Thesis advisor: Charles Hoffman / The second messenger cyclic 3’-5’ adenosine monophosphate (cAMP) signaling pathway plays an important physiological role in many organisms. Cyclic nucleotide phosphodiesterases (PDEs) regulate signal transduction by catalyzing the hydrolysis of cAMP and cGMP allowing for the downregulation of cyclic nucleotide levels. Human PDEs are encoded by 21 genes grouped into 11 families. The biological role of the most recently discovered PDE family (PDE11) remains poorly understood partly due to the lack of selective inhibitors. Mutations in the PDE11A gene have been linked to a wide range of diseases, such as Cushing Syndrome, which is a result of inactivating mutations expressed in adrenocortical tumors. Meanwhile, PDE11 levels are seen to increase in the ventral hippocampus as a function of aging, and is associated with a loss of social memory. Thus, the development of a selective PDE11 inhibitor could provide a potential therapeutic benefit to patients receiving long-term corticosteroid treatment by stimulating cortisol production by the adrenal gland, as well as to aging adults to maintain social memory. To address these needs, candidate PDE11 inhibitors related to a compound discovered by the Hoffman lab in a high throughput screen for PDE11 inhibitors are being synthesized by the Rotella laboratory. I have been evaluating these compounds using two fission yeast-based growth assays in complement with in vitro enzyme assays carried out by Dr. Jeremy Eberhard. Here I describe my role in the project, leading to the identification of a compound, SMQ2-57, which is a selective inhibitor of the PDE11 enzyme whose potency has been confirmed through both yeast-based assays and in vitro enzyme assays. In addition, I have taken both a forward and reverse genetic approach to identify PDE11A4 mutant alleles that confer resistance to inhibitor compounds as such knowledge could guide a rational drug design approach to produce more effective PDE11 inhibitors. Based on our results, SMQ2-57 could serve as a useful tool in understanding the biological role of PDE11. Meanwhile, data from my study of compound resistant mutant PDE11 alleles should allow for the characterization of the physical interaction between PDE11 and its inhibitors in an effort to guide a medicinal chemistry program to develop a more potent and drug-like PDE11 inhibitor. / Thesis (BS) — Boston College, 2023. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Scholar of the College. / Discipline: Biology.

Background: In recent years, students' screen time has increased, especially during the corona pandemic. As increased prevalence of neck pain and decreased physical activity (PA) have been reported during this period, it is of interest to study the relationship between these variables. Aim: To examine screen time, neck pain and the level of PA and the relationship between these variables in students studying full-time at Uppsala University. Method: A quantitative, descriptive and correlational cross-sectional study. PA was measured with the International Physical Activity Questionnaire, neck pain in days, and intensity with the Numeric Pain Rating Scale (NRS), and screen time in hours, for the past week. The data was collected using a web survey.   Results: Ninety-eight students answered the survey. Fifty-four percent of participants reported neck pain the past week. On average, students spent 18.5 hours on screen studies, and 41.3 hours on total screen time. The PA level averaged 2438 Metabolic Equivalent of Task in minutes. Median neck pain was one day with NRS 1. A low significant correlation was seen between: screen studies and number of days neck pain (r = 0.23; p = 0.028); total screen time and neck pain (r =0.26; p = 0.012); studies at screen and neck pain intensity (r = 0.23; p = 0.024); total screen time and neck pain intensity (r =0.26; p = 0.011). A low, non-significant correlation was seen between screen studies and total screen time and PA (r = 0.04/0.02; p = 0.713/0.881). Conclusion: Students spend a lot of time in front of screens and a majority of students reported low-intensity neck pain the past week. However, there was only a low correlation between screen time and neck pain, and between screen time and FA. / Bakgrund: Under de senaste åren har studenters skärmtid ökat, inte minst under corona-pandemin. Då ökad prevalensen av nacksmärta och minskad fysisk aktivitet (FA) har rapporterats under denna period, är det av intresse att studera sambandet mellan dessa variabler.  Syfte: Undersöka skärmtid, nacksmärta och nivån av FA och samband mellan dessa variabler hos studenter som studerar heltid på Uppsala universitet.  Metod: En kvantitativ, deskriptiv och korrelerande tvärsnittsstudie. FA mättes med International Physical Activity Questionnaire, nacksmärta i dagar, och intensitet med Numeric Pain Rating Scale (NRS), och skärmtid i timmar, för senaste veckan. Datan insamlades med en webenkät. Resultat: Nittioåtta studenter besvarade enkäten. Femtiofyra procent av deltagarna rapporterade nacksmärta senaste veckan. I genomsnitt spenderade studenterna 18,5 timmar på studier vid skärm, och 41,3 timmar på total skärmtid. Nivån FA var i genomsnitt 2438 Metabolic Equivalent of Task i minuter. Medianen för nacksmärta var en dag med NRS 1. Ett lågt signifikant samband sågs mellan: studier vid skärm och nacksmärta i antal dagar (r = 0,23; p = 0,028); total skärmtid och nacksmärta (r =0,26; p = 0,012); studier vid skärm och nacksmärtans intensitet (r = 0,23; p = 0,024); total skärmtid och nacksmärtans intensitet (r =0,26; p = 0,011). Ett lågt icke signifikant samband sågs mellan studier vid skärm respektive total skärmtid och FA (r = 0,04/0,02; p = 0,713/0,881).  Konklusion: Studenter spenderar mycket tid framför skärm och en majoritet av studenter rapporterade lågintensiv nacksmärta under senaste veckan. Dock förelåg enbart ett lågt samband mellan skärmtid och nacksmärta, samt mellan skärmtid och FA.

Despite the amount of people currently using technology and the overwhelming amount of data already presented on the topic of how technology affects a person's mental health, there seems to be little information on how the different types of activities on the different types of screens affect university student's mental states. This research study examined the amount of time that a University of Central Florida (UCF) student spends on what was defined as educational activities in front of screens and what was defined as recreational. The definitions of what is educational and what is recreational screen time came from a previously published study (Salzano et al., 2021). These dimensions of screen time have never been investigated like this before. This data was then compared to the student's current level of depression (among other factors) to see if more time per day, in a particular screen time group, affects a university student's mental state. This information is extremely important to investigate as understanding if certain activities affect a university student's mental health could lead us to lower the increasing level of depression in this country if those screen activities are limited (Duffy et al., 2019). In the end 449 currently enrolled UCF student responses were recorded and it was determined that the data did not support the hypothesis. According to this study the amount of screen time, whether it be educational or recreational, did not influence any aspect of a university student's mental health whether it be depression, stress, or mindfulness as there was no difference between any of the scores at the different screen time values. If this study was to be conducted again, perhaps more participants could be included, or a different scale of screen time could be used to obtain different results.

DAWDLE (DDL) is one of the eighteen genes in Arabidopsis thaliana that encodes a protein with a Fork-Head Associated domain, a phospho-threonine binding domain providing a role in DNA repair and cell cycle regulation. DDL also contains an arginine-rich N terminal domain with putative Nuclear Localization Signals and a region for RNA binding. Two ddl knockout alleles in the WS-2 ecotype exhibit a strong pleiotropic phenotype with developmental defects such as short root and hypocotyl, reduced fertility, and distorted organs. This developmentally delayed phenotype is due to reduced accumulation of microRNAs and the phenotype is similar to those displayed by mutants involved in microRNA biogenesis pathway, suggesting a function for DDL in the microRNA biogenesis. One of the goals of my research was to characterize DDL protein through a structureunction study. Twelve point mutants were isolated in a mutagenesis screen and a comparative phenotypic and molecular characterization of each mutant with wildtype (WT) plants was performed. This revealed a few functionally significant amino acid residues of DDL. Traits for comparison included hypocotyl and root length, plant height, fertility, and microRNA accumulation. While all the mutants displayed reduced fertility, some of them had significantly varying stem height, hypocotyl and root length, and microRNA accumulation compared to the WT. Another objective of my research was to identify components involved in the DDL pathway, which in-turn would contribute to discovering additional components in microRNA biogenesis pathway. One such component, ddl suppressor1 (dds1), was identified through a second site mutagenesis screen of ddl-2. Phenotypic and molecular characterization revealed that dds1 is a strong suppressor of ddl that was mapped on chromosome 3 of Arabidopsis. Another component identified was MODIFIER OF DDL (MDL), a natural variation between Col and WS-2 ecotype of Arabidopsis. The variation has been mapped to an interval consisting of 37 genes on chromosome 5. MDLCol is the dominant allele and imparts a weak phenotype to ddl knockouts, whereas the recessive MDLWS-2 does not modify a strong ddl knockout phenotype. ddl MDLCol does not display abnormality in microRNA accumulation unlike ddl MDLWS-2 indicating that MDL has a function related to microRNA biogenesis.

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