Search

This paper explores the enduring impact of freeway construction on urban neighborhoods and communities, focusing on Los Angeles. The legacy of freeways in Los Angeles, often and purposefully constructed through marginalized communities during the mid-20th century for the benefit of white suburbanites, is reflected in significant social, economic, and environmental symptoms today. This paper also examines de-freeway methods to reconnect these divided communities, assessing their need and effectiveness through data analysis and case studies.The case studies presented in this paper offer a diverse range of solutions. They include the capping of I-5 for Freeway Park in Seattle, the tunneling of the Central Artery for Boston's Big Dig, the activation of I-5 underpasses for Chicano Park in San Diego, and the creation of the Ricardo Lara embankment park along the I-105 freeway in Lynnwood. These examples provide valuable insights into the processes, challenges, and successes of de-freeway and community reconnection efforts, showcasing the adaptability of these solutions in different urban contexts.The paper introduces three design proposals for freeway sites across six communities in Los Angeles. These proposals are guided by urban reformation around freeways and incorporating urban design principles prioritizing social equity, environmental sustainability, and economic revitalization for the most vulnerable and impacted communities. The proposed designs aim to restore community cohesion and foster resilient urban ecosystems.This study contributes to the ongoing discourse on sustainable urban transformation and the reclamation of public spaces for community benefit by providing a comprehensive analysis of historical impacts and contemporary solutions. The paper's findings should help inform and guide urban planning and policy advocates and professionals inspired by the reconnecting communities movement, underscoring the need for innovative approaches to mending bifurcated and ecologically disadvantaged communities.

Atypical chemokine receptor 3 (ACKR3) is an arrestin-biased receptor that regulates extracellular chemokine levels through scavenging. The scavenging process restricts the availability of the chemokine agonist CXCL12 for the G protein-coupled receptor (GPCR) CXCR4 and requires phosphorylation of the ACKR3 C-terminus by GPCR kinases (GRKs). ACKR3 is phosphorylated by GRK2 and GRK5, but the mechanisms by which these kinases regulate the receptor are unresolved. Here we determined that GRK5 phosphorylation of ACKR3 results in more efficient chemokine scavenging and β-arrestin recruitment than phosphorylation by GRK2 in HEK293 cells. However, co-activation of CXCR4-enhanced ACKR3 phosphorylation by GRK2 through the liberation of Gβγ, an accessory protein required for efficient GRK2 activity. The results suggest that ACKR3 senses CXCR4 activation through a GRK2-dependent crosstalk mechanism, which enables CXCR4 to influence the efficiency of CXCL12 scavenging and β-arrestin recruitment to ACKR3. Surprisingly, we also found that despite the requirement for phosphorylation and the fact that most ligands promote β-arrestin recruitment, β-arrestins are dispensable for ACKR3 internalization and scavenging, suggesting a yet-to-be-determined function for these adapter proteins. Since ACKR3 is also a receptor for CXCL11 and opioid peptides, these data suggest that such crosstalk may also be operative in cells with CXCR3 and opioid receptor co-expression. Additionally, kinase-mediated receptor cross-regulation may be relevant to other atypical and G protein-coupled receptors that share common ligands. SIGNIFICANCE STATEMENT: The atypical receptor ACKR3 indirectly regulates CXCR4-mediated cell migration by scavenging their shared agonist CXCL12. Here, we show that scavenging and β-arrestin recruitment by ACKR3 are primarily dependent on phosphorylation by GRK5. However, we also show that CXCR4 co-activation enhances the contribution of GRK2 by liberating Gβγ. This phosphorylation crosstalk may represent a common feedback mechanism between atypical and G protein-coupled receptors with shared ligands for regulating the efficiency of scavenging or other atypical receptor functions.

Chemokine receptors, a subfamily of G-protein-coupled receptors (GPCRs), are responsible for cell migration during physiological processes as well as in diseases like inflammation and cancers. Here, we present a protocol for solubilizing, purifying, and reconstituting complexes of chemokine receptors with their ligands in nanodiscs, soluble lipid bilayers that mimic the native environment of membrane receptors. The protocol yields chemokine receptor complexes with sufficient purity and yield for structural and biophysical studies and should be applicable to other GPCRs.

ABSTRACTCrimean-Congo haemorrhagic fever orthonairovirus (CCHFV) is a tick-borne, risk group 4 pathogen that often causes a severe haemorrhagic disease in humans (CCHF) with high case fatality rates. The virus is believed to be maintained in a tick-vertebrate-tick ecological cycle involving numerous wild and domestic animal species; however the biology of CCHFV infection in these animals remains poorly understood. Here, we experimentally infect domestic sheep with CCHFV Kosovo Hoti, a clinical isolate representing high pathogenicity to humans and increasingly utilized in current research. In the absence of prominent clinical signs, the infection leads to an acute viremia and coinciding viral shedding, fever and markers for potential impairment in liver and kidney functions. A number of host responses distinguish the subclinical infection in sheep versus fatal infection in humans. These include an early reduction of neutrophil recruitment and its chemoattractant, IL-8, in the blood stream of infected sheep, whereas neutrophil infiltration and elevated IL-8 are features of fatal CCHFV infections reported in immunodeficient mice and humans. Several inflammatory cytokines that correlate with poor disease outcomes in humans and have potential to cause vascular dysfunction, a primary hallmark of severe CCHF, are down-regulated or restricted from increasing in sheep. Of particular interest, the detection of CCHFV RNA (including full-length genome) in a variety of sheep tissues long after the acute phase of infection indicates a widespread viral dissemination in the host and suggests a potentially long-term persisting impact of CCHFV infection. These findings reveal previously unrecognized aspects of CCHFV biology in animals.

Abstract Patient‐reported quality‐of‐life (QoL) and carer impacts are not reported after leucine‐rich glioma‐inactivated 1‐antibody encephalitis (LGI1‐Ab‐E). From 60 patients, 85% (51 out of 60) showed one abnormal score across QoL assessments and 11 multimodal validated questionnaires. Compared to the premorbid state, QoL significantly deteriorated (p

C-C chemokine receptor 2 (CCR2) is a dual-function receptor. Similar to other G protein-coupled chemokine receptors, it promotes monocyte infiltration into tissues in response to the chemokine CCL2, and, like atypical chemokine receptors (ACKRs), it scavenges chemokine from the extracellular environment. CCR2 therefore mediates CCL2-dependent signaling as a G protein-coupled receptor (GPCR) and also limits CCL2 signaling as a scavenger receptor. We investigated the mechanisms underlying CCR2 scavenging, including the involvement of intracellular proteins typically associated with GPCR signaling and internalization. Using CRISPR knockout cell lines, we showed that CCR2 scavenged by constitutively internalizing to remove CCL2 from the extracellular space and recycling back to the cell surface for further rounds of ligand sequestration. This process occurred independently of G proteins, GPCR kinases (GRKs), β-arrestins, and clathrin, which is distinct from other "professional" chemokine scavenger receptors that couple to GRKs, β-arrestins, or both. These findings set the stage for understanding the molecular regulators that determine CCR2 scavenging and may have implications for drug development targeting this therapeutically important receptor.

Background: Many underserved populations use Emergency Department (EDs) as primary sources of care, representing an important opportunity to provide infectious disease testing and linkage to care. We explored national ED testing trends and co-testing patterns for HIV, hepatitis C, and sexually transmitted infections (STIs). Methods: We used 2010–2019 Healthcare Cost and Utilization Project, Nationwide Emergency Department Sample data to estimate ED visit testing rates for HIV, hepatitis C, chlamydia, gonorrhea, and syphilis infections, identified by Current Procedural Terminology codes. Trends and co-testing (visit with tests for > 1 infection) patterns were analyzed by sociodemographic, hospital, and visit characteristics. Trends were evaluated as the average annual percentage change (AAPC) using the Joinpoint Regression. Results: During 2010–2019, testing events per 1000 visits (AAPCs) increased for HIV from 1.3 to 4.2 (16.3 %), hepatitis C from 0.4 to 2.2 (25.1 %), chlamydia from 9.1 to 16.0 (6.6 %), gonorrhea from 8.4 to 15.7 (7.4 %), and syphilis from 0.7 to 2.0 (12.9 %). Rate increases varied by several characteristics across infections. The largest AAPC increases were among visits by groups with lower base rate testing in 2010, including persons aged ≥ 65 years (HIV: 36.4 %), with Medicaid (HIV: 43.8 %), in the lowest income quintile (hepatitis C: 36.9 %), living in the West (syphilis: 49.4 %) and with non-emergency diagnoses (hepatitis C: 44.1 %). Co-testing increased significantly for all infections except hepatitis C. Conclusions: HIV, hepatitis C, and STI testing increased in EDs during 2010–2019; however, co-testing patterns were inconsistent. Co-testing may improve diagnosis and linkage to care, especially in areas experiencing higher rates of infection.

We studied calls of three sandpiper species to document species' similarities and differences. We hypothesized that functionally different calls would differ in degree of divergence. We studied two nuptial calls (complex 'Song' and rhythmically repeated aerial call, RRC) of males, and a general-purpose call ('alarm' trill, AT) given by parents of both sexes in the presence of humans and other potential predators, in great knot, Calidris tenuirostris (Horsfeld, 1821); surfbird, Calidris virgata (Gmelin, 1789); and red knot, Calidris canutus (Linnaeus, 1758). Calls diverged unevenly across species--RRCs and Song diverged the most and ATs the least. Vocalizations of great knot and surfbird were most similar to one another, in agreement with a recently proposed phylogeny Despite species differences in single acoustic traits, calls were evolutionarily conservative at higher structural levels, such as rhythmic temporal delivery of RRCs and harmonic structure (e.g., the fundamental frequency was suppressed in some call types). Some acoustic qualities that differed across species were similar across call types within species (e.g., tonality in red knot calls). Trait similarity across different calls suggests that a species' calls cannot evolve independently of one another: common mechanisms of vocal production across different calls may impede differentiation within a species' repertoire. Key words: evolutionary constraints, evolutionary rates, phylogeny, sandpiper, sexual selection, vocalization, Introduction Comparative studies marked the emergence of the study of animal behaviour (Lorenz 1941; Tinbergen 1959) and continue to contribute to our understanding of behavioural evolution (Ord and Martins 2010; [...]

Abstract Background No treatment other than platelet administration is known to protect against spontaneous hemorrhage in thrombocytopenic dogs. Objectives Primary: determine if treatment with ε‐aminocaproic acid (EACA) decreases the requirement for blood transfusions and improves outcome in dogs with severe thrombocytopenia. Secondary: find evidence of hyperfibrinolysis and determine the effect EACA administration on rapid (rTEG) and tissue plasminogen activator‐spiked (tPA‐rTEG) thromboelastography parameters. Animals Twenty‐seven dogs with severe thrombocytopenia were treated with EACA, and data from an additional 33 were obtained from the hospital database as historical control (HC) cohort. Methods Single arm clinical trial with HCs. The EACA group dogs received EACA (100 mg/kg IV followed by a constant‐rate infusion [CRI] of 400 mg/kg/24 hours). Thromboelastography before and during EACA infusion, hospitalization days, number of transfusions, and mortality were compared. Results No difference was found in number of transfusions per dog (median, interquartile range; 1, 0‐2.5 vs 0.9, 0‐2; P = .5) and hospitalization days (4, 4‐6 vs 4.5, 3.75‐6; P = .83) between HC and EACA groups, respectively, and no difference in survival was identified by log‐rank analysis (P = .15). Maximum amplitude on both rTEG and tPA‐rTEG increased after EACA administration (rTEG baseline: 23.6, 9.6‐38.9; post‐EACA: 27.3, 19.8‐43.2; P

Internationally a plethora of narratives within, beside and in opposition to multiculturalism has necessitated the rethinking of some key questions. Is multiculturalism apt for equitable representation? Can multiculturalism remain the hegemonic discourse and policy of diversity or is it destined to be supplanted? In this essay, we reconsider multiculturalism's changing currency and pedagogical potential, contextualized in the global multicultural city of Sydney, Australia. Our qualitative research is grounded in the voices and knowledge of "new youth," who self-identify as immigrant, multiracial, and/or queer -- (post)multicultural signifiers that are non-Indigenous and yet significantly differing from the previously taken for granted Eurocentric white heterosexual representations of the Australian nation. Through our in-depth interviews with these new youth -- who are also activist community workers -- we learned how they affectively make sense of multiculturalism and community. They are emotionally divested from multiculturalism that tinkers with ethnoracial categories/differences yet leave the structures of whiteness both opaque and intact. On the other hand, they see some value in but are ambivalent about multiculturalism's potential to make a difference to community work, struggles for justice, and their own identities and senses of belonging. Our findings, which have implications for diversity and social justice education, indicate the emergence of post-multicultural and/or alternative, complex articulations of diversity and belonging that unsettle fixed identity categories and conceptions of the nation and belonging and indeed multiculturalism itself.

Background Electronic nicotine delivery systems (“e-cigarettes”) are the nicotine product most commonly used by adolescents. Research, treatment, and policy could benefit from measures of adolescent e-cigarette beliefs about outcomes of use (ie, expectancies). In the current study, we developed and tested an adolescent electronic nicotine vaping expectancy measure. Methods A focus group with adolescents evaluated potential e-cigarette expectancy items. A panel of national experts assisted in revision of these items. Finally, items were administered to a sample of adolescents 14-17 years old (N = 267, Mean age 15.6, SD = 1.1, 50.9% Female, 50.2% Non-Hispanic White, 22.5% Non-Hispanic Black, 14.2% Hispanic) in a large Southeastern metropolitan area in the United States. Results Exploratory Factor Analysis revealed a four factor solution: Negative Consequences (Cronbach’s α = .92); Positive Reinforcement (α = .83); Negative Affect Reduction (α = .95); and Weight Control (α = .89). Subscales were significantly correlated with vaping susceptibility and lifetime vaping. Subscales successfully differentiated susceptible adolescents from confirmed non-susceptible adolescents, with susceptible adolescents reporting more positive expectancies, eg, Positive Reinforcement, M = 5.0, SD = 2.0 vs M = 3.0, SD = 2.1, P < .001, η 2 = 0.19, and less negative expectancies, M = 5.5, SD = 2.3 vs M = 6.5, SD = 2.6, P = .001, η 2 = 0.04. Similar results were found comparing adolescents who have never vaped nicotine with those who have vaped nicotine. Hierarchical linear regression demonstrated subscales were significant predictors of lifetime vaping after controlling for demographics, vaping ad exposure, and peer/family vaping. Conclusions A preliminary version of an adolescent expectancy measure appears reliable and valid based on expert input and pilot testing with adolescents. Promising results were found in the domains of concurrent validity, discriminant validity, and incremental validity. Future research and evaluation efforts will be able to use this tool to further prevention and treatment goals.

Norovirus is a major cause of foodborne disease and causes a large number of cases, hospitalizations, and deaths in the United States and globally (1-4). Specific treatments are not available, [...]

Growth of long bones and vertebrae is maintained postnatally by a long-lasting pool of progenitor cells. Little is known about the molecular mechanisms that regulate the output and maintenance of the cells that give rise to mature cartilage. Here we demonstrate that postnatal chondrocyte-specific deletion of a transcription factor Stat3 results in severely reduced proliferation coupled with increased hypertrophy, growth plate fusion, stunting and signs of progressive dysfunction of the articular cartilage. This effect is dimorphic, with females more strongly affected than males. Chondrocyte-specific deletion of the IL-6 family cytokine receptor gp130, which activates Stat3, phenocopied Stat3-deletion; deletion of Lifr, one of many co-receptors that signals through gp130, resulted in a milder phenotype. These data define a molecular circuit that regulates chondrogenic cell maintenance and output and reveals a pivotal positive function of IL-6 family cytokines in the skeletal system with direct implications for skeletal development and regeneration.

Self-control problems constitute a potential explanation for the underinvestment in preventive health in low-income countries. Behavioral economics offers a tool to solve such problems: commitment devices. We conduct a field experiment to evaluate the effectiveness of different types of theoretically motivated commitment contracts in increasing preventive doctor visits by hypertensive patients in rural India. Despite achieving high take-up of such contracts in some treatment arms, we find no effects on actual doctor visits or individual health outcomes. A substantial number of individuals pay for commitment but fail to follow through on the doctor visit, losing money without experiencing health benefits. We develop and structurally estimate a prespecified model of consumer behavior under present bias with varying levels of naiveté. The results are consistent with a large share of individuals being partially naive about their own self-control problems: sophisticated enough to demand some commitment but overly optimistic about whether a given level of commitment is sufficiently strong to be effective. The results suggest that commitment devices may in practice be welfare diminishing, at least in some contexts, and serve as a cautionary tale about their role in health care.