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The Ca 2+ -activated Cl - channel regulator CLCA1 potentiates the activity of the Ca 2+ -activated Cl - channel (CaCC) TMEM16A by directly engaging the channel at the cell surface, inhibiting its reinternalization and increasing Ca 2+ -dependent Cl - current (I CaCC ) density. We now present evidence of functional pairing between two other CLCA and TMEM16 protein family members, namely CLCA4 and the CaCC TMEM16B. Similar to CLCA1, (i) CLCA4 is a self-cleaving metalloprotease, and the N-terminal portion (N-CLCA4) is secreted; (ii) the von Willebrand factor type A (VWA) domain in N-CLCA4 is sufficient to potentiate I CaCC in HEK293T cells; and (iii) this is mediated by the metal ion-dependent adhesion site motif within VWA. The results indicate that, despite the conserved regulatory mechanism and homology between CLCA1 and CLCA4, CLCA4-dependent I CaCC are carried by TMEM16B, rather than TMEM16A. Our findings show specificity in CLCA/TMEM16 interactions and suggest broad physiological and pathophysiological links between these two protein families., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The high fitness cost of predation selects prey capable of detecting risk cues and responding in ways that reduce their vulnerability. While the impacts of auditory predator cues have been extensively researched in vertebrate prey, much less is known about invertebrate species' responses and their potential to affect the wider food web. We exposed larvae of Spodoptera exigua, a slow-moving and vulnerable herbivore hunted by aerial predators, to recordings of wasp buzzing (risk cue), mosquito buzzing (no-risk cue), or a no-sound control in both laboratory and field settings. In the laboratory, wasp buzzing (but not mosquito buzzing) reduced survival relative to the control; there was, however, no effect on time to or weight at pupation in survivors. In the field, wasp buzzing reduced caterpillar herbivory and increased plant biomass relative to the control treatment. In contrast, mosquito buzzing reduced herbivory less than wasp buzzing and had no effect on plant biomass. The fact that wasp cues evoked strong responses in both experiments, while mosquito buzzing generally did not, indicates that caterpillars were responding to predation risk rather than sound per se. Such auditory cues may have an important but largely unappreciated impacts on terrestrial invertebrate herbivores and their host plants., (© 2023 The Ecological Society of America.)

Many health care organizations made public commitments to become antiracist in the wake of George Floyd's murder. These actions raise questions about the appropriateness of health care's engagement in racial justice and social justice movements generally. We argue that health care organizations can be usefully thought of as having two roles: a functional role to care for the sick and a meta-role as an organizational citizen. Fulfilling the role of citizen may require participating in the pursuit of social justice, including efforts to achieve racial equity. The demands of these two roles will need to be balanced, but the role of organizational citizen has been largely ignored and merits serious attention., (© 2022 The Hastings Center.)

The secreted protein calcium-activated chloride channel regulator 1 (CLCA1) utilizes a von Willebrand factor type A (VWA) domain to bind to and potentiate the calcium-activated chloride channel TMEM16A. To gain insight into this unique potentiation mechanism, we determined the 2.0-Å crystal structure of human CLCA1 VWA bound to Ca 2+ . The structure reveals the metal-ion-dependent adhesion site (MIDAS) in a high-affinity "open" conformation, engaging in crystal contacts that likely mimic how CLCA1 engages TMEM16A. The CLCA1 VWA contains a disulfide bond between α3 and α4 in close proximity to the MIDAS that is invariant in the CLCA family and unique in VWA structures. Further biophysical studies indicate that CLCA1 VWA is preferably stabilized by Mg 2+ over Ca 2+ and that α6 atypically extends from the VWA core. Finally, an analysis of TMEM16A structures suggests residues likely to mediate interaction with CLCA1 VWA., Competing Interests: Declaration of Interests The authors declare no conflicts of interest., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Transplantation programs commonly rely on clinicians' judgments about patients' social support (care from friends or family) when deciding whether to list them for organ transplantation. We examine whether using social support to make listing decisions for adults seeking transplantation is morally legitimate, drawing on recent data about the evidence-base, implementation, and potential impacts of the criterion on underserved and diverse populations. We demonstrate that the rationale for the social support criterion, based in the principle of utility, is undermined by its reliance on tenuous evidence. Moreover, social support requirements may reinforce transplant inequities, interfere in patients' personal relationships, and contribute to biased and inconsistent listing procedures. As such, accommodating the needs of patients with limited social support would better balance ethical commitments to equity, utility, and respect for persons in transplantation. We suggest steps for researchers, transplantation programs, and policymakers to improve fair use of social support in transplantation.

Recent findings regarding the cellular biology and immunology of BST-2 (also known as tetherin) indicate that its function could be exploited as a universal replication inhibitor of enveloped respiratory viruses (e.g., influenza, respiratory syncytial virus, etc.). BST-2 inhibits viral replication by preventing virus budding from the plasma membrane and by inducing an antiviral state in cells adjacent to infection via unique inflammatory signaling mechanisms. This review presents the first comprehensive summary of what is currently known about BST-2 anti-viral function against respiratory viruses, how these viruses construct countermeasures to antagonize BST-2, and how BST-2 function might be targeted to develop therapies to treat respiratory virus infections. The authors address the current gaps in knowledge, including the need for mechanistic understanding of BST-2 antagonism by respiratory viruses, that should be bridged to achieve that goal., (© 2018 WILEY Periodicals, Inc.)

Over the past twenty-five years, thirty-seven states and the US Congress have passed mental health and substance use disorder (MH/SUD) parity laws to secure nondiscriminatory insurance coverage for MH/SUD services in the private health insurance market and through certain public insurance programs. However, in the intervening years, litigation has been brought by numerous parties alleging violations of insurance parity. We examine the critical issues underlying these legal challenges as a framework for understanding the areas in which parity enforcement is lacking, as well as ongoing areas of ambiguity in the interpretation of these laws. We identified all private litigation involving federal and state parity laws and extracted themes from a final sample of thirty-seven lawsuits. The primary substantive topics at issue include the scope of services guaranteed by parity laws, coverage of certain habilitative therapies such as applied behavioral analysis for autism spectrum disorders, credentialing standards for MH/SUD providers, determinations regarding the medical necessity of MH/SUD services, and the application of nonquantitative treatment limitations under the 2008 federal parity law. Ongoing efforts to achieve nondiscriminatory insurance coverage for MH/SUDs should attend to the major issues subject to private legal action as important areas for facilitating and monitoring insurer compliance., (Copyright © 2017 by Duke University Press.)

Calcium-activated chloride channels (CaCCs) are key players in transepithelial ion transport and fluid secretion, smooth muscle constriction, neuronal excitability, and cell proliferation. The CaCC regulator 1 (CLCA1) modulates the activity of the CaCC TMEM16A/Anoctamin 1 (ANO1) by directly engaging the channel at the cell surface, but the exact mechanism is unknown. Here we demonstrate that the von Willebrand factor type A (VWA) domain within the cleaved CLCA1 N-terminal fragment is necessary and sufficient for this interaction. TMEM16A protein levels on the cell surface were increased in HEK293T cells transfected with CLCA1 constructs containing the VWA domain, and TMEM16A-like currents were activated. Similar currents were evoked in cells exposed to secreted VWA domain alone, and these currents were significantly knocked down by TMEM16A siRNA. VWA-dependent TMEM16A modulation was not modified by the S357N mutation, a VWA domain polymorphism associated with more severe meconium ileus in cystic fibrosis patients. VWA-activated currents were significantly reduced in the absence of extracellular Mg 2+ , and mutation of residues within the conserved metal ion-dependent adhesion site motif impaired the ability of VWA to potentiate TMEM16A activity, suggesting that CLCA1-TMEM16A interactions are Mg 2+ - and metal ion-dependent adhesion site-dependent. Increase in TMEM16A activity occurred within minutes of exposure to CLCA1 or after a short treatment with nocodazole, consistent with the hypothesis that CLCA1 stabilizes TMEM16A at the cell surface by preventing its internalization. Our study hints at the therapeutic potential of the selective activation of TMEM16A by the CLCA1 VWA domain in loss-of-function chloride channelopathies such as cystic fibrosis., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Traditional fragment-based drug discovery (FBDD) relies heavily on structural analysis of the hits bound to their targets. Herein, we present a complementary approach based on diversity-oriented synthesis (DOS). A DOS-based fragment collection was able to produce initial hit compounds against the target GSK3β, allow the systematic synthesis of related fragment analogues to explore fragment-level structure-activity relationship, and finally lead to the synthesis of a more potent compound.

All insurance products sold on the health insurance exchanges established by the Affordable Care Act are required to offer mental health and substance use disorder benefits in compliance with requirements of the Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008 (MHPAEA). This column identifies two dimensions of parity compliance that consumers observe while shopping for insurance products offered on two state-run exchanges. The authors discuss a number of apparent discrepancies with the requirements of MHPAEA in these observable dimensions, emphasizing the potential impact of these factors on consumers' decisions about plan enrollment. The analysis reveals a nuanced picture of how insurance issuers are presenting behavioral health benefits to potential enrollees and illustrates broader concerns about parity compliance and the potential for selection on the exchanges. Four specific discrepancies are highlighted as areas for further evaluation.

Chloride transport proteins play critical roles in inflammatory airway diseases, contributing to the detrimental aspects of mucus overproduction, mucus secretion, and airway constriction. However, they also play crucial roles in contributing to the innate immune properties of mucus and mucociliary clearance. In this review, we focus on the emerging novel roles for a chloride channel regulator (CLCA1), a calcium-activated chloride channel (TMEM16A), and two chloride exchangers (SLC26A4/pendrin and SLC26A9) in chronic inflammatory airway diseases.

During antiviral defense, interferon (IFN) signaling triggers nuclear transport of tyrosine-phosphorylated STAT1 (PY-STAT1), which occurs via a subset of karyopherin alpha (KPNA) nuclear transporters. Many viruses, including Ebola virus, actively antagonize STAT1 signaling to counteract the antiviral effects of IFN. Ebola virus VP24 protein (eVP24) binds KPNA to inhibit PY-STAT1 nuclear transport and render cells refractory to IFNs. We describe the structure of human KPNA5 C terminus in complex with eVP24. In the complex, eVP24 recognizes a unique nonclassical nuclear localization signal (NLS) binding site on KPNA5 that is necessary for efficient PY-STAT1 nuclear transport. eVP24 binds KPNA5 with very high affinity to effectively compete with and inhibit PY-STAT1 nuclear transport. In contrast, eVP24 binding does not affect the transport of classical NLS cargo. Thus, eVP24 counters cell-intrinsic innate immunity by selectively targeting PY-STAT1 nuclear import while leaving the transport of other cargo that may be required for viral replication unaffected., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Propagation of chromatin states through DNA replication is central to epigenetic regulation and can involve recruitment of chromatin proteins to replicating chromatin through interactions with replication fork components. Here we show using a fully reconstituted T7 bacteriophage system that eukaryotic proteins are not required to tether the Polycomb complex PRC1 to templates during DNA replication. Instead, DNA binding by PRC1 can withstand passage of a simple replication fork.