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The human voltage-gated proton channel Hv1 is a drug target for cancer, ischemic stroke, and neuroinflammation. It resides on the plasma membrane and endocytic compartments of a variety of cell types, where it mediates outward proton movement and regulates the activity of NOX enzymes. Its voltage-sensing domain (VSD) contains a gated and proton-selective conduction pathway, which can be blocked by aromatic guanidine derivatives such as 2-guanidinobenzimidazole (2GBI). Mutation of Hv1 residue F150 to alanine (F150A) was previously found to increase 2GBI apparent binding affinity more than two orders of magnitude. Here, we explore the contribution of aromatic interactions between the inhibitor and the channel in the presence and absence of the F150A mutation, using a combination of electrophysiological recordings, classic mutagenesis, and site-specific incorporation of fluorinated phenylalanines via nonsense suppression methodology. Our data suggest that the increase in apparent binding affinity is due to a rearrangement of the binding site allowed by the smaller residue at position 150. We used this information to design new arginine mimics with improved affinity for the nonrearranged binding site of the wild-type channel. The new compounds, named “Hv1 Inhibitor Flexibles” (HIFs), consist of two “prongs,” an aminoimidazole ring, and an aromatic group connected by extended flexible linkers. Some HIF compounds display inhibitory properties that are superior to those of 2GBI, thus providing a promising scaffold for further development of high-affinity Hv1 inhibitors.

 

Patients suffering from medical conditions resulting in hand impairment experience difficulty in performing simple daily tasks, like getting dressed or using a pencil, resulting in a poorer quality of life. Rehabilitation attempts to help such individuals regain a sense of control and normalcy. In this context, recent advances in robotics have manifested in multiple designs of hand exoskeletons and exosuit gloves for assistance and rehabilitation. These designs are typically actuated using pneumatic, shape memory alloys and motor-tendon actuators. The proposed Motor Tendon Actuated Exosuit Glove (MTAEG) with an open palm is a soft material glove capable of both flexion and extension of all four fingers of the human hand. Its minimally invasive design maintains an open palm to facilitate haptic and tactile interaction with the environment. The MTAEG achieves flexion-extension motion with joint angles of 45° at the metacarpal joint which is 57% of the desired motion; 90° at the proximal interphalangeal joint which is 100% of the desired motion; and 50° at the distal interphalangeal joint which is 96% of the desired motion. The paper discusses the challenges in achieving the desired motion without the ability to directly model human tendons, and the inability to actuate joints individually. 

Abstract The Large Hadron Collider (LHC) at CERN will undergo major upgrades to increase the instantaneous luminosity up to 5–7.5×10 34 cm -2 s -1 . This High Luminosity upgrade of the LHC (HL-LHC) will deliver a total of 3000–4000 fb -1 of proton-proton collisions at a center-of-mass energy of 13–14 TeV. To cope with these challenging environmental conditions, the strip tracker of the CMS experiment will be upgraded using modules with two closely-spaced silicon sensors to provide information to include tracking in the Level-1 trigger selection. This paper describes the performance, in a test beam experiment, of the first prototype module based on the final version of the CMS Binary Chip front-end ASIC before and after the module was irradiated with neutrons. Results demonstrate that the prototype module satisfies the requirements, providing efficient tracking information, after being irradiated with a total fluence comparable to the one expected through the lifetime of the experiment. 

Abstract The Short Strip ASIC (SSA) is one of the four front-end chips designed for the upgrade of the CMS Outer Tracker for the High Luminosity LHC. Together with the Macro-Pixel ASIC (MPA) it will instrument modules containing a strip and a macro-pixel sensor stacked on top of each other. The SSA provides both full readout of the strip hit information when triggered, and, together with the MPA, correlated clusters called stubs from the two sensors for use by the CMS Level-1 (L1) trigger system. Results from the first prototype module consisting of a sensor and two SSA chips are presented. The prototype module has been characterized at the Fermilab Test Beam Facility using a 120 GeV proton beam.