Platinum Complexes and Zinc Finger Proteins: From Target Recognition to Fixation

Bioinorganic chemistry strives to understand the roles of metals in biological systems, whether in the form of naturally occurring or addition of non-essential metals to natural systems. Metal ions play vital roles in many cellular functions such as gene expression/regulation and DNA transcription and repair. The study of metal-protein-DNA/RNA interactions has been relatively unexplored. It is important to understand the role of metalloprotein interactions with DNA/RNA as this enhanced knowledge may lead to better understanding of diseases and therefore more effective treatments. A major milestone in the development of this field was the discovery of the cytotoxic properties of cisplatin in 1965 and its FDA approval in 1978. Since then, two other chemotherapeutic drugs containing platinum, carboplatin and oxaliplatin, have been used in the clinic. These three compounds are all bifunctional with the ligands surrounding platinum In the cis conformation and rearrangement of the ligands to the trans orientation results in a loss of cytotoxic properties due to rapid deactivation through binding to S-containing proteins. This enhanced reactivity yields new opportunities to study the reactions between proteins and DNA. One of the first crosslinking experiments used transplatin to crosslink NCp7 to viral RNA in order to understand how/where the protein bound to RNA. We have studied the interaction between cis and trans dinuclear platinum complexes and the C-terminal zinc finger (ZF). The trans complex reacts at a faster rate than the cis isomer and causes N- terminal specific cleavage of the ZF. The dinuclear structure plays a critical role in the peptide cleavage as studies with transplatin (the mononuclear derivative) does not result in cleavage. Monofunctional trans platinum-nucleobase complexes (MPNs) serve as a model for the binding of transplatin to DNA. This provides an interesting opportunity to study their reactions with S-containing proteins, such as HIV1 NCp7. MPNs have been shown to bind to the C-terminal ZF of HIV1 NCp7, resulting in zinc ejection. This occurs through a two-step process where the nucleobase π-stacks with Trp37 on the ZF, followed by covalent binding at the labile Cl site to Cys. MPNs have also shown antiviral activity in vitro. The labile Cl on MPNs reduces specificity of these compounds, as it leaves an available coordination site on the platinum center for binding to other S-proteins or DNA. Therefore, we have moved to an inert PtN4 coordination sphere, [Pt(dien)L]2+ (dien= diethylenetri- amine). Due to the strong bond between platinum and nitrogen, covalent reactions are highly unlikely to occur at rapid rates. The strength of the pi-stacking interaction between nucleobases (free and platinated) and the aromatic amino acid, tryptophan (Trp), showed an enhanced binding constant for platinated nucleobases. This was confirmed by density functional theory (DFT) calculations as the difference in energy between the HOMO of Trp and the LUMO of the nucleobase was smaller for the platinum complex. The studies were extended to the Trp-containing C-terminal ZF of HIV1 NCp7 and an increase in association constant was seen compared to free Trp. Reaction of PtN4 nucleobases compounds with a short amino acid sequence con- taining either Ala (no pi-stacking capabilities) or Trp (pi-stacking interactions) revealed an enhanced rate of reactivity for the Trp-containing peptide. This result supports the theory of a two-step reaction mechanism where the platinum-nucleobase complex recognizes the pep- tide through a pi-stacking interaction with Trp followed by covalent binding to the platinum center. The [Pt(dien)L]2+ motif allows for systematic modification of the structural elements surrounding platinum in a search for the most effective compound. Methylation of the dien ligand should, in theory, increase lipophilicity of the compounds, however, due to 2+ charge of the compounds, this simple association does not hold true. Analysis of the cellular accumulation profiles showed little change in the uptake with the addition of methyl groups to the dien ligand, in agreement with the non-linear change in lipophilicity. Modification of L using different nucleobases allows for the tuning of the strength of the π-stacking interaction between Trp and the platinum complex. The addition of inosine (which lacks a H-bonding donor/acceptor at the C2 position) resulted in a lower association constant with both N-AcTrp and the C-terminal zinc finger of HIV1 NCp7. Interestingly, the addition of xanthosine resulted in an ehanced pi-stacking interaction with the C-terminal zinc finger of HIV1 NCp7; likely as a results of the addition of a H-bonding donor (double-bonded O) at the C2 position. The ability of PtN4 nucleobase complexes to inhibit formation of the NCp7 complexation with viral RNA was studied by mass spectrometry and gel electrophoresis. Dissociation of the NCp7-RNA complex was seen upon addition of PtN4 compounds. These compounds were also able to retard formation of the NCp7-RNA complex when pre-incubated with the protein. These results have important implications as inhibition of complex formation between NCp7 and viral RNA has negative implications for viral replication. Despite the success of platinum-nucleobase compounds, it is important to evaluate all potential pi-stacking ligands. A series of pyridine- and thiazole-based compounds were evaluated for the strength of the pi-stacking interaction with N-AcTrp and the C-terminal ZF of HIV1 NCp7. There was notable increase in association constant for the platinum- DMAP (4-dimethylaminopyridine) complex compared to other ligands studied. This result highlights the importance of exploring multiple avenues for the design of specifically targeted inhibitors and further confirms the viability of the medicinal chemistry dual approach of target recognition (non-covalent) followed by target fixation (covalent)

Psychological Antecedents of Binge Drinking Among College Students

Binge drinking is often studied among college students because they have the highest alcohol consumption rate relative to any other group in the nation. The present study examines nine predictor variables to determine which psychological antecedents influence why some students are more likely to participate in binge drinking practices than others. For cross-validation purposes, after administering an online questionnaire to 1,786 college students, the sample was split into two groups. A multi-staged path analysis model was tested to explore factors that influence binge drinking, including: depression, worry, social isolation, social interaction anxiety, and five different time perspective dimensions. Only 7% of the variance in binge drinking could be accounted for on the basis of the predictor set. The amount of variance captured suggests that the set of predictors effective at explaining binge drinking among middle-aged adults is not consistent with what was found among college students in this study. Fully 33% of the variability in depression scores was captured on the basis of the antecedent predictors, and 29% of the variability in worry scores was explained. One novel aspect of this investigation is that time perspective had not previously been examined in relation to social isolation. Notably, this study revealed that four of the five time perspective dimensions were significant predictors of both social isolation and social interaction anxiety. The findings from this study suggest that it would be beneficial to explore other predictor variables in order to better explain binge drinking among college students

Student Perceptions and Learning After a Cognitive Load-Based Intervention to Reduce Multitasking Behaviors

With the influx of educational and personal technologies in the classroom, parents, faculty, and students must find strategies to limit the seductive pull of multitasking. The purpose of this study is to determine if an awareness training and experience using website-blocking software improves learning in a lecture course, and if this experience changes students' multitasking beliefs and planned future behavior with respect to multitasking. This was an experimental study for students in a graduate level occupational and physical therapy program. Students were randomized into two groups. The experimental group received a two-pronged intervention: an education session with awareness exercises on multitasking and a website-blocking software for student use during lectures. Five content knowledge exams were administered and analyzed for group differences in learning. Results: The findings in this study showed that the awareness training and experience using Freedom software did not significantly improve learning in the short-term. Although there was no significant change in student beliefs on their ability to multitask, students reported the amount of time spent multitasking in class decreased across courses, and students reported an increase in the use of strategies to help them maintain attention in class. This finding can be explained using the Theory of Planned Behavior's (Azjen, 1991) predictor of a change of perceived behavioral control by having additional strategies to implement when tempted to multitask which can in turn increase the student's intention to minimize their multitasking behaviors as shown by the decrease in the number of minutes spent multitasking in classes across the curriculum.Educatio

Differential impact of adverse childhood experiences and aging on brain health

Adverse childhood experiences (ACEs) are events composed of several forms of abuse that children under the age of 18 are subjected to. These events include forms of physical or emotional abuse, neglect, and household dysfunction. Experiencing trauma as a child has been linked to a variety of negative psychical, emotional, and psychological outcomes. This research aims to explore how ACEs influence brain health later in life. Additionally, the purpose of this research is to link these traumatic events to a biological marker of brain health (brain-derived neurotrophic factor; BDNF) and neurocognitive performance across two age cohorts. The data for this project was collected cross-sectionally through survey, cognitive testing, and blood samples on 106 women between the age of 18-25 and 65-85 in the state of Oklahoma. Veinous blood draws were completed to collect serum for analysis of BDNF levels. The Automated Neuropsychological Assessment Metrics (ANAM) and National Institute of Health Toolbox Cognition Battery (NIH-Toolbox) were used to assess neurocognitive function. Independent sample t-tests on age and cognition suggest that age is linked to poorer cognitive performance, with the older adult cohort showing significantly lower scores than the emerging adult cohort. An independent t-test observing age and BDNF suggests that age did not affect BDNF levels. When examining differences in cognitive scores using significance and effect size, the overall sample found individuals in the higher ACE group had higher cognitive scores. The cognitive batteries have subtests that capture different areas of cognition. When looking at the subtests separately, it is suggested that ACEs may be an underlying factor that contributes to increases in some cognitive functions as an adaptive trait and negatively to other cognitive domains, also as an adaptive trait. This suggests that ACEs may be associated with adaptive cognitive performance under some circumstances while harmful in others

Physical Activity, Physical Well-Being, and Psychological Well-Being: Associations with Life Satisfaction during the COVID-19 Pandemic among Early Childhood Educators

Seeking personal well-being and life satisfaction during a global pandemic can be daunting, such is the case for early care and education teachers who were considered non-health care essential workers during the COVID-19 pandemic. The potential changes in their physical activity, along with their overall physical and psychological well-being, may have ultimately influenced their life satisfaction. These changes included the potential for increased sedentary behaviors. Despite the high health risks associated with these factors during the pandemic, the role of physical activity in early care and education teachers’ well-being and life satisfaction remains largely unknown. The purpose of this study is to examine the associations of physical activity and sedentary behaviors with teacher well-being and life satisfaction during the COVID-19 pandemic. In doing so, we explored two competing models of the relationship between the teachers’ physical activity, well-being, and life satisfaction, one with physical activity as a mediator and the other with teachers’ well-being as a mediator. An online survey, that collected information on physical, psychological, and professional well-being, job demands, and life satisfaction, was completed by 1434 US ECE teachers in 46 states. To test our hypothesized models, we conducted confirmatory factor analyses, followed by structural equation modeling. Of the respondents, 77% were overweight or obese and only 39% met the recommended 150 min of moderate physical activity per week. They had a mean life satisfaction score that qualifies as slight satisfaction, they experience moderate stress, and, collectively, are approaching the threshold for depression yet still reflect moderate-to-high work commitment. The empirical test of our competing mediation models found the model where teacher well-being mediated the association between physical activity, sedentary behavior, and life satisfaction was the superior model. The relationships between physical activity, sedentary behavior, and overall well-being suggest that these modifiable risk factors can be addressed such that early care and education teachers can improve their overall physical and psychological well-being, along with their life satisfaction

Enhancement of the Physicochemical Properties of Pt(dien)(nucleobase) (2+) for HIVNCp7 Targeting

Physicochemical properties of coordination compounds can be exploited for molecular recognition of biomolecules. The inherent π-π stacking properties of [Pt(chelate)(N-donor)]2+([PtN4]) complexes were modulated by systematic variation of the chelate (diethylenetriamine and substituted derivatives) and N-donor (nucleobase or nucleoside) in the formally substitution-inert PtN4 coordination sphere. Approaches to target the HIV nucleocapsid protein HIVNCp7 are summarized building on (i) assessment of stacking interactions with simple tryptophan or tryptophan derivatives to (ii) the tryptophan-containing C-terminal zinc finger and (iii) to the full two-zinc finger peptide and its interactions with RNA and DNA. The xanthosine nucleoside was identified as having significantly enhanced stacking capability over guanosine. Correlation of the LUMO energies of the modified nucleobases with the DFT π-stacking energies shows that frontier orbital energies of the individual monomers can be used as a first estimate of the π-stacking strength to Trp. Cellular accumulation studies showed no significant correlation with lipophilicity of the compounds, but all compounds had very low cytotoxicity suggesting the potential for antiviral selectivity. The conceptual similarities between nucleobase alkylation and platination validates the design of formally substitution-inert coordination complexes as weak Lewis acid electrophiles for selective peptide targeting

Challenges in Working Conditions and Well-Being of Early Childhood Teachers by Teaching Modality during the COVID-19 Pandemic

While a global understanding of teacher well-being during the COVID-19 pandemic is beginning to emerge, much remains to be understood about what early childhood teachers have felt and experienced with respect to their work and well-being. The present mixed-method study examined early care and education (ECE) teachers’ working conditions and physical, psychological, and professional well-being during the COVID-19 pandemic using a national sample of 1434 ECE teachers in the U.S. We also explored differences in working conditions and well-being among in-person, online, and closed schools, given the unique challenges and risks that ECE teachers may have faced by teaching in these different modalities. From the results of an online survey, we found that in the early months of the pandemic, many ECE teachers faced stressful, challenging work environments. Some were teaching in new, foreign modes and formats, and those still teaching in person faced new challenges. We found many common issues and challenges related to psychological and physical well-being across the three teaching groups from the qualitative analysis, but a more complicated picture emerged from the quantitative analysis. After controlling for education and center type, we found that aspects of professional commitment were lower among those teachers teaching in person. Additionally, there were racial differences across several of our measures of well-being for teachers whose centers were closed. Upon closer examination of these findings via a moderation analysis with teacher modality, we found that Black and Hispanic teachers had higher levels of psychological well-being for some of our indicators when their centers were closed, yet these benefits were not present for Black and Hispanic teachers teaching in person.Open Access fees paid for in whole or in part by the University of Oklahoma Libraries.Ye

Supplemental Material - The Relation Between Adverse Childhood Experiences and Health Behaviors in Adult Women

Supplemental Material for The Relation Between Adverse Childhood Experiences and Health Behaviors in Adult Women by Karina Lauren Tavares and Cindy Eileen Tsotsoros in American Journal of Health Promotion</p