Symmetry deduction from spectral fluctuations in complex quantum systems

The spectral fluctuations of complex quantum systems, in appropriate limit, are known to be consistent with that obtained from random matrices. However, this relation between the spectral fluctuations of physical systems and random matrices is valid only if the spectra are desymmetrized. This implies that the fluctuation properties of the spectra are affected by the discrete symmetries of the system. In this work, it is shown that in the chaotic limit the fluctuation characteristics and symmetry structure for any arbitrary sequence of measured or computed levels can be inferred from its higher-order spectral statistics without desymmetrization. In particular, we consider a spectrum composed of $k>0$ independent level sequences with each sequence having the same level density. The $k$-th order spacing ratio distribution of such a composite spectrum is identical to its nearest neighbor counterpart with modified Dyson index $k$. This is demonstrated for the spectra obtained from random matrices, quantum billiards, spin chains and experimentally measured nuclear resonances with disparate symmetry features.Comment: Revised text and new figures. Final versio

Ataxia Telangiectasia Mutated Dysregulation Results in Diabetic Retinopathy

Ataxia telangiectasia mutated (ATM) acts as a defense against a variety of bone marrow (BM) stressors. We hypothesized that ATM loss in BM-hematopoietic stem cells (HSCs) would be detrimental to both HSC function and microvascular repair while sustained ATM would be beneficial in disease models of diabetes. Chronic diabetes represents a condition associated with HSC depletion and inadequate vascular repair. Gender mismatched chimeras of ATM(-/-) on wild type background were generated and a cohort were made diabetic using streptozotocin (STZ). HSCs from the STZ-ATM(-/-) chimeras showed (a) reduced self-renewal; (b) decreased long-term repopulation; (c) depletion from the primitive endosteal niche; (d) myeloid bias; and (e) accelerated diabetic retinopathy (DR). To further test the significance of ATM in hematopoiesis and diabetes, we performed microarrays on circulating angiogenic cells, CD34(+) cells, obtained from a unique cohort of human subjects with long-standing (>40 years duration) poorly controlled diabetes that were free of DR. Pathway analysis of microarrays in these individuals revealed DNA repair and cell-cycle regulation as the top networks with marked upregulation of ATM mRNA compared with CD34(+) cells from diabetics with DR. In conclusion, our study highlights using rodent models and human subjects, the critical role of ATM in microvascular repair in DR

Imbalances in Mobilization and Activation of Pro-Inflammatory and Vascular Reparative Bone Marrow-Derived Cells in Diabetic Retinopathy

Diabetic retinopathy is a sight-threatening complication of diabetes, affecting 65% of patients after 10 years of the disease. Diabetic metabolic insult leads to chronic low-grade inflammation, retinal endothelial cell loss and inadequate vascular repair. This is partly due to bone marrow (BM) pathology leading to increased activity of BM-derived pro-inflammatory monocytes and impaired function of BM-derived reparative circulating angiogenic cells (CACs). We propose that diabetes has a significant long-term effect on the nature and proportion of BM-derived cells that circulate in the blood, localize to the retina and home back to their BM niche. Using a streptozotocin mouse model of diabetic retinopathy with GFP BM-transplantation, we have demonstrated that BM-derived circulating pro-inflammatory monocytes are increased in diabetes while reparative CACs are trapped in the BM and spleen, with impaired release into circulation. Diabetes also alters activation of splenocytes and BM-derived dendritic cells in response to LPS stimulation. A majority of the BM-derived GFP cells that migrate to the retina express microglial markers, while others express endothelial, pericyte and Müller cell markers. Diabetes significantly increases infiltration of BM-derived microglia in an activated state, while reducing infiltration of BM-derived endothelial progenitor cells in the retina. Further, control CACs injected into the vitreous are very efficient at migrating back to their BM niche, whereas diabetic CACs have lost this ability, indicating that the in vivo homing efficiency of diabetic CACs is dramatically decreased. Moreover, diabetes causes a significant reduction in expression of specific integrins regulating CAC migration. Collectively, these findings indicate that BM pathology in diabetes could play a role in both increased pro-inflammatory state and inadequate vascular repair contributing to diabetic retinopathy

Student Success: Lessons from the Center for Student Enterprise

Student success is critically important to students, universities, and society. Measuring outcomes of programs is essential in determining what works and what doesn’t. Programs that improve outcomes should be analyzed and adopted by educational institutions at large. Research suggests that business schools prioritize case analysis over practical application leading to ‘low-integrative thinking’ (McCord and Michaelsen, 2015), a lack of practical knowledge, and effective communication. Experiential learning opportunities have been shown to overcome these challenges faced by business school students as it engages students intellectually and emotionally. Furthermore, experiential learning opportunities develop students holistically and effectively, preparing them for the competitive business world outside. This research aims to examine the post-graduate employment opportunities and graduate program acceptance rates of students who have participated in experiential learning. The experiential learning is set at Pace University’s Center for Student Enterprise. After evaluating the preference of professionals and students, the results showed that an undeniable majority of the participants prefer candidates with experiential learning experience on their resumes for a given job. This suggests a high correlation between employment with the Center for Student Enterprise and selection as the preferred candidate for hire. However, with regard to graduate program acceptance, noteworthy conclusions cannot be derived due to a low response rate. These results suggest that colleges and universities can contribute to engaging in more experiential learning opportunities for the success of their students. The current research provides an understanding of the relationship between experiential learning and student success. This relationship could be further explored by adopting a longitudinal study to identify the career paths of students who have been a part of experiential learning experiences

AI-Driven Financial Planning: A Study on Predictive Modelling

The integration of artificial intelligence (AI) in financial planning has revolutionized the domain of personal and institutional finance, primarily through the use of predictive modelling techniques. These models facilitate precise forecasting of market trends, asset prices, and individual financial behaviours. This research explores the evolution of AI-driven financial planning, focusing on the theoretical and practical dimensions of predictive modelling. Key components include time-series forecasting, reinforcement learning, explainable AI, and data preprocessing. Through rigorous analysis of real-world applications and model architectures, the study provides a comprehensive assessment of the technical landscape, challenges, and future prospects of AI in financial decision-making

Functional Problems: Prevalence In Secondary Care And Perceptions Of Doctors

1 Abstract 1.1 Title Functional problems: prevalence in secondary care and perceptions of doctors 1.2 Aims (a) To evaluate the prevalence of functional problems in general medicine, gastroenterology, gynaecology and psychiatry outpatient specialist clinics in a hospital setting in Sri Lanka and (b) To assess the perceptions of doctors in these specialties around functional problems in the UK and in Sri Lanka. 1.3 Methodology (a) Prevalence study: Functional problems were defined as those for which a cause could not be ascertained after clinical evaluation and investigations. The prevalence of functional problems was assessed over a three month period in each specialty clinic. The patients‘ records were reviewed at three and six months to confirm the diagnosis of a functional problem. (b) Perceptions of clinicians: Qualitative methodology was used to ascertain the perceptions of doctors in the two settings covering the three specialties. A grounded theory approach was used and sixty interviews were carried out. Emphasis was placed on identifying socio-cultural implications around perceived causations and the management of these functional problems. 1.4 Results (a) Prevalence study: The prevalence study ascertained that functional problems were the commonest diagnoses in the general medicine/gastroenterology and gynaecology clinics accounting for almost a fifth of patients. In psychiatry, functional problems were the fourth common diagnosis and accounted for nearly ten percent. Patients of all consultations with functional symptoms tended to be younger; there were long delays in iv making the diagnosis and a substantial proportion of patients were subjected to iatrogenic harm from invasive investigations and inappropriate therapeutic measures. (b) Perceptions study: The perceptions study revealed divergent views by doctors about what functional problems were, how they could be categorized and how best to manage them. Socio cultural factors were thought to be intricately linked to causation and outcomes. Nonetheless, most doctors tended to isolate the clinical presentation and management from the cultural context in the way they dealt with their patients. 1.5 Conclusions Functional problems were commonly seen and diagnosed in hospital outpatient clinics. The Sri Lankan prevalence was similar to that reported from the UK. In both cultural settings the doctors who were sensitive to socio-cultural factors used tools beyond pharmacotherapy and those who held improved quality of life as the goal of treatment as opposed to cure, reported greater success in managing people with these problems. v 1.6 Acknowledgements The School of Medicine and Health, Durham University, for granting a scholarship through Project Sri Lanka for the PhD, for fulfilling research training needs and providing accommodation during my stay in the UK The Faculty of Medicine, University of Ruhuna, for granting me study leave for three years Professor Pali Hungin, my supervisor in the School of Medicine and Health, Durham University, for helping convert the research idea to a PhD thesis Professor Martyn Evans, my second supervisor in the School of Medicine and Health, Durham University, for guidance and support Professor David Petley, Deputy Head (Research), Faculty of Social Sciences and Health, Durham University, for research support To Professor Susirith Mendis, Vice Chancellor and Professor Ranjith Senaratne, former Vice Chancellor of the University of Ruhuna, Professor Thilak Weerasooriya, Dean and Professor P.L. Ariyananda, former Dean, Faculty of Medicine, University of Ruhuna, for support in obtaining study leave and a travel grant Dr Chandanie Hewage, Head, Department of Psychiatry at the Faculty of Medicine, University of Ruhuna, for constant support and encouragement over the study leave period My colleagues in the Department of Psychiatry, Faculty of Medicine, for covering the additional work during my study leave period Mrs Alex Motley, for help with correspondence and formatting Dr Simon Stockley, General Practitioner, for assistance with the pilot study Dr Amanda Gash, Consultant Psychiatrist and Dr Suresh Babu, Consultant Psychiatrist at the Tees Esk and Wear Valleys NHS Trust, Dr Deepak Dwarakanath, Consultant Gastroenterologist and Dr Anne Ryall, Consultant Gynaecologist at North Tees and Hartlepool NHS Trust, who were the co investigators for the UK arm of the qualitative study My co-investigators from Sri Lanka for the prevalence study, Dr Gamini Jayawardene, Dr Gayani Punchihewa and Dr Ajith Jayasekera, Consultant Psychiatrists, from Teaching Hospital Karapitiya Galle, Professor Thilak Weerarathna and Dr Arosha Dissanayake, Consultant Physicians from Teaching Hospital Karapitiya Galle, Professor Malik Goonawardene and Dr Dammika Jayasooriya, Consultant Obstetricians from Teaching Hospital Mahamodera, Galle vi Dr Rachel Casiday, Dr Helen Hancock, Dr Helen Close, Dr Sharyn Maxwell, Dr Eileen Scott, Durham University, for helping with the methodological aspects of the research Professor James Mason, Director of Research, School of Medicine and Health, Durham University, for advice on statistical matters Dr J. Howse, Doctoral Researcher, Durham University, for second coding of transcripts Mrs Judith Walsh, Mrs Susan Williams, Durham University, for assistance with administrative matters Members of the NHS National Research Ethics Committee, Durham and Tees Valley Research Ethics Committee 2, and Research Ethics Committee, Faculty of Medicine, University of Ruhuna, for helping conduct an ethically sound research study Staff at the North Tees and Hartlepool NHS Trust, Research and Development Office for guidance on methodological and ethical aspects of the research Directors of Teaching Hospital Karapitiya, Galle and Teaching Hospital, Mahamodera, Galle, for permitting the analysis of patient records for the prevalence study All the participants in the research Mrs Barbara Hungin for encouragement and support Sri Lankan expatriate community for assistance with logistical aspects Staff at the Keenan House, where I was accommodated during my stay in the UK My family members for their constant encouragement and support during three long years of researchin

REWARD-RELATED BEHAVIORAL EFFECTS OF PRESCRIPTION OPIOIDS AS A FUNCTION OF PUTATIVE ACUTE AND CHRONIC PAIN-LIKE STATES IN MALE AND FEMALE C57BL/6 MICE

Pain is a leading cause of disability and the most common reason for clinical care. The field of pain research has focused on sex differences in the recent years with an expansive body of literature demonstrating sex-related differences in pain behavior and responsiveness to pharmacological interventions. Prescription opioids are potent analgesics and the mainstay for the clinical management of moderate-to-severe acute and chronic pain conditions. However, the long-term clinical use of prescription opioids for chronic pain remains controversial due to concerns about severe adverse effects, including tolerance, dependence, and addiction associated with opioid use. The non-medical use and abuse of prescription opioids has become a public health crisis, the problem even arising in a subset of chronic pain patients receiving opioid therapy. The vulnerability factors, specifically the role of pain in the propensity to prescription opioid abuse, are poorly understood. The present research project sought to investigate the propensity to opioid reward as a function of pain in male and female mice by incorporating acute (acetic acid-induced) visceral nociceptive and chronic chemotherapy (paclitaxel)-induced peripheral neuropathic pain models. Sexually dimorphic variations in the sensitivities of mice to nociceptive and allodynic behaviors were initially assessed using the two putative pain models. Following that, the two prescription opioids, morphine and oxycodone were examined under both pain contexts and the capacity of the two prescription opioids to produce reward-related behavioral effects were measured using drug discrimination, conditioned place preference, and intravenous drug self-administration procedures. The presence of acute noxious state but not chronic pain selectively attenuated the discriminative stimulus effects of the prescription opioid, morphine in male mice. The magnitude of modulation of the stimulus effects of opioids by the acute noxious state were further observed to be inversely related to the relative intrinsic antinociceptive effectiveness of the two opioids in reversing the acute noxious state and sex-specific sensitivities of mice to opioid-induced antinociception. In contrast, while no change was observed in opioid-reward as a function of the acute noxious state in both sexes, the presence of paclitaxel-induced chronic pain opioid-selectively and dose-selectively enhanced the conditioned rewarding effect of morphine (0.3 mg/kg dose), and the effect was more pronounced in male relative to female mice. These data were further supported by the self-administration results, in that the reinforcing efficacy (breakpoints under progressive ratio (PR) responding) and the incentive-motivational salience of morphine significantly increased in the presence of chronic pain in male mice, while non-selectively increasing regardless of the presence/absence of pain in female mice. Overall, the converging empirical evidence presented here suggest that these models provide preclinical tools to further understand the overlapping neurobiology of pain and opioid abuse, the behavioral effects of prescription opioids, and advance the development of novel sex-specific pain therapeutics with low addiction liability.Pharmaceutical Science

DEVELOPING AN IMMUNOMODULATORY STRATEGY USING BIOPHYSICAL CUES TO MODULATE MACROPHAGE PHENOTYPE FOR FRACTURE HEALING AND BONE REGENERATION

Chronic inflammation is a major cause of the pathogenesis of musculoskeletal diseases such as fragility, fracture, and nonunion. Studies have shown that modulating the immune phenotype of macrophages from proinflammatory to pro-healing can heal recalcitrant bone defects. Current therapeutic strategies predominantly apply biochemical cues, which often lack target specificity, and controlling their release kinetics in vivo is challenging spatially and temporally. We have developed a magnetic iron-oxide nanocomplexes (MNC)-based therapy for resolving chronic inflammation in the context of promoting fracture healing. Here, we show that MNC internalized macrophages, when coupled with an external magnetic field, can exert an intracellular magnetic force on the cytoskeleton to promote a pro-healing phenotype switch by altering cell shape and actin dynamics. The intracellular magnetic force perturbs actin polymerization, which significantly reduces nuclear to cytoplasm redistribution of MRTF-A and HDAC3, major drivers of inflammatory and osteogenic gene expression, respectively. The reduction in nuclear MRTF-A and HDAC3 levels due to intracellular magnetic force subsequently downregulates Nos2 gene expression, confirmed by quantitative PCR analysis. These findings may facilitate efforts to develop MNC-based resolution-centric therapeutic intervention to direct macrophage phenotype and function towards healing to supplement or replace the currently used anti-inflammatory therapies for fracture healing. Diabetes is a chronic metabolic disorder that can lead to diabetic myopathy and bone diseases. The etiology of musculoskeletal complications in such metabolic disorders and the interplay between the muscular and osseous systems are not well understood. Exercise training promises to prevent diabetic myopathy and bone disease and offers protection. Although the muscle-bone interaction is largely biomechanical, the muscle secretome has significant implications for bone biology. Uncoupling effects of biophysical and biochemical stimuli on the adaptive response of bone during exercise training may offer therapeutic targets for diabetic bone disease. Here, we have developed an in vitro model to elucidate the effects of mechanical strain on myokine secretion and its impact on bone metabolism decoupled from physical stimuli. We developed bone constructs using cross-linked gelatin, which facilitated osteogenic differentiation of osteoprogenitor cells. Then, muscle constructs were made from fibrin, which enabled myoblast differentiation and myotube formation. We investigated the myokine expression by muscle constructs under strain regimens replicating endurance (END) and high-intensity interval training (HIIT) in hyperglycemic conditions. In monocultures, both regimens induced higher expression of Il15 and Igf1, whereas END supported more myoblast differentiation and myotube maturation than HIIT. When co-cultured with bone constructs, HIIT regimen increased Glut4 expression in muscle constructs more than END, supporting higher glucose uptake. Likewise, the muscle constructs under the HIIT regimen promoted a healthier and more matured bone phenotype than END. Under static conditions, myostatin (Mstn) expression was significantly downregulated in muscle constructs co-cultured with bone constructs compared with monocultures. Together, our in vitro co-culture system allowed orthogonal manipulation of mechanical strain on muscle constructs while facilitating bone-muscle biochemical crosstalk. Such systems can provide an individualized microenvironment that allows decoupled biomechanical manipulation, help identify molecular targets, and develop engineered therapies for metabolic bone disease