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Dementia With Lewy Bodies: A Review of Disease-Modifying Therapies for α-Synucleinopathies
Get PDFAims: The global demographic transition has led to a growing ageing population. Neurodegenerative disease prevalence is high in the elderly, as aged brains accumulate molecular and cellular damage. Protein misfolding and aggregation are pathological processes underlying neurodegeneration, as seen in dementia. This coupled with oxidative stress, disrupted ubiquitin-proteosome system and neuroinflammation may contribute to neuronal damage/death. Lewy Body dementia (LBD) collectively refers to Parkinson’s disease (PD), Parkinson-disease dementia and dementia with Lewy bodies (DLB). It is characterised by Lewy Body (LB) deposits in the central nervous system, predominantly compromised of misfolded α-synuclein protein. Disease-modifying therapy (DMT) targets underlying protein misfolding and promotes LB clearance. To review international trials on DMT safety, tolerability and efficacy in DLB. To consider the molecular basis for protein misfolding and DMT in DLB. Methods: Two international registries (ClinicalTrials.gov; EU clinical trials register) were consulted to identify agents being tested in completed, ongoing and recruiting trials. Both databases were searched by disease “Lewy body dementia” or “LBD” or “alpha-synuclein pathology” and study type “interventional” for phase I–III trials. Trials solely investigating diagnostic biomarkers, approved symptomatic DLB treatment or PD without dementia symptoms were excluded from final analysis. Results: 11 trials were found studying DMTs for DLB. 10 out of the 11 trials were in phase II and one in phase I. The main agents investigated were tyrosine-kinase inhibitors (TKIs), phosphodiesterase-9 inhibitors, β-adrenergic agonists, and β GCase chaperones. Primary and secondary outcome measures were “safety/tolerability of agent”, “changes in cognitive function” or “changes in serum/CSF α synuclein levels”. Results from a phase I trial demonstrated a 3.85 and 3.5-point increase in mini-mental state examination scores at 6 months with nilotinib doses 300 mg and 150 mg, respectively. Contrastingly, only slight reduction in CSF/plasma α-synuclein was observed. Phase II trials for bosutinib versus placebo showed no significant difference in cognitive function. Trials for ambroxol, a β-GCase enzyme enhancing inhibitory chaperone, remain in recruiting stages but have proven drug tolerability due to fewer side effects. Data on CSF biomarker changes in DLB was unavailable. Conclusion: Current understanding of protein misfolding in α-synucleinopathies suggests that a single DMT may be insufficient in mixed pathology. Cocktail therapy targeting various misfolded proteins may be necessary for a cure. DMTs have limited use as most patients are diagnosed with advanced DLB. Sensitive diagnostic biomarkers with high specificity are required for accurate DLB diagnosis in the prodromal phase, a critical window for protein misfolding reversal with DMT.N/
Study on modelling and optimising controllers for heating systems in buildings
No full textThe UK, like the rest of the world, is working toward net-zero carbon emissions by 2050. A significant contributor to national emissions (17%) is domestic space heating, making efficient building design and retrofitting crucial. This thesis presents methodologies for simulating, controlling, and analysing domestic heating systems to reduce energy use while maintaining thermal comfort. The core framework, Inverse Dynamics-based Energy Assessment and Simulation (IDEAS), was enhanced into IDEAS+ to better align with the UK’s Standard Assessment Procedure (SAP) for building regulations. Key improvements include:
• A new thermal comfort algorithm for more accurate modelling of human heat perception and support for niche heating
systems.
• Dynamic free heat gain calculations, improving precision and SAP compliance.
• An updated optimum start method to optimize heating schedules based on system capacity.
IDEAS+ was first calibrated using direct electric heating, then applied to Gas Condensing Boilers (GCBs) and Air Source Heat Pumps (ASHPs). To further reduce emissions, optimizing control systems for dynamic energy markets was explored. Traditional optimization methods are slow, requiring iterative simulations. Instead, this thesis introduces a new method - OPTimal Inverse Control (OPTIC), which embeds cost-function optimization directly into IDEAS+’s inverse dynamics control. This allows real-time optimization alongside system operation, improving performance. OPTIC was tested with battery storage, dynamically adjusting to fluctuating energy prices and carbon intensity while ensuring thermal comfort.
Two case studies demonstrated simulation based and practical based applications. One was a block of flats in Eastbourne, modelled in IDEAS+ for retrofit analysis, then simulated with a heat pump network and OPTIC-controlled storage as a simulation only based study. Whilst, the other was a commercial property with PV arrays, heat pumps, and battery storage, controlled via an Industrial PC running OPTIC-based C++/C# code at the property in a practical application. These methods provide scalable solutions for reducing emissions in residential and commercial heating systems, supporting the UK’s net-zero targets
A Scoping review of the Underlying Aetiology of Cryptogenic Stroke: resulting in changes to secondary prevention, management and outcome
No full textIntroduction: Over a quarter of people who have experienced a stroke, have recurrent events and cross-sectional surveys indicate that some 1/3 of the burden of severe long-term disability due to cerebrovascular disease can be attributed to recurrent stroke. A third of transient ischaemic attacks (TIAs) and ischaemic strokes are of undetermined cause (ie, cryptogenic), potentially undermining secondary prevention. The last few decades have seen a quiet revolution in our appreciation of the potential for preventing recurrent events in stroke survivors, which, if put into practice, could have an enormous impact on the overall burden of stroke disease. Reducing the increasing number classified as cryptogenic stroke by finding the underlying aetiology, determines the choice of therapy and the most effective secondary preventive measures to take, highlighting the role thorough investigation plays. Available diagnostic protocols either fail to identify the aetiology after thorough or incomplete evaluation. Other factors contributing to this include variation in clinical practice as per preference of individual stroke physicians/ treating clinicians and variable availability of the diagnostic tools. Purpose: In this scoping review, studies focusing on discovering the underlying aetiology, the changes to management if any because of this discovery and outcome are reviewed. The extent to which the exists consensus, disagreement and gaps in clinical practice recommendations on aetiologic in acute ischaemic stroke. Method: Articles included were selected using a pre-determined inclusion and exclusion criteria to assess for eligibility. Searching of 4 electronic databases and handsearching of websites/reference lists was done, with data reporting aetiologic workup, outcome and changes (if any) of cryptogenic stroke was extracted. Quality was assessed using the Cochrane Collaboration’s tool for assessing the risk of bias. Results: Out of 1103 studies selected, 81 full-texted were fully reviewed out of which 36 were selected for yielding underlying aetiology of CS after advanced screening. Conclusion: There exists some acceptance about the Standard diagnostic workup needed after stroke but very little on more advanced investigations for the thorough or rarer underlying aetiology of cryptogenic stroke. This demonstrates missed opportunities to manage and institute the correct secondary prevention. Recommendations Further research is needed to effect policy changes that will ensure the existing knowledge on the where and when standard advanced diagnostic techniques are used in discovering the underlying aetiology of cryptogenic stroke
An ethnographic study exploring health visitors' engagement with fathers of children under five years old: A Bourdieusian perspective
No full textThe health visiting service within the United Kingdom (UK) provides an essential public health service for all families with children under the age of five years old, under the wider umbrella of the 0-19 service. Despite maternity and postnatal policy stipulating a ‘family-centred’ approach to care delivery, the wider literature suggests that fathers can often feel marginalised within the health visiting service. An indirect corollary to this is that men’s mental health (MH) illness has been steadily increasing over several years. This is an area that health visitors (HVs) are available to assess and offer support to fathers, yet do not appear to be doing.
A critical ethnographic approach was used to explore HVs engagement with fathers, through a combination of observations of HV practice, semi-structured interviews and field notes. The research took place in a health visiting service in the Northwest of England, with a sample of qualified HVs. Spradley’s framework for data analysis was employed to make sense of the findings and a Bourdieusian lens was used as a conduit for exploring individual HV practice within the wider scope of organisational custom and practice.
Three themes emerged from the findings which include man in a van - barriers to HV engagement with fathers; toxic masculinity and feminist health visiting - a disconnect; and the ‘forgotten husband’s club - father’s mental health and the health visiting service. The findings highlight that organisational barriers exist, which impede HV engagement with fathers, alongside toxic masculinity, which has gathered momentum as a concept in contemporary society. Similarly, men’s MH remains an underassessed area of practice for HVs, leaving fathers feeling ‘forgotten’ by services.
Implications for practice include policy review surrounding paternity leave, a review of commissioning of health visiting services, including delivery of universal antenatal contacts, designated electronic records for fathers and increased screening of paternal MH at routine HV contacts
Induced plant resistance and its influence on natural enemy use of plant-derived foods
Get PDFCrown Copyright © 2024 Published by Elsevier Inc.In response to herbivory, plants employ several inducible defenses to mitigate herbivore damage. These plant-induced responses can trigger subtle changes in plant metabolite composition, altering the profiles of plant-produced exudates such as (extra-) floral nectar and plant guttation. Natural enemies consume these plant-produced exudates, which serve as consistent and nutrient-dense food sources. There is mounting evidence that natural enemies' access to plant-produced exudates impacts their fitness, performance, and life history traits. Nonetheless, the role of induced plant defense on plant-produced exudates and the subsequent effect on natural enemies remains under-researched. This review, thus, highlights the potential role of induced plant defense on the profiles of plant-produced exudates, with a particular emphasis on altered metabolic changes affecting resource nutritional value and consequently the fitness and performance of natural enemies. Future directions and potential implications in biological control practices are also highlighted.Unfunde
The indirect effect of nectar-inhabiting yeasts on olfactory responses and longevity of two stink bug egg parasitoids
Get PDF© The Author(s) 2024.The version of record of this article, first published in [BioControl], is available online at Publisher’s website: http://dx.doi.org/10.1007/s10526-023-10237-yAdult parasitoids are well known to feed on sugar-rich resources such as floral nectar. Recently, an increasing body of evidence has shown that nectar is ubiquitously colonized by microorganisms and, as a consequence, microbial metabolic activity can affect several traits of floral nectar. Yet, how the fermentation of nectar by yeasts impacts the olfactory responses and performance of parasitoids is largely understudied, especially in the case of egg parasitoids. In this study, we investigated whether fermentation by the nectar yeasts Metschnikowia gruessii and M. reukaufii affects the olfactory responses of Trissolcus basalis and Ooencyrtus telenomicida, two egg parasitoid species associated with the southern green stink bug Nezara viridula. We also investigated how yeast fermentation affects the longevity and survival of the egg parasitoids. Results of static four-chamber olfactometer tests showed that nectar fermented by M. gruessii (but not by M. reukaufii) was attractive to both egg parasitoid species, whereas no significant yeast-mediated effects were found in terms of wasp longevity. Gas chromatography coupled with mass spectrometry (GC-MS) showed a clear separation of the volatile profiles among M. gruessii, M. reukaufii and non-fermented control nectar supporting the results of the insect bioassays. The results of our study highlight the need to consider the role of microbes when studying interactions between flower nectar and egg parasitoids and could have implications from a conservation biological control perspective.Open access funding provided by Università degli Studi di Palermo within the CRUI-CARE Agreement
Ethylene functions as a suppressor of volatile production in rice
Get PDFThis is a pre-copyedited, author-produced version of an article accepted for publication in [Journal of Experimental Botany] following peer review. The version of record [Mujiono, K., Tohi, T., Sobhy, I. S., Hojo, Y., Ho, N. T., Shinya, T., & Galis, I. (2020). Ethylene functions as a suppressor of volatile production in rice. Journal of Experimental Botany, 71(20), 6491-6511] is available online at: https://academic.oup.com/jxb/article/71/20/6491/5874908 [https://doi.org/10.1093/jxb/eraa341]We examined the role of ethylene in the production of rice (Oryza sativa) volatile organic compounds (VOCs), which act as indirect defense signals against herbivores in tritrophic interactions. Rice plants were exposed to exogenous ethylene (1 ppm) after simulated herbivory, which consisted of mechanical wounding supplemented with oral secretions (WOS) from the generalist herbivore larva Mythimna loreyi. Ethylene treatment highly suppressed VOCs in WOS-treated rice leaves, which was further corroborated by the reduced transcript levels of major VOC biosynthesis genes in ethylene-treated rice. In contrast, the accumulation of jasmonates (JA), known to control VOCs in higher plants, and transcript levels of primary JA response genes, including OsMYC2, were not largely affected by ethylene application. At the functional level, flooding is known to promote internode elongation in young rice via ethylene signaling. Consistent with the negative role of ethylene on VOC genes, the accumulation of VOCs in water-submerged rice leaves was suppressed. Furthermore, in mature rice plants, which naturally produce less volatiles, VOCs could be rescued by the application of the ethylene perception inhibitor 1-methylcyclopropene. Our data suggest that ethylene acts as an endogenous suppressor of VOCs in rice plants during development and under stress.We thank Atsushi Miyake (Okayama University) for help with development of GC-MS methods used for volatile measurements; Dr Hideyuki Matsuura (Hokkaido University) for providing deuterated jasmonate standards for LC-MS/MS; Dr Yasutaka Kubo (Okayama University) for providing 1-MCP; and Dr David Wari for checking the manuscript. This work was supported by Ohara Foundation and JSPS KAKENHI Grants (No. 24570026 and 16K08143 to IG, No. 18K05558 to TS). TT was supported by Pacific Leaders’ Educational Assistance for Development of State (Pacific-LEADS) from JICA (Japan International Cooperation Agency); ISS by the JSPS postdoctoral fellowship P13379; and KM by IsDB 4 in 1 Project by Ministry of Research, Technology, and Higher Education, Republic of Indonesia
Bacterial phylogeny predicts volatile organic compound composition and olfactory response of an aphid parasitoid
Get PDFThis is the peer reviewed version of the following article: [Goelen, T., Sobhy, I. S., Vanderaa, C., Wäckers, F., Rediers, H., Wenseleers, T., Jacquemyn, H., & Lievens, B. (2020). Bacterial phylogeny predicts volatile organic compound composition and olfactory response of an aphid parasitoid. Oikos, 129(9), 1415-1428], which has been published in final form at [https://doi.org/10.1111/oik.07301]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.There is increasing evidence that microorganisms emit a wide range of volatile compounds (mVOCs, microbial volatile organic compounds) that act as insect semiochemicals, and therefore play an important role in insect behaviour. Although it is generally believed that phylogenetically closely related microbes tend to have similar phenotypic characteristics and therefore may elicit similar responses in insects, currently little is known about whether the evolutionary history and phylogenetic relationships among microorganisms have an impact on insect–microbe interactions. In this study, we tested the hypothesis that phylogenetic relationships among 40 Bacillus strains isolated from diverse environmental sources predicted mVOC composition and the olfactory response of the generalist aphid parasitoid Aphidius colemani . Results revealed that phylogenetically closely related Bacillus strains emitted similar blends of mVOCs and elicited a comparable olfactory response of A. colemani in Y‐tube olfactometer bioassays, varying between attraction and repellence. Analysis of the chemical composition of the mVOC blends showed that all Bacillus strains produced a highly similar set of volatiles, but often in different concentrations and ratios. Benzaldehyde was produced in relatively high concentrations by strains that repel A. colemani , while attractive mVOC blends contained relatively higher amounts of acetoin, 2,3‐butanediol, 2,3‐butanedione, eucalyptol and isoamylamine. Overall, these results indicate that bacterial phylogeny had a strong impact on mVOC compositions and as a result on the olfactory responses of insects.Unfunde
Habitat-specific variation in gut microbial communities and pathogen prevalence in bumblebee queens (Bombus terrestris)
Get PDF© 2018 Bosmans et al.Gut microbial communities are critical for the health of many insect species. However, little is known about how gut microbial communities respond to anthropogenic changes and how such changes affect host-pathogen interactions. In this study, we used deep sequencing to investigate and compare the composition of gut microbial communities within the midgut and ileum (both bacteria and fungi) in Bombus terrestris queens collected from natural (forest) and urbanized habitats. Additionally, we investigated whether the variation in gut microbial communities under each habitat affected the prevalence of two important bumblebee pathogens that have recently been associated with Bombus declines (Crithidia bombi and Nosema bombi). Microbial community composition differed strongly among habitat types, both for fungi and bacteria. Fungi were almost exclusively associated with bumblebee queens from the forest habitats, and were not commonly detected in bumblebee queens from the urban sites. Further, gut bacterial communities of urban B. terrestris specimens were strongly dominated by bee-specific core bacteria like Snodgrassella (Betaproteobacteria) and Gilliamella (Gammaproteobacteria), whereas specimens from the forest sites contained a huge fraction of environmental bacteria. Pathogen infection was very low in urban populations and infection by Nosema was only observed in specimens collected from forest habitats. No significant relationship was found between pathogen prevalence and microbial gut diversity. However, there was a significant and negative relationship between prevalence of Nosema and relative abundance of the core resident Snodgrassella, supporting its role in pathogen defense. Overall, our results indicate that land-use change may lead to different microbial gut communities in bumblebees, which may have implications for bumblebee health, survival and overall fitness.This study was supported by KU Leuven (Postdoctoral Mandate, grant to L.B. (PDM/17/132)) and the Research Foundation Flanders (FWO) (grant to M.I.P. (12A0716N))
Development, consumption rates and reproductive biology of Orius albidipennis reared on various prey
No full textThis article is not available on ChesterRepThe predatory bug Orius albidipennis (Reuter) (Hemiptera: Anthocoridae) has tremendous potential as a biological control agent, especially in its native range around the Mediterranean Basin and East Africa. The need to exploit native biological control agents is growing in importance as concerns over the introduction of non-native species continue to increase. However, little is known of the effects of different prey on development and reproduction of O. albidipennis compared with other species of Orius. Therefore, we compared the development, survival, reproductive biology, and prey consumption of O. albidipennis when fed eggs of Ephestia kuehniella Zeller, Tetranychus urticae Koch, and Trialeurodes vaporariorum (Westwood), and larvae of Gynaikothrips ficorum (Marchal), under laboratory of 26 ± 1°C, 60 ± 10% RH and 16L:8D photoperiod. Individuals were reared from the neonate stage until death on one of the four prey types. The type of prey had profound effects on all measured performance traits. The highest survival rate was recorded for nymphs that were fed on E. kuehniella eggs, while the lowest survival rate was observed for those fed on T. vaporariorum eggs. The shortest nymphal period was recorded for nymphs fed on E. kuehniella eggs, while the longest was measured for those fed on T. urticae eggs. During the nymphal period, O. albidipennis consumed significantly more eggs of T. urticae than other prey types, whereas the lowest number of consumed prey were eggs of E. kuehniella. Adult females and males consumed significantly more T. urticae eggs than other types of prey. However, Orius albidipennis females showed the highest fecundity when fed on E. kuehniella eggs, and the lowest when fed on T. vaporariorum eggs. Adult females and males that fed on G. ficorum larvae had significantly longer life spans compared with those fed other prey. Because of their relatively rapid development and high fecundity, O. albidipennis fed E. kuehniella eggs had a significantly higher net reproductive rate (Ro) and intrinsic rate of increase (rm) than O. albidipennis fed other prey types. Overall, eggs of E. kuehniella were the most suitable diet for nymphs and adults of O. albidipennis. Although less suitable, O. albidipennis could survive and reproduce on the other prey types, which is a favourable attribute in biological control agents. These results on the effect of different prey types on development and reproduction of O. albidipennis will also contribute to the development of mass rearing programs for biological control agents in developing countries, such as Egypt.Unfunde
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