Pointing errors in non-metric virtual environments

There have been suggestions that human navigation may depend on representations that have no metric, Euclidean interpretation but that hypothesis remains contentious. An alternative is that observers build a consistent 3D representation of space. Using immersive virtual reality, we measured the ability of observers to point to targets in mazes that had zero, one or three ‘wormholes’ – regions where the maze changed in configuration (invisibly). In one model, we allowed the configuration of the maze to vary to best explain the pointing data; in a second model we also allowed the local reference frame to be rotated through 90, 180 or 270 degrees. The latter model outperformed the former in the wormhole conditions, inconsistent with a Euclidean cognitive map

Multicenter evaluation of a lateral-flow device test for diagnosing invasive pulmonary aspergillosis in ICU patients.

Published onlineClinical TrialJournal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tINTRODUCTION: The incidence of invasive pulmonary aspergillosis (IPA) in intensive care unit (ICU) patients is increasing, and early diagnosis of the disease and treatment with antifungal drugs is critical for patient survival. Serum biomarker tests for IPA typically give false-negative results in non-neutropenic patients, and galactomannan (GM) detection, the preferred diagnostic test for IPA using bronchoalveolar lavage (BAL), is often not readily available. Novel approaches to IPA detection in ICU patients are needed. In this multicenter study, we evaluated the performance of an Aspergillus lateral-flow device (LFD) test for BAL IPA detection in critically ill patients. METHODS: A total of 149 BAL samples from 133 ICU patients were included in this semiprospective study. Participating centers were the medical university hospitals of Graz, Vienna and Innsbruck in Austria and the University Hospital of Mannheim, Germany. Fungal infections were classified according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. RESULTS: Two patients (four BALs) had proven IPA, fourteen patients (sixteen BALs) had probable IPA, twenty patients (twenty-one BALs) had possible IPA and ninety-seven patients (one hundred eight BALs) did not fulfill IPA criteria. Sensitivity, specificity, negative predictive value, positive predictive value and diagnostic odds ratios for diagnosing proven and probable IPA using LFD tests of BAL were 80%, 81%, 96%, 44% and 17.6, respectively. Fungal BAL culture exhibited a sensitivity of 50% and a specificity of 85%. CONCLUSION: LFD tests of BAL showed promising results for IPA diagnosis in ICU patients. Furthermore, the LFD test can be performed easily and provides rapid results. Therefore, it may be a reliable alternative for IPA diagnosis in ICU patients if GM results are not rapidly available. TRIAL REGISTRATION: ClinicalTrials.gov NCT02058316. Registered 20 January 2014.PfizerOesterreichische Nationalbank (Anniversary Fund, project number 15346)

DNMT1 mutations found in HSANIE patients affect interaction with UHRF1 and neuronal differentiation

DNMT1 is recruited to substrate sites by PCNA and UHRF1 to maintain DNA methylation after replication. The cell cycle dependent recruitment of DNMT1 is mediated by the PCNA-binding domain (PBD) and the targeting sequence (TS) within the N-terminal regulatory domain. The TS domain was found to be mutated in patients suffering from hereditary sensory and autonomic neuropathies with dementia and hearing loss (HSANIE) and autosomal dominant cerebellar ataxia deafness and narcolepsy (ADCA-DN) and is associated with global hypomethylation and site specific hypermethylation. With functional complementation assays in mouse embryonic stem cells, we showed that DNMT1 mutations P496Y and Y500C identified in HSANIE patients not only impair DNMT1 heterochromatin association, but also UHRF1 interaction resulting in hypomethylation. Similar DNA methylation defects were observed when DNMT1 interacting domains in UHRF1, the UBL and the SRA domain, were deleted. With cell-based assays, we could show that HSANIE associated mutations perturb DNMT1 heterochromatin association and catalytic complex formation at methylation sites and decrease protein stability in late S and G2 phase. To investigate the neuronal phenotype of HSANIE mutations, we performed DNMT1 rescue assays and could show that cells expressing mutated DNMT1 were prone to apoptosis and failed to differentiate into neuronal lineage. Our results provide insights into the molecular basis of DNMT1 dysfunction in HSANIE patients and emphasize the importance of the TS domain in the regulation of DNA methylation in pluripotent and differentiating cells

The impact of working memory load on task execution and online plan adjustment during multitasking in a virtual environment

Three experiments investigated the impact of working memory load on online plan adjustment during a test of multitasking in young, nonexpert, adult participants. Multitasking was assessed using the Edinburgh Virtual Errands Test (EVET). Participants were asked to memorize either good or poor plans for performing multiple errands and were assessed both on task completion and on the extent to which they modified their plans during EVET performance. EVET was performed twice, with and without a secondary task loading a component of working memory. In Experiment 1, articulatory suppression was used to load the phonological loop. In Experiment 2, oral random generation was used to load executive functions. In Experiment 3, spatial working memory was loaded with an auditory spatial localization task. EVET performance for both good- and poor-planning groups was disrupted by random generation and sound localization, but not by articulatory suppression. Additionally, people given a poor plan were able to overcome this initial disadvantage by modifying their plans online. It was concluded that, in addition to executive functions, multiple errands performance draws heavily on spatial, but not verbal, working memory resources but can be successfully completed on the basis of modifying plans online, despite a secondary task load

Multicenter evaluation of a lateral-flow device test for diagnosing invasive pulmonary aspergillosis in ICU patients

Introduction: The incidence of invasive pulmonary aspergillosis (IPA) in intensive care unit (ICU) patients is increasing, and early diagnosis of the disease and treatment with antifungal drugs is critical for patient survival. Serum biomarker tests for IPA typically give false-negative results in non-neutropenic patients, and galactomannan (GM) detection, the preferred diagnostic test for IPA using bronchoalveolar lavage (BAL), is often not readily available. Novel approaches to IPA detection in ICU patients are needed. In this multicenter study, we evaluated the performance of an Aspergillus lateral-flow device (LFD) test for BAL IPA detection in critically ill patients. Methods: A total of 149 BAL samples from 133 ICU patients were included in this semiprospective study. Participating centers were the medical university hospitals of Graz, Vienna and Innsbruck in Austria and the University Hospital of Mannheim, Germany. Fungal infections were classified according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. Results: Two patients (four BALs) had proven IPA, fourteen patients (sixteen BALs) had probable IPA, twenty patients (twenty-one BALs) had possible IPA and ninety-seven patients (one hundred eight BALs) did not fulfill IPA criteria. Sensitivity, specificity, negative predictive value, positive predictive value and diagnostic odds ratios for diagnosing proven and probable IPA using LFD tests of BAL were 80%, 81%, 96%, 44% and 17.6, respectively. Fungal BAL culture exhibited a sensitivity of 50% and a specificity of 85%. Conclusion: LFD tests of BAL showed promising results for IPA diagnosis in ICU patients. Furthermore, the LFD test can be performed easily and provides rapid results. Therefore, it may be a reliable alternative for IPA diagnosis in ICU patients if GM results are not rapidly available. Trial registration: ClinicalTrials.gov NCT02058316. Registered 20 January 2014

Partial trisomy of the long arm of human chromosome 1 as demonstrated by in situ hybridization with 5S ribosomal RNA

In a newborn boy with multiple malformations, a tandem duplication was detected at the distal end of the long arm of one human chromosome 1. The Giemsa bands, 1q31 to 1q43–44, were repeated serially. Since 5S rRNA genes are located at 1q42–43, in situ hybridization of 125 I 5S rRNA with fixed chromosome preparations was used to confirm the chromosomal duplication. The infant exhibited numerous developmental and clinical abnormalities as might be expected with an abnormality of chromosome structure relating to a ribosome component.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47604/1/439_2004_Article_BF00390432.pd

Short-Term Memory Maintenance of Object Locations during Active Navigation: Which Working Memory Subsystem Is Essential?

The goal of the present study was to examine the extent to which working memory supports the maintenance of object locations during active spatial navigation. Participants were required to navigate a virtual environment and to encode the location of a target object. In the subsequent maintenance period they performed one of three secondary tasks that were designed to selectively load visual, verbal or spatial working memory subsystems. Thereafter participants re-entered the environment and navigated back to the remembered location of the target. We found that while navigation performance in participants with high navigational ability was impaired only by the spatial secondary task, navigation performance in participants with poor navigational ability was impaired equally by spatial and verbal secondary tasks. The visual secondary task had no effect on navigation performance. Our results extend current knowledge by showing that the differential engagement of working memory subsystems is determined by navigational ability

In Vivo Control of CpG and Non-CpG DNA Methylation by DNA Methyltransferases

The enzymatic control of the setting and maintenance of symmetric and non-symmetric DNA methylation patterns in a particular genome context is not well understood. Here, we describe a comprehensive analysis of DNA methylation patterns generated by high resolution sequencing of hairpin-bisulfite amplicons of selected single copy genes and repetitive elements (LINE1, B1, IAP-LTR-retrotransposons, and major satellites). The analysis unambiguously identifies a substantial amount of regional incomplete methylation maintenance, i.e. hemimethylated CpG positions, with variant degrees among cell types. Moreover, non-CpG cytosine methylation is confined to ESCs and exclusively catalysed by Dnmt3a and Dnmt3b. This sequence position–, cell type–, and region-dependent non-CpG methylation is strongly linked to neighboring CpG methylation and requires the presence of Dnmt3L. The generation of a comprehensive data set of 146,000 CpG dyads was used to apply and develop parameter estimated hidden Markov models (HMM) to calculate the relative contribution of DNA methyltransferases (Dnmts) for de novo and maintenance DNA methylation. The comparative modelling included wild-type ESCs and mutant ESCs deficient for Dnmt1, Dnmt3a, Dnmt3b, or Dnmt3a/3b, respectively. The HMM analysis identifies a considerable de novo methylation activity for Dnmt1 at certain repetitive elements and single copy sequences. Dnmt3a and Dnmt3b contribute de novo function. However, both enzymes are also essential to maintain symmetrical CpG methylation at distinct repetitive and single copy sequences in ESCs

Human Immunodeficiency Virus Infection and Diverse Physical Health Outcomes: An Umbrella Review of Meta-analyses of Observational Studies

BACKGROUND: Our aim was to assess both the credibility and strength of evidence arising from systematic reviews with meta-analyses of observational studies and physical health outcomes associated with human immunodeficiency virus (HIV) but not acquired immunodeficiency syndrome. METHODS: We performed an umbrella review of observational studies. Evidence was graded as convincing, highly suggestive, suggestive, weak, or nonsignificant. RESULTS: From 3413 studies returned, 20 were included, covering 55 health outcomes. Median number of participants was 18 743 (range 403-225 000 000). Overall, 45 (81.8%) of the 55 unique outcomes reported nominally significant summary results (P < .05). Only 5 outcomes (9.0%; higher likelihood of presence of breathlessness, higher chronic obstructive pulmonary disease [COPD] prevalence, maternal sepsis, higher risk of anemia, and higher risk of all fractures among people living with HIV [PLWHIV]) showed suggestive evidence, with P values < 10-3; only 3 (5.5%; higher prevalence of cough in cross-sectional studies, higher incidence of pregnancy-related mortality, and higher incidence of ischemic heart disease among PLWHIV in cohort studies) outcomes showed stronger evidence using a stringent P value (<10-6). None of the unique outcomes presented convincing evidence (Class I), yet 3 outcomes presented highly suggestive evidence, 5 outcomes presented suggestive evidence, and 37 outcomes presented weak evidence. CONCLUSIONS: Results show highly suggestive and suggestive evidence for HIV and the presence of a cough, COPD, ischemic heart disease, pregnancy-related mortality, maternal sepsis, and bone fractures. Public health policies should reflect and accommodate these changes, especially in light of the increases in the life expectancy and the incidence of comorbidities in this population