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We observed in PRESTO-Tango β-arrestin recruitment assays that the α1-adrenergic receptor (AR) antagonist prazosin activates chemokine (C-X-C motif) receptor (CXCR)4. This prompted us to further examine this unexpected pharmacological behavior. We screened a panel of 14 α1/2- and β1/2/3-AR antagonists for CXCR4 and atypical chemokine receptor (ACKR)3 agonist activity in PRESTO-Tango assays against the cognate agonist CXCL12. We observed that multiple α1-AR antagonists activate CXCR4 (CXCL12 = prazosin = cyclazosin > doxazosin) and ACKR3 (CXCL12 = prazosin = cyclazosin > alfuzosin = doxazosin = phentolamine > terazosin = silodosin = tamsulosin). The two strongest CXCR4/ACKR3 activators, prazosin and cyclazosin, were selected for a more detailed evaluation. We found that the drugs dose-dependently activate both receptors in β-arrestin recruitment assays, stimulate ERK1/2 phosphorylation in HEK293 cells overexpressing each receptor, and that their effects on CXCR4 could be inhibited with AMD3100. Both α1-AR antagonists induced significant chemical shift changes in the 1H-13C-heteronuclear single quantum correlation spectrum of CXCR4 and ACKR3 in membranes, suggesting receptor binding. Furthermore, prazosin and cyclazosin induced internalization of endogenous CXCR4/ACKR3 in human vascular smooth muscle cells (hVSMC). While these drugs did not in induce chemotaxis in hVSMC, they inhibited CXCL12-induced chemotaxis with high efficacy and potency (IC50: prazosin-4.5 nM, cyclazosin 11.6 pM). Our findings reveal unexpected pharmacological properties of prazosin, cyclazosin, and likely other α1-AR antagonists. The results of the present study imply that prazosin and cyclazosin are biased or partial CXCR4/ACKR3 agonists, which function as potent CXCL12 antagonists. Our findings could provide a mechanistic basis for previously observed anti-cancer properties of α1-AR antagonists and support the concept that prazosin could be re-purposed for the treatment of disease processes in which CXCR4 and ACKR3 are thought to play significant pathophysiological roles, such as cancer metastases or various autoimmune pathologies.

Recent observations suggest that atypical chemokine receptor (ACKR)3 and chemokine (C-X-C motif) receptor (CXCR)4 regulate human vascular smooth muscle function through hetero-oligomerization with α1-adrenoceptors. Here, we show that ACKR3 also regulates arginine vasopressin receptor (AVPR)1A. We observed that ACKR3 agonists inhibit arginine vasopressin (aVP)-induced inositol trisphosphate (IP3) production in human vascular smooth muscle cells (hVSMCs) and antagonize aVP-mediated constriction of isolated arteries. Proximity ligation assays, co-immunoprecipitation and bioluminescence resonance energy transfer experiments suggested that recombinant and endogenous ACKR3 and AVPR1A interact on the cell surface. Interference with ACKR3 : AVPR1A heteromerization using siRNA and peptide analogues of transmembrane domains of ACKR3 abolished aVP-induced IP3 production. aVP stimulation resulted in β-arrestin 2 recruitment to AVPR1A and ACKR3. While ACKR3 activation failed to cross-recruit β-arrestin 2 to AVPR1A, the presence of ACKR3 reduced the efficacy of aVP-induced β-arrestin 2 recruitment to AVPR1A. AVPR1A and ACKR3 co-internalized upon agonist stimulation in hVSMC. These data suggest that AVPR1A : ACKR3 heteromers are constitutively expressed in hVSMC, provide insights into molecular events at the heteromeric receptor complex, and offer a mechanistic basis for interactions between the innate immune and vasoactive neurohormonal systems. Our findings suggest that ACKR3 is a regulator of vascular smooth muscle function and a possible drug target in diseases associated with impaired vascular reactivity.

Prior studies have indicated that entheseal changes throughout the skeleton are largely reflective of age and body mass with mixed results concerning activity patterns. To add to this debate, this study tests the effectiveness of employing the New Coimbra method to record entheseal changes of the calcaneus (Calcaneal tendon enthesis), hallucal metatarsal (Peroneus longus m. tendon, and Tibialis anterior m. tendon entheses), and fifth metatarsal (Peroneus brevis m. tendon enthesis) to understand past activity patterns. Presence and severity of entheseal changes were scored for 71 white adults from the William M. Bass Donated Skeletal Collection, and these scores were contrasted according to age, sex, stature, body mass (BMI), and occupation. Spearman's rank correlations show that age has the greatest impact on changes for the Calcaneal tendon enthesis, the Peroneus brevis m. tendon enthesis, and the Tibialis anterior m. tendon enthesis. For all of these entheses, entheseal scores increase as age increases. Stature is the largest contributing factor to changes in the Peroneus longus m. tendon enthesis, and this relationship is negative: entheseal scores decrease as stature increases. BMI has a limited effect on entheseal changes in the foot skeleton, and this relationship may instead be mediated by gait differences related to stature. No statistically significant relationships between entheseal changes and occupational standing ranks were found, although this may be related to the ways in which occupations were recorded and ranked. It is possible that statistically significant effects of physical activity patterns on the expression of entheseal changes could be documented using other measurements of activity patterns beyond occupational standing. These findings support prior studies that established age as a major contributor to entheseal changes but show that stature also contributes to enthesis formation in the foot. [ABSTRACT FROM AUTHOR]

The purpose of this research is to update the Life Care Planning Surveys of 2001 and 2009 with longitudinal data over the course of 20 years regarding the process, methods, and protocols of life care planning. This research provides data to support and advance the practice of life care planning. The Life Care Plan Survey 2022 is a revision and replication of the 2001 and 2009 life care planning surveys. Areas addressed in the survey included: a) demographics; b) business practices; c) roles and functions of the life care planner; d) life care planning protocols; and e) future growth and development. Survey results describe the current state of life care planning practice; provide data on protocols/procedures used by life care planners; and identify areas of life care planning practice where further definition, refinement and/or research may be necessary. In addition to descriptive data, responses were analyzed in terms of similarities and differences related to field of practice, certification status, and amount of deposition experience. Results are expected to enhance life care planning practice by promoting continued discussion and consideration regarding roles, scope of practice, competencies, and standards of practice. [ABSTRACT FROM AUTHOR]

BackgroundRecently, we provided evidence that α1‐adrenergic receptors (ARs) in vascular smooth muscle are regulated by chemokine (C‐X‐C motif) receptor (CXCR) 4 and atypical chemokine receptor 3 (ACKR3). While we showed that CXCR4 controls α1‐ARs through formation of heteromeric receptor complexes in human vascular smooth muscle cells (hVSMCs), the molecular basis underlying cross‐talk between ACKR3 and α1‐ARs is unknown. Methods and ResultsWe show that ACKR3 agonists inhibit inositol trisphosphate production in hVSMCs on stimulation with phenylephrine. In proximity ligation assays and co‐immunoprecipitation experiments, we observed that recombinant and endogenous ACKR3 form heteromeric complexes with α1A/B/D‐AR. While small interfering RNA knockdown of ACKR3 in hVSMCs reduced α1B/D‐AR:ACKR3, CXCR4:ACKR3, and α1B/D‐AR:CXCR4 complexes, small interfering RNA knockdown of CXCR4 reduced α1B/D‐AR:ACKR3 heteromers. Phenylephrine‐induced inositol trisphosphate production from hVSMCs was abolished after ACKR3 and CXCR4 small interfering RNA knockdown. Peptide analogs of transmembrane domains 2/4/7 of ACKR3 showed differential effects on heteromerization between ACKR3, α1A/B/D‐AR, and CXCR4. While the transmembrane domain 2 peptide interfered with α1B/D‐AR:ACKR3 and CXCR4:ACKR3 heteromerization, it increased heteromerization between CXCR4 and α1A/B‐AR. The transmembrane domain 2 peptide inhibited ACKR3 but did not affect α1b‐AR in β‐arrestin recruitment assays. Furthermore, the transmembrane domain 2 peptide inhibited phenylephrine‐induced inositol trisphosphate production in hVSMCs and attenuated phenylephrine‐induced constriction of mesenteric arteries. Conclusionsα1‐ARs form hetero‐oligomeric complexes with the ACKR3:CXCR4 heteromer, which is required for α1B/D‐AR function, and activation of ACKR3 negatively regulates α1‐ARs. G protein–coupled receptor hetero‐oligomerization is a dynamic process, which depends on the relative abundance of available receptor partners. Endogenous α1‐ARs function within a network of hetero‐oligomeric receptor complexes.

Usability and accessibility have become increasingly important in computing curricula. This article briefly reviews how these concepts may be included in existing courses. The authors conducted a survey of student attitudes toward these issues at the start and end of a usability engineering course that included a group project with an accessibility component. Results of the survey indicate that students' awareness of issues related to usability and accessibility are increased after taking the course and completing the project. Our work and results are potentially valuable to CS educators in three ways: (1) They validate the usefulness of the survey instrument in assessing pedagogies in usability engineering, (2) They provide useful insights into the attitudes of CS majors relative to the important topics of usability and accessibility, and (3) They point to possible benefits of including usability and accessibility topics into CS curricula. (Contains 3 tables.)

Issues of educational equity and opportunity cannot be understood without regard to special education, as a key response to disabilities, disadvantages, and difficulties. Likewise, globalization cannot be understood without regard to cross-border migration and minority group status in society. Illuminating the nexus of these, research into disproportionality in special education, defined as the over- or under-representation of particular ethnic groups in such programs, shows that this, too, has become a global phenomenon. Comparing Canada, Germany, New Zealand and the USA, this article explores international trends in migration and discusses the globalization of ethnic group disproportionality--as a primary indicator of inequity in education. We conclude by questioning the functions of special education in an era of globalization and identifying the challenges ahead that these findings indicate. (Contains 5 tables.)

Many political scientists maintain that public policies diffuse across states and that proximate states, in particular, influence one another's policy activities. Using state-funded merit aid for college as its case, this article takes a new approach to the study of the diffusion phenomenon, leaving behind conventional techniques used by generations of innovation/diffusion scholars, and asks policy makers themselves to what they attribute state policy adoption. The authors' findings suggest that merit aid programs diffuse as a function of competition among neighboring states not only for students but also for revenue and ideas. Close policy communities and personal contacts among state policy makers and agency staff also condition policy adoption by spreading information about, and assessments of, educational innovations. (Contains 1 table, 1 figure, and 4 notes.)

This study considers why Florida has been the most aggressive state in adopting school vouchers. Vouchers are consistent with Florida's tradition of aggressive educational accountability policies, arising from the state's moderate social conservatism, openness to privatization, and state demographic characteristics. Even with this fertile political soil, vouchers probably would not have been adopted without the efforts of Governor Jeb Bush. The programs also rest on a shaky legal foundation because of the state's Blaine Amendment and constitutional provisions for "public" and "uniform" schools. The authors conclude that state-level voucher programs in Florida and other states are on uncertain political and legal ground. (Contains 2 tables and 19 endnotes.)

West Nile virus (WNV) typically leads to asymptomatic infection but can cause severe neuroinvasive disease or death, particularly in the elderly. Innate NK cells play a critical role in antiviral defenses, yet their role in human WNV infection is poorly defined. Here we demonstrate that NK cells mount a robust, polyfunctional response to WNV characterized by cytolytic activity, cytokine and chemokine secretion. This is associated with downregulation of activating NK cell receptors and upregulation of NK cell activating ligands for NKG2D. The NK cell response did not differ between young and old WNV-naïve subjects, but a history of symptomatic infection is associated with more IFN-γ producing NK cell subsets and a significant decline in a specific NK cell subset. This NK repertoire skewing could either contribute to or follow heightened immune pathogenesis from WNV infection, and suggests that NK cells could play an important role in WNV infection in humans.