Department of Medicine

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    Optimization of lead compounds into on-demand, non-hormonal contraceptives: leveraging a public-private drug discovery institute collaboration
    Balbach, Melanie; Fushimi, Makoto; Huggins, David; Steegborn, Clemens; Meinke, Peter; Levin, Lonny; Buck, Jochen (Oxford Academic, 2020-04)
    Efforts to develop new male or female non-hormonal, orally available contraceptives assume that to be effective and safe, targets must be (1) essential for fertility; (2) amenable to targeting by small-molecule inhibitors; and (3) restricted to the germline. In this perspective, we question the third assumption and propose that despite its wide expression, soluble adenylyl cyclase (sAC: ADCY10), which is essential for male fertility, is a valid target. We hypothesize that an acute-acting sAC inhibitor may provide orally available, on-demand, non-hormonal contraception for men without adverse, mechanism-based effects. To test this concept, we describe a collaboration between academia and the unique capabilities of a public-private drug discovery institute
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    Rising to the Challenge of COVID-19: Advice for Pulmonary and Critical Care and an Agenda for Research
    Niederman, Michael; Richeldi, Luca; Chotirmall, Sanjay; Bai, Chunxue (American Thoracic Society, 2020-05)
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    CIC is a Critical Regulator of Neuronal Differentiation
    Hwang, Inah; Pan, Heng; Yao, Jun; Elemento, Olivier; Zheng, Hongwu; Paik, Jihye (American Society for Clinical Investigation, 2020-03)
    Capicua (CIC), a member of the high mobility group (HMG)-box superfamily of transcriptional repressors, is frequently mutated in human oligodendrogliomas. But its function in brain development and tumorigenesis remains poorly understood. Here, we report that brain-specific deletion of Cic compromises developmental transition of neuroblast to immature neurons in mouse hippocampus and compromises normal neuronal differentiation. Combined gene expression and ChIP-seq analyses identified VGF as an important CIC-repressed transcriptional surrogate involved in neuronal lineage regulation. Aberrant VGF expression promotes neural progenitor cell proliferation by suppressing their differentiation. Mechanistically, we demonstrated that CIC represses VGF expression by tethering SIN3-HDAC to form a transcriptional corepressor complex. Mass spectrometry analysis of CIC-interacting proteins further identified BRG1 containing mSWI/SNF complex whose function is necessary for transcriptional repression by CIC. Together, this study uncovers a novel regulatory pathway of CIC-dependent neuronal differentiation and may implicate these molecular mechanisms in CIC-dependent brain tumorigenesis.
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    Central lateral thalamic nucleus stimulation awakens the cortex via modulation of cross-regional, laminar specific activity during general anesthesia
    Schiff, Nicholas (Elsevier, 2020-04-08)
    Experiments identify cortical layer specific effects during induced arousal from general anesthesia. In this issue of Neuron, Redinbaugh et al. (2020) find evidence that central lateral thalamic nucleus electrical stimulation reactivates the cortex by restoring deep-layer firing rates and modulating feedforward and feedback connectivity
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    Adding a Medicine to WHO Model List of Essential Medicines
    Kishore, Sandeep; Herbstman, Benjamin (Nature Publishing Group; Clinical Pharmacology & Therapeutics, 2009-03)
    Although the concept of essential medicines is not new, the processes that lead to placement of these medicines on the World Health Organization Model List of Essential Medicines are not well understood. Here, we describe the process by which we added a class of drugs, statins, to the Model List to help combat the growing global epidemic of cardiovascular disease.