A small molecule activator of p300/CBP histone acetyltransferase promotes survival and neurite growth in a cellular model of Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterised by motor and non-motor symptoms, resulting from the degeneration of nigrostriatal dopaminergic neurons and peripheral autonomic neurons. Given the limited success of neurotrophic factors in clinical trials, there is a need to identify new small molecule drugs and drug targets to develop novel therapeutic strategies to protect all neurons that degenerate in PD. Epigenetic dysregulation has been implicated in neurodegenerative disorders, while targeting histone acetylation is a promising therapeutic avenue for PD. We and others have demonstrated that histone deacetylase inhibitors have neurotrophic effects in experimental models of PD. Activators of histone acetyltransferases (HAT) provide an alternative approach for the selective activation of gene expression, however little is known about the potential of HAT activators as drug therapies for PD. To explore this potential, the present study investigated the neurotrophic effects of CTPB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide), which is a potent small molecule activator of the histone acetyltransferase p300/CBP, in the SH-SY5Y neuronal cell line. We report that CTPB promoted the survival and neurite growth of the SH-SY5Y cells, and also protected these cells from cell death induced by the neurotoxin 6-hydroxydopamine. This study is the first to investigate the phenotypic effects of the HAT activator CTPB, and to demonstrate that p300/CBP HAT activation has neurotrophic effects in a cellular model of PD.

Seawater carbonate chemistry and community metabolism during an experiment with a coral reef, 2003

The effect of elevated pCO2 on the metabolism of a coral reef community dominated by macroalgae has been investigated utilizing the large 2650 m3 coral reef mesocosm at the Biosphere-2 facility near Tucson, Arizona. The carbonate chemistry of the water was manipulated to simulate present-day and a doubled CO2 future condition. Each experiment consisted of a 1-2 month preconditioning period followed by a 7-9 day observational period. The pCO2 was 404 ± 63 ?atm during the present-day pCO2 experiment and 658 ± 59 ?atm during the elevated pCO2 experiment. Nutrient levels were low and typical of natural reefs waters (NO3? 0.5-0.9 ?M, NH4+ 0.4 ?M, PO43? 0.07-0.09 ?M). The temperature and salinity of the water were held constant at 26.5 ± 0.2°C and 34.4 ± 0.2 ppt. Photosynthetically available irradiance was 10 ± 2 during the present-day experiment and 7.4 ± 0.5 mol photons m?2 d?1 during the elevated pCO2 experiment. The primary producer biomass in the mesocosm was dominated by four species of macroalgae; Haptilon cubense, Amphiroa fragillisima, Gelidiopsis intricata and Chondria dasyphylla. Algal biomass was 10.4 mol C m?2 during the present-day and 8.7 mol C m?2 and during the elevated pCO2 experiments. As previously observed, the increase in pCO2 resulted in a decrease in calcification from 0.041 ± 0.007 to 0.006 ± 0.003 mol CaCO3 m?2 d?1. Net community production (NCP) and dark respiration did not change in response to elevated pCO2. Light respiration measured by a new radiocarbon isotope dilution method exceeded dark respiration by a factor of 1.2 ± 0.3 to 2.1 ± 0.4 on a daily basis and by 2.2 ± 0.6 to 3.9 ± 0.8 on an hourly basis. The 1.8-fold increase with increasing pCO2 indicates that the enhanced respiration in the light was not due to photorespiration. Gross production (GPP) computed as the sum of NCP plus daily respiration (light + dark) increased significantly (0.24 ± 0.03 vs. 0.32 ± 0.04 mol C m?2 d?1). However, the conventional calculation of GPP based on the assumption that respiration in the light proceeds at the same rate as the dark underestimated the true rate of GPP by 41-100% and completely missed the increased rate of carbon cycling due to elevated pCO2. We conclude that under natural, undisturbed, nutrient-limited conditions elevated CO2 depresses calcification, stimulates the rate of turnover of organic carbon, particularly in the light, but has no effect on net organic production. The hypothesis that an increase pCO2 would produce an increase in net production that would counterbalance the effect of decreasing saturation state on calcification is not supported by these data.

Growth and photosynthesis of a diatom Cylindrotheca closterium grown under elevated CO2 in the presence of solar UV radiation

The combination of elevated CO2 and the increased acidity in surface oceans is likely to have an impact on photosynthesis via its effects on inorganic carbon speciation and on the overall energetics of phytoplankton. Exposure to UV radiation (UVR) may also have a role in the response to elevated CO2 and acidification, due to the fact that UVR may variously impact on photosynthesis and because of the energy demand of UVR defense. The cell may gain energy by down-regulating the CO2 concentrating mechanism, which may lead to a greater ability to cope with UVR and/or higher growth rates. In order to clarify the interplay of cell responses to increasing CO2 and UVR, we investigated the photosynthetic response of the marine and estuarine diatom Cylindrotheca closterium f. minutissima cultured at either 390 (ambient) or 800 (elevated) ppmv CO2, while exposed to solar radiation with or without UVR (UVR, 280-400 nm). After a 6 day acclimation period, the growth rate of cells was little affected by elevated CO2 and no obvious correlation with the radiation dose (for both PAR and PAR + UV treatments) could be detected. However, the relative electron transport rate was reduced and was more sensitive to UVR in cells main - tained at elevated CO2 as compared to cells cultured at ambient CO2. The CO2 concentrating mechanism was down regulated at 800 ppmv CO2, but was apparently not completely switched off. These data are discussed with respect to their significance in the context of global climate change.

Everyday Enchantments and Secular Magic in Montréal

In this thesis I argue that dominant ways of imagining modernity constitute a modern imaginary that carries with it particular expectations concerning modern places, spaces, emotions, and affects as well as expectations concerning the place of religion and enchantment in the modern world. I argue that this modern imaginary and the expectations it entails works to conceal and trivialize supra-rational beliefs and behaviours in scholarship but also in the lives of individuals. I focus on one particular subset of the supra-rational beliefs and behaviours that modern imaginary conceals and trivializes, namely beliefs and behaviours associated with lucky and protective objects. I also focus on the ways the modern imaginary conceals the presence and prevalence of these objects and the beliefs and behaviours they entail in one particular context, namely Montréal, Québec. I argue that these supra-rational beliefs and behaviours constitute a subjunctive mode for understanding and experiencing daily life and describe how the modern imaginary works to discredit this subjunctive register. Finally, I argue that scholars must begin to recognize and examine this subjunctive mode and the playful engagement with half-belief it involves.

The relationship between changes in cardiovascular function and changes in VO2peak following SIT

Background: It is well known that sprint interval training (SIT), induces significant increases in peak oxygen uptake (VO2peak) at the group level. However, there have been only a few studies that have addressed the variability of VO2peak response following SIT, and precise mechanism(s) that may explain individual magnitude of response are unknown. Purpose: Therefore, the purpose of this thesis was to: 1) examine the inter-individual variability of the VO2peak response following SIT, 2) to inspect the relationship between changes in both central and peripheral measures and changes in VO2peak, and 3) to assess if peripheral or central adaptations play a role in whether an individual is a high or low responder with respect to VO2peak. Subjects: Twenty-two young, recreationally active males (age: 20.4 1.7 years; weight: 78.4 10.2 kg; VO2peak: 3.7 0.62 L/min) Methods: VO2peak (L/min), peak cardiac output (Qpeak [L/min]), and peak deoxygenated hemoglobin (HHbpeak [mM]) were measured before and after 16 sessions of SIT (Tabata Protocol) over four weeks. Peak a-vO2diff was calculated using a derivation of the Fick equation. Results: Due to a systematic error, HHbpeak could not be used to differentiate between individual responses. There was a large range of VO2peak response from pre to post testing (-4.75 to 32.18% change) and there was a significant difference between the Low Response Group (LRG) (n=8) and the High Response Group (HRG) (n=8) [f(1, 14)= 64.27, p<0.001]. Furthermore, there was no correlation between delta () VO2peak and Qpeak (r=-0.18, p=0.46) for all participants, nor was there an interaction effect between the Low and High Response Groups [f(1,11)=0.572, p=0.47]. Lastly, there was a significant correlation between VO2peak and peak a-vO2diff [r=0.692, p<0.001], and a significant interaction effect with peak a-vO2diff [f(1, 14)= 13.27, p<0.004] when comparing the HRG to the LRG. Conclusions: There was inter-individual variability of VO2peak response following 4 weeks of SIT, but central adaptations did not influence this variation. This suggests that peripheral adaptations may be responsible for VO2peak adaptation.

Diversity and Inclusion As the Key to Innovating Talent Management in Law Firms?

In this chapter we argue that there is a need to reconceptualise what we mean by talent in the legal profession beyond a view that the most valuable people are those who have the highest fee-earning potential or the best CV packed with excellent grades and exceptional experiences and extra curricula achievements. And further we need a more sophisticated understanding of how organisational decision-making may be structured to provide developmental opportunities to allow talent to be nurtured and to flourish on individual and team levels. In turn, we suggest that planning, management and accountability cycles within legal entities need to be strengthened so as to ensure creativity and success in a context in which it is possible to deliver on the promise of fair access and promotion. Consequently, this chapter explores the diversity problem within the legal profession(s), further it interrogates what is “talent”, and how and why we should seek to manage and develop it. It then evaluates how talent diversity has been managed in the legal professional context, examined through what we have categorised as three waves of diversity strategies. We interrogate why diversity initiatives have not been more successful given the efforts placed on them by professional bodies and firms themselves. We posit that by using diversity as a case study in talent management legal entities may develop a more effective approach to talent management generally within law firms that will be of benefit to all lawyers and support professionals rather than just those who are from traditionally low participation groups.

Questioning the merits and demerits of electronic communication in Social Work

This paper examines the social dynamics of electronic exchanges in the human services, particularly in social work. It focuses on the observable effects that email and texting have on the linguistic, relational and clinical rather than managerial aspects of the profession. It highlights how electronic communication is affecting professionals in their practice and learners as they become acculturated to social work. What are the gains and losses of the broad use of electronic devices in daily lay and professional, verbal and non-verbal communication? Will our current situation be seriously detrimental to the demeanor of future practitioners, their use of language, and their ability to establish close personal relationships? The paper analyzes social work linguistic and behavioral changes in light of the growth of electronic communication and offers a summary of merits and demerits viewed through a prism emerging from Baron’s (2000) analysis of human communication.

Of Marx and Makers: an Historical Perspective on Generative Justice

In Marxist frameworks “distributive justice” depends on extracting value through a centralized state. Many new social movements—peer to peer economy, maker activism, community agriculture, queer ecology, etc.—take the opposite approach, keeping value in its unalienated form and allowing it to freely circulate from the bottom up. Unlike Marxism, there is no general theory for bottom-up, unalienated value circulation. This paper examines the concept of “generative justice” through an historical contrast between Marx’s writings and the indigenous cultures that he drew upon. Marx erroneously concluded that while indigenous cultures had unalienated forms of production, only centralized value extraction could allow the productivity needed for a high quality of life. To the contrary, indigenous cultures now provide a robust model for the “gift economy” that underpins open source technological production, agroecology, and restorative approaches to civil rights. Expanding Marx’s concept of unalienated labor value to include unalienated ecological (nonhuman) value, as well as the domain of freedom in speech, sexual orientation, spirituality and other forms of “expressive” value, we arrive at an historically informed perspective for generative justice. 

Modest elevation in BNP in asymptomatic hypertensive patients reflects sub-clinical cardiac remodeling, inflammation and extracellular matrix changes

In asymptomatic subjects B-type natriuretic peptide (BNP) is associated with adverse cardiovascular outcomes even at levels well below contemporary thresholds used for the diagnosis of heart failure. The mechanisms behind these observations are unclear. We examined the hypothesis that in an asymptomatic hypertensive population BNP would be associated with sub-clinical evidence of cardiac remodeling, inflammation and extracellular matrix (ECM) alterations. We performed transthoracic echocardiography and sampled coronary sinus (CS) and peripheral serum from patients with low (n = 14) and high BNP (n = 27). Peripheral BNP was closely associated with CS levels (r = 0.92, p<0.001). CS BNP correlated significantly with CS levels of markers of collagen type I and III turnover including: PINP (r = 0.44, p = 0.008), CITP (r = 0.35, p = 0.03) and PIIINP (r = 0.35, p = 0.001), and with CS levels of inflammatory cytokines including: TNF-α (r = 0.49, p = 0.002), IL-6 (r = 0.35, p = 0.04), and IL-8 (r = 0.54, p<0.001). The high BNP group had greater CS expression of fibro-inflammatory biomarkers including: CITP (3.8±0.7 versus 5.1±1.9, p = 0.007), TNF-α (3.2±0.5 versus 3.7±1.1, p = 003), IL-6 (1.9±1.3 versus 3.4±2.7, p = 0.02) and hsCRP (1.2±1.1 versus 2.4±1.1, p = 0.04), and greater left ventricular mass index (97±20 versus 118±26 g/m(2), p = 0.03) and left atrial volume index (18±2 versus 21±4, p = 0.008). Our data provide insight into the mechanisms behind the observed negative prognostic impact of modest elevations in BNP and suggest that in an asymptomatic hypertensive cohort a peripheral BNP measurement may be a useful marker of an early, sub-clinical pathological process characterized by cardiac remodeling, inflammation and ECM alterations.

Arterial stiffness and arteriovenous fistula failure of maturation

PURPOSE: Increased arterial stiffness is a common finding in patients with end-stage renal disease. Following creation of an arteriovenous fistula (AVF), appropriate dilation of the feeding artery must occur to facilitate AVF maturation. Arterial stiffness may impair the arterial dilation required to facilitate AVF development and contribute to subsequent failure to mature (FTM). The aim of this pilot study was to investigate the association between measurements of central and peripheral arterial stiffness, and AVF FTM.

METHODS: Patients undergoing AVF creation in a single centre (Belfast City Hospital, UK) between January and December 2015 were invited to have their carotid-femoral pulse wave velocity (PWV), brachial-radial PWV and augmentation index (AI) measured prior to AVF creation. Subsequent AVF outcomes were identified.

RESULTS: Fifty-nine patients who had an AVF procedure were included in the final analysis (mean age 62 years); 50.8% had diabetes mellitus. The mean pre-operative arterial diameter for all AVFs was 3.9 mm. Average values for carotid-femoral PWV were 9.5 m/s, brachial-radial PWV 7.7 m/s and AI 25.6%. Using logistic regression, these arterial stiffness parameters did not predict AVF FTM: carotid-femoral PWV (P = 0.20), brachial-radial PWV (P = 0.13), AI (P = 0.50).

CONCLUSIONS: This is the largest study to date exploring the association between arterial stiffness and AVF FTM. The measured central and peripheral arterial stiffness parameters were not associated with AVF FTM. Further research is needed to define if non-invasive arterial physiological measurements would be clinically useful in the prediction of AVF FTM.

Temporal aggregation of migration counts can improve accuracy and precision of trends

Temporal replicate counts are often aggregated to improve model fit by reducing zero-inflation and count variability, and in the case of migration counts collected hourly throughout a migration, allows one to ignore nonindependence. However, aggregation can represent a loss of potentially useful information on the hourly or seasonal distribution of counts, which might impact our ability to estimate reliable trends. We simulated 20-year hourly raptor migration count datasets with known rate of change to test the effect of aggregating hourly counts to daily or annual totals on our ability to recover known trend. We simulated data for three types of species, to test whether results varied with species abundance or migration strategy: a commonly detected species, e.g., Northern Harrier, Circus cyaneus; a rarely detected species, e.g., Peregrine Falcon, Falco peregrinus; and a species typically counted in large aggregations with overdispersed counts, e.g., Broad-winged Hawk, Buteo platypterus. We compared accuracy and precision of estimated trends across species and count types (hourly/daily/annual) using hierarchical models that assumed a Poisson, negative binomial (NB) or zero-inflated negative binomial (ZINB) count distribution. We found little benefit of modeling zero-inflation or of modeling the hourly distribution of migration counts. For the rare species, trends analyzed using daily totals and an NB or ZINB data distribution resulted in a higher probability of detecting an accurate and precise trend. In contrast, trends of the common and overdispersed species benefited from aggregation to annual totals, and for the overdispersed species in particular, trends estimating using annual totals were more precise, and resulted in lower probabilities of estimating a trend (1) in the wrong direction, or (2) with credible intervals that excluded the true trend, as compared with hourly and daily counts.

The Creative Unconscious and the Pictorial Sign

Within The Creative Unconscious and Pictorial Sign I explore the dialogue that exists between social language and personal expression to understand how creativity is mediated. I consider how the involuntary inventiveness of artistic creativity and the structuring function of language come to negotiate what artists can experience and represent. My Doctoral practice attempts to question the influence of orthodox postmodernist views and allow sensual and direct experiences to be located within improvisation and spontaneous approaches to image making. I ask if it is possible for a humanistic and psychological interpretation of creativity to move beyond the copy and quotation that some postmodern theories of simulation and the hyperreal advance; but to retain the communicative function of visual expression and the model of a social form of signification instead of naïvely promoting unintelligible and personal languages.

Teaching Rules or Teaching Creativity: a Paradigm Shift

Structure is everything in a screenplay we are told. If indeed there are any rules to screenwriting then this would be carved in tablets of stone. Within pedagogical frameworks we are diligent in our instruction of the three acts, advocating it as a paradigm. We pass on tools for the analysis of character that are gleaned from psychology. But I have seen students struggle with this toolbox. They feel constrained by concrete techniques. So often seeing principles as rules, structure as restriction. The stifling of free-form ideas is further compounded by the plethora of books that claim the path to glory lies only in structural devices. Some even purport to have a formula, a simple prescriptive model that will bestow almost certain success. Yet this is an industry that abhors formula, that hungers for the fresh and the new. Without bravado, imagination and experimentation with character and form, the best structured screenplay in the world is merely a typing exercise. As educators we have a duty to retain a balance between letting a student’s mind dance and keeping them to the tempo. This study will compare a variety of diverse structures, from Hegel to Alcoholics Anonymous, Kubler Ross to Jung. It will analyse recent journal articles, on both new techniques in teaching creativity and new approaches to the instruction of screenwriting, to suggest a model of how best to inform the application of structure to HE students and keep creativity uppermost. A structure of emotional truth. An equal appreciation of both the tools of our craft and an imaginative exploration of character and world that can unlock our originality and our artistry.

Involving individuals in the manufacturing strategy formation : Strategic consensus among workers and managers

Decisions made and actions taken by individuals in the operations function impact the formation of a company’s manufacturing strategy (MS). Therefore, it is important that the MS is understood and agreed on by all employees, that is, strategic consensus among the individuals in the operations function is essential. This research contributes to the current body of knowledge by including a workers’ perspective on MS formation. It is the workers on the shop floor who bring the MS to life in the actual operations through their daily decisions and actions. The MS falls short if the priorities outlined do not materialise in practice as intended. The purpose of this research is to investigate how the individuals in the operations function perceive the MS in order to understand how these individuals are involved in the MS formation. The research is based on five studies, differing by evidence, as follows: one theoretical, three qualitative in the setting of small and medium-sized enterprises (SMEs), and one quantitative at a large company. Based on the findings presented in the six appended papers, the results show that empirically and conceptually, workers have been overlooked or given a passive role in the MS formation. Empirically, it is seen that workers and managers do not have a shared understanding of the underlying reasons for strategic priorities; hence, the level of strategic consensus is low. Furthermore, the level of strategic consensus varies among the different MS dimensions depending on their organisational level. Moreover, the empirical findings reveal that internal contextual factors influence the individuals’ perceptions of the MS and the possibilities for strategic consensus. Regarding the external context, the results show that major customers’ strategies influence the subcontractor SMEs’ MS formation. The usage of means of communication in the operations function has also shown to be of importance for how the MS is perceived. Conceptually, the findings indicate that the MS literature tends to treat individuals in the operations function in a deterministic manner; individuals on the shop floor are regarded as manufacturing resources. To ensure a successful MS formation process, where the patterns of the decisions made by the individuals in the operations function forms the MS, the view on human nature within the MS requires a more voluntaristic approach. This research suggests to view the MS formation as an iterative “patterning process” which builds on a reciprocal relationship between workers and managers. The introduction of the patterning process contributes to the research on MS formation by explaining the perception range within the hierarchical levels, by re-defining the hierarchical levels included in the MS formation and by detailing the activities in the MS formation.

Medical journals and Wikipedia: a global health matter

Approximately 7000 stillbirths occur daily worldwide, and the vast majority of them (98%) Approximately 7000 stillbirths occur daily worldwide, and the vast majority of them (98%) take place in low-income and middle-income countries (LMICs). Despite this enormous burden, progress to reduce the death toll is slow and insufficient. WHO released its Making every baby count guide in 2016, which includes strategies aimed at addressing the challenge of stillbirths. Given the flurry of activity and attention on stillbirths from the Lancet Stillbirth Epidemiology investigator group and WHO, we expect that the wealth of information about stillbirths that is generated will filter down in a timely manner to where it is needed most: the general public.