Biology subjects

Sampson, E.

Publications and source records attributed to Sampson, E..

4 recordsLinked to original sources

bioRxiv2023

The protein phosphatase PPKL is a key regulator of daughter parasite development in Toxoplasma gondii

Apicomplexan parasites, including Toxoplasma gondii, encode many plant-like proteins, which play significant roles and present attractive targets for drug development. In this study, we have characterized the plant-like protein phosphatase PPKL, which is unique to the parasite and absent in its mammalian host. We have shown that its localization changes as the parasite divides. In non-dividing parasites, it is present in the cytoplasm, nucleus, and preconoidal region. As the parasite begins division, PPKL is enriched in the preconoidal region and the cortical cytoskeleton of the nascent parasites. Later in the division, PPKL is present in the basal complex ring. Conditional knockdown of PPKL showed that it is essential for parasite propagation. Moreover, parasites lacking PPKL exhibit uncoupling of division, with normal DNA duplication but severe defects in forming daughter parasites. While PPKL depletion does not impair the duplication of centrosomes, it affects the rigidity and arrangement of the cortical microtubules. Both Co-Immunoprecipitation and proximity labeling identified the kinase DYRK1 as a potential functional partner of PPKL. Complete knockout of DYRK1 phenocopies lack of PPKL, strongly suggesting a functional relationship between these two signaling proteins. Global phosphoproteomics analysis revealed a significant increase in phosphorylation of the microtubule-associated proteins SPM1 in PPKL-depleted parasites, suggesting PPKL regulates the cortical microtubules by mediating the phosphorylation state of SPM1. More importantly, the phosphorylation of cell cycle-associated kinase Crk1, a known regulator of daughter cell assembly, is altered in PPKL-depleted parasites. Thus, we propose that PPKL regulates daughter parasite development by influencing the Crk1-dependent signaling pathway. ImportanceToxoplasma gondii can cause severe disease in immunocompromised or immunosuppressed patients and during congenital infections. Treating toxoplasmosis presents enormous challenges since the parasite shares many biological processes with its mammalian hosts, which results in significant side effects with current therapies. Consequently, proteins that are essential and unique to the parasite represent favorable targets for drug development. Interestingly, Toxoplasma, like other members of the phylum Apicomplexa, has numerous plant-like proteins, many of which play crucial roles and do not have equivalents in the mammalian host. In this study, we found that the plant-like protein phosphatase, PPKL, appears to be a key regulator of daughter parasite development. With the depletion of PPKL, the parasite shows severe defects in forming daughter parasites. This study provides novel insights into the understanding of parasite division and offers a new potential target for the development of antiparasitic drugs.

cell biology↗

bioRxiv2018

Key components of the delirium syndrome and mortality: greater impact of acute change and disorganised thinking in a prospective cohort study

BackgroundDelirium increases the risk of mortality during an acute hospital admission. Full syndromal delirium (FSD) is associated with greatest risk and subsyndromal delirium (SSD) is associated with intermediate risk, compared to patients with no delirium - suggesting a dose-response relationship. It is not clear how individual diagnostic symptoms of delirium influence the association with mortality. Our objectives were to measure the prevalence of FSD and SSD, and assess the effect that FSD, SSD and individual symptoms of delirium (from the Confusion Assessment Method-short version (s-CAM)) have on mortality rates.\n\nMethodsExploratory analysis of a prospective cohort (aged [≥] 70 years) with acute (unplanned) medical admission (4/6/2007-4/11/2007). The outcome was mortality (data censored 6/10/2011). The principal exposures were FSD and SSD compared to no delirium (as measured by the CAM), along with individual delirium symptoms on the CAM. Cox regression was used to estimate the impact FSD and SSD and individual CAM items had on mortality.\n\nResultsThe cohort (n=610) mean age was 83 (SD 7); 59% were female. On admission, 11% had FSD and 33% had SSD. Of the key diagnostic symptoms for delirium, 17% acute onset, 19% inattention, 17% disorganised thinking and 17% altered level of consciousness. Unadjusted analysis found FSD had an increased hazard ratio (HR) of 2.31 (95%CI 1.71, 3.12), for SSD the HR was 1.26 (1.00, 1.59). Adjusted analysis remained significant for FSD (1.55 95%CI 1.10, 2.18) but nonsignificant for SSD (HR=0.92 95% CI 0.70, 1.19). Two CAM items were significantly associated with mortality following adjustment: acute onset and disorganised thinking.\n\nConclusionWe observed a dose-response relationship between mortality and delirium, FSD had the greatest risk and SSD having intermediate risk. The CAM items \"acute onset\" and \"disorganised thinking\" drove the associations observed. Clinically, this highlights the necessity of identifying individual symptoms of delirium.

epidemiology↗

bioRxiv2018

The Delirium and Population Health Informatics Cohort study protocol: ascertaining the determinants and outcomes from delirium in a whole population.

BackgroundDelirium affects 25% of older inpatients and is associated with long-term cognitive impairment and future dementia. However, no population studies have systematically ascertained cognitive function before, cognitive deficits during, and cognitive impairment after delirium. Therefore, there is a need to address the following question: does delirium, and its features (including severity, duration, and presumed aetiologies), predict long-term cognitive impairment, independent of cognitive impairment at baseline?\n\nMethodsThe Delirium and Population Health Informatics Cohort (DELPHIC) study is an observational population-based cohort study based in the London Borough of Camden. It is recruiting 2000 individuals aged [≥]70 years and prospectively following them for two years, including daily ascertainment of all inpatient episodes for delirium. Daily inpatient assessments include the Memorial Delirium Assessment Scale, the Observational Scale for Level of Arousal, and the Hierarchical Assessment of Balance and Mobility. Data on delirium aetiology is also collected. The primary outcome is the change in the modified Telephone Interview for Cognitive Status at two years.\n\nDiscussionDELPHIC is the first population sample to assess older persons before, during and after hospitalisation. The cumulative incidence of delirium in the general population aged [≥]70 will be described. DELPHIC offers the opportunity to quantify the impact of delirium on cognitive and functional outcomes. Overall, DELPHIC will provide a real-time public health observatory whereby information from primary, secondary, intermediate and social care can be integrated to understand how acute illness is linked to health and social care outcomes.

epidemiology↗

bioRxiv2017

Delirium, frailty and mortality: interactions in a prospective study of hospitalized older people

BackgroundIt is unknown if the association between delirium and mortality is consistent for individuals across the whole range of health states. A bimodal relationship has been proposed, where delirium is particularly adverse for those with underlying frailty, but may have a smaller effect (perhaps even protective) if it is an early indicator of acute illness in fitter people. We investigated the impact of delirium on mortality in a cohort simultaneously evaluated for frailty.\n\nMethodsWe undertook an exploratory analysis of a cohort of consecutive acute medical admissions aged [≥]70. Delirium on admission was ascertained by psychiatrists. A Frailty Index (FI) was derived according to a standard approach. Deaths were notified from linked national mortality statistics. Cox regression was used to estimate associations between delirium, frailty and their interactions on mortality.\n\nResultsThe sample consisted of 710 individuals. Both delirium and frailty were independently associated with increased mortality rates (delirium: HR 2.4, 95%CI 1.8-3.3, p<0.01; frailty (per SD): HR 3.5, 95%CI 1.2-9.9, p=0.02). Estimating the effect of delirium in tertiles of FI, mortality was greatest in the lowest tertile: tertile 1 HR 3.4 (95%CI 2.1-5.6); tertile 2 HR 2.7 (95%CI 1.5-4.6); tertile 3 HR 1.9 (95% CI 1.2-3.0).\n\nConclusionWhile delirium and frailty contribute to mortality, the overall impact of delirium on admission appears to be greater at lower levels of frailty. In contrast to the hypothesis that there is a bimodal distribution for mortality, delirium appears to be particularly adverse when precipitated in fitter individuals.

epidemiology↗