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Neuromuscular Activity Determines, at Least in Part, the Motoneuron, Nerve and Muscle Properties Under Normal Conditions and After Nerve Injury
Get PDFWhether pattern or amount of daily activity determines neuromuscular properties is the focus of this review. The fast-to-slow conversion of many properties of fast-twitch muscles, by stimulating their nerves electrically with the continuous low-frequency pattern typical of slow motoneurons, argued that muscle properties are determined by their pattern of activity. However, the composition of the motor units (MUs) in almost all muscles is heterogeneous, with the MUs grouped into slow, fast-fatigue-resistant and fast-fatigable types that match corresponding histochemical fiber types. Nonetheless, their contractile forces lie on a continuum, with MUs recruited into activity in order of their size. This ‘size principle’ of MU organization and function applies in normally innervated and reinnervated muscles and, importantly, begs the question of whether it is the amount rather than the pattern of the MU activation that determines their properties. Experimental evidence that uniform daily amounts of ~<0.5, 5%, and 50% ES, converted motoneuron, nerve, and muscle properties to one physiological and histochemical type, argued in favor of the amount of activity determining MU properties. Yet, that the properties were not confined to the expected narrow range argued that factors other than the pattern and/or amount of neuromuscular activity must be considered. These include the progressive increase in the synaptic inputs onto motoneurons. The range of the effects of endurance and intermittent exercise programs on healthy subjects and those suffering nerve injuries and disease is also consistent with the argument that factors other than pattern or amount of neuromuscular activity should be investigated
Exploring the Relationship of Cognitive Disengagement Syndrome and Attention Deficit/Hyperactivity Disorder with Emotional Dysregulation: A Twin Study in Childhood and Adolescence
Get PDFData on the genetic and environmental factors underlying the co-occurrence of Cognitive Disengagement Syndrome (CDS), Attention Deficit Hyperactivity Disorder (ADHD), and Emotional Dysregulation (ED) are limited. This study aimed to explore the nature of the associations between CDS, ADHD with ED, and to assess the role of shared etiological factors in explaining their comorbidity. We analyzed a sample of 400 Italian twin pairs aged 8–18, from Northern Italy and enrolled in the Italian Twin Registry. Bivariate genetic analyses were conducted using parent-rated CBCL scores for CDS, ADHD, and ED. For both CDS–ED and ADHD–ED associations, the best-fitting models were Cholesky AE models (−2LL = −849.167 and −339.030, respectively; p > 0.05), suggesting that the covariation was mainly due to additive genetic factors (CDS–ED—A = 0.81, 95% CI [0.66–0.95]; ADHD–ED—A = 0.86, 95% CI [0.75–0.95]). More than half of the genes were shown to be shared among the phenotypes. Non-shared environmental contributions were smaller (CDS–ED—E = 0.19, 95% CI [0.05–0.34]; ADHD–ED—E = 0.14, 95% CI [0.05–0.25]), indicating interrelated but distinct constructs. Despite some limitations, particularly the exclusive use of the CBCL, findings highlight the importance of monitoring ED symptoms in individuals with CDS or ADHD, and vice versa
Immune Microenvironment in Oral Potentially Malignant Disorders and Oral Cancer: A Narrative Review
Get PDFMultiple studies have investigated the impact of the tumor immune microenvironment (TIME) on oral squamous cell carcinoma (OSCC), with most focusing on three key cellular components: lymphocytes, macrophages, and neutrophils, as well as the molecular mechanisms underlying inflammation-mediated OSCC invasion. Although the specific roles of each cell type vary depending on their subtypes and the characteristics of OSCC, several consistent patterns have been identified. TIME plays a critical role at every stage of OSCC progression, from tumor initiation and growth to invasion and metastasis. Understanding the communication signals–the language–between tumor cells and the TIME, encoded through various proteins secreted by immune cells, is essential for controlling tumor progression and developing effective treatments for OSCC. This review provides an overview of how TIME influences the progression of the Oral Potentially Malignant Disorders (OPMDs) to OSCC as well as OSCC’s invasion, focusing on the contributions of various immune cells within the TIME. Additionally, we discuss recent advances in immunotherapy for OSCC, highlighting strategies to enhance immune responses and improve treatment outcomes
Diagnostic, Therapeutic, and Prognostic Applications of Artificial Intelligence (AI) in the Clinical Management of Brain Metastases (BMs)
Get PDFBrain metastases (BMs) are the most common intracranial tumors in adults. Their heterogeneity, potential multifocality, and complex biomolecular behavior pose significant diagnostic and therapeutic challenges. Artificial intelligence (AI) has the potential to revolutionize BM diagnosis by facilitating early lesion detection, precise imaging segmentation, and non-invasive molecular characterization. Machine learning (ML) and deep learning (DL) models have shown promising results in differentiating BMs from other intracranial tumors with similar imaging characteristics—such as gliomas and primary central nervous system lymphomas (PCNSLs)—and predicting tumor features (e.g., genetic mutations) that can guide individualized and targeted therapies. Intraoperatively, AI-driven systems can enable optimal tumor resection by integrating functional brain maps into preoperative imaging, thus facilitating the identification and safeguarding of eloquent brain regions through augmented reality (AR)-assisted neuronavigation. Even postoperatively, AI can be instrumental for radiotherapy planning personalization through the optimization of dose distribution, maximizing disease control while minimizing adjacent healthy tissue damage. Applications in systemic chemo- and immunotherapy include predictive insights into treatment responses; AI can analyze genomic and radiomic features to facilitate the selection of the most suitable, patient-specific treatment regimen, especially for those whose disease demonstrates specific genetic profiles such as epidermal growth factor receptor mutations (e.g., EGFR, HER2). Moreover, AI-based prognostic models can significantly ameliorate survival and recurrence risk prediction, further contributing to follow-up strategy personalization. Despite these advancements and the promising landscape, multiple challenges—including data availability and variability, decision-making interpretability, and ethical, legal, and regulatory concerns—limit the broader implementation of AI into the everyday clinical management of BMs. Future endeavors should thus prioritize the development of generalized AI models, the combination of large and diverse datasets, and the integration of clinical and molecular data into imaging, in an effort to maximally enhance the clinical application of AI in BM care and optimize patient outcomes
Checkpoint-Dependent Sensitivities to Nucleoside Analogues Uncover Specific Patterns of Genomic Instability
Get PDFNucleoside analogues are used as drugs and as labels in laboratory-based research. However, the effect of different nucleoside analogue mechanism(s) on cell sensitivity or mutagenesis is unclear. This is particularly important in cancer treatments where checkpoint proteins and DNA damage factors are often mutated. We tested six nucleoside analogues in fission yeast, Schizosaccharomyces pombe. We found that the mutations in the DNA replication checkpoint cause unique sensitivity profiles towards chemotherapeutic nucleoside analogues (gemcitabine, 5-fluorouracil, cytarabine) and the non-clinical analogue bromodeoxyuridine. Antiretroviral compounds, zidovudine and lamivudine, did not alter cell growth. We compared half-maximal inhibitory concentration (IC50) doses between checkpoint deficient yeast strains, examining culture growth and DNA mis-segregation. Intriguingly, gemcitabine and bromodeoxyuridine doses above the IC50 promoted better growth. Above each compound’s IC50 dose we saw that cells were insensitive to nucleoside analogue re-exposure, particularly in DNA replication checkpoint mutants (cds1∆, rad3∆). Thus, pairing nucleoside analogue use with personal genomics may inform drug choice, dose, and schedule. Finally, these data indicate that resistance may be predictable, informing clinical strategy
Random Permutation Codes: Lossless Source Coding of Non-Sequential Data
Get PDFThis thesis deals with the problem of communicating and storing non-sequential data. We investigate this problem through the lens of lossless source coding, also sometimes referred to as lossless compression, from both an algorithmic and information-theoretic perspective.
Lossless compression algorithms typically preserve the ordering in which data points are compressed. However, there are data types where order is not meaningful, such as collections of files, rows in a database, nodes in a graph, and, notably, datasets in machine learning applications.
Compressing with traditional algorithms is possible if we pick an order for the elements and communicate the corresponding ordered sequence. However, unless the order information is somehow removed during the encoding process, this procedure will be sub-optimal, because the order contains information and therefore more bits are used to represent the source than are truly necessary.
In this work we give a formal definition for non-sequential objects as random sets of equivalent sequences, which we refer to as \emph{Combinatorial Random Variables} (CRVs). The definition of equivalence, formalized as an equivalence relation, establishes the non-sequential data type represented by the CRV. The achievable rates of CRVs is fully characterized as a function of the equivalence relation as well as the data distribution.
The optimal rates of CRVs are achieved within the family of \emph{Random Permutation Codes} (RPCs) developed in later chapters. RPCs randomly select one-of-many possible sequences that can represent the instance of the CRV. The selection is done through sampling with bits-back coding \cite{townsend2019practical, frey1996free} and asymmetric numeral systems \cite{duda2009asymmetric}, and guarantees the achievability of the optimal rate.
Specialized RPCs are given for the case of multisets, graphs, and partitions/clusterings, providing new algorithms for compression of databases, social networks, and web data in the JSON file format. The computational and memory complexity of RPCs is discussed and shown to be attractive for the applications considered.Ph.D
Managing Empire: The Rubber Economy of the Bay of Bengal, 1927-1945
Get PDF"Managing Empire: The Rubber Economy of the Bay of Bengal, 1927-1945," follows the reproduction of the British Empire through the rubber plantation complex of India, Ceylon, and Malaya during the Great Depression and Second World War. The Depression shook the foundations of the empire in the Indian Ocean. Collapsing commodity prices threatened millions of pounds of British investment in plantations, stressing an empire financially exhausted by war. With agricultural commodities in freefall, the empire saw mass unemployment, the collapse of inter-Asian commercial and credit markets, the potential transfer of British plantation assets to American investors, and waves of anti-colonial mobilization and communal violence. Drawing on official, business, and press archives in the UK, India, Malaysia, and Singapore, I show how planters, businessmen, statesmen, and colonial officials built a coalition to preserve European command, subject to inter- and intra-class conflict, anti-colonial mobilizations, and militant labour movements. Engaging with the historiography of empire, capitalism, business, and labour in South and Southeast Asia, I argue that the plantation complex was crucial to globalization and fragmentation across empires in the Bay of Bengal.I argue that the rubber economy, including its commodity, capital, and labour markets, was a laboratory for new frameworks of British imperial power, exercised through international economic governance aimed at preserving European command over Asian land, markets, and labour. These experiments in economic diplomacy depended on a professional class of statesmen, civil servants, company directors, and professional managers stretching across colonies, metropoles, and even empires. The rubber economy – its workers, managers, traders, and regulators, both European and Asian – was a pivot point of the empire, depending on negotiations in boardrooms, courts, the press, and on estates. Significant contradictions posed by the drive to preserve European command over Asian economic life resulted in waves of proto nationalization across the Bay of Bengal, emanating from colonial states and militant associational movements of labour unions and anti-colonial nationalists. This interwar experiment of managerial interventions in inter-colonial economic life temporarily protected British capital in the Bay of Bengal while incubating the era of decolonization and partition after the Second World War.Ph.D
Structural fire comparison of char depth and explicit temperature thermal damage models
Get PDFChar depths in fire damaged timber are often used as a substitute to infer equivalent fire resistance for tests without structural load applied. However, the thermal profile in mass timber can differ markedly between compartment fires with a cooling phase and fixed duration standard furnace tests. This technical note evaluates publicly available temperature and charring data from a fully developed open plan mass timber fire test to compare structural capacity throughout the fire based on two thermal damage models. The first method uses measured char depth and an assumed zero-strength layer, while the second method utilises the measured temperature profile. Both damage models were applied to the same structural calculations. The results show that, in absence of sprinkler or fire service intervention, structural capacity reduction is more severe when actual temperatures are considered. These outcomes are of interest to interpret data from fire tests with respect to fire resistance.The presentation of the authors' names and (or) special characters in the title of the pdf file of the accepted manuscript may differ slightly from what is displayed on the item page. The information in the pdf file of the accepted manuscript reflects the original submission by the author
Deterioration mechanism of adhesion properties of FRP-soil interface induced by moisture
Get PDFThe deterioration of FRP-soil interfacial adhesion due to water intrusion has been a core issue in geotechnical engineering, but its microscopic mechanism remains unclear. In this study, molecular dynamics (MD) simulation method is employed to reveal the microscopic deterioration mechanism of water on adhesion properties of epoxy-quartz (i.e., FRP-soil subsystem) interface, the structural and dynamic characteristics of interlayer water film. The steered molecular dynamics (SMD) pulling simulation and the modified Bell’s model are used to evaluate the adhesion energy of epoxy-quartz interface in dry and wet cases. The simulation results show that (1) the interfacial water film weakens adhesion strength of epoxy-quartz interface, playing a dual role in “interface isolation” and “lubrication”, aggravating the interfacial debonding. (2) The work of adhesion, maximum pulling force, PMF, and adhesion energy of dry system are significantly higher than those of wet system. (3) The interlayer water film has a distinct layered structure: bound, free, and sparse water layers, which have different angle orientations and density distributions. (4) The diffusion coefficient increases with the rising thickness of free water layer, which may trigger a capillary-seepage effect and aggravate interface deterioration. This study provides atomic-scale insights into moisture-induced FRP-soil interface failure mechanism.The presentation of the authors' names and (or) special characters in the title of the pdf file of the accepted manuscript may differ slightly from what is displayed on the item page. The information in the pdf file of the accepted manuscript reflects the original submission by the author
The Genetic Architecture of Active Music Engagement and its Relationship to Neurobiological Function and Health
Get PDFActive music engagement (AME), i.e., playing a musical instrument or singing in everyday life, is an underappreciated epidemiological trait and neurobiological marker of health, especially in aging populations. Although clinical studies have shown that playing a musical instrument or singing can be harnessed to rehabilitate neurological functioning, few studies have examined AME within a genetic epidemiological framework. Prior genetic studies have shown that AME is moderately heritable in adults but have not explored its molecular underpinnings. This dissertation comprises two works that investigate the genetic architecture of AME, its relationships to neurobiological function, and shared genetic etiology with human health. In Chapter 1, I introduce background on prior approaches to studying AME, the current genetic epidemiological approach, and the motivations for studying AME’s connection to cognition, motor, speech and language, and psychiatric risk/mental health resilience. In Chapter 2, I conducted a genome-wide association study (GWAS) that was designed to examine the function of the common genetic variation associated with AME and its shared genetic variation with aging-related health traits and musical rhythm abilities. The primary findings were that the top independent genomic loci associated with AME were also implicated in affecting gene expression in the cerebellum, the heritability (h2SNP=10%) was enriched for regulatory function in brain-cell types, and AME showed significant positive genetic correlations with cognition, language, motor function, social engagement, and mental health resilience, albeit increased mood disorder risk. Additionally, two-sample Mendelian randomization analyses revealed potential evidence for a directional influence of musical rhythm abilities on AME. Chapter 3 is a pre-registered study in which I investigated the shared genetic architecture between AME and motor behaviour and neuromotor traits by testing associations with 24 polygenic scores (PGSs) in four distinct cohorts (total N=32,198). After multiple testing corrections, higher PGSs for walking pace were associated with greater AME within the Canadian Longitudinal Study on Aging (CLSA) and in the meta-analysis across four cohorts. Chapter 4 synthesizes these findings and discusses future directions. Together, this dissertation provides novel insights into the genetic architecture of AME and its functional relevance to brain structure. Cross-trait analyses from Chapters 2 and 3 illustrate how the genetic architecture of AME is a transdiagnostic marker of health, especially in aging.Ph.D