An epigenetic role for noncoding RNAs and intragenic DNA methylation

A report on the Keystone Symposium 'Epigenetics: Regulation of Chromatin Structure in Development and Disease', Breckenridge, USA, 11-16 April 2007

Multiple motor memories are learned to control different points on a tool.

Skillful object manipulation requires learning the dynamics of objects, linking applied force to motion 1 ,2 . This involves the formation of a motor memory 3 ,4 , which has been assumed to be associated with the object, independent of the point on the object that one chooses to control. Importantly, in manipulation tasks, different control points on an object, such as the rim of a cup when drinking or its base when setting it down, can be associated with distinct dynamics. Here we show that opposing dynamic perturbations, which interfere when controlling a single location on an object, can be learned when each is associated with a separate control point. This demonstrates that motor memory formation is linked to control points on the object, rather than the object per se . We also show that the motor system only generates separate memories for different control points if they are linked to different dynamics, allowing efficient use of motor memory. To account for these results, we develop a normative switching state-space model of motor learning, in which the association between cues (control points) and contexts (dynamics) is learned rather than fixed. Our findings uncover an important mechanism through which the motor system generates flexible and dexterous behavior

Motor memories of object dynamics are categorically organized.

The ability to predict the dynamics of objects, linking applied force to motion, underlies our capacity to perform many of the tasks we carry out on a daily basis. Thus, a fundamental question is how the dynamics of the myriad objects we interact with are organized in memory. Using a custom-built three-dimensional robotic interface that allowed us to simulate objects of varying appearance and weight, we examined how participants learned the weights of sets of objects that they repeatedly lifted. We find strong support for the novel hypothesis that motor memories of object dynamics are organized categorically, in terms of families, based on covariation in their visual and mechanical properties. A striking prediction of this hypothesis, supported by our findings and not predicted by standard associative map models, is that outlier objects with weights that deviate from the family-predicted weight will never be learned despite causing repeated lifting errors

Association between purchase of over-the-counter medications and ovarian cancer diagnosis in the Cancer Loyalty Card Study (CLOCS):observational case-control study

BACKGROUND: Over-the-counter (OTC) medications are frequently used to self-care for nonspecific ovarian cancer symptoms prior to diagnosis. Monitoring such purchases may provide an opportunity for earlier diagnosis. OBJECTIVE: The aim of the Cancer Loyalty Card Study (CLOCS) was to investigate purchases of OTC pain and indigestion medications prior to ovarian cancer diagnosis in women with and without ovarian cancer in the United Kingdom using loyalty card data. METHODS: An observational case-control study was performed comparing purchases of OTC pain and indigestion medications prior to diagnosis in women with (n=153) and without (n=120) ovarian cancer using loyalty card data from two UK-based high street retailers. Monthly purchases of pain and indigestion medications for cases and controls were compared using the Fisher exact test, conditional logistic regression, and receiver operating characteristic (ROC) curve analysis. RESULTS: Pain and indigestion medication purchases were increased among cases 8 months before diagnosis, with maximum discrimination between cases and controls 8 months before diagnosis (Fisher exact odds ratio [OR] 2.9, 95% CI 2.1-4.1). An increase in indigestion medication purchases was detected up to 9 months before diagnosis (adjusted conditional logistic regression OR 1.38, 95% CI 1.04-1.83). The ROC analysis for indigestion medication purchases showed a maximum area under the curve (AUC) at 13 months before diagnosis (AUC=0.65, 95% CI 0.57-0.73), which further improved when stratified to late-stage ovarian cancer (AUC=0.68, 95% CI 0.59-0.78). CONCLUSIONS: There is a difference in purchases of pain and indigestion medications among women with and without ovarian cancer up to 8 months before diagnosis. Facilitating earlier presentation among those who self-care for symptoms using this novel data source could improve ovarian cancer patients' options for treatment and improve survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT03994653; https://clinicaltrials.gov/ct2/show/NCT03994653

Excitation of Kaluza-Klein gravitational mode

We investigate excitation of Kaluza-Klein modes due to the parametric resonance caused by oscillation of radius of compactification. We consider a gravitational perturbation around a D-dimensional spacetime, which we compactify on a (D-4)-sphere to obtain a 4-dimensional theory. The perturbation includes the so-called Kaluza-Klein modes, which are massive in 4-dimension, as well as zero modes, which is massless in 4-dimension. These modes appear as scalar, vector and second-rank symmetric tensor fields in the 4-dimensional theory. Since Kaluza-Klein modes are troublesome in cosmology, quanta of these Kaluza-Klein modes should not be excited abundantly. However, if radius of compactification oscillates, then masses of Kaluza-Klein modes also oscillate and, thus, parametric resonance of Kaluza-Klein modes may occur to excite their quanta. In this paper we consider part of Kaluza-Klein modes which correspond to massive scalar fields in 4-dimension and investigate whether quanta of these modes are excited or not in the so called narrow resonance regime of the parametric resonance. We conclude that at least in the narrow resonance regime quanta of these modes are not excited so catastrophically.Comment: 15 pages LaTeX, submitted to Phys.Rev.

Epigenetic memory in response to environmental stressors

Exposure to environmental stressors, toxicants, and nutrient deficiencies can affect DNA in several ways. Some exposures cause damage and alter the structure of DNA, but there is increasing evidence that the same or other environmental exposures, including those that occur during fetal development in utero, can cause epigenetic effects that modulate DNA function and gene expression. Some epigenetic changes to DNA that affect gene transcription are at least partially reversible (i.e., they can be enzymatically reversed after cessation of exposure to environmental agents), but some epigenetic modifications seem to persist, even for decades. To explain the effects of early life experiences (such as famine and exposures to other stressors) on the long-term persistence of specific patterns of epigenetic modifications, such as DNA methylation, we propose an analogy with immune memory. We propose that an epigenetic memory can be established and maintained in self-renewing stem cell compartments. We suggest that the observations on early life effects on adult diseases and the persistence of methylation changes in smokers support our hypothesis, for which a mechanistic basis, however, needs to be further clarified. We outline a new model based on methylation changes. Although these changes seem to be mainly adaptive, they are also implicated in the pathogenesis and onset of diseases, depending on individual genotypic background and types of subsequent exposures. Elucidating the relationships between the adaptive and maladaptive consequences of the epigenetic modifications that result from complex environmental exposures is a major challenge for current and future research in epigenetics.-Vineis, P., Chatziioannou, A., Cunliffe, V. T., Flanagan, J. M., Hanson, M., Kirsch-Volders, M., Kyrtopoulos, S. Epigenetic memory in response to environmental stressors

Separate motor memories are formed when controlling different implicitly specified locations on a tool.

Skillful manipulation requires forming and recalling memories of the dynamics of objects linking applied force to motion. It has been assumed that such memories are associated with entire objects. However, we often control different locations on an object, and these locations may be associated with different dynamics. We have previously demonstrated that multiple memories can be formed when participants are explicitly instructed to control different visual points marked on an object. A key question is whether this novel finding generalizes to more natural situations in which control points are implicitly defined by the task. To answer this question, we used objects with no explicit control points and tasks designed to encourage the use of distinct implicit control points. Participants moved a handle, attached to a robotic interface, to control the position of a rectangular object ("eraser") in the horizontal plane. Participants were required to move the eraser straight ahead to wipe away a column of dots ("dust"), located to either the left or right. We found that participants adapted to opposing dynamics when linked to the left and right dust locations, even though the movements required for these two contexts were the same. Control conditions showed this learning could not be accounted for by contextual cues or the fact that the task goal required moving in a straight line. These results suggest that people naturally control different locations on manipulated objects depending on the task context and that doing so affords the formation of separate motor memories. NEW & NOTEWORTHY Skilled manipulation requires forming motor memories of object dynamics, which have been assumed to be associated with entire objects. However, we recently demonstrated that people can form multiple memories when explicitly instructed to control different visual points on an object. In this article we show that this novel finding generalizes to more natural situations in which control points are implicitly defined by the task

The use of human papillomavirus DNA methylation in cervical intraepithelial neoplasia : A systematic review and meta-analysis

Background: Methylation of viral DNA has been proposed as a novel biomarker for triage of human papillomavirus (HPV) positive women at screening. This systematic review and meta-analysis aims to assess how methylation levels change with disease severity and to determine diagnostic test accuracy (DTA) in detecting high-grade cervical intra-epithelial neoplasia (CIN). Methods: We performed searches in MEDLINE, EMBASE and CENTRAL from inception to October 2019. Studies were eligible if they explored HPV methylation levels in HPV positive women. Data were extracted in duplicate and requested from authors where necessary. Random-effects models and a bivariate mixed-effects binary regression model were applied to determine pooled effect estimates. Findings: 44 studies with 8819 high-risk HPV positive women were eligible. The pooled estimates for positive methylation rate in HPV16 L1 gene were higher for high-grade CIN (>= CIN2/high-grade squamous intra-epithelial lesion (HSIL) (95% confidence interval (95%CI:72.7% (47 8-92.2))) vs. low-grade CIN (= CIN2/HSIL vs. = CIN2/HSIL vs. Interpretation: Higher HPV methylation is associated with increased disease severity, whilst HPV16 L1/L2 genes demonstrated high diagnostic accuracy to detect high-grade CIN in HPV16 positive women. Direct clinical use is limited by the need for a multi-genotype and standardised assays. Next-generation multiplex HPV sequencing assays are under development and allow potential for rapid, automated and low-cost methylation testing. (C) 2019 The Authors. Published by Elsevier B.V.Peer reviewe