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Co-authored by academic staff and older adult community members, this paper reports on an incidental and pragmatic co-design model grounded in a round table friendship-informed approach. Interdisciplinary academics met with residents of a proximate retirement community, sharing open discussions with no agenda, including improving engagement between the two communities. The ensuing co-designed programme of outreach activities was of myriad mutual benefits: the retirement community benefited through opportunities for meaningful engagement via inter-generational knowledge-sharing, social connection, and access to expertise and equipment, whilst the University benefited across Learning and Teaching, Research, Engagement, and Commercialisation sectors. This pragmatic co-design approach described resulted in equitable contributions to knowledge generation, exchange, and translation in an interdirectional way. We argue that future research can adopt such an approach, exhibiting potential across all forms of community engaged research. [ABSTRACT FROM AUTHOR]

Local (cell-level) signaling environments, regulated by autocrine and paracrine signaling, and modulated by cell organization, are hypothesized to be fundamental stem cell fate control mechanisms used during development. It has, however, been challenging to demonstrate the impact of cell-level organization on stem cell fate control and to relate stem cell fate outcomes to autocrine and paracrine signaling. We address this fundamental problem using a combined in silico and experimental approach in which we directly manipulate, using laminar fluid flow, the local impact of endogenously secreted gp130-activating ligands and their activation of signal transducer and activator of transcription3 (STAT3) signaling in mouse embryonic stem cells (mESC). Our model analysis predicted that flow-dependent changes in autocrine and paracrine ligand binding would impact heterogeneity in cell- and colony-level STAT3 signaling activation and cause a gradient of cell fate determination along the direction of flow. Interestingly, analysis also predicted that local cell density would be inversely proportional to the degree to which endogenous secretion contributed to cell fate determination. Experimental validation using functional activation of STAT3 by secreted factors under microfluidic perfusion culture demonstrated that STAT3 activation and consequently mESC fate were manipulable by flow rate, position in the flow field, and local cell organization. As a unique demonstration of how quantitative control of autocrine and paracrine signaling can be integrated with spatial organization to elicit higher order cell fate effects, this work provides a general template to investigate organizing principles due to secreted factors. [ABSTRACT FROM AUTHOR]

Abstract: This is the second of two papers in which we study a mathematical model of cytoskeleton-induced neuron death. Recent evidence indicates that aggravated assembly or destruction of the cytoskeleton can trigger programmed death in neurons, by mechanisms as yet poorly understood. In our model, assembly control of the neuronal cytoskeleton interacts with both cellular stress levels and cytosolic free radical concentrations to trigger neurodegeneration. This trigger mechanism is further modulated by a diffusible toxic factor released from dying neurons. In the companion report we established that the model relates the observed general patterns of neuron decline to specific scales of cytoskeleton reorganization and cell–cell interaction strength. In this paper we study the transit of neurons through states intermediate between initial viability and cell death in our model. We find that the stochastic flow of neuron fate, from viability to cell death, self-organizes into two distinct temporal phases. There is a rapid relaxation of the initial neuron population to a more disordered phase that is long-lived, or metastable, with respect to the time scales of change in single cells. Strikingly, cellular egress from this metastable phase follows the one-hit kinetic pattern of exponential decline now established as a principal hallmark of cell death in neurodegenerative disorders. Intermediate state metastability may therefore be an important element in the systems biology of one-hit neurodegeneration. [Copyright &y& Elsevier]

Abstract: Much experimental evidence shows that the cytoskeleton is a downstream target and effector during cell death in numerous neurodegenerative diseases, including Parkinson''s, Huntington''s, and Alzheimer''s diseases. However, recent evidence indicates that cytoskeletal dysfunction can also trigger neuronal death, by mechanisms as yet poorly understood. This is the first of two papers in which we study a mathematical model of cytoskeleton-induced neuron death. In our model, assembly control of the neuronal cytoskeleton interacts with both cellular stress levels and cytosolic free radical concentrations to trigger neurodegeneration. This trigger mechanism is further modulated by the presence of cell interactions in the form of a diffusible toxic factor released by dying neurons. We find that, consistent with empirical observations, our model produces one-hit exponential and sigmoid patterns of cell dropout. In all cases, cell dropout is exponential-tailed and described accurately by a gamma distribution. The transition between exponential and sigmoidal is gradual, and determined by a synergetic interaction between the magnitude of fluctuations in cytoskeleton assembly control and by the degree of cell coupling. We conclude that a single mechanism involving neuron interactions and fluctuations in cytoskeleton assembly control is compatible with the experimentally observed range of neuronal attrition kinetics. [Copyright &y& Elsevier]

Abstract: Neurodegenerative disorders are an insidious group of diseases characterized by severe physical and cognitive effects that often have devastating consequences for the lives of affected individuals and their families. One feature common to a significant proportion of these diseases is that affected neurons commit to undergoing an active form of degeneration known as programmed cell death, or apoptosis. Although intense effort over the past several years has resulted is a remarkable increase in our understanding of the molecular events involved in neurodegeneration, our knowledge regarding the cellular and tissue properties that determine the temporal patterns of neuronal attrition is limited. We recently demonstrated that neurodegenerative kinetics in various diseases fit well to exponential decay functions, and proposed a universal one-hit switch mechanism in which mutant and injured neurons exist in a viable state characterized by an increased but constant risk of initiating apoptosis (Nature, 406, p. 195). Here we show that a heavy-tailed stretched exponential function is better able to account for neurodegenerative kinetic data. Moreover, normalization of all available data according to their corresponding best-fit stretched exponential parameters suggest that the generalized model is consistent with a universal mechanism of neuronal cell death that is greatly improved over the constant risk model. In contrast to the original model in which all cells exhibit an identical risk of initiating apoptosis, the stretched exponential model is consistent with each neuron experiencing a constant risk that is different from that experienced by other cells in the degenerating population, perhaps due to spatial differences in the cellular microenvironment. Intriguingly, the predicted distribution of risk across the cell population can be fit by a power-law function, further suggesting that scale-free properties of degenerating neuronal tissues might act as potent regulators of the kinetics of cell death in neural tissue. [Copyright &y& Elsevier]

Abstract: We recently demonstrated that cell loss kinetics in diverse forms of neurodegeneration (ND) suggests a universal death switch mechanism in which each cell is at a constant risk to initiate apoptosis. We proposed that mutant and injured neurons exist in a viable state typified by an increased risk of initiating death processes [Clarke, Collins, Leavitt, Andrews, Hayden, Lumsden, McInnes, A one-hit model of cell death in inherited neuronal degenerations, Nature 406 (2000) 195–199]. To date, however, measurements of cell death risk have been available only as averages across the affected cell population. Here we develop and apply a method of death kinetic analysis in which the risk factors vary across the neuronal population, as for example due to regional heterogeneities in the cellular microenvironment. We find that most cases of ND for which cell loss data has been obtained are better explained by death risks that vary from cell to cell, compared to death risk that is constant across the neuronal population. Strikingly, a common form of the frequency distribution defining the death risk heterogeneity is shared across most of these cases. This first characterization of the kinetic heterogeneity in one-hit neuronal death, therefore, suggests that the wide variety of ND now known may share mechanisms through which regional differences in the cellular microenvironment modulate the kinetics of cell loss. [Copyright &y& Elsevier]

Retinitis pigmentosa (RP) is an inherited disease affecting approximately 1 : 4000 individuals in North America. It is characterized clinically by the gradual apoptotic death of photoreceptor cells that occurs nonuniformly across the surface of the retina. Recently, it has been demonstrated that the time of death of many individual photoreceptors is random, a fact that must be reconciled with the spatiotemporal patterns of photoreceptor degeneration that are observed in patients with RP. One possible explanation is that a diffusible toxic factor is released by dying photoreceptors and induces adjacent cells to likewise undergo apoptosis. To determine if such a mechanism can result in patchy distributions of photoreceptor death, as frequently observed in RP patients, we studied cell attrition produced by a bistable biochemical switch in an idealized one-dimensional retina. We found that with a reasonable choice of parameter values, our model was able to produce patterns of cell death resembling those observed in RP. In the context of this model, patches on the order of histologically observable size could develop from a single release event, but their rates of formation were independent of the concentration of toxic factor released. Instead, factor concentration affected the overall rate of cell death, the number of degenerating patches, and their distribution across the retina. [Copyright &y& Elsevier]

Reports on the kinetics of neuronal death and utilizes models of photoreceptor degeneration in order to illustrate how the risk of cell death remains constant or decreases exponentially with age. Background regarding premature neuronal death and general assumptions of it; Diseases examined in the study including Parkinson's and Huntington's; Conclusion that some environmental factors are related to cell death.

Abstract The ventral septal area (VSA) is considered to be critically involved in the control of the height and duration of fever. The major excitatory input to this region of the brain is glutamatergic, and the aim of this study was to investigate possible modulation of this synapse by metabotropic glutamate (mGlu) receptors. Whole-cell patch recordings were made from individual VSA neurons voltage-clamped at -60 mV. Activation of either group I or group II mGlu receptors (by bath application of 3,5-dihydroxyphenylglycine (DHPG) or (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG-IV), respectively) produced a long-lasting depression of synaptic transmission which in both cases was insensitive to the N-methyl-d-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5). In contrast, application of (S)-2-amino-4-phosphonobutyric acid (L-AP4), a group III mGlu receptor agonist, had a biphasic effect on synaptic transmission in the VSA, first eliciting a transient depression of transmission during drug application, followed by a marked and sustained potentiation of synaptic transmission upon drug washout. The response elicited by L-AP4 was dependent on NMDA receptor activation, as in the presence of D-AP5 the potentiation was replaced by an underlying long-term depression (LTD) of transmission. These data provide the first evidence that metabotropic glutamate receptor agonists can induce both NMDA receptor-dependent and -independent modulation of synaptic transmission in the VSA. [ABSTRACT FROM AUTHOR]

To date, 118 loci have been associated with photoreceptor degenerative disease. In this review, we will discuss recent advances in the identification of genes that cause progressive photoreceptor cell death when mutated. We will focus on 12 genes isolated within the last two years that have been shown to be photoreceptor-specific, or that have provided insight into photoreceptor biology and the mechanisms of photoreceptor cell death. To aid in understanding the biologic basis for these diseases, we also briefly review photoreceptor biology. Finally, we report on recent advances towards the treatment of these disorders. [ABSTRACT FROM AUTHOR]

The homologous membrane proteins Rom-1 and peripherin-2 are localized to the disk rims of photoreceptor outer segments (ass), where they associate as tetramers and larger oligomers Disk rims are thought to be critical for disk morphogenesis, OS renewal and the maintenance of OS structure, but the molecules which regulate these processes are unknown. Although peripherin-2 is known to be required for as formation (because Prph2[sup -/-] mice do not form OSs; ref. 6), and mutations in RDS (the human homologue of Prph2) cause retinal degeneration, the relationship of Rom-1 to these processes is uncertain. Here we show that Rom1[sup -/-] mice form ass in which peripherin-2 homotetramers are localized to the disk rims, indicating that peripherin-2 alone is sufficient for both disk and as morphogenesis. The disks produced in Rom1[sup -/-] mice were large, rod OSs were highly disorganized (a phenotype which largely normalized with age) and rod photoreceptors died slowly by apoptosis. Furthermore, the maximal photoresponse of Rom1[sup -/-] rod photoreceptors was lower than that of controls. We conclude that Rom-1 is required for the regulation of disk morphogenesis and the viability of mammalian rod photoreceptors, and that mutations in human ROM1 may cause recessive photoreceptor degeneration. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To examine the effect of empagliflozin on liver fat content in individuals with and without type 2 diabetes (T2D) and the relationship between the decrease in liver fat and other metabolic actions of empagliflozin. RESEARCH DESIGN AND METHODS: Thirty individuals with T2D and 27 without were randomly assigned to receive in double-blind fashion empagliflozin or matching placebo (2:1 ratio) for 12 weeks. Participants underwent 75-g oral glucose tolerance testing and measurement of liver fat content with MRS before therapy and at study end. Hepatic glucose production before the start of therapy was measured with 3-3H-glucose. RESULTS: Empagliflozin caused an absolute reduction of 2.39% ± 0.79% in liver fat content compared with an increase of 0.91% ± 0.64% in participants receiving placebo (P < 0.007 with ANOVA). The decrease in liver fat was comparable in both individuals with diabetes and those without (2.75% ± 0.81% and 1.93% ± 0.78%, respectively; P = NS). The decrease in hepatic fat content caused by empagliflozin was strongly correlated with baseline liver fat content (r = −0.62; P < 0.001), decrease in body weight (r = 0.53; P < 0.001), and improvement in insulin sensitivity (r = −0.51; P < 0.001) but was not related to the decrease in fasting plasma glucose or HbA1c or the increase in hepatic glucose production. CONCLUSIONS: Empagliflozin is effective in reducing liver fat content in individuals with and without T2D. The decrease in liver fat content is independent of the decrease in plasma glucose concentration and is strongly related to the decrease in body weight and improvement in insulin sensitivity. [ABSTRACT FROM AUTHOR]

• Analyse the impact of climate change on road transport systems. • Develop a risk prediction tool to reduce climate impact on roads. • Conduct economic analysis of various measures to reduce climate impact on roads. • Conduct an empirical study to provide useful insights for rational risk based climate adaptation. This paper aims to analyse the impacts of climate change to the current and predicted future situations of road transportation in the UK and evaluate the corresponding adaptation plans to cope with them. A conceptual framework of long-term adaptation planning for climate change in road systems is proposed to ensure the resilience and sustainability of road transport systems under various climate risks such as flooding and increased temperature. To do so, an advanced Fuzzy Bayesian Reasoning (FBR) model is first employed to evaluate the climate risks in the UK road transport networks. This modelling approach can tackle the high uncertainty in risk data and thus facilitate the development of the climate adaptation framework and its application in the UK road sector. To examine the feasibility of this model, a nationwide survey is conducted among the stakeholders to analyse the climate risks, in terms of the timeframe of climate threats, the likelihood of occurrence, the severity of consequences, and infrastructure resilience. From the modelling perspective, this work brings novelty by expanding the risk attribute "the severity of consequence" into three sub-attributes including economic loss, damage to the environment, and injuries and/or loss of life. It advances the-state-of-the-art technique in the current relevant literature from a single to multiple tier climate risk modelling structure. Secondly, an Evidential Reasoning (ER) approach is used to prioritise the best adaptation measure(s) by considering both the risk analysis results from the FBR and the implementation costs simultaneously. The main new contributions of this part lie in the rich raw data collected from the real world to provide useful practical insights for achieving road resilience when facing increasing climate risk challenges. During this process, a qualitative analysis of several national reports regarding the impacts posed by climate change, risk assessment and adaptation measures in the UK road sector is conducted for the relevant decision data (i.e. risk and cost). It is also supplemented by an in-depth interview with a senior planner from Highways England. The findings provide road planners and decision makers with useful insights on identification and prioritisation of climate threats as well as selection of cost-effective climate adaptation measures to rationalise adaptation planning. [ABSTRACT FROM AUTHOR]

Summary The neural stem cell decision to self-renew or differentiate is tightly regulated by its microenvironment. Here, we have asked about this microenvironment, focusing on growth factors in the embryonic cortex at a time when it is largely comprised of neural precursor cells (NPCs) and newborn neurons. We show that cortical NPCs secrete factors that promote their maintenance, while cortical neurons secrete factors that promote differentiation. To define factors important for these activities, we used transcriptome profiling to identify ligands produced by NPCs and neurons, cell-surface mass spectrometry to identify receptors on these cells, and computational modeling to integrate these data. The resultant model predicts a complex growth factor environment with multiple autocrine and paracrine interactions. We tested this communication model, focusing on neurogenesis, and identified IFNγ, Neurturin (Nrtn), and glial-derived neurotrophic factor (GDNF) as ligands with unexpected roles in promoting neurogenic differentiation of NPCs in vivo. [ABSTRACT FROM AUTHOR]

Investigates the photoreceptor death in mouse models of digenic and dominant retinitis pigmentosa. Deficiency of RDS encodes rds/peripherin (rds); Nuclease protection analysis of retina RNA; Relation of ROM1 gene with rds.

• Conduct critical analysis on climate adaptation study in transportation. • Introduce a new classification method with reference to diverse key topics. • Identify the research gaps through statistical and qualitative analysis. • Guide future research directions in transport adaptation to climate change. With the occurrence of more frequent and intense climate change events, transportation systems, including their infrastructure and operations become increasingly vulnerable. However, the existing research related to climate risks, adaptation and planning in the transport sector is still at an embryonic stage. Understanding such, this paper presents a critical review on climate risks, adaptation strategies and planning in the context of road and rail transportation systems. It aims to conduct a rigorous survey, to highlight any significant research gaps not addressed in past studies and to analyse current emerging topics to guide future directions. It critically dissects the selected papers by categorising them into several dimensions to reveal the status quo and potential challenges, including climate risk assessment, transport asset management, climate planning and policy, and adaptation of transport infrastructure to climate change. It will provide valuable references for future research and constructive insights and empirical guidance on climate adaptation, risk analysis, transport planning and other important relevant topics. [ABSTRACT FROM AUTHOR]

• Analyse the impact of climate change on rail transport systems. • Explore the uncertainties in climate risk data. • Develop new climate risk analysis methods using advanced uncertainty modelling. • Develop a risk prediction tool to reduce climate impact on rails. • Conduct a UK national wide empirical study to provide useful insights for rail network adaptation to climate change. Climate change poses critical challenges for rail infrastructure and operations. However, the systematic analysis of climate risks and the associated costs of tackling them, particularly from a quantitative perspective, is still at an embryonic phase due to the kaleidoscopic nature of climate change impacts and lack of precise climatic data. To cope with such challenges, an advanced Fuzzy Bayesian Reasoning (FBR) model is applied in this paper to understand climate threats of the railway system. This model ranks climate risks under high uncertainty in data and comprehensively evaluates these risks by taking account of infrastructure resilience and specific aspects of severity of consequence. Through conducting a nationwide survey on the British railway system, it dissects the status quo of primary climate risks. The survey implies that the top potential climate threats are heavy precipitation and floods. The primary risks caused by the climate threats are bridges collapsing and bridge foundation damage due to flooding and landslips. The findings can aid transport planners to prioritise climate risks and develop rational adaptation measures and strategies. [ABSTRACT FROM AUTHOR]