Development of IKATP Ion Channel Blockers Targeting Sulfonylurea Resistant Mutant KIR6.2 Based Channels for Treating DEND Syndrome

Introduction: DEND syndrome is a rare channelopathy characterized by a combination of developmental delay, epilepsy and severe neonatal diabetes. Gain of function mutations in the KCNJ11 gene, encoding the KIR6.2 subunit of the IKATP potassium channel, stand at the basis of most forms of DEND syndrome. In a previous search for existing drugs with the potential of targeting Cantú Syndrome, also resulting from increased IKATP, we found a set of candidate drugs that may also possess the potential to target DEND syndrome. In the current work, we combined Molecular Modelling including Molecular Dynamics simulations, with single cell patch clamp electrophysiology, in order to test the effect of selected drug candidates on the KIR6.2 WT and DEND mutant channels.Methods: Molecular dynamics simulations were performed to investigate potential drug binding sites. To conduct in vitro studies, KIR6.2 Q52R and L164P mutants were constructed. Inside/out patch clamp electrophysiology on transiently transfected HEK293T cells was performed for establishing drug-channel inhibition relationships.Results: Molecular Dynamics simulations provided insight in potential channel interaction and shed light on possible mechanisms of action of the tested drug candidates. Effective IKIR6.2/SUR2a inhibition was obtained with the pore-blocker betaxolol (IC50 values 27–37 μM). Levobetaxolol effectively inhibited WT and L164P (IC50 values 22 μM) and Q52R (IC50 55 μM) channels. Of the SUR binding prostaglandin series, travoprost was found to be the best blocker of WT and L164P channels (IC50 2–3 μM), while Q52R inhibition was 15–20% at 10 μM.Conclusion: Our combination of MD and inside-out electrophysiology provides the rationale for drug mediated IKATP inhibition, and will be the basis for 1) screening of additional existing drugs for repurposing to address DEND syndrome, and 2) rationalized medicinal chemistry to improve IKATP inhibitor efficacy and specificity.

Stereoselective Nanocarbon Imides Featuring 12-fold [5]helicenes

Despite the great progress in research on chiral molecular nanocarbons containing multiple helicenes, controlling the stereoselectivity is still a major challenge, especially when attempting to increase the number of helicene moieties. Herein, a novel molecular nanocarbon imides composed of C204 skeleton and eighteen imide groups was successfully synthesized via an inside–out ring closing strategy involving repeated Suzuki–Miyaura coupling for C–C bond formation and photocyclic aromatization. Because of the presence of quad–core twelvefold [5]helicenes, there are, in theory, more than one hundred stereoisomers. However, only one pair of stereoisomers with D3 symmetry was observed. Despite the large and rigid skeleton, the (3M,3M,3M,3M)+(3P,3P,3P,3P) enantiomers were successfully separated by chiral HPLC, and the chiroptical properties were investigated by CD spectroscopy.

Book Review: From the inside out: The fight for environmental justice within government agencies by Jill Harrison

In From the Inside Out: The Fight for Environmental Justice within Government Agencies (MIT Press, 2019), Jill Harrison offers a nuanced study of why U.S. state agencies fail at implementing robust environmental justice (EJ) policies. Through a rigorous interview and ethnographic based methodology Harrison details the discourses, ideologies, and everyday practices and through which government agency staff, daily, undermine and even outright reject EJ policies and programs. The book is a richly empirical study that makes valuable contributions to academic and activist understandings of the government's failure to respond meaningfully to environmental injustices, and offers specific recommendations for how to reform government agencies. It is a timely monograph as EJ advocates seek to reimagine government agencies in the wake of the Trump administration, and in the context of an expanded public consciousness of racism following the killing of George Floyd and subsequent uprisings during the summer of 2020.

Phosphoantigens are Molecular Glues that Promote Butyrophilin 3A1/2A1 Association Leading to Vγ9Vδ2 T Cell Activation

Tumor cells and pathogen-infected cells are presented to human γδ T cells based on "inside-out" signaling in which metabolites called phosphoantigens (pAgs) inside target cells are recognized by the intracellular domain of a butyrophilin protein (BTN3A1), leading to an extracellular conformational change. Here, we report that pAgs function as molecular "glues" that initiate a heteromeric association between the intracellular domains of BTN3A1 and the structurally similar BTN2A1. Working with both exogenous and endogenous pAgs, we used x-ray crystallography, mutational studies, cellular assays, synthetic probe as well as molecular dynamics investigations to determine how pAgs glue intracellular BTN3A1 and BTN2A1 together for the "inside-out" signaling that triggers γδ T cell activation. This γδ T cell-specific mode of antigen sensing creates opportunities for the development of alternative immunotherapies against cancer and infectious diseases that do not involve αβ T cells.

The Collision of the Experiential and Existential in the Brain/Heart-Mind/Soul Continuum

Focused in the physical, people are primarily experiential learners. Yet with the creation and sophistication of measurement techniques at the turn of the century, an understanding of experiential learning from the inside-out began to expand through neuroscience. There was recognition that people are holistic beings, and that the heart and mind are an integrated, biological, and complex part of the embodied human system. And within this system, through research in neuroscience, there are hints of what is possible. There is a brain/heart-mind/soul continuum, which brings to mind and to soul the potential for an existential state of learning while focused in the physical/etheric reality. Whether played out in the “virtual reality” of the mind or psychecology educational games, this existential state of creating, imagining, experiencing, and learning can fully engage our creative imagination while simultaneously engaging our higher mental faculties. In essence, through existential experiencing we are creating a symmetry, becoming the mirror of our soul. As above, so below.

Metal Pollution of the Solar White Dwarf by Solar System Small Bodies

White dwarfs (WDs) often show metal lines in their spectra, indicating accretion of asteroidal material. Our Sun is to become a WD in several gigayears. Here, we examine how the solar WD accretes from the three major small body populations: the main belt asteroids (MBAs), Jovian Trojan asteroids (JTAs), and trans-Neptunian objects (TNOs). Owing to the solar mass loss during the giant branch, 40% of the JTAs are lost but the vast majority of MBAs and TNOs survive. During the WD phase, objects from all three populations are sporadically scattered onto the WD, implying ongoing accretion. For young cooling ages ≲100 Myr, accretion of MBAs predominates; our predicted accretion rate ∼106 g s−1 falls short of observations by two orders of magnitude. On gigayear timescales, thanks to the consumption of the TNOs that kicks in ≳100 Myr, the rate oscillates around 106–107 g s−1 until several gigayears and drops to ∼105 g s−1 at 10 Gyr. Our solar WD accretion rate from 1 Gyr and beyond agrees well with those of the extrasolar WDs. We show that for the solar WD, the accretion source region evolves in an inside-out pattern. Moreover, in a realistic small body population with individual sizes covering a wide range as WD pollutants, the accretion is dictated by the largest objects. As a consequence, the accretion rate is lower by an order of magnitude than that from a population of bodies of a uniform size and the same total mass and shows greater scatter.