interdisciplinary approach
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Understanding antiretroviral phosphorylation and dephosphorylation using mass spectrometry imaging-based enzyme histochemistry
PROJECT SUMMARY Our overall goal is to understand the mechanistic differences in the activation and deactivation of two widely used first-line antiretroviral drugs: tenofovir (TFV) and emtricitabine (FTC) in colonic tissues. HIV is a global health problem and roughly 1.3 million people became newly infected with HIV globally in 2022. Pre-exposure prophylaxis (PrEP) is an HIV prevention strategy where HIV-negative individuals use antiretrovirals to reduce the risk of HIV infection. Specifically, oral fixed-dose combinations of two antiretrovirals, namely, TFV (TFV; prescribed as TFV disoproxil fumarate or TFV alafenamide prodrugs) and FTC are FDA-approved for HIV PrEP. The pharmacologically active forms of TFV and FTC are TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP), respectively, and these phosphorylated metabolites are found in cells. Unfortunately, high variability in the responses of TFV and FTC can lead to poor clinical outcomes, including therapeutic failure. However, the molecular mechanisms responsible for the observed variability in TFV and FTC responses are poorly understood. Although the observed variability in TFV and FTC drug responses is likely to be multifactorial, alterations in drug activation and deactivation can contribute to the observed variability in drug responses. Phosphorylation of TFV is known and recent studies suggest that nucleotidases may involve in the dephosphorylation of TFV metabolites. Although the kinases that phosphorylate FTC in peripheral blood mononuclear cells are known, the kinases that are responsible for the phosphorylation of FTC in putative sites of HIV infection such as colonic tissues are yet to be determined. Notably, unprotected receptive anal intercourse has a 20-fold higher risk of HIV transmission than vaginal intercourse. Thus, understanding the biotransformation of TFV and FTC in colonic tissue is important since it is a susceptible tissue to HIV infection. Recently, we have reported the enzymatic activities of nucleotidases toward the pharmacologically active metabolites of TFV and FTC in vitro. However, the mechanistic details of the biotransformation of the above drugs in HIV susceptible tissues such as colonic tissues are yet to be elucidated. Gaining a mechanistic understanding of the biotransformation of TFV and FTC in putative sites of HIV infection is important to improve their therapeutic efficacy. As such, in this application, we propose an innovative mass spectrometry imaging-based interdisciplinary approach to understand the biotransformation of TFV and FTC in the colon. Aim 1 will establish the role of nucleotide kinases and nucleotidases in regulating TFV and FTC metabolites in colonic cells mechanistically. Aim 2 will characterize the region- and cell-type-specific expression patterns, as well as enzymatic activities of nucleotide kinases and nucleotidases in situ. The proposed project will provide novel understandings of TFV and FTC activating and deactivating mechanisms that can be leveraged to optimize the therapeutic efficacy of the above drugs.
The quest for the cortical algorithm
The cortical algorithm hypothesis states that there is one common computational framework to solve diverse cognitive problems such as vision, voice recognition and motion control. In my talk, I propose a strategy to guide the search for this algorithm and I present a few ideas on how some of its components might look like. I'll explain why a highly interdisciplinary approach is needed from neuroscience, computer science, mathematics and physics to make further progress in this important question.
A developmental-cognitive perspective on the impact of adolescent social media use
Concerns about the impact of social media use on adolescent well-being and mental health are common. While the amount of research in this area has increased rapidly over the last 5 years, most outputs are still marred by a multitude of limitations. These shortcomings have left our understanding of social media effects severely limited, holding back both scientific discovery and policy interventions. This talk discusses how developmental, cognitive and neuroscientific approaches might provide a new and improved way of studying social media effects. It will detail new studies in support of this idea, and raise potential avenues for collaborative work across the Cambridge Neuroscience community. As the digital world now (re)shapes what it means for us to live, communicate and develop, only an interdisciplinary approach will allow us to truly understand its impacts.
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