Remember to forget: does strategic retrieval from the list before the last enable forgetting of the most recent information

Successful forgetting in list-method directed forgetting procedures has only been observed when new information is encoded following the forget cue. A recent study, however, observed forgetting of the most recent information without post-cue encoding (Racsmány et al., 2018), putatively because proactive interference from previously learned to-be-remembered information is sufficient to cause forgetting. In three Experiments, I aimed to replicate the recent findings and provide an alternative explanation that post-cue encoding occurs covertly. In the forget condition, participants studied two lists of words with a forget cue after the second list, while in the remember condition both lists were cued to-be-remembered. Free recall tests followed each pair of lists. Experiment 1 resulted in no significant directed forgetting effects and thus failed to replicate Racsmány et al.’s results. However, minor changes to the procedure in Experiments 2 and 3 resulted in significant forgetting of the most recent list. The findings indicate that directed forgetting of the most recent information is possible, and that participants may do so by strategically retrieving earlier learned to-be-remembered information. Previous research indicates that explicit retrieval of earlier-leaned information causes a contextual shift, resulting in forgetting of target information

Array-Based FMR1 Sequencing and Deletion Analysis in Patients with a Fragile X Syndrome–Like Phenotype

Background: Fragile X syndrome (FXS) is caused by loss of function mutations in the FMR1 gene. Trinucleotide CGG-repeat expansions, resulting in FMR1 gene silencing, are the most common mutations observed at this locus. Even though the repeat expansion mutation is a functional null mutation, few conventional mutations have been identified at this locus, largely due to the clinical laboratory focus on the repeat tract. Methodology/Principal Findings: To more thoroughly evaluate the frequency of conventional mutations in FXS-like patients, we used an array-based method to sequence FMR1 in 51 unrelated males exhibiting several features characteristic of FXS but with normal CGG-repeat tracts of FMR1. One patient was identified with a deletion in FMR1, but none of the patients were found to have other conventional mutations. Conclusions/Significance: These data suggest that missense mutations in FMR1 are not a common cause of the FXS phenotype in patients who have normal-length CGG-repeat tracts. However, screening for small deletions of FMR1 may be of clinically utility

Efficient generation of vesicular stomatitis virus (VSV)-pseudotypes bearing morbilliviral glycoproteins and their use in quantifying virus neutralising antibodies

Morbillivirus neutralising antibodies are traditionally measured using either plaque reduction neutralisation tests (PRNTs) or live virus microneutralisation tests (micro-NTs). While both test formats provide a reliable assessment of the strength and specificity of the humoral response, they are restricted by the limited number of viral strains that can be studied and often present significant biological safety concerns to the operator. In this study, we describe the adaptation of a replication-defective vesicular stomatitis virus (VSVΔG) based pseudotyping system for the measurement of morbillivirus neutralising antibodies. By expressing the haemagglutinin (H) and fusion (F) proteins of canine distemper virus (CDV) on VSVΔG pseudotypes bearing a luciferase marker gene, neutralising antibody titres could be measured rapidly and with high sensitivity. Further, by exchanging the glycoprotein expression construct, responses against distinct viral strains or species may be measured. Using this technique, we demonstrate cross neutralisation between CDV and peste des petits ruminants virus (PPRV). As an example of the value of the technique, we demonstrate that UK dogs vary in the breadth of immunity induced by CDV vaccination; in some dogs the neutralising response is CDV-specific while, in others, the neutralising response extends to the ruminant morbillivirus PPRV. This technique will facilitate a comprehensive comparison of cross-neutralisation to be conducted across the morbilliviruses

Nacre tablet thickness records formation temperature in modern and fossil shells

Nacre, the iridescent outer lining of pearls and inner lining of many mollusk shells, is composed of periodic, parallel, organic sheets alternating with aragonite (CaCO_3) tablet layers. Nacre tablet thickness (TT) generates both nacre's iridescence and its remarkable resistance to fracture. Despite extensive studies on how nacre forms, the mechanisms controlling TT remain unknown, even though they determine the most conspicuous of nacre's characteristics, visible even to the naked eye. Thermodynamics predicts that temperature (T) will affect both physical and chemical components of biomineralized skeletons. The chemical composition of biominerals is well-established to record environmental parameters, and has therefore been extensively used in paleoclimate studies. The physical structure, however, has been hypothesized but never directly demonstrated to depend on the environment. Here we observe that the physical TT in nacre from modern and fossil shallow-water shells of the bivalves Pinna and Atrina correlates with T as measured by the carbonate clumped isotope thermometer. Based on the observed TT vs. T correlation, we anticipate that TT will be used as a paleothermometer, useful to estimate paleotemperature in shallow-water paleoenvironments. Here we successfully test the proposed new nacre TT thermometer on two Jurassic Pinna shells. The increase of TT with T is consistent with greater aragonite growth rate at higher T, and with greater metabolic rate at higher T. Thus, it reveals a complex, T-dependent biophysical mechanism for nacre formation

Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer’s Disease

The phosphoinositide phosphatase synaptojanin 1 (SYNJ1) is a key regulator of synaptic function. We first tested whether SYNJ1 contributes to phenotypic variations in familial Alzheimer’s disease (FAD) and show that SYNJ1 polymorphisms are associated with age of onset in both early- and late-onset human FAD cohorts. We then interrogated whether SYNJ1 levels could directly affect memory. We show that increased SYNJ1 levels in autopsy brains from adults with Down syndrome (DS/AD) are inversely correlated with synaptophysin levels, a direct readout of synaptic integrity. We further report age-dependent cognitive decline in a mouse model overexpressing murine Synj1 to the levels observed in human sporadic AD, triggered through hippocampal hyperexcitability and defects in the spatial reproducibility of place fields. Taken together, our findings suggest that SYNJ1 contributes to memory deficits in the aging hippocampus in all forms of AD

Generating chromosome geometries in a minimal cell from cryo-electron tomograms and chromosome conformation capture maps

Macromolecular Biochemistr

Kepler Certified False Positive Table

This document describes the Kepler Certied False Positive table hosted at the Exoplanet Archive1, herein referred to as the CFP table. This table is the result of detailed examination by the Kepler False Positive Working Group (FPWG) of declared false positives in the Kepler Object of Interest (KOI) tables (see, for example, Batalha et al. (2012); Burke et al.(2014); Rowe et al. (2015); Mullally et al. (2015); Coughlin et al. (2015b)) at the Exoplanet Archive. A KOI is considered a false positive if it is not due to a planet orbiting the KOI's target star. The CFP table contains all KOIs in the Exoplanet Archive cumulative KOI table. The purpose of the CFP table is to provide a list of certified false positive KOIs. A KOI is certified as a false positive when, in the judgement of the FPWG, there is no plausible planetary interpretation of the observational evidence, which we summarize by saying that the evidence for a false positive is compelling. This certification process involves detailed examination using all available data for each KOI, establishing a high-reliability ground truth set. The CFP table can be used to estimate the reliability of, for example, the KOI tables which are created using only Kepler photometric data, so the disposition of individual KOIs may differ in the KOI and CFP tables. Follow-up observers may find the CFP table useful to avoid observing false positives

Daily low-dose prednisolone to prevent relapse of steroid-sensitive nephrotic syndrome in children with an upper respiratory tract infection:PREDNOS2 RCT

BACKGROUND: Most children with steroid-sensitive nephrotic syndrome have relapses that are triggered by upper respiratory tract infections. Four small trials, mostly in children already taking maintenance corticosteroid in countries of different upper respiratory tract infection epidemiology, showed that giving daily low-dose prednisone/prednisolone for 5-7 days during an upper respiratory tract infection reduces the risk of relapse. OBJECTIVES: To determine if these findings were replicated in a large UK population of children with relapsing steroid-sensitive nephrotic syndrome on different background medication or none. DESIGN: A randomised double-blind placebo-controlled trial, including a cost-effectiveness analysis. SETTING: A total of 122 UK paediatric departments, of which 91 recruited patients. PARTICIPANTS: A total of 365 children with relapsing steroid-sensitive nephrotic syndrome (mean age 7.6 ± 3.5 years) were randomised (1 : 1) according to a minimisation algorithm based on background treatment. Eighty children completed 12 months of follow-up without an upper respiratory tract infection. Thirty-two children were withdrawn from the trial (14 prior to an upper respiratory tract infection), leaving a modified intention-to-treat analysis population of 271 children (134 and 137 children in the prednisolone and placebo arms, respectively). INTERVENTIONS: At the start of an upper respiratory tract infection, children received 6 days of prednisolone (15 mg/m2) or an equivalent dose of placebo. MAIN OUTCOME MEASURES: The primary outcome was the incidence of first upper respiratory tract infection-related relapse following any upper respiratory tract infection over 12 months. The secondary outcomes were the overall rate of relapse, changes in background treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, change in Achenbach Child Behaviour Checklist score and quality of life. Analysis was by intention-to-treat principle. The cost-effectiveness analysis used trial data and a decision-analytic model to estimate quality-adjusted life-years and costs at 1 year, which were then extrapolated over 16 years. RESULTS: There were 384 upper respiratory tract infections and 82 upper respiratory tract infection-related relapses in the prednisolone arm, and 407 upper respiratory tract infections and 82 upper respiratory tract infection-related relapses in the placebo arm. The number of patients experiencing an upper respiratory tract infection-related relapse was 56 (42.7%) and 58 (44.3%) in the prednisolone and placebo arms, respectively (adjusted risk difference -0.024, 95% confidence interval -0.14 to 0.09; p = 0.70). There was no evidence that the treatment effect differed when data were analysed according to background treatment. There were no significant differences in secondary outcomes between treatment arms. Giving daily prednisolone at the time of an upper respiratory tract infection was associated with increased quality-adjusted life-years (0.9427 vs. 0.9424) and decreased average costs (£252 vs. £254), when compared with standard care. The cost saving was driven by background therapy and hospitalisations after relapse. The finding was robust to sensitivity analysis. LIMITATIONS: A larger number of children than expected did not have an upper respiratory tract infection and the sample size attrition rate was adjusted accordingly during the trial. CONCLUSIONS: The clinical analysis indicated that giving 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of steroid-sensitive nephrotic syndrome in UK children. However, there was an economic benefit from costs associated with background therapy and relapse, and the health-related quality-of-life impact of having a relapse. FUTURE WORK: Further work is needed to investigate the clinical and health economic impact of relapses, interethnic differences in treatment response, the effect of different corticosteroid regimens in treating relapses, and the pathogenesis of individual viral infections and their effect on steroid-sensitive nephrotic syndrome. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10900733 and EudraCT 2012-003476-39. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 3. See the NIHR Journals Library website for further project information

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest