The rockefeller university

Sound-evoked displacement responses at the outer hair cell-Deiters' cell junction (OHC-DC) are of significant interest in cochlear mechanics, as OHCs are believed to be in part responsible for active tuning enhancement and amplification. Motion in the cochlea is three-dimensional, and the architecture of the organ of Corti complex (OCC) suggests the presence and mechanical importance of all three components of motion. Optical coherence tomography (OCT) displacement measurements of OHC-DC motion from different experimental preparations often show disparate results, potentially due to OCT measuring only the motion component along the beam axis. In this work, we show that narrow elliptical motion at the OHC-DC - nearly along a straight line, where towards-base longitudinal motion is in phase with towards-scala-media transverse motion - can explain two such preparation-dependent differences. We present longitudinal and transverse components of displacement responses from the OHC-DC in the gerbil base in response to moderately high-level sound stimuli that exhibit precisely this near-lineal motion. The results show the potential for active longitudinal energy transfer in the OCC.

G protein-coupled receptors (GPCRs) comprise a family of heptahelical membrane proteins that mediate intracellular and intercellular transmembrane signaling. Defects in GPCR signaling pathways are implicated in the pathophysiology of many diseases, including cardiovascular disease, endocrinopathies, immune disorders, and cancer. Although GPCRs are attractive drug targets, only a small number of Food and Drug Administration-approved anticancer therapeutics target GPCRs. Targeted protein degradation (TPD) technology allows for the direct modulation of the cellular expression level of a protein of interest. TPD methods such as proteolysis-targeting chimeras (PROTACs) use the ubiquitin-proteasome system to degrade a protein of interest selectively. Although the PROTAC system has not been widely applied to GPCRs and other membrane proteins, there is evidence that PROTACs or other TPD methods could be applied to the GPCRome. Current GPCR PROTACs show the feasibility of using PROTACs to degrade GPCRs; however, the degradation mechanism for some of these GPCR PROTACs is uncertain. Additional studies aimed at elucidating the degradation mechanism of GPCRs with PROTACs are necessary. Discovery of new allosteric intracellular small molecule binders of GPCRs will be required for the development of intracellularly oriented PROTACs. Promising early results in targeted degradation of GPCRs suggest that TPD drug discovery platforms will be useful in developing PROTACs targeting pathological GPCRs. Significance Statement: Aberrant signaling of G protein-coupled receptors (GPCRs) can contribute to the pathophysiology of cancer. Although GPCRs are generally highly attractive drug targets, many individual GPCRs are currently undrugged using traditional drug discovery approaches. Targeted protein degradation technologies, such as proteolysis-targeting chimeras, provide a new approach to drug discovery for targeting previously undruggable GPCRs relevant to the molecular pathophysiology of cancer. (c) 2024 The Author(s). Published by Elsevier Inc. on behalf of American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

The 39th International Society for Animal Genetics conference (ISAG) was held for the first time in Africa under the theme 'Animal genetics for a sustainable future' in 2023. The conference convened scientists, policy makers, industry professionals, and students from interdisciplinary fields to share and discuss the latest developments in the space of animal genetics. Since its inception as a society, ISAG has sought to provide a platform advocating for a just and equitable future in animal genetics. At the 39th ISAG conference, this commitment towards furthering inclusion in animal genetic science was progressed with two new offerings to attendees. The first session guided discussions on the political, ethical, legal, socioeconomic, and cultural dynamics that present barriers to participating in and benefitting from the genomic and genetic science fraternity. This session also included principles of social justice, specifically equity, diversity, and inclusion, towards enacting fairness in an unfair world, and focused on constraints related to sustainability in animal genetics. The second session used the important tradition of storytelling to transfer knowledge and wisdom from experienced scientists to upcoming researchers. Experienced scientists shared lived experiences on educational and career paths, challenges, and opportunities, providing networking and opportunities for further mentoring. Here, we report on these equity-based actions and their relevance to address the urgent continent-specific and global disparities in animal genetics to move towards a sustainable future.

With current treatments addressing only a fraction of pathogens and new viral threats constantly evolving, there is a critical need to expand our existing therapeutic arsenal. To speed the rate of discovery and better prepare against future threats, we establish a high-throughput platform capable of screening compounds against 40 diverse viral proteases simultaneously. This multiplex approach is enabled by using cellular biosensors of viral protease activity combined with DNA-barcoding technology, as well as several design innovations that increase assay sensitivity and correct for plate-to-plate variation. Among >100,000 compound-target interactions explored within our initial screen, a series of broad-acting inhibitors against coronavirus proteases were uncovered and validated through orthogonal assays. A medicinal chemistry campaign was performed to improve one of the inhibitor's potency while maintaining its broad activity. This work highlights the power of multiplex screening to efficiently explore chemical space at a fraction of the time and costs of previous approaches.

The E-cadherin-beta-catenin-alpha E-catenin (cadherin-catenin) complex couples the cytoskeletons of neighboring cells at adherens junctions (AJs) to mediate force transmission across epithelia. Mechanical force and auxiliary binding partners converge to stabilize the cadherin-catenin complex's inherently weak binding to actin filaments (F-actin) through unclear mechanisms. Here, we show that afadin's coiled-coil (CC) domain and vinculin synergistically enhance the cadherin-catenin complex's F-actin engagement. The cryo-electron microscopy (cryo-EM) structure of an E-cadherin-beta-catenin-alpha E-catenin-vinculin-afadin-CC supra-complex bound to F-actin reveals that afadin-CC bridges adjacent alpha E-catenin actin-binding domains along the filament, stabilizing flexible alpha E-catenin segments implicated in mechanical regulation. These cooperative binding contacts promote the formation of supra-complex clusters along F-actin. Additionally, cryo-EM variability analysis links supra-complex binding along individual F-actin strands to nanoscale filament curvature, a deformation mode associated with cytoskeletal forces. Collectively, this work elucidates a mechanistic framework by which vinculin and afadin tune cadherin-catenin complex-cytoskeleton coupling to support AJ function across varying mechanical regimes.

It is not uncommon that a published paper offers unintended insights, unnoticed by its authors. This was to a substantial degree the case with a recent publication addressing the effects of endometriosis on IVF. Using donor-recipient cycles as the study population to isolate recipient effects, the well-executed study demonstrated only mildly adverse outcome effects of endometriosis on IVF cycle outcomes, to a substantial degree laying to rest this still controversial issue. In the process, however, the study also raised some very interesting - but left undiscussed - insights into a host of other issues with considerable relevance to endometriosis and IVF practice in the USA and UK. These are the subject of this communication.

The macaque cerebral cortex contains concentrations of neurons that prefer faces over inanimate objects. Although these so-called face patches are thought to be specialized for the analysis of facial signals, their exact tuning properties remain unclear. For example, what happens when an object by chance resembles a face? Everyday objects can sometimes, through the accidental positioning of their internal components, appear as faces. This phenomenon is known as face pareidolia. Behavioral experiments have suggested that macaques, like humans, perceive illusory faces in such objects. However, it is an open question whether such stimuli would naturally stimulate neurons residing in cortical face patches. To address this question, we recorded single unit activity from four fMRI-defined face-selective regions: the anterior medial (AM), anterior fundus (AF), prefrontal orbital (PO), and perirhinal cortex (PRh) face patches. We compared neural responses elicited by images of real macaque faces, pareidolia-evoking objects, and matched control objects. Contrary to expectations, we found no evidence of a general preference for pareidolia-evoking objects over control objects. Although a subset of neurons exhibited stronger responses to pareidolia-evoking objects, the population responses to both categories of objects were similar, and collectively much less than to real macaque faces. These results suggest that neural responses in the four regions we tested are principally concerned with the analysis of realistic facial characteristics, whereas the special attention afforded to face-like pareidolia stimuli is supported by activity elsewhere in the brain.