The Mre11-CDK2 Interaction in the DNA Damage Response.

MRN (Mre11, Rad50, and NBS1) complex consists of highly conserved proteins integral to DNA double-strand break (DSB) signaling and repair. The unique MRN complex architecture allows direct binding to damaged DNA ends, DSB detection, and activation of cellular repair systems. Defects in the MRN complex lead to cancer predisposition, neurodegeneration, and immunodeficiency. MRN is required to initiate homologous recombination, the predominant repair pathway during the S and G2 phases of the cell cycle. Mre11 provides the nuclease activity needed for resection, while the NBS1 subunit interacts with ATM kinase, the master regulator of the DNA damage response (DDR) signaling cascade. The nuclease activity of Mre11 are required but alone are insufficient for resection; tumor suppressor BRCA1 and CtIP protein are also needed. CtIP is responsible for cell-cycle regulation of resection, while the major cyclin-dependent kinase (CDK) in S-phase is CDK2 bound to Cyclin A. Phosphorylation of CtIP by CDK2 allows the MRN-CtIP-BRCA1 resection complex to assemble, providing maximum resection capacity for homologous recombination. Mre11 controls these events through direct interaction with CDK2 which is required for CtIP phosphorylation and interaction with BRCA in normal cells. This observation demonstrates the important functions of MRN in both the DDR and in normal cell cycle regulation. The DDR has been extensively studied, but the role of CDK2 within the DDR remains unclear. The work presented here includes the following investigations: 1) the impact of DNA damage on the Mre11-CDK2/Cyclin A interaction, 2) whether change in the Mre11-CDK2/Cyclin A interaction is ATM-dependent, and 3) whether alterations in the activity of CDK2 indicate DDR participation. To examine the effect of DNA damage on the Mre11-CDK2/Cyclin A complex, I exposed mammalian cells to ionizing radiation and evaluated the interaction of endogenous Mre11 and CDK2/Cyclin A. These data indicate that DNA damage induces rapid dissociation of the Mre11-CDK2/Cyclin A complex dependent on ATM kinase activity and correlative to a reduction in CDK2 activity. This suggests that the Mre11-CDK2/Cyclin A complex dissociation causes a reduction in CDK2 activity, thereby contributing to the delay of cell cycle progression in S-phase, allowing for DNA repair proteins to restore DNA integrity.PhDToxicologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/108856/1/toddafes_1.pd

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

The changing nature of childhood environments: investigating Children’s Interactions with digital voice assistants in light of a new paradigm

Based on the theoretical framework of the New Ontological Category Hypothesis (NOCH), this piece of doctoral research (work in progress) investigates the nature of children’s interactions with commercial Digital Voice Assistants (DVAs), such as Alexa, Google Assistant, or Siri. In a nutshell, NOCH challenges the notion of anthropomorphism and argues that intelligently behaving machines, such as voice assistants, could become ontological categories in their own right within children’s emerging understanding of the world. A methodological strategy is briefly outlined in order to explore NOCH with respect to children’s relative self-disclosure, that is, how children self-disclose personal insights when they interact with DVAs, on the one hand, and humans, on the other hand

The changing nature of childhood environments: investigating Children’s Interactions with digital voice assistants in light of a new paradigm

Based on the theoretical framework of the New Ontological Category Hypothesis (NOCH), this piece of doctoral research (work in progress) investigates the nature of children’s interactions with commercial Digital Voice Assistants (DVAs), such as Alexa, Google Assistant, or Siri. In a nutshell, NOCH challenges the notion of anthropomorphism and argues that intelligently behaving machines, such as voice assistants, could become ontological categories in their own right within children’s emerging understanding of the world. A methodological strategy is briefly outlined in order to explore NOCH with respect to children’s relative self-disclosure, that is, how children self-disclose personal insights when they interact with DVAs, on the one hand, and humans, on the other hand

Innovators’ freedom to challenge our paradigms: Why the Copernican legacy should guide our progression through the incipient age of artificial intelligence

Despite originating from the innovative, yet niche work of an astronomically interested polymath living in the gloomy aftermath of the European medieval period, the Copernican Revolution is considered to be the historical progenitor of many freedoms that we enjoy in modern secularised societies. But while the notion of the Copernican Revolution primarily refers to its role as the igniter of a singular chain reaction with historical momentum, I argue that Copernicus’ true legacy stands for a freedom in itself that has not lost its significance ever since its birth in the dead of the 16th-century: innovators’ freedom to challenge the prevailing paradigms of their times. This essay is meant to be a thought-provoking treatise in defence of this freedom. Firstly, based on a brief historical excursus I derive the argument why innovators’ influence on societal paradigms has always been a main driver of societal progression. Secondly, I consider why innovations related to the recent advancements in Artificial Intelligence (AI) may be the portents of another paradigm shift. Thirdly, I discuss why and how innovators’ freedom to challenge the prevailing paradigms of our time is worth defending