Statin regulated ERK5 stimulates tight junction formation and reduces permeability in human cardiac endothelial cells

The MEKK3/MEK5/ERK5 signaling axis is required for cardiovascular development in vivo. We analyzed the physiological role of ERK5 in cardiac endothelial cells and the consequence of activation of this kinase by the statin class of HMG Co‐A reductase inhibitor drugs. We utilized human cardiac microvascular endothelial cells (HCMECs) and altered ERK5 expression using siRNA mediated gene silencing or overexpression of constitutively active MEK5 and ERK5 to reveal a role for ERK5 in regulating endothelial tight junction formation and cell permeability. Statin treatment of HCMECs stimulated activation of ERK5 and translocation to the plasma membrane resulting in co‐localization with the tight junction protein ZO‐1 and a concomitant reduction in endothelial cell permeability. Statin mediated activation of ERK5 was a consequence of reduced isoprenoid synthesis following HMG Co‐A reductase inhibition. Statin pretreatment could overcome the effect of doxorubicin in reducing endothelial tight junction formation and prevent increased permeability. Our data provide the first evidence for the role of ERK5 in regulating endothelial tight junction formation and endothelial cell permeability. Statin mediated ERK5 activation and the resulting decrease in cardiac endothelial cell permeability may contribute to the cardioprotective effects of statins in reducing doxorubicin‐induced cardiotoxicity

Twelve weeks of supervised exercise improves self-reported symptom burden and fatigue in chronic kidney disease : a secondary analysis of the ‘ExTra CKD’ trial

Background Chronic kidney disease (CKD) patients experience a high symptom burden including fatigue, sleep difficulties, muscle weakness and pain. These symptoms reduce levels of physical function (PF) and activity, and contribute to poor health-related quality of life (HRQoL). Despite the gathering evidence of positive physiological changes following exercise in CKD, there is limited evidence on its effect on self-reported symptom burden, fatigue, HRQoL and physical activity. Methods Thirty-six patients [mean ± SD 61.6 ± 11.8 years, 22 (61%) females, estimated glomerular filtration rate: 25.5 ± 7.8 mL/min/1.73 m2] not requiring renal replacement therapy underwent 12 weeks (3 times/week) of supervised aerobic exercise (AE), or a combination (CE) of AE plus resistance training. Outcomes included self-reported symptom burden, fatigue, HRQoL and physical activity. Results Exercise reduced the total number of symptoms reported by 17% and had favourable effects on fatigue in both groups. AE reduced the frequency of ‘itching’, ‘impotence’ and ‘shortness of breath’ symptoms, and the intrusiveness for symptoms of ‘sleep disturbance’, ‘loss of muscular strength/power’, ‘muscle spasm/stiffness’ and ‘restless legs’. The addition of resistance exercise in the CE group saw a reduction in ‘loss of muscular strength/power’. No changes were seen in subjective PF or physical activity levels. AE increased self-efficacy for physical activity. Conclusions Supervised exercise had favourable effects on symptom frequency and intrusiveness, including substantial improvements in fatigue. Although the intervention did not improve self-reported physical activity levels, AE increased patients’ self-efficacy for physical activity. These favourable changes in self-reported outcomes support the important role of exercise in CKD

The association of physical function and physical activity with all-cause mortality and adverse clinical outcomes in non-dialysis chronic kidney disease : a systematic review

Objective: People with nondialysis-dependent chronic kidney disease (CKD) and renal transplant recipients (RTRs) have compromised physical function and reduced physical activity (PA) levels. Whilst established in healthy older adults and other chronic diseases, this association remains underexplored in CKD. We aimed to review the existing research investigating poor physical function and PA with clinical outcome in nondialysis CKD. Data sources: Electronic databases (PubMed, MEDLINE, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials) were searched until December 2017 for cohort studies reporting objective or subjective measures of PA and physical function and the associations with adverse clinical outcomes and all-cause mortality in patients with nondialysis CKD stages 1–5 and RTRs. The protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42016039060). Review methods: Study quality was assessed using the Newcastle-Ottawa Scale and the Agency for Healthcare and Research Quality (AHRQ) standards. Results: A total of 29 studies were included; 12 reporting on physical function and 17 on PA. Only eight studies were conducted with RTRs. The majority were classified as ‘good’ according to the AHRQ standards. Although not appropriate for meta-analysis due to variance in the outcome measures reported, a coherent pattern was seen with higher mortality rates or prevalence of adverse clinical events associated with lower PA and physical function levels, irrespective of the measurement tool used. Sources of bias included incomplete description of participant flow through the study and over reliance on self-report measures. Conclusions: In nondialysis CKD, survival rates correlate with greater PA and physical function levels. Further trials are required to investigate causality and the effectiveness of physical function and PA interventions in improving outcomes. Future work should identify standard assessment protocols for PA and physical function

Testing a word is not a test of word learning

Although vocabulary acquisition requires children learn names for multiple things, many investigations of word learning mechanisms teach children the name for only one of the objects presented. This is problematic because it is unclear whether children's performance reflects recall of the correct name-object association or simply selection of the only object that was singled out by being the only object named. Children introduced to one novel name may perform at ceiling as they are not required to discriminate on the basis of the name per se, and appear to rapidly learn words following minimal exposure to a single word. We introduced children to four novel objects. For half the children, only one of the objects was named and for the other children, all four objects were named. Only children introduced to one word reliably selected the target object at test. This demonstration highlights the over-simplicity of one-word learning paradigms and the need for a shift in word learning paradigms where more than one word is taught to ensure children disambiguate objects on the basis of their names rather than their degree of salience

Clonal Dynamics Reveal Two Distinct Populations of Basal Cells in Slow-Turnover Airway Epithelium.

Epithelial lineages have been studied at cellular resolution in multiple organs that turn over rapidly. However, many epithelia, including those of the lung, liver, pancreas, and prostate, turn over slowly and may be regulated differently. We investigated the mouse tracheal epithelial lineage at homeostasis by using long-term clonal analysis and mathematical modeling. This pseudostratified epithelium contains basal cells and secretory and multiciliated luminal cells. Our analysis revealed that basal cells are heterogeneous, comprising approximately equal numbers of multipotent stem cells and committed precursors, which persist in the basal layer for 11 days before differentiating to luminal fate. We confirmed the molecular and functional differences within the basal population by using single-cell qRT-PCR and further lineage labeling. Additionally, we show that self-renewal of short-lived secretory cells is a feature of homeostasis. We have thus revealed early luminal commitment of cells that are morphologically indistinguishable from stem cells.This study was supported by the Medical Research Council (G0900424 to E.R.), European Union grant EuroSyStem (200720; FP7/2008), the Newton Trust (to E.R.), the Wellcome Trust (098357/Z/12/Z to B.D.S.). Core grants from the Wellcome Trust (092096) and Cancer Research UK (C6946/A14492).This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.celrep.2015.06.01

Behavioural and molecular characterisation of the Dlg2 haploinsufficiency rat model of genetic risk for psychiatric disorder

Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD-93 protein reduction) a novel clinically relevant Dlg2+/− rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N-Methyl-D-aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD-93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2+/− rats show a potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, and partially dissimilar to behavioural deficits previously reported in Dlg2+/− mouse models demonstrating issues surrounding the comparison of models with different aetiology and species. Intact performance on many of the behavioural domains assessed here, such as anxiety and reward processing, will remove these as confounds when continuing investigation into this model using more complex cognitive tasks

The senescent secretome drives PLVAP expression in cultured human hepatic endothelia to promote monocyte transmigration

Liver sinusoidal endothelial cells (LSEC) undergo significant phenotypic change in chronic liver disease (CLD), and yet the factors that drive this process and the impact on their function as a vascular barrier and gatekeeper for immune cell recruitment are poorly understood. Plasmalemma-vesicle-associated protein (PLVAP) has been characterized as a marker of LSEC in CLD; notably we found that PLVAP upregulation strongly correlated with markers of tissue senescence. Furthermore, exposure of human LSEC to the senescence-associated secretory phenotype (SASP) led to a significant upregulation of PLVAP. Flow-based assays demonstrated that SASP-driven leukocyte recruitment was characterized by paracellular transmigration of monocytes while the majority of lymphocytes migrated transcellularly. Knockdown studies confirmed that PLVAP selectively supported monocyte transmigration mediated through PLVAP's impact on LSEC permeability by regulating phospho-VE-cadherin expression and endothelial gap formation. PLVAP may therefore represent an endothelial target that selectively shapes the senescence-mediated immune microenvironment in liver disease. [Abstract copyright: © 2023 The Author(s).

Comparison of built environment adaptations to heat exposure and mortality during hot weather, West Midlands region, UK.

There is growing recognition of the need to improve protection against the adverse health effects of hot weather in the context of climate change. We quantify the impact of the Urban Heat Island (UHI) and selected adaptation measures made to dwellings on temperature exposure and mortality in the West Midlands region of the UK. We used 1) building physics models to assess indoor temperatures, initially in the existing housing stock and then following adaptation measures (energy efficiency building fabric upgrades and/or window shutters), of representative dwelling archetypes using data from the English Housing Survey (EHS), and 2) modelled UHI effect on outdoor temperatures. The ages of residents were combined with evidence on the heat-mortality relationship to estimate mortality risk and to quantify population-level changes in risk following adaptations to reduce summertime heat exposure. Results indicate that the UHI effect accounts for an estimated 21% of mortality. External shutters may reduce heat-related mortality by 30-60% depending on weather conditions, while shutters in conjunction with energy-efficient retrofitting may reduce risk by up to 52%. The use of shutters appears to be one of the most effective measures providing protection against heat-related mortality during periods of high summer temperatures, although their effectiveness may be limited under extreme temperatures. Energy efficiency adaptations to the dwellings and measures to increase green space in the urban environment to combat the UHI effect appear to be less beneficial for reducing heat-related mortality