Psychosis and Apathy in Parkinson’s disease

Increasingly recognized as a heterogenous syndromic condition with multi- neurotransmitter dysfunction involving complex endophenotypes, the modern management options for Parkinson’s disease (PD) have evolved far beyond mere motor symptom control alone. Subtype-specific strategies for PD in the context of personalised medicine, with consideration of external influential factors such as age, personality, treatment preferences, cultural beliefs, lifestyle, socioeconomics, genetic framework, as well as comorbidities, are now regarded as the modern and holistic approach. The focus of this thesis is on the two key non-motor symptoms of psychosis and apathy in PD, as well as their connections with each other. These are the two neuropsychiatric entities for which identification remains a challenge despite more than a decade of expanding research, and for which there is still much to be understood. For PD psychosis, the lack of a comprehensive and disease-specific instrument was the critical point of contention regarding the efficacy and safety of pimavanserin, the only medication licensed by the United States in 2016 for the treatment of psychosis in Parkinson’s disease. For PD apathy, doubt remains on whether it is a clinically meaningful syndrome in PD, with its pervasive intersections with other established neuropsychiatric symptoms such as depression and anxiety. As part of my efforts to investigate for potential risk factors for the phenotypic expression of neuropsychiatric symptoms in PD (specifically psychosis and apathy), I strove to determine if there are shared genetic risk factors between PD and psychiatric disorders, I conducted a large case-control genetic association study involving 1291 subjects. I found a borderline association between CLCN3 genetic variant (rs62333164) and PD in our Asian population, suggesting a potential overlap of genetic risk factors between the two disease groups. Further validation in independent cohorts and meta-analyses involving larger samples will be warranted, as identification of shared genetic factors can help facilitate stratification of PD patients at risk of neuropsychiatric complications and selection for clinical drug trials. Narrative reviews were conducted to establish a solid background on the phenomenology as well as kinetics of both psychosis and apathy (Chapters 1 and 2). A comprehensive review into the existing instruments that quantify psychosis severity in PD was completed, with an in-depth analysis of the strengths and limitations of each scale developed since 2008. All this information were then assimilated into the configuration of the Psychosis Severity Scale of Parkinson’s disease, or Psy-PD. After going through cognitive pre-testing and standardised validation methods among a cohort of patients recruited at the King’s College Hospital Parkinson’s Foundation Centre of Excellence in the UK, the Psy-PD was demonstrated to be a feasible and acceptable scale, with appropriate basic clinimetric attributes to measure psychosis severity in PD. Subsequently the results of two cohort studies conducted across two different locations (London, Singapore) looking at apathy among PwPs revealed that apathy exists independent of psychosis, depression, and anxiety in PD, and supports the prevailing notion of a complex non- dopaminergic circuit involvement in terms of pathogenesis. The prevalence of apathy is also ubiquitous in PD, regardless of ethnic boundaries or geographical disparities. Our research findings supported the growing recognition of non-motor endophenotypes of PD and suggested the existence of a specific clinical phenotype that is associated with a poor quality of life in PD. This proposed clinical phenotype of concurrent psychosis and apathy (without depression) in PD is significantly associated with a higher non-motor burden and reduced quality of life, compared to other phenotypes explored. The research done for this academic work have increased our understanding about the range and nature of the two debilitating neuropsychiatric features of psychosis and apathy in PD. I hope that the findings will establish the groundwork for large-scale longitudinal research studies focusing on clinical and behavioural biomarkers towards refining a more holistic approach in terms of identification and management

Microcrystalline Dolomite in a Middle Permian Volcanic Lake: Insights on Primary Dolomite Formation in a Non-Evaporitic Environment

Lacustrine dolomite nucleation commonly occurs in modern and Neogene evaporitic alkaline lakes. As a result, ancient lacustrine microcrystalline dolomite has been conventionally interpreted to be formed in evaporitic environments. This study, however, suggests a non-evaporitic origin of dolomite precipitated in a volcanic–hydrothermal lake, where hydrothermal and volcanic processes interacted. The dolomite occurs in lacustrine fine-grained sedimentary rocks in the middle Permian Lucaogou Formation in the Santanghu intracontinental rift basin, north-west China. Dolostones are composed mainly of nano-sized to micron-sized dolomite with a euhedral to subhedral shape and a low degree of cation ordering, and are interlaminated and intercalated with tuffaceous shale. Non-dolomite minerals, including quartz, alkaline feldspars, smectite and magnesite mix with the dolomite in various proportions. The 87Sr/86Sr ratios (0.704528 to 0.705372, average = 0.705004) and δ26Mg values (−0.89 to −0.24‰, average = −0.55‰) of dolostones are similar to those of mantle rocks, indicating that the precipitates mainly originated from fluids that migrated upward from the mantle and were subject to water–rock reactions at a great depth. The δ18O values (−3.1 to −22.7‰, average = −14.0‰) of the dolostones indicate hydrothermal influence. The trace and rare earth element concentrations suggest a saline, anoxic and volcanic–hydrothermally-influenced subaqueous environment. In this subaqueous environment of Lucaogou lake, locally high temperatures and a supply of abundant Mg2+ from a deep source induced by volcanic–hydrothermal activity formed favourable chemical conditions for direct precipitation of primary dolomite. This study\u27s findings deepen the understanding of the origin and processes of lacustrine primary dolomite formation and provide an alternative possibility for environmental interpretations of ancient dolostones

Phase Control on Surface for the Stabilization of High Energy Cathode Materials of Lithium Ion Batteries.

The development of high energy electrode materials for lithium ion batteries is challenged by their inherent instabilities, which become more aggravated as the energy densities continue to climb, accordingly causing increasing concerns on battery safety and reliability. Here, taking the high voltage cathode of LiNi0.5Mn1.5O4 as an example, we demonstrate a protocol to stabilize this cathode through a systematic phase modulating on its particle surface. We are able to transfer the spinel surface into a 30 nm shell composed of two functional phases including a rock-salt one and a layered one. The former is electrochemically inert for surface stabilization while the latter is designated to provide necessary electrochemical activity. The precise synthesis control enables us to tune the ratio of these two phases, and achieve an optimized balance between improved stability against structural degradation without sacrificing its capacity. This study highlights the critical importance of well-tailored surface phase property for the cathode stabilization of high energy lithium ion batteries

AGROBEST: an efficient Agrobacterium-mediated transient expression method for versatile gene function analyses in Arabidopsis seedlings

Background: Transient gene expression via Agrobacterium-mediated DNA transfer offers a simple and fast method to analyze transgene functions. Although Arabidopsis is the most-studied model plant with powerful genetic and genomic resources, achieving highly efficient and consistent transient expression for gene function analysis in Arabidopsis remains challenging. Results: We developed a highly efficient and robust Agrobacterium-mediated transient expression system, named AGROBEST (Agrobacterium-mediated enhanced seedling transformation), which achieves versatile analysis of diverse gene functions in intact Arabidopsis seedlings. Using β-glucuronidase (GUS) as a reporter for Agrobacterium-mediated transformation assay, we show that the use of a specific disarmed Agrobacterium strain with vir gene pre-induction resulted in homogenous GUS staining in cotyledons of young Arabidopsis seedlings. Optimization with AB salts in plant culture medium buffered with acidic pH 5.5 during Agrobacterium infection greatly enhanced the transient expression levels, which were significantly higher than with two existing methods. Importantly, the optimized method conferred 100% infected seedlings with highly increased transient expression in shoots and also transformation events in roots of ~70% infected seedlings in both the immune receptor mutant efr-1 and wild-type Col-0 seedlings. Finally, we demonstrated the versatile applicability of the method for examining transcription factor action and circadian reporter-gene regulation as well as protein subcellular localization and protein–protein interactions in physiological contexts. Conclusions: AGROBEST is a simple, fast, reliable, and robust transient expression system enabling high transient expression and transformation efficiency in Arabidopsis seedlings. Demonstration of the proof-of-concept experiments elevates the transient expression technology to the level of functional studies in Arabidopsis seedlings in addition to previous applications in fluorescent protein localization and protein–protein interaction studies. In addition, AGROBEST offers a new way to dissect the molecular mechanisms involved in Agrobacterium-mediated DNA transfer

Theoretical Corrections of RDR_D and RD∗R_{D^*}

$R_{D^{(*)}}$ is the ratio of branching ratio $\overline{B} \rightarrow D^{(*)}\tau\overline{\nu}_{\tau}$ to $\overline{B} \rightarrow D^{(*)}l\overline{\nu}_{l}$. There is a gap of $2\sigma_{exp}$ or more between its experimental value and the prediction under the standard model(SM). People extend the MSSM with the local gauge group $U(1)_X$ to obtain the $U(1)_X$SSM. Compared with MSSM, $U(1)_X$SSM has more superfields and effects. In $U(1)_X$SSM, we research the decays $\overline{B} \rightarrow D^{(*)}l\overline{\nu}_{l}$ and calculate $R_{D^{(*)}}$. The obtained numerical results of $R_{D^{(*)}}$ are further corrected under $U(1)_X$SSM, which is much better than the SM predictions. After correction, the theoretical value of $R_{D^{(*)}}$ can reach in one $\sigma_{exp}$ range of the averaged experiment central value

Mesenchymal stem cells alleviate bacteria‐induced liver injury in mice by inducing regulatory dendritic cells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102718/1/hep26670.pd

Macrophages and pulmonary fibrosis: a bibliometric and visual analysis of publications from 1990 to 2023

BackgroundThe role of macrophages in the symptomatic and structural progression of pulmonary fibrosis (PF) has garnered significant scholarly attention in recent years. This study employs a bibliometric approach to examine the present research status and areas of focus regarding the correlation between macrophages and PF, aiming to provide a comprehensive understanding of their relationship.MethodologyThe present study employed VOSviewer, CiteSpace, and Microsoft Excel software to visualize and analyze various aspects such as countries, institutions, authors, journals, co-cited literature, keywords, related genes, and diseases. These analyses were conducted using the Web of Science core collection database.ResultsA comprehensive collection of 3,479 records pertaining to macrophages and PF from the period of 1990 to 2023 was obtained. Over the years, there has been a consistent increase in research literature on this topic. Notably, the United States and China exhibited the highest level of collaboration in this field. Through careful analysis, the institutions, authors, and prominent journals that hold significant influence within this particular field have been identified as having the highest publication output. The pertinent research primarily concentrates on the domains of Biology and Medicine. The prevailing keywords encompass pulmonary fibrosis, acute lung injury, idiopathic pulmonary fibrosis, and others. Notably, TGFβ1, TNF, and CXCL8 emerge as the most frequently studied targets, primarily associated with signaling pathways such as cytokine–cytokine receptor interaction. Additionally, cluster analysis of related diseases reveals their interconnectedness with ailments such as cancer.ConclusionThe present study employed bibliometric methods to investigate the knowledge structure and developmental trends in the realm of macrophage and PF research. The findings shed light on the introduction and research hotspots that facilitate a more comprehensive understanding of macrophages and PF

Epidemic Pleurodynia Caused by Coxsackievirus B3 at a Medical Center in Northern Taiwan

Epidemic pleurodynia is seldom reported in Southeast Asia and there has been no report from Taiwan. We conducted a retrospective chart review of children = 18 years of age in the National Taiwan University Hospital from January 1 to December 31, 2005. Epidemic pleurodynia was defined as an acute illness characterized by sharp localized pain over the chest or upper abdomen. Patients with known heart diseases or pulmonary consolidations were excluded. In total, 28 patients met the case definition of epidemic pleurodynia. Coxsackievirus B3 (CB3) was isolated in 15 (60%) of the 25 throat swab specimens. Four (14%) of the 28 patients presented chest wall tenderness and only one (6%) of the 18 patients tested had an elevated creatinine kinase level. Twenty-one (75%) of the 28 patients described pleuritic chest pains and 10 (45%) of the 22 chest radiographies exhibited pulmonary infiltrates or pleural effusions. Six patients were observed with tonsillar exudates and one was confirmed to have a CB3 urinary tract infection. The clinical features and radiological findings suggest that CB3-associated epidemic pleurodynia might be a disease of the pleura and occasionally spreads to nearby tissues, resulting in chest wall myositis, pulmonary infiltrates and myopericarditis