmid-based rescue. In two separate cases, the results revealed functional differences between virus- and plasmid-derived mu2. Ala substitutions within the NTP-binding motif of T1L mu2 also abrogated its rescue capacity, suggesting that the NTPase or RTPase activity of mu2 is additionally required for effective viral growth.

Protein-protein associations are vital to cellular functions. Here we describe a helpful new method to demonstrate protein-protein associations inside cells based on the capacity of orthoreovirus protein muNS to form large cytoplasmic inclusions, easily visualized by light microscopy, and to recruit other proteins to these structures in a specific manner. We introduce this technology by the identification of a sixth orthoreovirus protein, RNA-dependent RNA polymerase lambda3, that was recruited to the structures through an association with muNS. We then established the broader utility of this technology by using a truncated, fluorescently tagged form of muNS as a fusion platform to present the mammalian tumor suppressor p53, which strongly recruited its known interactor simian virus 40 large T antigen to the muNS-derived structures. In both examples, we further localized a region of the recruited protein that is key to its recruitment. Using either endogenous p53 or a second fluorescently tagged fusion of p53 with the rotavirus NSP5 protein, we demonstrated p53 oligomerization as well as p53 association with another of its cellular interaction partners, the CREB-binding proteins, within the inclusions. Furthermore using the p53-fused fluorescent muNS platform in conjunction with three-color microscopy, we identified a ternary complex comprising p53, simian virus 40 large T antigen, and retinoblastoma protein. The new method is technically simple, uses commonly available resources, and is adaptable to high throughput formats.

Oxidative stress has long been associated with normal aging and age-related neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, it is now evident that reactive oxygen species (ROS) such as superoxide (O(2-*)) and hydrogen peroxide (H(2)O(2)) also play pivotal roles in normal cell signaling. The focus of the present study was to examine the effects of the antioxidant enzymes CuZnSOD (SOD1) and catalase, which produce and remove H(2)O(2), respectively, on long-term potentiation (LTP) forms of synaptic plasticity during aging. Consistent wth previous studies, LTP, when induced in vitro in CA1 of the hippocampus with a high-frequency stimulation protocol, is significantly reduced in slices from older mice (22-26 months) relative to younger mice (2-4 months). Neither knockout of the endogenous catalase gene (Cat KO) nor acute enzymatic treatment with SOD1 altered LTP in slices from adult mice. Conversely, enzymatic applications of SOD1 inhibited LTP in slices from older mice. A much different set of results emerges with exogenous applications of catalase to hippocampal slices. Catalase significantly inhibited LTP in slices from adult mice but reversed age-related LTP deficits in slices from older mice. Measurements of H(2)O(2) showed that exogenous treatments with catalase lowered H(2)O(2) in synapse-enriched synaptoneurosome (SN) fractions prepared from adult mice. Notably, SNs from both Cat KO and old mice were deficient in removing extracellular challenges of H(2)O(2). Overall, the results suggest that dynamic alterations in extracellular H(2)O(2) metabolism affect synaptic plasticity in the hippocampus during aging.

Case studies of individuals reporting recovered memories of childhood sexual abuse suggest that some overestimate their prior forgetting of the abuse. People reporting recovered or continuous memories of childhood sexual abuse and control subjects reporting no history of abuse participated in two experiments examining this "forgot it all along" phenomenon. Participants in Experiment 1 were more likely to forget that they had previously recalled a studied item if they were cued to think of it differently on two recall tests than if they were cued to think of it in the same way on the two tests. This effect was stronger for recovered-memory participants than for continuous-memory and control participants. In Experiment 2, participants recalled autobiographical events three times over a period of 4 months. Much as in Experiment 1, they underestimated prior remembering when the events had been recalled in a different emotional frame (positive vs. negative) on the previous occasion. This underestimation was more pronounced for recovered-memory participants than for continuous-memory and control participants.

An underlying theme common to prominent theoretical accounts of cognition in schizophrenia is that information processing is disproportionately influenced by recently/currently encountered information relative to the influence of previously learned information. In this study, the authors tested this account by using the hindsight bias or knew-it-all-along (KIA) paradigm, which demonstrates that newly acquired knowledge influences recall of past events. In line with the account that patients with schizophrenia display a disproportionately strong influence of recently encountered information relative to the influence of previously learned information, patients displayed a KIA effect that was significantly greater than in controls. This result is discussed in the context of the cognitive underpinnings of the KIA effect and delusion formation., (((c) 2006 APA, all rights reserved).)

We investigated the effect of choice feeding two diets with different selenium (Se) content to young and old moderately Se-deficient laying hens on serum Se (SSe), glutathione peroxidase (GPX), vitamin E, creatine kinase (CK), aspartate aminotransferase (ASAT), thyroxine (T4) and triiodothyronine (T3). Each of two consecutive study parts (I and II) with the same hens and treatments began with a 6-week baseline period (Medium-Se diet), followed by a 9-week depletion period (Low-Se or Medium-Se diet), followed by a 6-week choice period with two different diets offered simultaneously (Medium-Se/Low-Se, Medium-Se/High-Se, or Low-Se/High-Se). During both depletion periods, SSe and GPX gradually decreased, whereas T4 gradually increased in hens fed Low-Se confirming gradual Se-depletion. T3 decreased transiently in young hens only. As reported earlier, Se-deficient hens preferred High-Se over Low-Se diet during the first 3 weeks of choice feeding in part I, not however in part II. This preference resulted in higher SSe in these hens. GPX activity did not reflect feed preference, probably because Se-intake exceeded Se-requirement for maximal GPX activity. In Part II, hens depleted with Low-Se diet had higher SSe when previously offered High-Se diet in either combination, than when offered Low-Se/Medium-Se, presumably due to Se-stores built during choice feeding in part I, which possibly prevented development of Se-deficiency in part II. In addition, in older hens, Se depletion proceeded faster, whereas Se-repletion by choice feeding was slower than in young hens, indicating the increase in Se requirement with advancing age. Vitamin E, ASAT and CK remained largely unchanged by the treatments.

Arnold and Lindsay (2002) found that individuals more often failed to remember they had previously recalled an item if that item had been cued in a qualitatively different way on two recall occasions: the "forgot-it-all-along" (FIA) effect. Experiment 1 was designed to determine if the FIA effect arises because participants incorrectly believe they have not been previously tested for an item, or because they incorrectly believe they have failed to recall the item when previously tested. Experiment 2 measured participants' confidence in their incorrect prior-recall judgements, and Experiment 3 tested participants' ability to "recover" their previous recollection when the prior-recall context was restored. Results indicated that participants usually believed they had not previously been cued for the items they failed to remember previously recalling; they were often confident in their incorrect judgements of prior non-remembering; and re-introducing the context of prior remembering sometimes enabled them to recapture their memories of previous recall.

Mammalian orthoreoviruses are believed to replicate in distinctive, cytoplasmic inclusion bodies, commonly called viral factories or viroplasms. The viral nonstructural protein muNS has been implicated in forming the matrix of these structures, as well as in recruiting other components to them for putative roles in genome replication and particle assembly. In this study, we sought to identify the regions of muNS that are involved in forming factory-like inclusions in transfected cells in the absence of infection or other viral proteins. Sequences in the carboxyl-terminal one-third of the 721-residue muNS protein were linked to this activity. Deletion of as few as eight residues from the carboxyl terminus of muNS resulted in loss of inclusion formation, suggesting that some portion of these residues is required for the phenotype. A region spanning residues 471 to 721 of muNS was the smallest one shown to be sufficient for forming factory-like inclusions. The region from positions 471 to 721 (471-721 region) includes both of two previously predicted coiled-coil segments in muNS, suggesting that one or both of these segments may also be required for inclusion formation. Deletion of the more amino-terminal one of the two predicted coiled-coil segments from the 471-721 region resulted in loss of the phenotype, although replacement of this segment with Aequorea victoria green fluorescent protein, which is known to weakly dimerize, largely restored inclusion formation. Sequences between the two predicted coiled-coil segments were also required for forming factory-like inclusions, and mutation of either one His residue (His570) or one Cys residue (Cys572) within these sequences disrupted the phenotype. The His and Cys residues are part of a small consensus motif that is conserved across muNS homologs from avian orthoreoviruses and aquareoviruses, suggesting this motif may have a common function in these related viruses. The inclusion-forming 471-721 region of muNS was shown to provide a useful platform for the presentation of peptides for studies of protein-protein association through colocalization to factory-like inclusions in transfected cells.

Background: The reovirus M1 genome segment encodes the mu2 protein, a structurally minor component of the viral core, which has been identified as a transcriptase cofactor, nucleoside and RNA triphosphatase, and microtubule-binding protein. The mu2 protein is the most poorly understood of the reovirus structural proteins. Genome segment sequences have been reported for 9 of the 10 genome segments for the 3 prototypic reoviruses type 1 Lang (T1L), type 2 Jones (T2J), and type 3 Dearing (T3D), but the M1 genome segment sequences for only T1L and T3D have been previously reported. For this study, we determined the M1 nucleotide and deduced mu2 amino acid sequences for T2J, nine other reovirus field isolates, and various T3D plaque-isolated clones from different laboratories., Results: Determination of the T2J M1 sequence completes the analysis of all ten genome segments of that prototype. The T2J M1 sequence contained a 1 base pair deletion in the 3' non-translated region, compared to the T1L and T3D M1 sequences. The T2J M1 gene showed approximately 80% nucleotide homology, and the encoded mu 2 protein showed approximately 71% amino acid identity, with the T1L and T3D M1 and mu2 sequences, respectively, making the T2J M1 gene and mu2 proteins amongst the most divergent of all reovirus genes and proteins. Comparisons of these newly determined M1 and mu2 sequences with newly determined M1 and mu2 sequences from nine additional field isolates and a variety of laboratory T3D clones identified conserved features and/or regions that provide clues about mu2 structure and function., Conclusions: The findings suggest a model for the domain organization of mu2 and provide further evidence for a role of mu2 in viral RNA synthesis. The new sequences were also used to explore the basis for M1/mu2-determined differences in the morphology of viral factories in infected cells. The findings confirm the key role of Ser/Pro208 as a prevalent determinant of differences in factory morphology among reovirus isolates and trace the divergence of this residue and its associated phenotype among the different laboratory-specific clones of type 3 Dearing.

Human neonates infected with herpes simplex virus 1 (HSV-1) develop one of three distinct patterns of infection: (i) infection limited to the skin, eye or mouth; (ii) infection of the CNS; or (iii) disseminated infection. The disseminated form usually involves the liver, adrenal gland, and lung, and resembles the clinical picture of bacterial sepsis. This spectrum of symptoms in HSV-1-infected neonates suggests that inflammatory cytokines play a significant role in the pathogenesis of the disease. Recent studies suggest that the Toll-like receptors (TLRs) may play an important role in the induction of inflammatory cytokines in response to viruses. TLRs are mammalian homologues of Toll, a Drosophila protein that is essential for host defense against infection. Engagement of TLRs by bacterial, viral, or fungal components leads to the production and release of cytokines and other antimicrobial products. Here, we demonstrate that TLR2 mediates the inflammatory cytokine response to HSV-1 by using both transfected cell lines and knockout mice. Studies of infected mice revealed that HSV-1 induced a blunted cytokine response in TLR2(-/-) mice. Brain levels of monocyte chemoattractant protein 1 chemokine were significantly lower in TLR2(-/-) mice than in either wild-type or TLR4(-/-) mice. TLR2(-/-) mice had reduced mortality compared with wild-type mice. The differences between TLR2(-/-) mice and both wild-type and TLR4(-/-) mice in the induction of monocyte chemoattractant protein 1, brain inflammation, or mortality could not be accounted for on the basis of virus levels. Thus, these studies suggest the TLR2-mediated cytokine response to HSV-1 is detrimental to the host.

Cells infected with mammalian reoviruses contain phase-dense inclusions, called viral factories, in which viral replication and assembly are thought to occur. The major reovirus nonstructural protein mu NS forms morphologically similar phase-dense inclusions when expressed in the absence of other viral proteins, suggesting it is a primary determinant of factory formation. In this study we examined the localization of the other major reovirus nonstructural protein, sigma NS. Although sigma NS colocalized with mu NS in viral factories during infection, it was distributed diffusely throughout the cell when expressed in the absence of mu NS. When coexpressed with mu NS, sigma NS was redistributed and colocalized with mu NS inclusions, indicating that the two proteins associate in the absence of other viral proteins and suggesting that this association may mediate the localization of sigma NS to viral factories in infected cells. We have previously shown that mu NS residues 1 to 40 or 41 are both necessary and sufficient for mu NS association with the viral microtubule-associated protein mu 2. In the present study we found that this same region of micro NS is required for its association with sigma NS. We further dissected this region, identifying residues 1 to 13 of mu NS as necessary for association with sigma NS, but not with mu 2. Deletion of sigma NS residues 1 to 11, which we have previously shown to be required for RNA binding by that protein, resulted in diminished association of sigma NS with mu NS. Furthermore, when treated with RNase, a large portion of sigma NS was released from mu NS coimmunoprecipitates, suggesting that RNA contributes to their association. The results of this study provide further evidence that mu NS plays a key role in forming the reovirus factories and recruiting other components to them.

We developed a laboratory analogue of the "forgot-it-all-along" effect that J. W. Schooler, M. Bendiksen, and Z. Ambadar (1997) proposed for cases of "recovered memories" in which individuals had forgotten episodes of talking about the abuse when they were supposedly amnestic for it. In Experiment 1, participants studied homographs with disambiguating context words; in Test 1 they received studied- or other-context words as cues; and in Test 2 they received studied-context cues and judged whether they had recalled each item during Test 1. In Experiment 2, retrieval cues were manipulated on both tests. In Experiment 3, both the studied- and other-context cues corresponded to the same meaning of each homograph. In Experiment 4, Test 1 was free recall, and studied- versus other-context cues were presented in Test 2. Participants more often forgot that they had previously recalled an item if they were cued to think of it differently on the two tests.