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Functional Analysis Of The Zebrafish Orthologs Of Host Cell Factor 1 Gene
No full textHost Cell Factor C1 (HCFC1) is a transcriptional co-activator factor that regulates the expression of over 5000 different downstream target genes in human cells. Missense mutations in the HCFC1 gene cause methylmalonic acidemia homocysteinemia cblX type (cblX). cblX, a multiple congenital anomaly syndrome (MCA) characterized by abnormal brain development, craniofacial abnormalities, metabolic deficits, and intractable epilepsy. Published studies suggest that HCFC1 regulates neural precursor proliferation, number, and differentiation. However, these results were derived from studies that were performed with nonsense alleles or transient knockdown approaches. Although these results demonstrate the importance of HCFC1 in brain development, they do not replicate the same type of missense mutation present in cblX patients. Therefore, our laboratory created a missense homozygous viable hcfc1aco64/co64 (co64) germline mutation in developing zebrafish. The mutation is in the kelch protein interaction domain, which is the region mutated in cblX patients. The co64 allele carries a two amino acid missense substitution created by CRISPR/Cas9 technology. In my research, we characterized the cellular, behavioral, and molecular phenotypes in the co64 allele. We observed hypolocomotion and abnormal brain development characterized by increased neural precursor cells and reduced radial glial cells. To continue investigating the possible mechanisms associated with cblX and intellectual disability, we used CRISPR/Cas9 to induce mutations in the zebrafish hcfc1b gene. Zebrafish have two HCFC1 orthologs and previous studies have been limited to the hcfc1a paralog. Since HCFC1 is a multidomain protein we targeted multiple domains of the protein. We successfully identified 2 novel germline alleles in the hcfc1b gene and performed basic characterization of the expression of molecular markers associated with brain development. Collectively, our analysis provided strong evidence for a function for HCFC1 in brain development and our novel model alleles will help to fully characterize HCFC1 gene function.
Keywords: zebrafish, multiple congenital anomalies, cblX, neural precursor cells, HCFC1, intellectual disabilit
Development Of A Novel Autoantibody Panel For Prostate Cancer Detection Based On Immunoproteomic Profiling And Cancer Driver Genes
No full textProstate cancer (PCa) is the second most frequent cancer in males with 1.47 million new cases and 396,700 deaths worldwide in 2022. It is the second leading cause of cancer-related deaths among males in the United States with over 35,000 estimated deaths in 2024. PCa is a type of indolent cancer that can progress to an advanced metastatic castration-resistant (mCRPC) stage if not detected and treated early. Screening precancerous lesions or early tumor detection is an effective strategy to reduce the mortality of cancer. Despite the development of effective screening methods, such as the prostate-specific antigen (PSA) test, the specificity and sensitivity of current diagnostic tests for PCa are still suboptimal, leading to unnecessary biopsies or overtreatment. It is imperative to identify novel blood-based biomarkers that could complement PSA for the early detection of PCa with high sensitivity and specificity. This would be of enormous benefit to high-risk groups, including men of African Ancestry and certain Hispanic/Latino subgroups, who have higher PCa incidence and poor survival rates compared to other groups. Genomic alterations can drive tumorigenesis, and understanding the immune response to those alterations may aid in developing new targets for diagnosis and therapy. Tumor-associated antigens (TAAs) are self-antigens that are abnormally expressed in tumors. Autoantibodies against TAAs have been considered as reporters of early carcinogenesis and indicators of cancer prognosis. These autoantibodies are abundant, detectable, and stable in the patientâ??s circulating blood. This study aimed to profile autoantibodies to common TAAs, and autoantibodies to overexpressed proteins or driver gene-related proteins (DRPs) in PCa. First, the Luminex technology was used to evaluate a panel of anti-TAAs autoantibodies in PCa, which included 14 common cancer-related autoantibodies. A total of 163 serum samples were screened to determine the levels of the autoantibodies, twelve autoantibodies exhibited significantly high frequencies ranging from 19.8% to 51.6% in the PCa group. The results of Luminex were further confirmed by enzyme-linked immunosorbent assay (ELISA). In addition, 29 targets including 14 overexpressed proteins, and 15 DRPs were screened via serological proteome analysis, and bioinformatics analysis respectively. ELISA was then performed to assess their corresponding autoantibodies in 293 serum samples. Nineteen autoantibodies showed significantly higher serum levels in PCa group than in normal controls. A panel with four AAbs (PIK3CA, SPOP, IF4H, HSP60) was developed, showing an AUC of 0.901. A differential autoantibody response to these four TAAs was observed in racially/ethnically diverse PCa populations, with autoantibodies to PIK3CA and IF4H detected at significantly higher frequencies in Hispanic American and African American patients compared to European American patients. The panel was evaluated across six other common cancers including 445 serum samples, showing potential for multi-cancer detection. The expression of the four TAAs targeted by autoantibodies was analyzed by IHC and high expression of all these TAAs was found in PCa tissues. These findings suggest that overexpressed proteins or DRPs may have altered immunogenicity, leading to the production of corresponding autoantibodies. Identifying autoantibodies associated with altered TAA expression in PCa could offer novel opportunities for discovering autoantibody-based biomarkers and novel therapeutic targets. Additionally, an optimized multi-autoantibody panel can improve the potential of using autoantibodies as biomarkers, and it can serve as a relatively simple tool to evaluate large numbers of patient samples for cancer detection
Intrinsic, Doped And Alloyed Gallium Oxide Films For Optoelectronics
No full textDue to the impressive advancement of present technology and increasing energy consumption, there is increasing demand for energy-efficient multifunctional devices based on low-cost, eco-friendly material systems. Gallium oxide (Ga2O3) is an emerging semiconductor with potential for the next generation of power electronics and optoelectronic devices due to its ultra-wide bandgap of 4.8 eV and high theoretical breakdown voltage of 8 MV/cm among other intrinsic properties. Some of the possible applications of β-Ga2O3 include ultra-violet (UV) solar blind photodetectors, field effect transistors, solar cells, and chemical sensors. However, to utilize its full potential, understanding the mechanistic aspects of thin film growth and optimization of the phase and properties is desirable. In recent years, significant attention directed towards the structure, characteristics, and performance of Ga2O3 thin films by a wide variety of physical and chemical methods in addition to using a variety of dopants, alloying elements, and processing techniques. In the present work, we adopted pulsed-laser deposition (PLD), which is quite successful in preparing high quality oxides. PLD has been explored for the epitaxial growth of superconducting oxides, but the efforts are relatively scarce towards Ga2O3 and its polymorphs. On the other hand, among other physical deposition methods, PLD facilitates high-quality multi-component films because of the extensive target selection and controllable processing conditions. Therefore, in this project, we directed our efforts to deposit both intrinsic and alloyed Ga2O3 films using PLD. We systematically investigated the effect of processing conditions and variable dopants (or alloying elements) to establish the road map to optimize the unique and otherwise not possible phases of Ga2O3. In our research, specific attention was directed towards the Ga2O3 alloyed with W and Sn in order to design efficient materials for advanced photodetectors. The PLD samples were characterized using a wide variety of analytical techniques including X-ray diffraction (XRD), transmission electron microscopy (TEM), atom-probe tomography (APT), X-ray photoelectron spectroscopy (XPS). These studies allowed us to understand the structure, phase, microstructures, and surface chemistry of the samples and the effect of W and Sn as dopants into Ga2O3. The effect of processing conditions on the optical properties of the W- Ga2O3 and Sn-Ga2O3 PLD films studied by ultraviolet-visible (UV-Vis) spectroscopy and photoluminescence (PL) measurements. Lastly, the fabricated films were integrated deep UV-photodetectors, which were characterized to demonstrate their functional device performance. The processing conditions were optimized to produce high quality PLD Ga2O3 films with demonstrated performance in deep UV-photodetectors
Conjuring the Moon
No full textConjuring The Moon wrestles with the question of why we as women still submit to norms created by men who can’t possibly understand our reality. Why should we support ideologies that claim to represent us while actively working against us? Why should we conform to a system that positions us as inessential Other? The speaker of this book aspires to liberate herself from such burdens. Conjuring the Moon encapsulates one woman\u27s search for the feminine divine within herself, her religion, and her environment; but as empowering as this search may be, it remains inextricably connected to her social and historical role as inessential Other. Narrated primarily from a first-person point-of-view, a consistent, evolving I, inspired by myself, the poems in this book present a woman longing for feminine divinity in a world that reduces her status to inessential Other
McFadden\u27s Discrete Choice and Softmax under Interval (and Other) Uncertainty: Revisited
No full textStudies of how people actually make decisions have led to an empirical formula that predicts the probability of different decisions based on the utilities of different alternatives. This formula is known as McFadden\u27s formula, after a Nobel prize winning economist who discovered it. A similar formula -- known as softmax -- describes the probability that the classification predicted by a deep neural network is correct, based on the neural network\u27s degrees of confidence in the object belonging to each class. In practice, we usually do not know the exact values of the utilities -- or of the degrees of confidence. At best, we know the intervals of possible values of these quantities. For different values from these intervals, we get, in general, different probabilities. It is desirable to find the range of all possible values of these probabilities. In this paper, we provide a feasible algorithm for computing these ranges
How to Gauge Inequality and Fairness: A Complete Description of All Decomposable Versions of Theil Index
No full textIn general, in statistics, the most widely used way to describe the difference between different elements of a sample if by using standard deviation. This characteristic has a nice property of being decomposable: e.g., to compute the mean and standard deviation of the income overall the whole US, it is sufficient to compute the number of people, mean, and standard deviation over each state; this state-by-state information is sufficient to uniquely reconstruct the overall standard deviation. However, e.g., for gauging income inequality, standard deviation is not very adequate: it provides too much weight to outliers like billionaires, and thus, does not provide us with a good understanding of how unequal are incomes of the majority of folks. For this purpose, Theil introduced decomposable modifications of the standard deviation that is now called Theil indices. Crudely speaking, these indices are based on using logarithm instead of the square. Other researchers found other another decomposable modifications that use power law. In this paper, we provide a complete description of all decomposable versions of the Theil index. Specifically, we prove that the currently known functions are the only one for which the corresponding versions of the Theil index are decomposable -- so no other decomposable versions are possible. A similar result was previously proven under the additional assumption of linearity; our proof shows that this result is also true in the general case, without assuming linearity
Why Two Fish Follow Each Other but Three Fish Form a School: A Symmetry-Based Explanation
No full textRecent experiments with fish has shown an unexpected strange behavior: when two fish of the same species are placed in an aquarium, they start following each other, while when three fish are placed there, they form (approximately) an equilateral triangle, and move in the direction (approximately) orthogonal to this triangle. In this paper, we use natural symmetries -- such as rotations, shifts, and permutation of fish -- to show that this observed behavior is actually optimal. This behavior is not just optimal with respect to one specific optimality criterion, it is optimal with respect to any optimality criterion -- as long as the corresponding comparison between two behaviors does not change under rotations, shifts, and permutations
Is Inflation Caused by Conflict?
Get PDFWe offer a critique of a paper recently published Lorenzoni and Werning (2023) that seeks to make an original contribution to the hypothesis that inflation is primarily caused by conflict and reconcile the Post-Keynesian and New-Keynesian traditions. L&W’s paper has two sections. In the first they develop a barter model that allows them to prove that inflation can occur with conflict and without money. In the second section they incorporate the conflict hypothesis into a broader framework compatible with New Keynesian models. We question the logical consistency and empirical validity of the barter model and the testability of the model with staggered pricing assumptions. We also trace the ideological roots of inflation as conflict hypothesis and highlight the policy implications that must be logically derived from it
Why Green Wavelength Is Closer to Blue Than to Red and How It Is Related to Computations: Information-Based Explanation
No full textIn our previous papers, we analyzed the idea of using light signals of three basic color -- red, green, and blue -- to speed up computations, in particular fuzzy-related computations. A natural question is: why red, green, and blue? Why not select some other colors: e.g., from the wavelength viewpoint, green is much closer to blue than to green, so why not select colors whose distribution is more even? In this paper, we show that if we consider this problem from the information viewpoint, then the corresponding equal-information criterion indeed implies that the intermediate wavelength should be closer to the smaller of the two remaining wavelengths than to the larger of these two. This result also explains why in human perception, green is closer to blue than to red. It also partially explains why green-blue color blindness it not the most frequent one -- which, from the viewpoint of differences in wavelength, sounds paradoxical