Pentameric ligand-gated ion channels (pLGICs) mediate intercellular communication at synapses through the opening of an ion pore in response to the binding of a neurotransmitter. Despite the increasing availability of high-resolution structures of pLGICs, a detailed understanding of the functional isomerization from closed to open (gating) and back is currently missing. Here, we provide the first atomistic description of the transition from open to closed (un-gating) in the glutamate-gated chloride channel (GluCl) from Caenorhabditis Elegans. Starting with the active-state structure solved in complex with the neurotransmitter -glutamate and the positive allosteric modulator (PAM) ivermectin, we analyze the spontaneous relaxation of the channel upon removal of ivermectin by explicit solvent/membrane Molecular Dynamics (MD) simulations. The μs-long trajectories support the conclusion that ion-channel deactivation is mediated by two distinct quaternary transitions, i.e. a global receptor twisting followed by the radial expansion (or blooming) of the extracellular domain. At variance with previous models, we show that pore closing is exclusively regulated by the global twisting, which controls the position of the β1-β2 loop relative to the M2-M3 loop at the EC/TM domain interface. Additional simulations with -glutamate restrained to the crystallographic binding mode and ivermectin removed indicate that the same twisting isomerization is regulated by agonist binding at the orthosteric site. These results provide a structural model for gating in pLGICs and suggest a plausible mechanism for the pharmacological action of PAMs in this neurotransmitter receptor family. The simulated un-gating converges to the X-ray structure of GluCl resting state both globally and locally, demonstrating the predictive character of state-of-art MD simulations.

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Anthrax Lethal Factor (LF) is a zinc-dependent metalloprotease, one of the virulence factor of anthrax infection. Three forms of the anthrax infection have been identified: cutaneous (through skin), gastrointestinal (through alimentary tract), and pulmonary (by inhalation of spores). Anthrax toxin is composed of protective antigen (PA), lethal factor (LF), and edema factor (EF). Protective antigen mediates the entry of Lethal Factor/Edema Factor into the cytosol of host cells. Lethal factor (LF) inactivates mitogen-activated protein kinase kinase inducing cell death, and EF is an adenylyl cyclase impairing host defenses. In the past few years, extensive studies are undertaken to design inhibitors targeting LF. The current review focuses on the small molecule inhibitors targeting LF activity and its structure activity relationships (SAR).

During the COVID-19 pandemic, surface disinfection using prevailing chemical disinfection methods had several limitations. Due to cost-inefficiency and the inability to disinfect shaded places, static UVC lamps cannot address these limitations properly. Moreover, the average market price of the prevailing UVC robots is huge, approximately 55,165 USD. In this research firstly, a requirement elicitation study was conducted using a semi-structured interview approach to reveal the requirements to develop a cost-effective UVC robot. Secondly, a semi-autonomous robot named UVC-PURGE was developed based on the revealed requirements. Thirdly, a two-phased evaluation study was undertaken to validate the effectiveness of UVC-PURGE to inactivate the SARS-CoV-2 virus and the capability of semi-autonomous navigation in the first phase and to evaluate the usability of the system through a hybrid approach of SUPR-Q forms and subjective evaluation of the user feedback in the second phase. Pre-treatment swab testing revealed the presence of both Gram-positive and Gram-Negative bacteria at 17 out of 20 test surfaces in the conducted tests. After the UVC irradiation of the robot, the microbial load was detected in only 2 (1D and 1H) out of 17 test surfaces with significant reductions (95.33% in 1D and 90.9% in 1H) of microbial load. Moreover, the usability evaluation yields an above-average SUPR-Q score of 81.91% with significant scores in all the criteria (usability, trust, loyalty, and appearance) and the number of positive themes from the subjective evaluation using thematic analysis is twice the number of negative themes. Additionally, compared with the prevailing UVC disinfection robots in the market, UVC-PURGE is cost-effective with a price of less than 800 USD. Moreover, small form factor along with the real time camera feedback in the developed system helps the user to navigate in congested places easily. The developed robot can be used in any indoor environment in this prevailing pandemic situation and it can also provide cost-effective disinfection in medical facilities against the long-term residual effect of COVID-19 in the post-pandemic era.INDEX TERMS COVID-19, UVC robot, medical robotics, infection control, disinfection methods.