Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition

Protein phosphatase 2A (PP2A) holoenzymes target broad substrates by recognizing short motifs via regulatory subunits. PP2A methylesterase 1 (PME-1) is a cancer-promoting enzyme and undergoes methylesterase activation upon binding to the PP2A core enzyme. Here, we showed that PME-1 readily demethylates different families of PP2A holoenzymes and blocks substrate recognition in vitro. The high-resolution cryoelectron microscopy structure of a PP2A-B56 holoenzyme–PME-1 complex reveals that PME-1 disordered regions, including a substrate-mimicking motif, tether to the B56 regulatory subunit at remote sites. They occupy the holoenzyme substrate-binding groove and allow large structural shifts in both holoenzyme and PME-1 to enable multipartite contacts at structured cores to activate the methylesterase. B56 interface mutations selectively block PME-1 activity toward PP2A-B56 holoenzymes and affect the methylation of a fraction of total cellular PP2A. The B56 interface mutations allow us to uncover B56-specific PME-1 functions in p53 signaling. Our studies reveal multiple mechanisms of PME-1 in suppressing holoenzyme functions and versatile PME-1 activities derived from coupling substrate-mimicking motifs to dynamic structured cores

Relationships between paranoid thinking, self-esteem and the menstrual cycle.

This study aimed to investigate whether paranoid experiences and levels of self-esteem fluctuate over the menstrual cycle and whether levels of self-esteem are lower when perceived persecution is felt to be deserved. Measures of anxiety, depression, persecution, deservedness and self-esteem were completed on-line by 278 women over their menstrual cycle. Responses were compared at the paramenstrual (3 days before and after menses onset) and mid-cycle phase. At the paramenstrual phase persecution, negative self-esteem, anxiety and depression were higher and positive self-esteem was lower than at mid-cycle. A greater proportion of women experienced persecution as deserved at the paramenstrual phase. This was associated with higher depression and negative self-esteem scores. Increased levels of deservedness significantly strengthened the relationship between persecution and negative, but not positive, self-esteem. These findings suggest that the paramenstrual phase is a time of vulnerability to increased paranoid experiences, an increased likelihood that feelings of persecution will feel deserved and lowered self-esteem. The findings support the view that interpersonal sensitivities may be key to menstrual cycle symptoms and have an impact on relationships. Further, the study illustrated that ideas developed for psychosis could make a valuable contribution to understanding and managing this aspect of menstruation-related distress

Consensus standards of healthcare for adults and children with inflammatory bowel disease in the UK

Objective Symptoms and clinical course during inflammatory bowel disease (IBD) vary among individuals. Personalised care is therefore essential to effective management, delivered by a strong patient-centred multidisciplinary team, working within a well-designed service. This study aimed to fully rewrite the UK Standards for the healthcare of adults and children with IBD, and to develop an IBD Service Benchmarking Tool to support current and future personalised care models. Design Led by IBD UK, a national multidisciplinary alliance of patients and nominated representatives from all major stakeholders in IBD care, Standards requirements were defined by survey data collated from 689 patients and 151 healthcare professionals. Standards were drafted and refined over three rounds of modified electronic-Delphi. Results Consensus was achieved for 59 Standards covering seven clinical domains; (1) design and delivery of the multidisciplinary IBD service; (2) prediagnostic referral pathways, protocols and timeframes; (3) holistic care of the newly diagnosed patient; (4) flare management to support patient empowerment, self-management and access to specialists where required; (5) surgery including appropriate expertise, preoperative information, psychological support and postoperative care; (6) inpatient medical care delivery (7) and ongoing long-term care in the outpatient department and primary care setting including shared care. Using these patient-centred Standards and informed by the IBD Quality Improvement Project (IBDQIP), this paper presents a national benchmarking framework. Conclusions The Standards and Benchmarking Tool provide a framework for healthcare providers and patients to rate the quality of their service. This will recognise excellent care, and promote quality improvement, audit and service development in IBD

Investigating the use of 3-D full-waveform inversion to characterize the host rock at a geological disposal site

The U.K. government has a policy to dispose of higher activity radioactive waste in a geological disposal facility (GDF), which will have multiple protective barriers to keep the waste isolated and to ensure no harmful quantities of radioactivity are able to reach the surface. Currently no specific GDF site in the United Kingdom has been chosen but, once it has, the site is likely to be investigated using seismic methods. In this study, we explore whether 3-D full-waveform inversion (FWI) of seismic data can be used to map changes in physical properties caused by the construction of the site, specifically tunnel-induced fracturing. We have built a synthetic model for a GDF located in granite at 1000 m depth below the surface, since granite is one of the candidate host rocks due to its high strength and low permeability and the GDF could be located at such a depth. We use an effective medium model to predict changes in P-wave velocity associated with tunnel-induced fracturing, within the spatial limits of an excavated disturbed zone (EdZ), modelled here as an increase in fracture density around the tunnel. We then generate synthetic seismic data using a number of different experimental geometries to investigate how they affect the performance of FWI in recovering subsurface P-wave velocity structure. We find that the location and velocity of the EdZ are recovered well, especially when data recorded on tunnel receivers are included in the inversion. Our findings show that 3-D FWI could be a useful tool for characterizing the subsurface and changes in fracture properties caused during construction, and make a suite of suggestions on how to proceed once a potential GDF site has been identified and the geological setting is known

A systematic review of self-report measures of paranoia

Paranoia can be conceptualized as consisting of a hierarchy of cognitions, ranging from commonly experienced thoughts about less severe perceived threats, up to less common, persecutory thoughts about extreme threats, which are associated with distressing psychosis. This review systematically appraises self-report paranoia questionnaires validated for use among the general population; the type of paranoia assessed, measurement or psychometric properties, and subsequent validation with clinical samples are all considered. A systematic literature search was performed using PubMed, Web of Science, and PsycINFO databases. Study methodologies and measurement properties were evaluated according to COnsenus-based Standards for the selection of health-based Measurement Instruments (Mokkink et al., 2012). Twenty-six studies, describing the validation of nine paranoia-related questionnaires, were identified. Questionnaires were reviewed in relation to the hierarchy of paranoia; with 2 questionnaires assessing “low-level” paranoia, 4 assessing persecutory thoughts, and the remainder assessing paranoia across this continua. Questionnaires assessing the full hierarchy of paranoid thoughts, alongside associated dimensions such as preoccupation, conviction, and distress, offer the most comprehensive assessment of paranoia in both nonclinical and clinical populations. Of the measures which do this, the Green et al. (2008) Paranoid Thoughts Scale had the strongest evidence for its measurement properties and is, therefore, recommended as the most reliable and valid self-report assessment of paranoia currently available. However, this review illustrated that generally paranoia questionnaires lack high quality evidence for their measurement properties. Implications of these findings for clinical practice and research are discussed

Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition

Protein phosphatase 2A (PP2A) holoenzymes target broad substrates by recognizing short motifs via regulatory subunits. PP2A methylesterase 1 (PME-1) is a cancer-promoting enzyme and undergoes methylesterase activation upon binding to the PP2A core enzyme. Here, we showed that PME-1 readily demethylates different families of PP2A holoenzymes and blocks substrate recognition in vitro. The high-resolution cryoelectron microscopy structure of a PP2A-B56 holoenzyme-PME-1 complex reveals that PME-1 disordered regions, including a substrate-mimicking motif, tether to the B56 regulatory subunit at remote sites. They occupy the holoenzyme substratebinding groove and allow large structural shifts in both holoenzyme and PME-1 to enable multipartite contacts at structured cores to activate the methylesterase. B56 interface mutations selectively block PME-1 activity toward PP2A-B56 holoenzymes and affect the methylation of a fraction of total cellular PP2A. The B56 interface mutations allow us to uncover B56-specific PME-1 functions in p53 signaling. Our studies reveal multiple mechanisms of PME-1 in suppressing holoenzyme functions and versatile PME-1 activities derived from coupling substrate-mimicking motifs to dynamic structured cores