Biology subjects

Lurie, A.

Publications and source records attributed to Lurie, A..

3 recordsLinked to original sources

bioRxiv2024

Assembly and lipid-gating of LRRC8A:D volume-regulated anion channels

Volume-regulated anion channels (VRACs) are ubiquitously expressed vertebrate ion channels that open in response to hypotonic swelling. VRACs assemble as heteromers of LRRC8A and LRRC8B-E subunits, with different subunit combinations resulting in channels with different properties. Recent studies have described the structures of LRRC8A:C VRACs, but how other VRACs assemble, and which structural features are conserved or variant across channel assemblies remains unknown. Herein, we used cryo-EM to determine structures of a LRRC8A:D VRAC with a 4:2 subunit stoichiometry, which we captured in two conformations. The presence of LRRC8D subunits increases hydrophobicity and widens the selectivity filter, which may explain the unique substrate selectivity of LRRC8D-containing VRACs. The structures reveal lipids bound inside the channel pore, similar to those observed in LRRC8A:C VRACs. Using electrophysiological experiments, we confirmed that pore lipids block conduction in the closed state, demonstrating that lipid-gating is a general property of VRACs. Finally, we observe that LRRC8D subunit incorporation disrupts packing of the cytoplasmic LRR domains, increasing channel dynamics and opening lateral fenestrations, which we speculate are necessary for pore lipid evacuation and channel activation.

biophysics↗

bioRxiv2024

Current Reporting Practices in Human Neuroscience Research

Concerns for the replicability, reliability, and generalizability of human neuroimaging research have led to intense debates over sample size and open science practices, with more recent attention on the contributions of sampling and recruitment practices. Key to understanding the state of neuroscience research is an assessment of reporting practices that influence replicability, reliability, and generalizability. In this structured review, we evaluated reporting practice across three domains: (1) demographic (e.g., reporting participant race-ethnicity, age, any measure of socioeconomic position), (2) methodological (e.g., reporting recruitment methods, inclusion and exclusion criteria, why participants were excluded from analyses), and (3) open science and generalizability (e.g., analyses were preregistered, target population was stated). Included were 919 published MRI and fMRI studies from 2019 in nine top-ranked journals (N = 3,856 records screened). Reporting across domains was infrequent, with participant racial or ethnic identity (14.8%), reasons for missing imaging data (31.2%), and identification of a target population (19.4%) being particularly low/underreported. Reporting likelihood varied by study characteristics (e.g., participant age group) and was correlated across domains. The median sample size of studies was 55 participants. Study sample size, reporting frequency, was positively associated with two-year citation counts, providing some evidence that the complete reporting of demographic characteristics, methodological decisions, and open science and generalizability practices may not be as valued as study sample size. Recommendations for structural interventions at the journal level are proposed.

neuroscience↗

bioRxiv2019

The expression of YAP1 is increased in high-grade prostatic adenocarcinoma but is reduced in neuroendocrine prostate cancer

BACKGROUNDAfter long-term androgen deprivation therapy, 25-30% prostate cancer (PCa) acquires an aggressive neuroendocrine (NE) phenotype. Dysregulation of YAP1, a key transcription coactivator of the Hippo pathway, has been related to cancer progression. However, its role in neuroendocrine prostate cancer (NEPC) has not been assessed.\n\nMETHODSImmunohistochemistry was used to evaluate YAP1 protein levels during PCa initiation and progression. YAP1 knockdown and luciferase reporter assays were used to evaluate the ability of YAP1 to modulate Wnt/beta-Catenin signaling.\n\nRESULTSYAP1 expression was present in the basal epithelial cells in benign prostatic tissues, lost in low grade PCa, but elevated in high grade prostate adenocarcinomas. Interestingly, the expression of YAP1 was reduced/lost in both human and mouse NEPC. Finally, YAP1 knockdown in PCa cells activates Wnt/beta-Catenin signaling, which has been implicated in NE differentiation of PCa, supporting a functional involvement of the loss of YAP1 expression in NEPC development.\n\nCONCLUSIONSThe expression of YAP1 is elevated in high grade prostate adenocarcinomas while lost in NEPC. Reduced YAP1 activates Wnt/beta-Catenin signaling in PCa cells. These results suggest that when applied to PCa patients, YAP1 inhibitors shall be used with caution.

cancer biology↗