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MOBOCERTINIB ANTAGONIZES MULTIDRUG RESISTANCE IN ABCB1- AND ABCG2-OVEREXPRESSING CANCER CELLS
Get PDFThe resistance of cancer cells to multiple drugs, known as multidrug resistance (MDR), remains a significant obstacle that leads to the ineffectiveness of cancer chemotherapy. The overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1 and ABCG2, has been strongly correlated with MDR. There is an urgent need to explore and identify novel inhibitors targeting ABCB1 and ABCG2 to overcome the related MDR. Mobocertinib (TAK-788) is an orally administered, irreversible EGFR/HER2 inhibitor approved for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations. This study reveals that mobocertinib has the potential to reverse ABCB1- and ABCG2-mediated MDR. The molecular docking analysis showed a high binding affinity score for mobocertinib with both ABCB1 and ABCG2 models, signifying the strong interaction between mobocertinib and these two proteins. The MTT assay demonstrated the capability of mobocertinib to reverse MDR mediated by ABCB1 and ABCG2 in cancer cells. In addition, the employment of the HEK293 double-transfected model and the ABCB1 and ABCG2 gene knockout cell model underscored the specific inhibitory effects of mobocertinib on ABCB1- and ABCG2-associated MDR. Mechanistic assays unveiled that mobocertinib enhances drug accumulation by inhibiting the drug efflux function of ABCB1 and ABCG2. This inhibitory effect of mobocertinib on the ATPase activity of ABCB1 and ABCG2 was concentration-dependent. Furthermore, within a treatment period of up to 72 h, mobocertinib demonstrated no influence on the expression levels or subcellular localization of ABCB1 and ABCG2. In the tumor-bearing mouse model, mobocertinib boosted the antitumor effect of topotecan, resulting in tumor regression with the treatment and exhibiting a consistent trend in reversal studies. In summary, our study uncovers a novel potential for repurposing mobocertinib as a dual inhibitor of ABCB1 and ABCG2, and suggests the combination of mobocertinib with substrate drugs as a strategy to counteract MDR
Brexit and the Spillover Phenomenon: Scotland, Northern Ireland, and Gibraltar
Get PDFIn my research, I examined the consequences of Brexit and the spillover phenomenon. Even though the United Kingdom left the European Union on 31 December 2020 with a deal, the resulting challenges are not solved at all in 2024 either – Brexit has brought to the surface such conflicts that London considered dealt with a long time ago. However, questions of autonomy and independence are not so easy to resolve; they have their roots in history, and in this uncertain situation, they came to the fore again.
Northern Ireland, Gibraltar, and Scotland have always meant sources of conflict for the British, which seems to be reinforced by Brexit. Spain demanded the renegotiation of the issue of Gibraltar; tensions between the ‘two Irelands’ re-emerged on the Irish border, while Scotland has been considering another referendum to leave Great Britain and possibly rejoin the EU. Furthermore, this is happening in an era when nationalism and the idea of the nation-state are gaining momentum across Europe.
My question is whether Northern Ireland, Scotland, and Gibraltar want to continue without London. If yes, what are their chances? Can they function independently, or can they join a country that is already in the EU? Could this exit bring about the disintegration of the United Kingdom? If yes, that would be the problem of every country in Europe, as that could set a precedent for every other minority within the continent
A QUALITATIVE INQUIRY TO THE IMPACT OF PEER TEACHING ON UNDERGRADUATE CHEMISTRY STUDENTS
Get PDFThis study investigates the impact of peer teaching on undergraduate STEM majors, particularly those who serve as peer teachers for introductory chemistry courses. While previous research has predominantly focused on the benefits of peer tutoring for the tutored students, the reciprocal impact on peer teachers remains underexplored. The main purpose of this study is to quantify the differences between peer teachers and comparable students who do not engage in teaching, with a specific focus on problem-solving approaches and the ability to explain STEM concepts. The assessment included coding students\u27 work to reveal strategy use and provide a means of comparison through administering a ranking survey as another metric. The results indicate more frequent problem-solving strategy use and better-written explanations among peer teachers. The significance of this study lies in its potential implications for educational practices in higher education. By demonstrating that peer teachers experience problem-solving and explanatory writing gains, the research highlights the benefits of peer teaching programs: enhancing the learning outcomes for both the students and the peer teachers themselves
POVERTY AND INEQUALITY: A NEW DEAL FOR AMERICA’S MOST DISADVANTAGED COMMUNITIES
Get PDFThe United States, often hailed as the most affluent nation globally, paradoxically grapples with rates of poverty, disadvantage, and inequality that surpass those of its advanced democratic counterparts. The persistence of poverty and inequality in the United States have often been justified by beliefs of welfare dependency, “free market” thinking and utilitarianism. This master\u27s thesis explores the far-reaching moral, political, and economic consequences of America’s high rates of poverty and inequality. It contends that federal action is urgently needed on more robust social programs that target poverty, such as affordable housing, accessible healthcare, greater worker protections, and deepened social capital investments in high poverty communities that have historically been exploited
EFFECTS OF POLICE HIRING & TRAINING ON CIVILIAN COMPLAINTS: A CASE STUDY OF THE NASSAU COUNTY, NY POLICE DEPARTMENT
Get PDFPolice agencies and administrations continue to face public scrutiny, consequential poor policing, and costly litigation from within their communities. Newly hired Police officers, trained in the latest police science, can lead to fewer received civilian complaints from the communities they serve. Without established literature and studies, agency leadership and policy-makers\u27 decision-making are constrained to quantifying spreadsheet data, which rarely alter the totality of any micro-level police-related interactions. Therefore, this study asks, how does the amount of newly hired police officers affect the number of civilian complaints received? Theories applied include Risk Management, Societal Security, and Conflict Criminology. The Nassau County Police Department is examined as a reasonable reflection of policing. This mixed methods case study utilized a multivariate analysis of continuous variables and surveyed 431 Nassau County law enforcement professionals. The analysis revealed a statistically insignificant relationship between increased police recruits and decreased complaints. Significant differences (0.000\u3c0.05) in different demographics found black complainants (M=55.75) are likely to file the most complaints while Asian complainants (M=5.75) are the least likely to file complaints. White civilian complainants filed more complaints following NYS Executive Order 203 effective date of April 1, 2021 (p=0.006\u3e0.05). Race and the specific criminal justice database are determining factors in the total number of arrests reported (F(1,4)=4.269, p=0.005\u3c0.05) and age ((F(10,131)=11.767, p=0.000\u3c0.05) determined whether an arrest is made. According to FBI data, police reform training did not significantly contribute to crime rates (p=0.326\u3e0.05), while NYS data showed improvement following police reform training (p=0.026\u3c0.05). Further suggested research should explore the cost-benefit of overtime over new hires, practical and relevant training, and the effectiveness of current recruitment practices
A UBIQUITIN-BASED PROTEOMIC ANALYSIS OF HF-STZ DIABETIC RAT LIVERS
No full textType 2 diabetes, an epidemic affecting an estimated 500 million people worldwide, is characterized by a combination of impaired glucose homeostasis and various extents of beta cell dysfunction and insulin resistance. Post-translational modifications (PTMs) of key players in the insulin signaling pathway are known to contribute to insulin resistance by regulating the activity and function of proteins such as IR, IRS, and Akt. Sustained hyperglycemia, inflammation, and obesity-induced lipid alterations activate serine/threonine kinases that phosphorylate insulin signaling proteins, leading to their deactivation. However, little is known about ubiquitination’s effect on insulin resistance. The ubiquitin-proteasome system regulates various cellular processes, and the aberrant function of this system is linked to various human ailments, such as neurodegenerative diseases, cancer, and immune disorders. Ubiquitination is a multistep process that utilizes E3 enzymes to ligate the C-terminal glycine of ubiquitin, a 76 amino acid tag, to target proteins. The addition of further ubiquitin molecules using various lysine (K) residues can build poly-ubiquitin chains of different topologies. The structural and functional diversity of ubiquitin linkages imparts unique abilities of this PTM in controlling normal physiology and pathophysiology. Moreover, several studies have implicated E3 ubiquitin ligases in the development of insulin resistance. Therefore, we studied hepatic ubiquitination patterns in a high-fat diet and low-dose streptozotocin (HF-STZ) animal model of diabetes. Affinity pull-down and proteomics techniques were employed to explore differential ubiquitination as well as K48- and K63-linkage-specific differences between control and diabetic animals. Both overall and linkage-specific ubiquitination were higher in diabetic rat livers. Bioinformatic analysis of the top 150 protein hits in each ubiquitination category revealed enrichment in metabolic processes involving glucose and lipid metabolism. Our study provides insight into hepatic ubiquitination in an animal model of insulin resistance. The identified ubiquitinated proteins could serve as potential targets for the pharmacotherapy of type 2 diabetes and merit further investigation
INTERPLAY BETWEEN RNA EDITING AND ALTERNATIVE SPLICING MODULATES BIOPHYSICAL AND PHARMACOLOGICAL PROPERTIES OF THE ION CHANNEL CAV1.3
Get PDFAlternative splicing and adenosine-to-inosine (A-to-I) RNA editing are post-transcriptional mechanisms that promote proteomic diversity in the brain. The impact of RNA editing on brain physiology is underscored by its association with the etiology and pathogenesis of various neurological and neurodegenerative diseases. Alternative splicing of exon 43 within the CaV1.3 C-terminus produces long (CaV1.3L) and short (CaV1.343S) variants exhibiting distinct gating and pharmacological properties. While the physiological role of CaV1.3 A-to-I RNA editing in brain function is still unfolding, recent findings indicate that unedited CaV1.3 channels display larger calcium influx and enhanced neuronal excitability, suggesting that A-to-I RNA editing may act as a negative regulator of neuronal calcium signaling. However, it remains unclear which specific splice variants of CaV1.3 undergo RNA editing. We discovered an unexpected link between alternative splicing and RNA editing, where generation of the CaV1.343S variant results in a 3-fold increase in RNA editing at the IQ site. The CaV1.343S variant undergoes significant A-to-I RNA editing at 2 sites within its calmodulin-binding IQ domain, giving rise to 3 different edited variants. Functional analysis revealed that A-to-I RNA editing markedly decreases current density and induces a depolarizing shift in the current window, aligning the edited short variant\u27s properties with those of the long variant. Our findings suggest that A-to-I RNA editing serves as a physiological mechanism regulating the \u27short\u27 gating properties of the CaV1.343S variant and positions A-to-I RNA editing of CaV1.343S variant as a neuroprotective physiological mechanism that prevents calcium overload, especially in neurons susceptible to calcium toxicity
THE IMPACT OF PRINCIPAL LEADERSHIP ON STUDENT ACHIEVEMENT OUTCOMES IN K-12 EDUCATION
No full textThe purpose of this quantitative scholarly research study was to ascertain to what extent a principal’s leadership contributes to an increase in student achievement outcomes in K-12 education in New York City. The study used the Learning Environment Survey from 2021 and English Language Arts testing data from 2018 for third, fourth, and fifth grades. Two research questions guided this study. First, what are the factors of principal leadership that emerge from the Learning Environment Survey? Second, to what extent do these factors, as a proxy for principal leadership, have an influence on student achievement outcomes, in K-12 education? Four factors emerged from the data: 1) Leadership Support Factor, 2) Professional Development Factor, 3) Leader Expectations Factor, and 4) Professional Knowledge Factor. These four align with the five key attributes of effective principals proposed by the Wallace Foundation. Using multiple regression analysis, three of the factors were shown to have no statistically significant impact on student achievement as measured by ELA scores: Professional Development, Leader Expectations, and Professional Knowledge Factor. The Leadership Support Factor was a significant predictor of ELA achievement for all three grade levels (i.e., Grade 3, Grade 4, and Grade 5). Finally, implications for future practice is discussed
The Mediation of Financial Behavior to Financial Literacy and Spending Habits of Gen Z: An Exploratory Factor Analysis
Get PDFThe study aims to explain the relationship of financial literacy with spending habits and behavior. Financial behavior is a mediator of Generation Z. Financial literacy is a very important dimension in making financial decisions, and this research highlighted the direct and indirect impacts that financial literacy exerts on spending behavior. Data is collected from 317 respondents using a structured questionnaire measuring financial literacy, financial behavior, and spending behavior. Correlation, regression, mediation analysis, and Structural Equation Modeling have been used in evaluating these relationships. Financial literacy directly reflects a strong relationship with spending behavior, and its coefficient is 1.167. Financial behavior, therefore, exercises a strong mediation effect on this relationship with a mediation coefficient of 0.797, thus indicating that financial behavior is an essential tool in successfully translating financial knowledge into responsible spending. From these findings, greater financial literacy and responsible financial behavior may increase the aggregate financial efficacy of Generation Z. Although the current study heavily focuses on the fact that financial literacy and behavior are highly associated with financial well-being, it shows that targeted financial literacy education programs on either behavior or financial literacy enhance healthier spending behavior. The scope of future studies involves considering the role of income and personality characteristics as well as an elongation of the time horizon to uncover the impact of financial literacy on shifts in the individual\u27s financial well-being