Human aquaporins: regulators of transcellular water flow

Background: Emerging evidence supports the view that (AQP) aquaporin water channels are regulators of transcellular water flow. Consistentwith their expression in most tissues, AQPs are associatedwith diverse physiological and pathophysiological processes. Scope of review: AQP knockout studies suggest that the regulatory role of AQPs, rather than their action as passive channels, is their critical function. Transport through all AQPs occurs by a common passive mechanism, but their regulation and cellular distribution varies significantly depending on cell and tissue type; the role of AQPs in cell volumeregulation (CVR) is particularly notable. This reviewexamines the regulatory role of AQPs in transcellular water flow, especially in CVR.We focus on key systems of the human body, encompassing processes as diverse as urine concentration in the kidney to clearance of brain oedema. Major conclusions: AQPs are crucial for the regulation of water homeostasis, providing selective pores for the rapidmovement ofwater across diverse cellmembranes and playing regulatory roles in CVR. Gatingmechanisms have been proposed for human AQPs, but have only been reported for plant andmicrobial AQPs. Consequently, it is likely that the distribution and abundance of AQPs in a particular membrane is the determinant of membrane water permeability and a regulator of transcellular water flow. General significance: Elucidating the mechanisms that regulate transcellular water flow will improve our understanding of the human body in health and disease. The central role of specific AQPs in regulating water homeostasis will provide routes to a range of novel therapies. This article is part of a Special Issue entitled Aquaporins

Direct and Legacy Effects of Long-Term Elevated CO2 on Fine Root Growth and Plant-Insect Interactions

Increasing atmospheric CO2 concentrations alter leaf physiology, with effects that cascade to communities and ecosystems. Yet, responses over cycles of disturbance and recovery are not well known, because most experiments span limited ecological time. We examined the effects of CO2 on root growth, herbivory and arthropod biodiversity in a woodland from 1996 to 2006, and the legacy of CO2 enrichment on these processes during the year after the CO2 treatment ceased. We used minirhizotrons to study root growth, leaf censuses to study herbivory and pitfall traps to determine the effects of elevated CO2 on arthropod biodiversity. Elevated CO2 increased fine root biomass, but decreased foliar nitrogen and herbivory on all plant species. Insect biodiversity was unchanged in elevated CO2. Legacy effects of elevated CO2 disappeared quickly as fine root growth, foliar nitrogen and herbivory levels recovered in the next growing season following the cessation of elevated CO2. Although the effects of elevated CO2 cascade through plants to herbivores, they do not reach other trophic levels, and biodiversity remains unchanged. The legacy of 10yr of elevated CO2 on plant-herbivore interactions in this system appear to be minimal, indicating that the effects of elevated CO2 may not accumulate over cycles of disturbance and recovery

Aquaporin expression in the human and canine intervertebral disc during maturation and degeneration

The intervertebral disc (IVD) is a highly hydrated tissue, the rich proteoglycan matrix imbibes water, enabling the disc to withstand compressive loads. During ageing and degeneration increased matrix degradation leads to dehydration and loss of function. Aquaporins (AQP) are a family of transmembrane channel proteins that selectively allow the passage of water in and out of cells and are responsible for maintaining water homeostasis in many tissues. Here, the expression of all 13 AQPs at gene and protein level was investigated in human and canine non‐degenerate and degenerate IVDs to develop an understanding of the role of AQPs during degeneration. Furthermore, in order to explore the transition of notochordal cells (NCs) towards nucleus pulposus (NP) cells, AQP expression was investigated in canine IVDs enriched in NCs to understand the role of AQPs in IVD maturation. AQP0, 1, 2, 3, 4, 5, 6, 7 and 9 were expressed at gene and protein level in both non‐degenerate and degenerate human NP tissue. AQP2 and 7 immunopositivity increased with degeneration in human NP tissue, whereas AQP4 expression decreased with degeneration in a similar way to AQP 1 and 5 shown previously. All AQP proteins that were identified in human NP tissue were also expressed in canine NP tissue. AQP2, 5, 6 and 9 were found to localise to vacuole‐like membranes and cell membranes in NC cells. In conclusion, AQPs were abundantly expressed in human and canine IVDs. The expression of many AQP isotypes potentially alludes to multi‐faceted functions related to adaption of NP cells to the conditions they encounter within their microenvironment in health and degeneration. The presence of AQPs within the IVD may suggest an adaptive role for these water channels during the development and maintenance of the healthy, mature IVD

Associations between APOE and low-density lipoprotein cholesterol genotypes and cognitive and physical capability: the HALCyon programme

The APOE ε2/3/4 genotype has been associated with low-density lipoprotein cholesterol (LDL-C) and Alzheimer disease. However, evidence for associations with measures of cognitive performance in adults without dementia has been mixed, as it is for physical performance. Associations may also be evident in other genotypes implicated in LDL-C levels. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, genotypic information was obtained for APOE ε2/3/4, rs515135 (APOB), rs2228671 (LDLR) and rs629301 (SORT1) from eight cohorts of adults aged between 44 and 90+years. We investigated associations with four measures of cognitive (word recall, phonemic fluency, semantic fluency and search speed) and physical capability (grip strength, get up and go/walk speed, timed chair rises and ability to balance) using meta-analyses. Overall, little evidence for associations between any of the genotypes and measures of cognitive capability was observed (e.g. pooled beta for APOE ε4 effect on semantic fluency z score=- 0.02; 95% CI=- 0.05 to 0.02; p value=0.3; n=18,796). However, there was borderline evidence within studies that negative effects of APOE ε4 on nonverbal ability measures become more apparent with age. Few genotypic associations were observed with physical capability measures. The findings from our large investigation of middle-aged to older adults in the general population suggest that effects of APOE on cognitive capability are at most modest and are domain- and age-specific, while APOE has little influence on physical capability. In addition, other LDL-C-related genotypes have little impact on these traits. © The Author(s) 2014

Age-Dependent Changes in Heparan Sulfate in Human Bruch's Membrane: Implications for Age-Related Macular Degeneration

Citation: Keenan TDL, Pickford CE, Holley RJ, et al. Age-dependent changes in heparan sulfate in human Bruch's membrane: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci. 2014;55:5370-5379. DOI:10.1167/ iovs.14-14126 PURPOSE. Heparan sulfate (HS) has been implicated in age-related macular degeneration (AMD), since it is the major binding partner for complement factor H (CFH) in human Bruch's membrane (BrM), and CFH has a central role in inhibiting complement activation on extracellular matrices. The aim was to investigate potential aging changes in HS quantity and composition in human BrM. METHODS. Postmortem human ocular tissue was obtained from donors without known retinal disease. The HS was purified from BrM and neurosensory retina, and after digestion to disaccharides, fluorescently labeled and analyzed by reverse-phase HPLC. The HS and heparanase-1 were detected by immunohistochemistry in macular tissue sections from young and old donors, and binding of exogenously applied recombinant CCP6-8 region of CFH (402Y and 402H variants) was compared. RESULTS. Disaccharide analysis demonstrated that the mean quantity of HS in BrM was 50% lower (P ¼ 0.006) in old versus young donors (average 82 vs. 32 years). In addition, there was a small, but significant decrease in HS sulfation in old BrM. Immunohistochemistry revealed approximately 50% (P ¼ 0.02) less HS in macular BrM in old versus young donors, whereas heparanase-1 increased by 24% in old macular BrM (P ¼ 0.56). In young donor tissue the AMD-associated 402H CCP6-8 bound relatively poorly to BrM, compared to the 402Y form. In BrM from old donors, this difference was significantly greater (P ¼ 0.019). CONCLUSIONS. The quantity of HS decreases substantially with age in human BrM, resulting in fewer binding sites for CFH and especially affecting the ability of the 402H variant of CFH to bind BrM. Keywords: Bruch's membrane, heparan sulfate, AMD A ge-related macular degeneration (AMD) is the leading cause of blindness in developed countries. 1,2 Genetic and biochemical evidence has strongly implicated dysregulation of the complement system in disease pathogenesis. 20 Importantly, the amount of MAC in human BrM/choroid is significantly higher in individuals who are homozygous for the CFH 402H polymorphism. 21 A novel potential mechanism linking the Y402H polymorphism and AMD risk was suggested by the finding that the main binding partner of CFH in human macular BrM is heparan sulfate (HS), and that the 402H form of CFH binds poorly to human BrM HS, in comparison with the 402Y form

A horizon scan of issues affecting UK forest management within 50 years

Forests are in the spotlight: they are expected to play a pivotal role in our response to society’s greatest challenges, such as the climate and biodiversity crises. Yet, the forests themselves, and the sector that manages them, face a range of interrelated threats and opportunities. Many of these are well understood, even if the solutions remain elusive. However, there are also emerging trends that are currently less widely appreciated. We report here the results of a horizon scan to identify developing issues likely to affect UK forest management within the next 50 years. These are issues that are presently under-recognized but have potential for significant impact across the sector and beyond. As the forest management sector naturally operates over long timescales, the importance of using good foresight is self-evident. We followed a tried-and-tested horizon scanning methodology involving a diverse Expert Panel to collate and prioritize a longlist of 180 issues. The top 15 issues identified are presented in the Graphical Abstract. The issues represent a diverse range of themes, within a spectrum of influences from environmental shocks and perturbations to changing political and socio-economic drivers, with complex emerging interactions between them. The most highly ranked issue was ‘Catastrophic forest ecosystem collapse’, reflecting agreement that not only is such collapse a likely prospect but it would also have huge implications across the sector and wider society. These and many of the other issues are large scale, with far-reaching implications. We must be careful to avoid inaction through being overwhelmed, or indeed to merely focus on ‘easy wins’ without considering broader ramifications. Our responses to each of the challenges and opportunities highlighted must be synergistic and coherent, involving landscape-scale planning. A more adaptive approach to forest management will be essential, encouraging continual innovation and learning. The 15 horizon scan issues presented here are a starting point on which to build further research, prompt debate and action, and develop evidence-based policy and practice. We hope that this stimulates greater recognition of how our forests and sector may need to change to be fit for the future. In some cases, these changes will need to be fundamental and momentous

Inadvertent environmentalism and the action–value opportunity: reflections from studies at both ends of the generational spectrum

This is an Accepted Manuscript of an article published by Taylor & Francis in Local Environment on 22/11/2013, available online: doi: 10.1080/13549839.2013.852524A recent turn towards a more contextually sensitive apprehension of the challenge of making everyday life less resource hungry has been partly underwritten by widespread evidence that the environmental values people commonly profess to hold do not often translate into correspondingly low impact actions. Yet sometimes the contexts of everyday life can also conspire to make people limit their consumption without ever explicitly connecting this to the environmental agenda. This paper considers this phenomenon with reference to UK studies from both ends of the generational spectrum. The first questioned how older people keep warm at home during winter and the second examined how young people get rid of no longer wanted possessions. Both found that, though the respondents involved were acting in certain ways that may be deemed comparatively low impact, they were hitherto relatively indifferent to the idea of characterising these actions as such. We outline three ways in which sustainability advocates might respond to the existence of such “inadvertent environmentalists” and consider how they might inspire studies that generate fresh intervention ideas instead of lingering on the dispiriting recognition that people do not often feel able to act for the environment.Nuffield Foundation/Economic and Social Research Counci

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers: Washington University School of Medicine (n=134) and Yale School of Medicine (n=49). We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza (n=54), and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV, n=22). We demonstrate that circulating markers of complement activation are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., angiopoietin-2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials

A collaborative approach to forecasting product–service systems (PSS)

Copyright @ Springer-Verlag London Limited 2010. The final version of this article may be viewed at the link below.This paper examines the forecasting implications for product–service systems (PSS) applications in manufacturing firms. The approach taken is to identify the scope of operations for PSS applications by identifying all the activities associated with the service deployment in the telecom sector. The paper then develops a revenue model for manufacturing firms providing PSS applications. The revenue model identifies three generic revenue streams that provide the basis for discussion on the differences in forecasting approaches, including collaborative approaches based on PSS staff being geographically co-located

Identification and molecular mechanisms of the rapid tonicity-induced relocalization of the aquaporin 4 channel

The aquaporin family of integral membrane proteins is comprised of channels that mediate cellular water flow. Aquaporin 4 (AQP4) is highly expressed in the glial cells of the central nervous system and facilitates the osmotically-driven pathological brain swelling associated with stroke and traumatic brain injury. Here we show that AQP4 cell surface expression can be rapidly and reversibly regulated in response to changes of tonicity in primary cortical rat astrocytes and in transfected HEK293 cells. The translocation mechanism involves protein kinase A (PKA) activation, influx of extracellular calcium and activation of calmodulin. We identify five putative PKA phosphorylation sites and use site-directed mutagenesis to show that only phosphorylation at one of these sites, serine- 276, is necessary for the translocation response. We discuss our findings in the context of the identification of new therapeutic approaches to treating brain oedema