Pyrazole scaffold synthesis, functionalization, and applications in Alzheimer\u27s disease and Parkinson\u27s disease treatment (2011-2020)

The remarkable prevalence of pyrazole scaffolds in a versatile array of bioactive molecules ranging from apixaban, an anticoagulant used to treat and prevent blood clots and stroke, to bixafen, a pyrazole-carboxamide fungicide used to control diseases of rapeseed and cereal plants, has encouraged both medicinal and organic chemists to explore new methods in developing pyrazole-containing compounds for different applications. Although numerous synthetic strategies have been developed in the last 10 years, there has not been a comprehensive overview of synthesis and the implication of recent advances for treating neurodegenerative disease. This review first presents the advances in pyrazole scaffold synthesis and their functionalization that have been published during the last decade (2011-2020). We then narrow the focus to the application of these strategies in the development of therapeutics for neurodegenerative diseases, particularly for Alzheimer\u27s disease (AD) and Parkinson\u27s disease (PD)

Impact of ageing on mitochondrial complex expression and islet cell composition in mtDNA mutator mice and human pancreas

Ph. D. Thesis.Age-related cumulative mitochondrial mutations can cause mitochondrial dysfunction. The mitochondrial DNA mutator mouse (PolgAmut/mut) is a model of premature ageing and has been previously shown to develop impaired insulin secretion with age. Normal human ageing has been associated with islet β-cell dysfunction and the change of islet cell composition. The overall aim was to explore the impact of ageing on mitochondrial complex expression and islet cell composition in PolgAmut/mut mice and human pancreas. Immunofluorescence was used to study mitochondrial respiratory chain protein expression (complex I and IV) by normalizing to mitochondrial mass marker (Tomm20). This technique was also applied to the study of islet cell composition with proliferation marker Ki67. Experiments were conducted on pancreas tissue from PolgAmut/mut mice and age-matched wild type (WT) mice at two ages: 3 months (young) and 11 months(old). Some of the PolgAmut/mut mice underwent exercise training from 4 months of age. Non-diabetic normal human pancreas tissue from two age groups: 20~40 years (young) and 60~80 years (old) were also studied for mitochondrial complex expression and islet cell composition. The findings of the first three result chapters described the impact of ageing in mtDNA mutator mice model. Complex I expression was decreased in islets from young PolgAmut/mut mice, and it persisted with age in comparison with the WT mice. Investigation of islet cell composition identified an increase in absolute α-cell number with age in the PolgAmut/mut mice that contributed to a decreased β:α ratio in islets from the old PolgAmut/mut mice versus the age-matched WT mice. Ki67 examination showed that increased α-cell proliferation contributed to the increase in α-cell mass. Islet cell subtype analysis in old PolgAmut/mut mice revealed that the complex I deficiency was greater in the α-cells compared with the β-cells, suggesting that the increased α-cell proliferation observed in old PolgAmut/mut mouse islets maybe a direct response to complex I deficiency. Although none of these mice developed diabetes with age, decreased insulin expression was discovered in the pancreatic islets of the old PolgAmut/mut mice. Endurance exercise did not have significant impact on mitochondrial complex expression nor islet cell composition in old PolgAmut/mut mice. The last result chapter explored the impact of ageing in human pancreatic tissues from non-diabetic donors. Tomm20 expression was higher in pancreatic islets from old versus young donors, but there was no difference in complex I and IV expression. Whole islet cell number and absolute β-cell number were lower in the old versus young islets, but there was no significant difference in the β:α ratio. Taken together, my findings show that mitochondrial dysfunction alters pancreatic islet cell composition in response to ageing in the PolgAmut/mut mice. In non-diabetic human islets, there is no evidence of altered mitochondrial subunit expression but Tomm20 expression was increased in the islets from old donors appears to reflect a compensatory increase in mitochondrial mass

The Role of Vitamin D in Controlling and Managing Glycaemic Control in Patients with Type 2 Diabetes (D4D)

University of Technology Sydney. Faculty of Science.: There is growing evidence indicating the link between serum 25-hydroxy-vitamin D (25(OH)D) level and Type 2 Diabetes Mellitus (T2DM). Many large cohort observational studies have confirmed an inverse association between serum 25(OH)D level and T2DM risks, while Randomised Control Trials (RCTs) have presented inconsistent results. It was therefore decided to conduct a literature review of current RCTs to identify limitations, design and conduct a more rigorous RCT, i.e. D4D trial, to evaluate the association between serum 25(OH)D level and T2DM. : D4D trial was a long-term, multi-centre, single-blind, four-arm parallel-group trial. Eligible participants were randomised to receive vitamin D from interventions: 1) 10-15 µg/day (400-600 IU/day) from food, 2) 12.5 µg/day (500 IU/day) from sunlight exposure, 3) 12.5 µg/day (500 IU/day) from supplements or 4) waitlist without intervention, for nine months. Serum 25(OH)D level, HbA1c and lipids levels were measured at baseline, 3rd, and 9th month after the intervention. : 60 participants were recruited in the D4D trial, with 15 participants per intervention group. Results suggested serum 25(OH)D was inversely associated with HbA1c level but was not statistically significant. Detailed results as following: 1) Serum 25(OH)D level in Diet group at 9th month was significantly increased compared to Waitlist group (p=0.0068) and Supplement group (p=0.0392), 2) Serum 25(OH)D in Diet group at 9th month was significantly increased compared to baseline (p=0.0166) and 3rd month (p=0.0268); 3) Serum 25(OH)D level in Sun exposure group at 3rd month and in Supplement group at 9th month was significantly increased compared to their baseline (p=0.0361 and p=0.0319); 4) HbA1c level in Diet group (p=0.0279) at 9th month was significantly reduced compared to Waitlist group, 5) HbA1c level in Diet group (p=0.0039) and Supplement Group (p=0.0332) at 3rd month and Diet group (p=0.0299) at 9th month also presented significant decreases compared to baseline, 6) Lipids levels were not significantly changed by the interventions. : Dietary vitamin D is the most effective source to increase Serum 25(OH)D levels and improve glycaemic control among T2DM patients. Vitamin D from sun and supplements requires a large dosage and a medium to long intervention time to show the effects. Future well-designed clinical trials should assess the vitamin D from natural lifestyle interventions to distinguish vitamin D’s effect on glycaemic control from the confounding factors and generate feasible and patient-oriented suggestions

Characterization and Correction of the Scattering Background Produced by Dust on the Objective Lens of the Lijiang 10-cm Coronagraph

Scattered light from the objective lens, directly exposed to the intense sunlight, is a dominant source of stray light in internally occulted coronagraphs. The variable stray light, such as the scatter from dust on the objective lens, can produce varying scattering backgrounds in coronal images, significantly impacting image quality and data analysis. Using data acquired by the Lijiang 10-cm Coronagraph, the quantitative relationship between the distribution of dust on the objective lens and the resulting scattering backgrounds background is analyzed. Two empirical models for the scattering background are derived, and used to correct the raw coronal data. The second model, which depends on three parameters and performs better, shows that the scattering-background distribution varies with angle, weakens with increasing height, and enhances with increasing dust level on the objective lens. Moreover, we find that the dust on the center of the objective lens can contribute more significantly to the scattering background than on the edge. This study not only quantitatively confirms the significant impact of the stray light produced by dust on the objective lens of the coronagraph, but also corrects the coronal data with this stray light for the first time. Correcting for dust-scattered light is crucial for the high-precision calibration of ground-based coronagraph data, enabling a more accurate analysis of coronal structures. Furthermore, our model is envisioned to support the provision of reliable observational data for future routine coronal magnetic-field measurements using ground-based coronagraphs.Comment: 18 pages, 14 figrue

Skeleton-of-Thought: Large Language Models Can Do Parallel Decoding

This work aims at decreasing the end-to-end generation latency of large language models (LLMs). One of the major causes of the high generation latency is the sequential decoding approach adopted by almost all state-of-the-art LLMs. In this work, motivated by the thinking and writing process of humans, we propose "Skeleton-of-Thought" (SoT), which guides LLMs to first generate the skeleton of the answer, and then conducts parallel API calls or batched decoding to complete the contents of each skeleton point in parallel. Not only does SoT provide considerable speed-up (up to 2.39x across 11 different LLMs), but it can also potentially improve the answer quality on several question categories in terms of diversity and relevance. SoT is an initial attempt at data-centric optimization for efficiency, and reveal the potential of pushing LLMs to think more like a human for answer quality.Comment: Technical report, work in progres

Automaticity in processing spatial-numerical associations: Evidence from a perceptual orientation judgment task of Arabic digits in frames.

Human adults are faster to respond to small/large numerals with their left/right hand when they judge the parity of numerals, which is known as the SNARC (spatial-numerical association of response codes) effect. It has been proposed that the size of the SNARC effect depends on response latencies. The current study introduced a perceptual orientation task, where participants were asked to judge the orientation of a digit or a frame surrounding the digit. The present study first confirmed the SNARC effect with native Chinese speakers (Experiment 1) using a parity task, and then examined whether the emergence and size of the SNARC effect depended on the response latencies (Experiments 2, 3, and 4) using a perceptual orientation judgment task. Our results suggested that (a) the automatic processing of response-related numerical-spatial information occurred with Chinese-speaking participants in the parity task; (b) the SNARC effect was also found when the task did not require semantic access; and (c) the size of the effect depended on the processing speed of the task-relevant dimension. Finally, we proposed an underlying mechanism to explain the SNARC effect in the perceptual orientation judgment task