Division of labour between PP2A-B56 isoforms at the centromere and kinetochore

PP2A-B56 is a serine/threonine phosphatase complex that regulates several major mitotic processes, including sister chromatid cohesion, kinetochore-microtubule attachment and the spindle assembly checkpoint. We show here that these key functions are divided between different B56 isoforms that localise to either the centromere or kinetochore. The centromeric isoforms rely on a specific interaction with Sgo2, whereas the kinetochore isoforms bind preferentially to BubR1 and other proteins containing an LxxIxE motif. In addition to these selective binding partners, Sgo1 helps to anchor PP2A-B56 at both locations: it collaborates with BubR1 to maintain B56 at the kinetochore and it helps to preserve the Sgo2/B56 complex at the centromere. A series of chimaeras were generated to map the critical region in B56 down to a small C-terminal loop that regulates the key interactions and defines B56 localisation. Together, this study describes how different PP2A-B56 complexes utilise isoform-specific interactions to control distinct processes during mitosis

USP9X limits mitotic checkpoint complex turnover to strengthen the spindle assembly checkpoint and guard against chromosomal instability

Faithful chromosome segregation during mitosis depends on the spindle assembly checkpoint (SAC), which delays progression through mitosis until every chromosome has stably attached to spindle microtubules via the kinetochore. We show here that the deubiquitinase USP9X strengthens the SAC by antagonizing the turnover of the mitotic checkpoint complex produced at unattached kinetochores. USP9X thereby opposes activation of anaphase-promoting complex/cyclosome (APC/C) and specifically inhibits the mitotic degradation of SAC-controlled APC/C substrates. We demonstrate that depletion or loss of USP9X reduces the effectiveness of the SAC, elevates chromosome segregation defects, and enhances chromosomal instability (CIN). These findings provide a rationale to explain why loss of USP9X could be either pro- or anti-tumorigenic depending on the existing level of CIN. Skowyra et al. show the deubiquitinase USP9X limits activation of the ubiquitin ligase APC/C during mitosis. Loss of USP9X causes chromosomal instability (CIN), which can promote cancer. This work also provides a rationale for targeting USP9X when it is expressed in cancer cells with high levels of CIN

Host-linked soil viral ecology along a permafrost thaw gradient

Climate change threatens to release abundant carbon that is sequestered at high latitudes, but the constraints on microbial metabolisms that mediate the release of methane and carbon dioxide are poorly understood1,2,3,4,5,6,7. The role of viruses, which are known to affect microbial dynamics, metabolism and biogeochemistry in the oceans8,9,10, remains largely unexplored in soil. Here, we aimed to investigate how viruses influence microbial ecology and carbon metabolism in peatland soils along a permafrost thaw gradient in Sweden. We recovered 1,907 viral populations (genomes and large genome fragments) from 197 bulk soil and size-fractionated metagenomes, 58% of which were detected in metatranscriptomes and presumed to be active. In silico predictions linked 35% of the viruses to microbial host populations, highlighting likely viral predators of key carbon-cycling microorganisms, including methanogens and methanotrophs. Lineage-specific virus/host ratios varied, suggesting that viral infection dynamics may differentially impact microbial responses to a changing climate. Virus-encoded glycoside hydrolases, including an endomannanase with confirmed functional activity, indicated that viruses influence complex carbon degradation and that viral abundances were significant predictors of methane dynamics. These findings suggest that viruses may impact ecosystem function in climate-critical, terrestrial habitats and identify multiple potential viral contributions to soil carbon cycling

The prevalence of malnutrition (MUST and MNA-SF), frailty and physical disability and relationship with mortality in older care home residents

Background & Aims: Currently, there is lack of universal consensus on the use of effective malnutrition screening tools. Although malnutrition, frailty and physical disability are interrelated and associated with mortality in older people, there is a paucity of research in care home settings. With a high co-prevalence of these conditions, understanding their interconnectedness can provide a holistic view of an older person's health condition. The purpose of this study was to examine the prevalence of malnutrition (and risk) frailty and physical disability among care home residents using different methods, as well as the associations between markers of malnutrition (MUST and MNA-SF), physical function (Barthel Index, BI), frailty (Edmonton Frailty Scale, EFS), and all-cause mortality in care home residents.// Methods: In Lincoln, UK, 508 residents from care homes underwent screening for malnutrition (MNA-SF and MUST), frailty (EFS), and physical function (BI) as part of standard comprehensive geriatric assessment (CGA) between November 2015 and January 2018. Prevalence of conditions were assessed and MNA-SF, MUST, EFS, and BI-specific survival in each category were compared using Kaplan-Meier survival analysis (KMSA) with log-rank test. Multivariable analyses were conducted using the Cox proportional hazard model to identify prognostic factors that were statistically significant in care home residents.// Results: There was significant discordance between malnutrition risk measured by MUST and MNA-SF. The percentage of patients ‘at risk’/‘medium risk’ and ‘malnourished’/‘high risk’ was 25.3%/49.9% for MNA and for 19.6%/31.57% for MUST. The prevalence of frailty measured by EFS was high with the percentage of residents with severe frailty being 70.9%. Only 8.6% of patients were functionally independent. The association between malnutrition risk (MUST) and mortality was not significant. MNA-SF appeared to be a better tool at predicting mortality in older care home residents (p < 0.001). Furthermore, the association between frailty (EFS) and mortality was significant (p < 0.01).// Conclusions: This study found high levels of malnutrition, frailty, and disability among UK care home residents, and a discordance between MUST and MNA-SF scoring patterns. The MNA-SF and EFS were better predictors of mortality than MUST and BI, highlighting the need for sensitive tools in assessing malnutrition and frailty risks in this population

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Bilingualism: The foreign language effect does not extend to rational decision making

This research investigated if the foreign language effect extended to rationality. Four groups (English speaking monolingual group; Polish speaking monolingual group; Bilingual Polish group who were presented with decision task in English; Bilingual Polish group who were presented with decision task in Polish) completed a series of decision scenarios. The results highlighted that: 1) bilingual individuals did not display more rationality in general (or in specific decision scenarios); 2) the presentation of a decision in a non-native language did not aid rational decision making in bilinguals. The paper suggests that the foreign language effect may not increase the chances of bilingual individuals being more rational decision makers in general, but may promote more rational behaviour in specific decision contexts

Evidence on the reach and impact of the social physical activity phenomenon parkrun : a scoping review

The aim of this study was to conduct a scoping review of parkrun literature for evidence of its reach, health impact and appeal whilst identifying gaps for future research. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR). Six databases were searched according to search terms set a priori. Empirical studies of any design were included if they provided data on participation in, or benefits of, parkrun and were in English. Two authors conducted the searches independently and screened results by title and abstract, followed by full text reviews. A total of 235 records were screened and 15 studies were eligible; 12 were conducted in the UK and three in Australia. Seven were qualitative interview studies, six were quantitative, and two used mixed methods. parkrun reaches groups traditionally underrepresented in other organised sports or physical activity such as women, the insufficiently active and those aged over 35 years. Participants showed sustained improvements in fitness, physical activity levels, and body mass index with a dose–response effect with participation frequency. Qualitative data shows parkrun's location in pleasant environments with opportunities for informal social interaction engages priority groups such as individuals with mental health issues, women and children. The small evidence base suggests parkrun has good reach, and can positively impact participants’ health and wellbeing. The data, however, are currently UK-centric and gaps in research on non-participants, long term health impacts and operationally relevant factors should be addressed

A chemical-genetic system to rapidly inhibit the PP2A-B56 phosphatase reveals a role at metaphase kinetochores

Serine-threonine phosphatases have been challenging to study because of the lack of specific inhibitors. Their catalytic domains are druggable, but these are shared or very similar between individual phosphatase complexes, precluding their specific inhibition. Instead, phosphatase complexes often achieve specificity by interacting with short linear motifs (SLiMs) in substrates or their binding partners. We develop here a chemical-genetic system to rapidly inhibit these interactions within the PP2A-B56 family. Drug-inducible recruitment of ectopic SLiMs (“directSLiMs”) is used to rapidly block the SLiM-binding pocket on the B56 regulatory subunit, thereby displacing endogenous interactors and inhibiting PP2A-B56 activity within seconds. We use this system to characterise PP2A-B56 substrates during mitosis and to identify a role for PP2A-B56 in allowing metaphase kinetochores to properly sense tension and maintain microtubule attachments. The directSLiMs approach can be used to inhibit any other phosphatase, enzyme or protein that uses a critical SLiM-binding interface, providing a powerful strategy to inhibit and characterise proteins once considered “undruggable”.</p

Appetite, food intake, and gut hormone responses to glycomacropeptide protein ingestion in older adults: : A feasibility, acceptability, and pilot study

We would like express huge gratitude to our participants for taking part, and for making data collection such an enjoyable experience for the research team. We would like to thank our students Vicky Catterall, Beth Minion, Joe Ashworth, Monty Hardcastle, and Anna Brooks for supporting data collection. We also thank Agropur Ingredients (Eden Prairie, MN, USA) for providing GMP.Peer reviewe

Investigating the prevalence of malnutrition, frailty and physical disability and the association between them amongst older care home residents

BACKGROUND: Malnutrition, frailty and physical disability are inter-related, more prevalent in the older population and increase the risk of adverse health outcomes. Thus, screening is essential, especially in the understudied care home setting where the population is vulnerable and at higher risk of malnutrition. Furthermore, prevalence may vary depending upon screening tools used. The aims of this study were to: 1) investigate the prevalence of 1) malnutrition risk using Mini Nutritional Assessment - Short Form (MNA-SF) and Malnutrition Universal Screening Tool (MUST), 2) frailty using the Edmonton Frailty Scale (EFS), 3) physical disability using the Barthel Index (BI) and (4) examine the association between variables and coexistence of states. METHODS: Screening for malnutrition (MNA-SF and MUST) and frailty (EFS) was performed as part of a comprehensive geriatric assessment (CGA) in 527 residents from 17 care homes in Lincoln, UK. Mean age of the group was 85.6 ± 7.6 years and body mass index, BMI 23.0 ± 5.1 kg/m2. RESULTS: A high prevalence of malnutrition risk was detected: 41.4% by MNA-SF and 25.5% by MUST (high risk/malnourished). Furthermore, there was a clear discordance between MNA-SF and MUST scoring of malnutrition; for example, the percentage of those identified as being at low risk was 18.8% using the MNA-SF and 57.0% using the MUST. In addition, there was a high prevalence of severe frailty by EFS (69.6%) and functional impairment by BI (62.0%). There was good association between some variables (P < 0.001) and 33.4% of residents had coexistence of all three states of malnutrition, frailty and physical disability. CONCLUSIONS: Malnutrition risk, frailty and physical disability are highly prevalent in care home residents and interrelated. However, prevalence varies depending on the screening tool used. More research should be conducted in the care home setting to improve daily clinical practice as screening may impact upon subsequent treatment and care modalities and clinical outcomes