Boosting Long-term Memory via Wakeful Rest: Intentional Rehearsal is not Necessary, Automatic Consolidation is Sufficient.

<div><p>People perform better on tests of delayed free recall if learning is followed immediately by a short wakeful rest than by a short period of sensory stimulation. Animal and human work suggests that wakeful resting provides optimal conditions for the consolidation of recently acquired memories. However, an alternative account cannot be ruled out, namely that wakeful resting provides optimal conditions for intentional rehearsal of recently acquired memories, thus driving superior memory. Here we utilised non-recallable words to examine whether wakeful rest boosts long-term memory, even when new memories could not be rehearsed intentionally during the wakeful rest delay. The probing of non-recallable words requires a recognition paradigm. Therefore, we first established, via Experiment 1, that the rest-induced boost in memory observed via free recall can be replicated in a recognition paradigm, using concrete nouns. In Experiment 2, participants heard 30 non-recallable non-words, presented as ‘foreign names in a bridge club abroad’ and then either rested wakefully or played a visual spot-the-difference game for 10 minutes. Retention was probed via recognition at two time points, 15 minutes and 7 days after presentation. As in Experiment 1, wakeful rest boosted recognition significantly, and this boost was maintained for at least 7 days. Our results indicate that the enhancement of memory via wakeful rest is <i>not</i> dependent upon intentional rehearsal of learned material during the rest period. We thus conclude that consolidation is <i>sufficient</i> for this rest-induced memory boost to emerge. We propose that wakeful resting allows for superior memory consolidation, resulting in stronger and/or more veridical representations of experienced events which can be detected via tests of free recall and recognition.</p></div

Anxiety Detection Leveraging Mobile Passive Sensing

Anxiety disorders are the most common class of psychiatric problems affecting both children and adults. However, tools to effectively monitor and manage anxiety are lacking, and comparatively limited research has been applied to addressing the unique challenges around anxiety. Leveraging passive and unobtrusive data collection from smartphones could be a viable alternative to classical methods, allowing for real-time mental health surveillance and disease management. This paper presents eWellness, an experimental mobile application designed to track a full-suite of sensor and user-log data off an individual's device in a continuous and passive manner. We report on an initial pilot study tracking ten people over the course of a month that showed a nearly 76% success rate at predicting daily anxiety and depression levels based solely on the passively monitored features

Enhanced mitochondrial genome analysis: bioinformatic and long-read sequencing advances and their diagnostic implications

Introduction: Primary mitochondrial diseases (PMDs) comprise a large and heterogeneous group of genetic diseases that result from pathogenic variants in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Widespread adoption of next-generation sequencing (NGS) has improved the efficiency and accuracy of mtDNA diagnoses; however, several challenges remain. Areas covered: In this review, we briefly summarize the current state of the art in molecular diagnostics for mtDNA and consider the implications of improved whole genome sequencing (WGS), bioinformatic techniques, and the adoption of long-read sequencing, for PMD diagnostics. Expert opinion: We anticipate that the application of PCR-free WGS from blood DNA will increase in diagnostic laboratories, while for adults with myopathic presentations, WGS from muscle DNA may become more widespread. Improved bioinformatic strategies will enhance WGS data interrogation, with more accurate delineation of mtDNA and NUMTs (nuclear mitochondrial DNA segments) in WGS data, superior coverage uniformity, indirect measurement of mtDNA copy number, and more accurate interpretation of heteroplasmic large-scale rearrangements (LSRs). Separately, the adoption of diagnostic long-read sequencing could offer greater resolution of complex LSRs and the opportunity to phase heteroplasmic variants

Identification of patients for clinical risk assessment by prediction of cardiovascular risk using default risk factor values

Abstract Background To identify high risk patients without cardiovascular disease requires assessment of risk factors. Primary care providers must therefore determine which patients without cardiovascular disease should be highest priority for cardiovascular risk assessment. One approach is to prioritise patients for assessment using a prior estimate of their cardiovascular risk. This prior estimate of cardiovascular risk is derived from risk factor data that are routinely held in electronic medical records, with unknown blood pressure and cholesterol levels replaced by default values derived from national survey data. This paper analyses the test characteristics of using such a strategy for identification of high risk patients. Methods Prior estimates of Framingham cardiovascular risk were derived in a population obtained from the Health Survey for England 2003. Receiver operating characteristics curves were constructed for using a prior estimate of cardiovascular risk to identify patients at greater than 20% ten-year cardiovascular risk. This was compared to strategies using age, or diabetic and antihypertensive treatment status to identify high risk patients. Results The area under the curve for a prior estimate of cardiovascular risk calculated using minimum data (0.933, 95% CI: 0.925 to 0.941) is significantly greater than for a selection strategy based on age (0.892, 95% CI: 0.882 to 0.902), or diabetic and hypertensive status (0.608, 95% CI: 0.584 to 0.632). Conclusion Using routine data held on primary care databases it is possible to identify a population at high risk of cardiovascular disease. Information technology to help primary care prioritise patients for cardiovascular disease prevention may improve the efficiency of cardiovascular risk assessment.</p

P-rex1 cooperates with PDGFRβ to drive cellular migration in 3D microenvironments

Expression of the Rac-guanine nucleotide exchange factor (RacGEF), P-Rex1 is a key determinant of progression to metastasis in a number of human cancers. In accordance with this proposed role in cancer cell invasion and metastasis, we find that ectopic expression of P-Rex1 in an immortalised human fibroblast cell line is sufficient to drive multiple migratory and invasive phenotypes. The invasive phenotype is greatly enhanced by the presence of a gradient of serum or platelet-derived growth factor, and is dependent upon the expression of functional PDGF receptor β. Consistently, the invasiveness of WM852 melanoma cells, which endogenously express P-Rex1 and PDGFRβ, is opposed by siRNA of either of these proteins. Furthermore, the current model of P-Rex1 activation is advanced through demonstration of P-Rex1 and PDGFRβ as components of the same macromolecular complex. These data suggest that P-Rex1 has an influence on physiological migratory processes, such as invasion of cancer cells, both through effects upon classical Rac1-driven motility and a novel association with RTK signalling complexes

Genome Wide Transcriptome Analysis of Dendritic Cells Identifies Genes with Altered Expression in Psoriasis

Activation of dendritic cells by different pathogens induces the secretion of proinflammatory mediators resulting in local inflammation. Importantly, innate immunity must be properly controlled, as its continuous activation leads to the development of chronic inflammatory diseases such as psoriasis. Lipopolysaccharide (LPS) or peptidoglycan (PGN) induced tolerance, a phenomenon of transient unresponsiveness of cells to repeated or prolonged stimulation, proved valuable model for the study of chronic inflammation. Thus, the aim of this study was the identification of the transcriptional diversity of primary human immature dendritic cells (iDCs) upon PGN induced tolerance. Using SAGESeq approach, a tag-based transcriptome sequencing method, we investigated gene expression changes of primary human iDCs upon stimulation or restimulation with Staphylococcus aureus derived PGN, a widely used TLR2 ligand. Based on the expression pattern of the altered genes, we identified non-tolerizeable and tolerizeable genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (Kegg) analysis showed marked enrichment of immune-, cell cycle- and apoptosis related genes. In parallel to the marked induction of proinflammatory mediators, negative feedback regulators of innate immunity, such as TNFAIP3, TNFAIP8, Tyro3 and Mer are markedly downregulated in tolerant cells. We also demonstrate, that the expression pattern of TNFAIP3 and TNFAIP8 is altered in both lesional, and non-lesional skin of psoriatic patients. Finally, we show that pretreatment of immature dendritic cells with anti-TNF-α inhibits the expression of IL-6 and CCL1 in tolerant iDCs and partially releases the suppression of TNFAIP8. Our findings suggest that after PGN stimulation/restimulation the host cell utilizes different mechanisms in order to maintain critical balance between inflammation and tolerance. Importantly, the transcriptome sequencing of stimulated/restimulated iDCs identified numerous genes with altered expression to date not associated with role in chronic inflammation, underlying the relevance of our in vitro model for further characterization of IFNprimed iDCs

Autosomal dominant optic atrophy and cataract “plus” phenotype including axonal neuropathy

Objective To characterize the phenotype in individuals with OPA3-related autosomal dominant optic atrophy and cataract (ADOAC) and peripheral neuropathy (PN). Methods Two probands with multiple affected relatives and one sporadic case were referred for evaluation of a PN. Their phenotype was determined by clinical ± neurophysiological assessment. Neuropathologic examination of sural nerve and skeletal muscle, and ultrastructural analysis of mitochondria in fibroblasts were performed in one case. Exome sequencing was performed in the probands. Results The main clinical features in one family (n = 7 affected individuals) and one sporadic case were early-onset cataracts (n = 7), symptoms of gastrointestinal dysmotility (n = 8), and possible/confirmed PN (n = 7). Impaired vision was an early-onset feature in another family (n = 4 affected individuals), in which 3 members had symptoms of gastrointestinal dysmotility and 2 developed PN and cataracts. The less common features among all individuals included symptoms/signs of autonomic dysfunction (n = 3), hearing loss (n = 3), and recurrent pancreatitis (n = 1). In 5 individuals, the neuropathy was axonal and clinically asymptomatic (n = 1), sensory-predominant (n = 2), or motor and sensory (n = 2). In one patient, nerve biopsy revealed a loss of large and small myelinated fibers. In fibroblasts, mitochondria were frequently enlarged with slightly fragmented cristae. The exome sequencing identified OPA3 variants in all probands: a novel variant (c.23T>C) and the known mutation (c.313C>G) in OPA3. Conclusions A syndromic form of ADOAC (ADOAC+), in which axonal neuropathy may be a major feature, is described. OPA3 mutations should be included in the differential diagnosis of complex inherited PN, even in the absence of clinically apparent optic atrophy

A combinatorial TIR1/AFB–Aux/IAA co-receptor system for differential sensing of auxin

The plant hormone auxin regulates virtually every aspect of plant growth and development. Auxin acts by binding the F-box protein transport inhibitor response 1 (TIR1) and promotes the degradation of the AUXIN/INDOLE-3-ACETIC ACID (Aux/IAA) transcriptional repressors. Here we show that efficient auxin binding requires assembly of an auxin co-receptor complex consisting of TIR1 and an Aux/IAA protein. Heterologous experiments in yeast and quantitative IAA binding assays using purified proteins showed that different combinations of TIR1 and Aux/IAA proteins form co-receptor complexes with a wide range of auxin-binding affinities. Auxin affinity seems to be largely determined by the Aux/IAA. As there are 6 TIR1/AUXIN SIGNALING F-BOX proteins (AFBs) and 29 Aux/IAA proteins in Arabidopsis thaliana, combinatorial interactions may result in many co-receptors with distinct auxin-sensing properties. We also demonstrate that the AFB5–Aux/IAA co-receptor selectively binds the auxinic herbicide picloram. This co-receptor system broadens the effective concentration range of the hormone and may contribute to the complexity of auxin response