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Effects of melatonin treatment on 5-mC regulation in 5XFAD mouse model of Alzheimer's disease
No full textpublished_or_final_versionBiomedical SciencesMasterMaster of Research in Medicin
Exploring the determinants of type 2 diabetes using metabolomics and proteomics data via Mendelian randomization
No full textType 2 diabetes (T2D) is projected to impact over 1.3 million people worldwide by 2050. Known risk factors may not have fully explained differences in the aetiology of T2D highlighting the need for alternative approaches in elucidating the factors driving these patterns. Advances in high-throughput omics technologies, such as proteomics and metabolomics, have enabled the identification of novel disease determinants. However, these omics studies suffer from the same methodological limitations - confounding and selection bias - as conventional observational designs.
Mendelian randomization (MR), a study design that utilizes genetic instruments randomly allocated at conception, is more resistant to confounding, and so provides more reliable evidence for causal inference. Using summary statistics from large genome-wide association studies (GWAS) (N ≤1,812,017), this thesis explored the determinants of T2D by investigating the role of amino acids in T2D and glycaemic traits and by identifying the proteomics linkage between metabolic dysfunction-associated steatotic liver disease (MASLD), a disease causally linked to T2D, and T2D. This thesis also explored the complementary question of the differential impact of glycaemic traits and liability to T2D on circulating metabolites using two-sample MR, two-step MR, and cis-MR analyses.
Using all nine proteogenic amino acids available in the UK Biobank summary statistics, alanine was associated with higher T2D risk, fasting glucose and glycated haemoglobin and with lower fasting insulin, whereas isoleucine may explain the positive association of branched-chain amino acids with T2D. Among 4,907 circulating proteins, alcohol dehydrogenase 1B (ADH1B), a key alcohol-metabolizing enzyme, may partially mediate the mechanistic link of MASLD with T2D. Regarding the metabolomic profiling of glycaemic traits, liability to T2D shared a signature with insulin, but not other glycaemic traits, highlighting the hyperglycemia-independent role of insulin in the pathophysiology of T2D.
This thesis provides evidence for dietary guidelines and recommendations on amino acids intake and supplementation. My study also showed ADH1B has a dual role, taking part in the pathophysiological pathway of both alcohol and non-alcoholic fatty liver disease. Moreover, the heterogeneity in metabolomic signatures for different glycaemic criteria provides insights to the association of T2D with other metabolic diseases, providing an opportunity to reduce the T2D burden and T2D-related mortality.published_or_final_versionPublic HealthDoctoralDoctor of Philosoph
Two essays on the externalities of corporate financial reporting
No full textThis thesis consists of two chapters that investigate the externalities of corporate financial reporting from the aspects of local entrepreneurship and bank loans, respectively. Corporate misreporting not only reflects management negligence or even a lack of ethical commitment on the part of the company involved, but also generates significant externalities of misreported information, leading to misjudgements among other economically-connected entities. Specifically, in the first chapter I investigate whether public firms’ accounting overstatements, identified through ex post non-reliance over-restatements and SEC investigations, have any effects on the quantity and quality of entrepreneurship in the same region and industry. Using data from a survey of U.S. labour forces, I find a significant positive association between accounting overstatements and the likelihood of local entrepreneurs starting their businesses in the same state-industry. Following the instrumental-variable approach, I use firm’ geographical proximity to SEC offices as the instrumental variable (IV) and find that the positive association survives the test of causal inference. Consistent with the notion that overstated firm performance inflates perceived entrepreneurial returns via information intermediaries and enhances local entrepreneurs’ access to external financing, the positive association between firm’s overstatements and local entrepreneurship is more pronounced when these overstatements imply higher potential returns for entrepreneurs, the dissemination of overstated accounting information is more extensive, or growth in external financing is greater. In additional analyses, I provide suggestive evidence that local entrepreneurs are misled by public firms’ overstatements. In particular, those ventures established during the periods of overstatements tend to have lower growth potential, leading to the deteriorated growth of local GDP in the subsequent periods. Accordingly, local entrepreneurs significantly slow down their pace to establish new business after the revelation of public firm’s accounting overstatements. Collectively, these findings underscore the negative externalities of overstated firm performance for local entrepreneurship and local regions’ long-term economic developments.
The second chapter of this thesis is based my co-authored work that examines whether private firms’ disclosure affects the loan-pricing for public firms in the same country-industry. Using global syndicated loan data, we find a reduced loan spread for public firms with more disclosures made by private firms in the same country-industry. This finding is consistent with the view of positive spillover effects of private firms’ financial reporting, suggesting that private firms’ disclosure helps banks ex ante evaluate public firms’ credit risk and reduce the information asymmetry between lenders and borrowers. The positive effect is more pronounced when the disclosing private firms have greater economic importance in the industry or have greater economic similarity as the focal public firm. Moreover, consistent with the notion that banks rely more on private firm disclosure when these banks lack the access to the focal public firm’s information, we show that the effect of private firm disclosure on loan spreads is more pronounced for those banks with less prior lending experience in the borrower’s industry, for those banks with lower monitoring intensity, and for those public firms with greater information opacity. Overall, these findings support the view that private firm disclosure generates positive externalities for the loan market by reducing the information asymmetry between the public firms and lending banks.published_or_final_versionBusinessDoctoralDoctor of Philosoph
Combining ultrafast optics and condensed matter physics : experiments on high harmonic generation and its source
No full textIntense femtosecond pulses generated from Chirped Pulse Amplification (CPA)
and Optical Parametric Amplification (OPA)-based laser systems enable us to moni-
tor electron motion in various energy regimes, and with a greater time resolution. By
studying the multi-photon processes occurring during laser-matter interactions, we
can decipher matter’s electronic and optical properties. To achieve this purpose, we
conducted experiments in two directions: the generation of shorter laser pulses, and
the high-harmonic spectroscopy of solid-state media.
In this thesis, I demonstrated experiments in nonlinear pulse compression using
perturbative optics. This principle was applied to two different pulses with centre
wavelength of 515 nm and ∼ 800 nm, respectively. The 515 nm pulse was the second
harmonic generation (SHG) of 1030 nm, with a spectral width of 4.7 nm. After two
stages of spectral broadening, the spectrum was expanded to 26.2 nm. After proper
dispersion compensation, the resulting pulse was measured to be 18 ± 2 fs. Moreover,
we developed an optional pulse compression plan that resulted in a shorter pulse, suit-
able for HHG experiments. For the ∼ 800 nm pulse, by only one spectral broadening
stage, the Fourier-transform limit was broadened to ∼ 7.3 fs.
High harmonic generation (HHG), an extremely nonlinear process, resolves elec-
tron motion in gaseous and solid-state media through both real space and momentum
space pictures. The main focus along this direction was the HHG from bulk-state and 2d-state materials. For the experiment performed with bulk-state materials, a
complete setup including a beamline adapted to different input pulses and an extreme
ultraviolet (XUV) spectrometer chamber was constructed. By performing the static
HHG experiments using SiO2 and MgO materials, we analysed the special interference
patterns in high harmonic spectra that are related to the sample thickness, carrier en-
velope phase (CEP), intensity and pulse duration of the input pulse. In addition, the
dynamic measurement from crystalline SiO2 is noteworthy, from which the information
of lattice vibration and electron-phonon interaction can extracted from time-resolved
high harmonic spectroscopy.
The next experiment focused on the interaction between 2d materials and infrared
(IR) pulses. I illustrated the setup construction and proved its effectiveness. This
setup is adaptable to different input pulses, allowing for high-precision imaging of
2d materials up to the micrometre level, as well as high-efficiency signal generation
and collection. Dynamic measurements were also set to be conducted. Additionally,
two options to have high-quality background-free measurements were presented. Via
this unique setup, we successfully measured the orientation-dependent high harmonic
spectra from 2d Ruddlesden Popper (R-P) perovskite material, which matches well
with its crystal structure. In transmission geometry, two orders of wave mixing signal
emerged in 800 nm - 2100 nm pump-probe experiments, which can reflect electron dy-
namics in multi-layer h-BN. Moreover, by using reflection geometry, high harmonics
of 2100 nm pulse up to the 7th order were recorded, which is rarely published in any
other experimental works.published_or_final_versionPhysicsDoctoralDoctor of Philosoph
Numerical methods for dispersion relation calculation for photonic crystals
No full textThis thesis develops efficient numerical methods for computing the dispersion relation in photonic crystals (PhCs), which governs the frequency–wave vector dependence and underlies the formation of photonic band gaps. Accurate and efficient computation of dispersion relations is essential for designing photonic devices such as waveguides and resonators.
We begin by formulating the parameterized Helmholtz eigenvalue problem arising from Maxwell equations via the Bloch-Floquet theorem. A regularity analysis is carried out for the associated band functions, establishing their piecewise analyticity and identifying singularities. These results provide a theoretical foundation for designing effective approximation strategies.
Two numerical approaches are proposed. The first is a global polynomial interpolation method over the irreducible Brillouin zone, based on carefully selected sampling points. The second is a local hp-adaptive sampling algorithm, which refines the mesh near singularities and assigns polynomial degrees adaptively. This method achieves exponential convergence when singularities are finite, and first-order convergence otherwise, thus capturing fine-scale spectral features while maintaining computational efficiency. To demonstrate practical effectiveness, we apply the proposed methods to shape optimization problems aimed at maximizing band gaps in 3D photonic crystals. The adaptive method is extended to 3D settings and validated through numerical experiments, showing improved performance over traditional approaches.
We further explore deep learning techniques for band structure prediction. A supervised learning framework based on the U-Net architecture is introduced, incorporating transfer learning and super-resolution to reconstruct high-resolution band diagrams from coarse data. Numerical results show that the learning-based approach can accurately approximate dispersion relations with significantly reduced computational cost.
Overall, this thesis integrates rigorous mathematical analysis, numerical algorithms, and machine learning techniques, providing a unified and efficient framework for PhC band structure computation. The methods developed here lay the groundwork for future advances in high-precision photonic device design.published_or_final_versionMathematicsDoctoralDoctor of Philosoph
Optogenetic functional magnetic resonance imaging investigation of brain network dynamics
No full textUnderstanding how the brain rapidly processes neural information through large-scale network dynamics is fundamental to neuroscience. Resting-state functional magnetic resonance imaging (rsfMRI) has emerged as a robust, non-invasive imaging technique for mapping brain-wide functional networks, with significant correlations to sensory, behavioral, and cognitive task performance. Previous studies have primarily used sensory and cognitive tasks to investigate the role of rsfMRI networks in neural information processing. However, these external stimuli often evoke complex, long-lasting neural activities that intermingle and cascade with information flows from multiple parallel pathways. At present, whether rsfMRI networks can accommodate fast, sensitive neural information processing, including the underlying mechanisms, remains unclear. The primary objective of this doctoral work is to develop and implement the integration of cutting-edge neuromodulation, simultaneous rsfMRI with electrophysiology recordings, and dynamic network analysis for in vivo examination of the dynamic nature of brain-wide rsfMRI networks and their contributions to prompt neural information flow and processing.
In this study, we reveal brain-wide rsfMRI network dynamics (i.e., states and their transitions) that enable rapid information processing through flexible activity-triggered network reconfiguration in rodent models. Using data-driven dynamic network analysis, we uncovered transient rsfMRI network states and their transitions with specific evolving spatiotemporal patterns. By applying single-pulse optogenetic stimulation to the somatosensory thalamus, we bypassed parallel sensory pathways typically engaged by external stimuli and avoided the complex cascades and excessive synchronization of neural populations caused by prolonged or repetitive stimulation. We demonstrated that this approach exhibited hierarchical somatosensory neural activity propagation and minimized disruption of ongoing spontaneous neural activities, allowing us to uniquely study the mechanisms behind rsfMRI network dynamics. Single-pulse stimulation rapidly altered the probability profiles of states and occurrence rates of their transitions, with alterations occurring within approximately 2 s and normalizing around 10 s. Specifically, following activation of a single somatosensory thalamic activity input, rsfMRI network states and transitions associated with internally-oriented information processing were rapidly suppressed and diverted through the basal forebrain and hypothalamus to strengthen externally-oriented (i.e., sensory) processes. Simultaneous rsfMRI and electrophysiology measurements in the somatosensory and cingulate cortices demonstrated that intra-regional wide-band and inter-regional narrow-band (i.e., slow oscillations) neural activity synchronizations directly drove rsfMRI network dynamics and their reconfiguration to support the rapid processing of the single thalamic input.
Taken together, our study uncovers the fast interactions between spatiotemporal neural activity synchronizations and brain-wide rsfMRI networks in processing a single neural input. They demonstrate the intrinsic capability of rsfMRI networks to rapidly process neural activity, allowing the brain to respond to ever-changing demands.published_or_final_versionElectrical and Electronic EngineeringDoctoralDoctor of Philosoph
Controlling, coaxing and love: domestic power dynamics and ideal patriarchal family in Liaozhai Zhiyi = kong zhi, you hong yu ai: "liao zhai zhi yi" zhong de qi qie quan li guan xi yu li xiang fu quan zhi jia ting
No full textAmong the 491 chapters of "Liaozhai Zhiyi," there are more than 150 stories dedicated to depicting the order within the family. However, unlike secular novels such as "Dream of the Red Chamber" or caizijiaren romances such as "Pingshan Lengyan"in Ming and Qing dynasties, "Liaozhai" focuses not on the intricate ethical relationships within a large clan, nor on the fantastical world against the backdrop of a prestigious household. Instead, its gaze is cast upon the small family unit consisted of a husband, wife, and concubines and the social order carried behind the inter-relationships of these individuals. The wife-concubine relationships stem from the authors’ meticulous observation of real-life family, resulting in a delicate depiction with originality, while also conveying the author’s moral commitment to the family order.
Upon classifying and summarizing these stories, it is apparent that the author consciously employs certain character relationship models and narrative models to describe and guide the interaction patterns between wives and concubines within the family, supplemented by some archetypal female character images. Through the power dynamics between wives and concubines and the creation of typical female characters in these short vernacular texts, Pu Songling(1640-1715) expresses his rethinking of the patriarchal family system and proposes ways to amend it, thereby preserving its longevity.
This report will provide examples from multiple texts about domestic life in "Liaozhai", conduct an in-depth close reading of them, and analyze how they reconstruct the ideal power structures between wives and concubines through models of "control", "coax", and "love". Furthermore, it will explore how male literati, represented by Pu Songling, respond to and reshape the changing gender order within the family in his time.
(272 words)
在《聊齋誌異》的491個篇章中，有多達一百五十餘篇故事致力於描寫家庭內部的日常生活秩序；不過與《紅樓夢》等明清世情小說或《平山冷燕》等才子佳人小說不同，《聊齋》的著眼點既不在龐大宗族體系中複雜的倫理關係，亦不是以顯赫門第為背景的浪漫主義的夢幻世界，而是將視野投射在夫、妻與妾組成的小家庭及其所承載的社會秩序。妻妾之間的女性關係既本於作者對現實中家庭生活的細緻觀察，從而被描寫得細膩動人不失新意，而又充滿了作者本人對家庭秩序理當如何的道德寄託。
對這些故事進行分類歸納，會發現作者有意識地運用一些人物關係模型和敘事模型，來描述與指導家庭中妻妾的相處模式，並補綴以一些被典型化的人物形象。而通過這些短篇文言文本中對妻妾之間權力關係的架構與典型女性人物的塑造，蒲松齡（1640-1715）表達了他對父權制度家庭的重新思考，並提出了修補的方式，以維護其長久的生命力。
本報告將會例舉《聊齋》中多篇有關家庭的文本，對其進行深入的細讀，進而剖析它們如何通過“控制”、“誘哄”與“愛”等模型來重構自己理想的妻妾權力關係，並進一步探討以蒲松齡為代表的清初男性文人如何回應與重塑應時代而變動的家庭內部性別秩序。published_or_final_versionChineseMasterMaster of Philosoph
Streamlining the Journey of Research Into Clinical Practice: Making Your Patients and Practice Flourish: When to Fuse? An Evidence Based Review of Treatment Strategies in Degenerative Spondylolisthesis
No full textStudy DesignLiterature review.ObjectiveTo provide a concise review of outcomes of decompression and fusion (D + F) vs decompression (D) alone for degenerative lumbar spondylolisthesis (DLS).Methods6 articles were selected, including 3 randomized clinical trials (RCT), 2 meta-analyses, and 1 radiographic cohort study. Summarized factors affecting the outcomes of D + F vs D alone for DLS and provide expert level clinical recommendations.ResultsGhogawala included DLS patients showing improved SF-36 scores (P = 0.046) and lower re-operation rates (P = 0.05) in D + F patients compared to D alone. Forsth, included patients with stenosis both with and without DLS, and showed no difference in any reported outcome measure or reoperation rate. Austevoll included DLS patients that found that D alone was non-inferior to D + F in the primary outcome measure of ODI reduction at 2-year after surgery. Gadjradi included studies showing higher morbidity in the D + F group, as compared to D alone. Shukla included studies which found there was no difference in the raw patient outcome scores at final follow-up. Blumenthal included DLS patients who received D and reported disc height of >6.5 mm, facet angle >50°, and dynamic motion >1.25 mm were associated with high re-operation rates (45%, 39%, and 54% respectively).ConclusionsThe RCT’s and meta-analyses report contradictory conclusions and no blanket statement regarding the efficacy of D + F vs D alone can be made for all patients with DLS. Surgeons should closely review pre-operative imaging for signs of instability in order to better identify appropriate patients for each indication.</p
SARS-CoV-2 infectivity can be modulated through bacterial grooming of the glycocalyx
Get PDFThe gastrointestinal (GI) tract is a site of replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and GI symptoms are often reported by patients. SARS-CoV-2 cell entry depends upon heparan sulfate (HS) proteoglycans, which commensal bacteria that bathe the human mucosa are known to modify. To explore human gut HS-modifying bacterial abundances and how their presence may impact SARS-CoV-2 infection, we developed a task-based analysis of proteoglycan degradation on large-scale shotgun metagenomic data. We observed that gut bacteria with high predicted catabolic capacity for HS differ by age and sex, factors associated with coronavirus disease 2019 (COVID-19) severity, and directly by disease severity during/after infection, but do not vary between subjects with COVID-19 comorbidities or by diet. Gut commensal bacterial HS-modifying enzymes reduce spike protein binding and infection of authentic SARS-CoV-2, suggesting that bacterial grooming of the GI mucosa may impact viral susceptibility.published_or_final_versio
A tumor necrosis factor-α–responsive cryptic promoter drives overexpression of the human endogenous retrovirus ERVK-7
Get PDFEndogenous retroviruses (ERVs) shape human genome functionality and influence disease pathogenesis, including cancer. ERVK-7, a significant ERV, acts as an immune modulator and prognostic marker in lung adenocarcinoma (LUAD). Although ERVK-7 overexpression has been linked to the amplification of the 1q22 locus in approximately 10% of LUAD cases, it predominantly arises from alternative regulatory mechanisms. Our findings indicate that the canonical 5′ long terminal repeat of ERVK-7 is methylated and inactive, necessitating the use of alternative upstream promoters. We identified two novel transcripts, ERVK-7.long and ERVK-7.short, arising from distinct promoters located 2.8 and 13.8 kb upstream of the 5′ long terminal repeat of ERVK-7, respectively. ERVK-7.long is predominantly overexpressed in LUAD. Through comprehensive epigenetic mapping and single-cell transcriptomics, we demonstrate that ERVK-7.long activation is predetermined by cell lineage, specifically in small airway epithelial cells, where its promoter displays tumor-specific H3K4me3 modifications. Single-cell RNA-Seq further reveals a distinct enrichment of ERVK-7.long in LUAD tumor cells and alveolar type 2 epithelial cells, underscoring a cell type–specific origin. In addition, inflammatory signaling significantly influences ERVK-7 expression; tumor necrosis factor-α enhances ERVK-7.long, whereas interferon signaling preferentially augments ERVK-7.short by differential recruitment of NF-κB/RELA and interferon regulatory factor to their respective promoters. This differential regulation clarifies the elevated ERVK-7 expression in LUAD compared with lung squamous cell carcinoma. Our study elucidates the complex regulatory mechanisms governing ERVK-7 in LUAD and proposes these transcripts as potential biomarkers and therapeutic targets, offering new avenues to improve patient outcomes.published_or_final_versio