is an enormous protein essential for hearing, balance, and proper eyesight. There are over 100 mutations in CDH23 that affect these processes with varying severity, some leading to deafness, balance disorders, and progressive blindness (Usher Syndrome). In the inner ear, CDH23 makes up the upper half of a proteinaceous filament known as the tip link, which is essential for hearing. Upon stimulation by sound or head movements, the tip link is stretched and conveys force to open the ion channels in the inner ear, thereby leading to the conversion of vibrational stimulus into electrical signals interpreted by the brain as sound. CDH23 is a non-classical cadherin with 27 extracellular cadherin (EC) repeats and a membrane adjacent domain (MAD28). The EC repeats are connected by a linker region containing highly conserved residues that bind calcium ions essential for tip-link function. Electron microscopy images suggest that CDH23 exists as a cis-homodimer within the tip link, however, the structural elements mediating this dimerization are not well determined. To better understand innerear mechanotransduction at the molecular level, we have solved high-resolution X-ray crystal structures of 18 CDH23 EC repeats along with 13 of the 26 EC linker regions (Jaiganesh et al., 2018). Here, we present several biochemical experiments that suggest potential sites of parallel dimerization on the extracellular domain of CDH23. Additionally, we present structures of various fragments of CDH23 allowing for closer analysis of deafness causing mutations. These results provide information on the cis-homodimerization of CDH23 and provide deeper insights about how mutations can result in inherited deafness.

Intestinal bacteria, including the facultative pathogen Vibrio cholerae, can adapt to a wide range of osmotic environments. In high-osmolarity media, bacteria accumulate small compatible metabolites to maintain turgor pressure, but under drastic osmotic down-shifts bacteria are able to avoid mechanical rupture by rapidly releasing these metabolites through mechanosensitive (MS) channels. Previous experiments on V. cholerae have identified two major types of MS channels - MscS and MscL. We functionally examine these channels specific roles in Vibrio osmotic rescuing via genetic modification, bacterial patch-clamp electrophysiology, and stopped-flow light scattering. The light scattering kinetics revealed that WT Vibrio cells were capable of releasing up to 10% of their total non-aqueous content within ~30 ms. To investigate each channels individual contribution to V. cholerae osmotic permeability response, we generated and characterized the first individual ∆mscS, ∆mscL, and double ∆mscL ∆mscS mutants in V. cholerae O395. Both mutants lacking MscS exhibited delayed osmolyte release kinetics and decreased osmotic survival rates compared to WT. Surprisingly, the ∆mscL mutant had comparable kinetics to WT, but a much higher osmotic survival, whereas ∆mscS had low survival, comparable to the double ∆mscL ∆mscS mutant. The data indicate that MscS is much more efficient in osmotic adjustment and is up-regulated in the absence of MscL, whereas in the absence of the low-threshold MscS, MscL even becomes toxic. Kinetic modeling of the cell swelling process and channel activation reveals the advantage of low-threshold MscS in curbing tension surges in Vibrio and its role in proper termination of the osmotic permeability response.

The leadership and advisory boards of American science agencies are largely organized according to the ideas set forth by an influential scientist, Dr. Vannevar Bush, after World War II. Although American science agencies are publicly funded, only experts control what research is funded and how each agency operates. Wielding his unique position of power after the war, Dr. Vannevar Bush suppressed the ideas of his adversary, Senator Harley Kilgore, resulting in the absence of public accountability and citizen input that defines American science agencies today. We argue that citizens must have a seat at the table in the leadership of science agencies to promote trust in science, reduce inequity, increase efficiency, embrace democratic principles, and address the needs of the American people. By providing a mechanism for non-expert citizens to influence the direction of American science agencies, Congress can now finally rectify the double-cross of Senator Harley Kilgore by Dr. Vannevar Bush.