Structural Determinants Research Articles

Familial clustering of dysbiotic oral and fecal microbiomes in juvenile dermatomyositis

Juvenile dermatomyositis (JDM) is a rare immune-mediated disease of childhood with putative links to microbial exposures. In this multi-center, prospective, observational cohort study, we evaluated whether JDM is associated with discrete oral and gut microbiome signatures. We generated 16S rRNA sequencing data from fecal, saliva, supragingival, and subgingival plaque samples from JDM probands (n = 28). To control for genetic and environmental determinants of microbiome community structure, we also profiled microbiomes of unaffected family members (n = 27 siblings, n = 26 mothers, and n = 17 fathers). Sample type (oral-vs-fecal) and nuclear family unit were the predominant variables explaining variance in microbiome diversity, more so than having a diagnosis of JDM. The oral and gut microbiomes of JDM probands were more similar to their own unaffected siblings than they were to the microbiomes of other JDM probands. In a sibling-paired within-family analysis, several potentially immunomodulatory bacterial taxa were differentially abundant in the microbiomes of JDM probands compared to their unaffected siblings, including Faecalibacterium (gut) and Streptococcus (oral cavity). While microbiome features of JDM are often shared by unaffected family members, the loss or gain of specific fecal and oral bacteria may play a role in disease pathogenesis or be secondary to immune dysfunction in susceptible individuals.

Exploring the role of E. faecalis enterococcal polysaccharide antigen (EPA) and lipoproteins in evasion of phagocytosis.

Enterococcus faecalis is an opportunistic pathogen frequently causing nosocomial infections. The virulence of this organism is underpinned by its capacity to evade phagocytosis, allowing dissemination in the host. Immune evasion requires a surface polysaccharide produced by all enterococci, known as the enterococcal polysaccharide antigen (EPA). EPA consists of a cell wall-anchored rhamnose backbone substituted by strain-specific polysaccharides called 'decorations', essential for the biological activity of this polymer. However, the structural determinants required for innate immune evasion remain unknown, partly due to a lack of suitable validated assays. Here, we describe a quantitative, invitro assay to investigate how EPA decorations alter phagocytosis. Using the E. faecalis model strain OG1RF, we demonstrate that a mutant with a deletion of the locus encoding EPA decorations can be used as a platform strain to express heterologous decorations, thereby providing an experimental system to investigate the inhibition of phagocytosis by strain-specific decorations. We show that the aggregation of cells lacking decorations is increasing phagocytosis and that this process does not involve the recognition of lipoproteins by macrophages. Collectively, our work provides novel insights into innate immune evasion by enterococci and paves the way for further studies to explore the structure/function relationship of EPA decorations.

Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors: A Case Study on KRasG12C.

Covalent drugs might bear electrophiles to chemically modify their targets and have the potential to target previously undruggable proteins with high potency. Covalent binding of drug-size molecules includes a noncovalent recognition provided by secondary interactions and a chemical reaction leading to covalent complex formation. Optimization of their covalent mechanism of action should involve both types of interactions. Noncovalent and covalent binding steps can be characterized by an equilibrium dissociation constant (KI) and a reaction rate constant (kinact), respectively, and they are affected by both the warhead and the scaffold of the ligand. The relative contribution of these two steps was investigated on a prototypic drug target KRASG12C, an oncogenic mutant of KRAS. We used a synthetically more accessible nonchiral core derived from ARS-1620 that was equipped with four different warheads and a previously described KRAS-specific basic side chain. Combining these structural changes, we have synthesized novel covalent KRASG12C inhibitors and tested their binding and biological effect on KRASG12C by various biophysical and biochemical assays. These data allowed us to dissect the effect of scaffold and warhead on the noncovalent and covalent binding event. Our results revealed that the atropisomeric core of ARS-1620 is not indispensable for KRASG12C inhibition, the basic side chain has little effect on either binding step, and warheads affect the covalent reactivity but not the noncovalent binding. This type of analysis helps identify structural determinants of efficient covalent inhibition and may find use in the design of covalent agents.

Preparation and Characterization of Zn(II)-Stabilized Aβ42 Oligomers.

Aβ oligomers are being investigated as cytotoxic agents in Alzheimer's disease (AD). Because of their transient nature and conformational heterogeneity, the relationship between the structure and activity of these oligomers is still poorly understood. Hence, methods for stabilizing Aβ oligomeric species relevant to AD are needed to uncover the structural determinants of their cytotoxicity. Here, we build on the observation that metal ions and metabolites have been shown to interact with Aβ, influencing its aggregation and stabilizing its oligomeric species. We thus developed a method that uses zinc ions, Zn(II), to stabilize oligomers produced by the 42-residue form of Aβ (Aβ42), which is dysregulated in AD. These Aβ42-Zn(II) oligomers are small in size, spanning the 10-30 nm range, stable at physiological temperature, and with a broad toxic profile in human neuroblastoma cells. These oligomers offer a tool to study the mechanisms of toxicity of Aβ oligomers in cellular and animal AD models.

Leveraging biosocial methods to examine and address structural determinants of health and promote health equity

BackgroundBiosocial approaches in nursing research have largely focused on the ways that social determinants of health influence individual-level outcomes, including symptom management, family and social support, and educational interventions. PurposeTheoretical, methodological, and practical strategies are needed to expand current biosocial methods for nursing science and focus on upstream, structural determinants of health and the policies that underlie health inequities. MethodsThis paper summarizes presentations given at the 2023 Council for the Advancement of Nursing Science Advanced Methods Conference, Biosocial Methods to Advance Health Equity, in a panel titled “Individual, community, systems and policy related to biosocial methods.” DiscussionNurses are uniquely positioned to examine upstream, structural determinants of health by leveraging expertise in biosocial methods, collaborating with interdisciplinary researchers and community members, and advocating for policy change. By conducting theory-grounded biosocial research, nurse researchers can significantly advance scientific knowledge and promote health equity for individuals and communities. ConclusionNurse scientists are conducting research using biosocial methods and provide recommendations for expansion of this approach in the field.

What Would Equitable Harm Reduction Look Like?

Structural determinants of health frameworks must express antiracism to be effective, but racial and ethnic inequities are widely documented, even in harm reduction programs that focus on person-centered interventions. Harm reduction strategies should express social justice and health equity, resist stigma and discrimination, and mitigate marginalization experiences among people who use drugs (PWUD). To do so, government and organizational policies that promote harm reduction must acknowledge historical and ongoing patterns of racializing drug use. This article gives examples of such racialization and offers recommendations about how harm reduction programming can most easily and effectively motivate equitable, antiracist care for PWUD.

The anti-tubercular callyaerins target the Mycobacterium tuberculosis-specific non-essential membrane protein Rv2113.

Spread of antimicrobial resistances urges a need for new drugs against Mycobacterium tuberculosis (Mtb) with mechanisms differing from current antibiotics. Previously, callyaerins were identified as promising anti-tubercular agents, representing a class of hydrophobic cyclopeptides with an unusual (Z)-2,3-di-aminoacrylamide unit. Here, we investigated the molecular mechanisms underlying their antimycobacterial properties. Structure-activity relationship studies enabled the identification of structural determinants relevant for antibacterial activity. Callyaerins are bacteriostatics selectively active against Mtb, including extensively drug-resistant strains, with minimal cytotoxicity against human cells and promising intracellular activity. By combining mutant screens and various chemical proteomics approaches, we showed that callyaerins target the non-essential, Mtb-specific membrane protein Rv2113, triggering a complex dysregulation of the proteome, characterized by global downregulation of lipid biosynthesis, cell division, DNA repair, and replication. Our study thus identifies Rv2113 as a previously undescribed Mtb-specific drug target and demonstrates that also non-essential proteins may represent efficacious targets for antimycobacterial drugs.

Leveraging Key Informant Interviews to Inform Intervention Development: The Greater Lawndale Healthy Work Project.

The Greater Lawndale Healthy Work project is a sequential mixed methods community based participatory research project that examines work as a structural determinant of health and builds community capacity for healthy work in a predominantly Black and Latinx community in Chicago known as Greater Lawndale (GL). We interviewed community leaders in GL as key informants to understand the barriers to healthy work and inform intervention development. We conducted a directed content analysis of transcripts from 20 key informants and coded the social ecology and type of intervention. Every key informant mentioned at least one asset in GL, showing an opportunity to employ a capacity-oriented approach to intervention development. Key informants suggested a variety of interventions to address precarious work across levels of the social ecology, with individual and community level interventions being the most salient. Through this approach, we were able to navigate tensions and challenges in conducting research for community-wide change. Key informant stakeholder interviews can be leveraged to meaningfully inform intervention development and support the development of multi-level, sustainable, and culturally acceptable interventions that advance health equity.

Corporate Debt Dynamics: Sectoral Clustering Analysis Using NACE Classification in Slovakia

Research background: Many authors are currently exploring the impact of the industry on the financial structure of enterprises since there are statistically significant differences across various sectors, exposing the industry as a critical factor influencing corporate indebtedness. Clusters of sectors with homogeneous patterns of indebtedness and comparable levels of debt in various economic conditions may be determined, and, therefore, firms and their debt levels should be systematically examined and evaluated. Purpose of the article: The main aim of this paper is to evaluate the level of debt in the Slovak environment on a sample of 19,480 firms from various sectors and to identify the relationships among them to identify sectors with homogeneous patterns of indebtedness and, consequently, comprehend which sectors are the most stable and independent. Methods: Because NACE classification provides a framework for gathering and presenting statistical data based on many economic sectors, the number of input data was reduced based on cluster analysis. Using Ward's hierarchical clustering method using squared Euclidean distance, selected indebtedness ratios were used to define the sectors with comparable debt levels. To determine if there were statistically significant differences between the calculated debt ratios related to the economic sector, the Kruskal-Wallis test was performed. Subsequently, as the results indicated significant differences across various indebtedness ratios, a post hoc analysis was performed. Findings & Value added: A group of NACE activities in which enterprises are sufficiently comparable that it is appropriate to evaluate their debt levels using the chosen indebtedness ratios are considered to be in sectors C, F, G and H, which included to tertiary sector, while the sectors K, R and S may also be grouped in one cluster, while form the secondary sector. The key relevance of our findings is the benchmarking of selected sectors about indebtedness, which may be used to further examine their growth in each of the V4 nations, which is an essential area for the evolution of the European economy as a whole. Studies considering a relatively significant amount of capital structure determinants may be beneficial to owners and managers, regulators, and financial institutions since debt policy affects firm performance, value, and survival.

Struktur Modal dan UKM : A Systematic Literature Review

This systematic literature review (SLR) aims to provide a comprehensive overview of the existing research on the impact of capital structure on small and medium-sized enterprises (SMEs). The study synthesizes and analyzes findings from various studies to identify key trends, gaps, and areas for future research. The SLR covers factors influencing SMEs' capital structure decisions, including internal factors like company size, profitability, and growth opportunities, and external factors such as market conditions, industry characteristics, and regulatory environment. Our findings reveal that the capital structure significantly affects SMEs' financial performance and sustainability. Debt financing offers growth potential but increases financial risk, while equity financing provides stability and reduces risk but dilutes ownership. The optimal mix of debt and equity varies based on specific SME characteristics and external conditions. Additionally, the capital structure influences SMEs' ability to attract external financing and impacts their overall growth and profitability. The review also highlights the need for more focused research on the determinants of capital structure in SMEs, the role of external financing sources, and the relationship between capital structure and firm performance over time. Longitudinal studies and investigations into macroeconomic factors' impact on SMEs' capital structure decisions are recommended for future research.

The impact of sheep grazing on shrub communities at the Afrikaner and Hereford grazing trials at Grootfontein in the Eastern Upper Karoo

In the Nama-Karoo, grazing by livestock is an important driver of Karoo shrub composition. Many different breeds of livestock are farmed in the Nama-Karoo, and the stocking rate varies greatly over the region. In this study we examine how grazing by dorper and merino sheep applied at three stocking rates affected two Karoo shrublands on a long-term grazing trial at Grootfontein in the eastern Karoo. The effects of grazing treatment on shrub communities at two sites of the Afrikaner-Hereford grazing trial differed greatly and were measurable after ten years of rest. At the sandier, grassier Afrikaner site, heavy grazing by dorper sheep had a significant effect on shrub composition, density and cover, whereas the effect of grazing treatment was less pronounced at the Hereford site. Lenient grazing by merino sheep resulted in a vastly different community compared to all other grazing treatments. Individual Karoo shrub species responded differently to grazing treatment. Overall shrub recruitment has faltered for all but three species, and populations were dominated by intermediate-sized and large individuals. Results indicate that grazing management, animal type and stocking rate are important determinants of Nama-Karoo rangeland composition and structure with evidence of a legacy effect longer than ten years.

Prevalence and socio-economic determinants of growth and developmental delays among Iranian children aged under five years: A cross sectional study

BackgroundThe main cause of growth and development delays remains unknown, but it can occur as an interaction between genetic, environmental, and socio-economic factors.ObjectiveThe aim of the study was to investigate the prevalence and social determinants of growth and developmental delays among children aged under five years in Qazvin, Iran.MethodsA cross-sectional study was conducted between January 2019 to December 2020 with participation of 1800 mothers with children aged 4–60 months who were referred to comprehensive health centers in Qazvin city, Iran. Structural and intermediate social determinants of health were assessed including: parents and children socio-demographic characteristics, families’ living and economic status, parents’ behavioral factors, household food security, mother’s general health, and perceived social support. Children’s growth was assessed based on their anthropometric assessment and their development was assessed using their age-specific Ages and Stages Questionnaire. Data were analyzed using univariable and multivariable logistic regression models using SPSS software version 24 and Stata version 14.ResultsThe prevalence of developmental problems in each domain were 4.28% for personal and social delay, 5.72% for gross motor delay, 6.5% for communication delay, 6.72% for fine motor delay, and 8% for problem-solving delay. The prevalence of weight growth delays was 13.56% and height growth delays was 4.66%. Communication, gross motor, and problem-solving delays were higher among children whose fathers’ smoked cigarettes. Fine motor delays were lower among mothers with education status of high school diploma and university degree vs. the under diploma group. Personal and social delay was significantly higher among families with fair economic status and lower among children when their fathers were employed (vs. unemployed). Weight and height growth delays were higher among mothers who had experienced pregnancy complications and household food insecure families, respectively.ConclusionThere are different predictors of growth and developmental delay problems among Iranian children aged under five years including fathers’ smoking, families’ economic status, and household food insecurity as well as history of mothers’ pregnancy complications. The present study’s findings can be used to screen for at-risk of growth and developmental delays among children and could help in designing and implementation of timely interventions.

Deciphering Structural Traits for Thermal and Kinetic Stability across Protein Family Evolution through Ancestral Sequence Reconstruction.

Natural proteins are frequently marginally stable, and an increase in environmental temperature can easily lead to unfolding. As a result, protein engineering to improve protein stability is an area of intensive research. Nonetheless, since there is usually a high degree of structural homology between proteins from thermophilic organisms and their mesophilic counterparts, the identification of structural determinants for thermoadaptation is challenging. Moreover, in many cases, it has become clear that the success of stabilization strategies is often dependent on the evolutionary history of a protein family. In the last few years, the use of ancestral sequence reconstruction (ASR) as a tool for elucidation of the evolutionary history of functional traits of a protein family has gained strength. Here, we used ASR to trace the evolutionary pathways between mesophilic and thermophilic kinases that participate in the biosynthetic pathway of vitamin B1 in bacteria. By combining biophysics approaches, X-ray crystallography, and molecular dynamics simulations, we found that the thermal stability of these enzymes correlates with their kinetic stability, where the highest thermal/kinetic stability is given by an increase in small hydrophobic amino acids that allow a higher number of interatomic hydrophobic contacts, making this type of interaction the main support for stability in this protein architecture. The results highlight the potential benefits of using ASR to explore the evolutionary history of protein sequence and structure to identify traits responsible for the kinetic and thermal stability of any protein architecture.

How employment-focused social procurement tackles health inequities: an investigation of Australia’s construction industry using determinants of health theory

With public and private clients in the construction industry increasingly using social procurement to achieve their social responsibility goals, it is important to develop theory-informed approaches for understanding how and to what extent social procurement creates social value. The research presented in this article uses social determinants of health (SDOH) theory to develop a case study of an employment-focused social procurement initiative in Australia’s construction industry. The case study shows how the employment-focused social procurement initiative used cross-sector intermediation to alleviate structural barriers to employment, including siloing in the employment services sector, unsupported pathways from training into employment in construction, and negative stereotypes of people who face structural barriers to employment. Using SDOH theory, the paper frames these barriers to employment as ‘upstream’ and ‘midstream’ structural determinants of health inequities. The research finds that the initiative’s impacts on determinants of health inequities are enabled and limited by commercial factors including project location and duration, status of the principal contractor, and insider knowledge of timing and requirements of new jobs.

A Structure-Activity Investigation of the Fungal Metabolite (-)-TAN-2483B: Inhibition of Bruton's Tyrosine Kinase.

The natural product (-)-TAN-2483B is a fungal secondary metabolite which displays promising anti-cancer and immunomodulatory activity. Our previous syntheses of (-)-TAN-2483B and sidechain analogues uncovered inhibitory activity against Bruton's tyrosine kinase (Btk), an established drug target for various leukaemia and immunological diseases. A structure-based computational study using ensemble docking and molecular dynamics was performed to determine plausible binding modes for (-)-TAN-2483B and analogues in the Btk binding site. These hypotheses guided the design of new analogues which were synthesised and their inhibitory activities determined, providing insights into the structural determinants of the furopyranone scaffold that confer both activity and selectivity for Btk. These findings offer new perspectives for generating optimised (-)-TAN-2483B-based kinase inhibitors for the treatment of leukaemia and immunological diseases.

Healthcare Industries' Capital Structure Determinants: Evident Listed Companies on the Indonesian Stock Exchang

Healthcare Industries' Capital Structure Determinants: Evident Listed Companies on the Indonesian Stock Exchang

Optimization of quenched fluorescent peptide substrates of SARS-CoV-2 3CLpro main protease (Mpro) from proteomic identification of P6-P6' active site specificity.

SARS-CoV-2 3C-like main protease (3CLpro) is essential for protein excision from the viral polyprotein. 3CLpro inhibitor drug development to block SARS-CoV-2 replication focuses on the catalytic non-prime (P) side for specificity and potency, but the importance of the prime (P') side in substrate specificity and for drug development remains underappreciated. We determined the P6-P6' specificity for 3CLpro from >800 cleavage sites that we identified using Proteomic Identification of Cleavage site Specificity (PICS). Cleavage occurred after the canonical P1-Gln and non-canonical P1-His and P1-Met residues. Moreover, P3 showed a preference for Arg/Lys and P3' for His. Essential H-bonds between the N-terminal Ser1 of protomer-B in 3CLpro dimers form with P1-His, but not with P1-Met. Nonetheless, cleavage occurs at P1-Met456 in native MAP4K5. Elevated reactive oxygen species in SARS-CoV-2 infection oxidize methionines. Molecular simulations revealed P1-MetOX forms an H-bond with Ser1 and notably, strong positive cooperativity between P1-Met with P3'-His was revealed, which enhanced peptide-cleavage rates. The highly plastic S3' subsite accommodates P3'-His that displays stabilizing backbone H-bonds with Thr25 lying central in a "'threonine trio" (Thr24-Thr25-Thr26) in the P'-binding domain I. Molecular docking simulations unveiled structure-activity relationships impacting 3CLpro-substrate interactions, and the role of these structural determinants was confirmed by MALDI-TOF-MS cleavage assays of P1'- and P3'-positional scanning peptide libraries carrying a 2nd optimal cut-site as an internal positive control. These data informed the design of two new and highly soluble 3CLproquenched-fluorescent peptide substrates for improved FRET monitoring of 3CLpro activity with 15× improved sensitivity over current assays.IMPORTANCEFrom global proteomics identification of >800 cleavage sites, we characterized the P6-P6' active site specificity of SARS-CoV-2 3CLpro using proteome-derived peptide library screens, molecular modeling simulations, and focussed positional peptide libraries. In P1', we show that alanine and serine are cleaved 3× faster than glycine and the hydrophobic small amino acids Leu, Ile, or Val prevent cleavage of otherwise optimal non-prime sequences. In characterizing non-canonical non-prime P1 specificity, we explored the unusual P1-Met specificity, discovering enhanced cleavage when in the oxidized state (P1-MetOX). We unveiled unexpected amino acid cooperativity at P1-Met with P3'-His and noncanonical P1-His with P2-Phe, and the importance of the threonine trio (Thr24-Thr25-Thr26) in the prime side binding domain I in defining prime side binding in SARS-CoV-2 3CLpro. From these analyses, we rationally designed quenched-fluorescence natural amino acid peptide substrates with >15× improved sensitivity and high peptide solubility, facilitating handling and application for screening of new antiviral drugs.

Determinants of Intention to Use HIV Pre-exposure Prophylaxis and Condom Use Among a Sample of Cisgender Female Sex Workers Working Mostly Outdoors in Madrid, Spain

There is scant knowledge regarding pre-exposure prophylaxis (PrEP) use among female sex workers (FSWs) in Europe. Spain recognized FSWs as a population at high risk of acquiring HIV and granted them subsidized access to PrEP when the medication first became nationally available in 2019. Nevertheless, FSWs represented just 0.2% of PrEP users in 2022. A total of 102 HIV-negative FSWs reached through field activities of local NGOs located in Madrid were interviewed between January and March 2022. Participants were selected through convenience sampling over a fixed recruitment period. FSWs completed a 73-item survey with questions about individual, occupational, social, and structural determinants. The objective of this study was to identify (1) the prevalence of intention to use oral PrEP and its determinants, and (2) the prevalence of inconsistent condom use, which is the risk factor that qualifies FSWs for subsidized PrEP in the national health system, and its determinants. Importantly, the study sample overrepresented street-based FSWs (71.6%). A quarter (25.5%) of the study participants used condoms inconsistently. PrEP awareness was low (9.8%), but intention to use PrEP was high (72.5%). Intention to use oral PrEP was significantly associated with feeling protected against HIV by taking PrEP and perceiving insufficient protection by condom use alone. Inconsistent condom use was significantly associated with frequent heroin/cocaine use, having clients who inject drugs, and willingness to take PrEP despite it not protecting 100% against HIV infection. FSWs, in this specific sample, are likely to benefit from targeted PrEP awareness campaigns and implementation projects that prioritize those who use drugs and are more likely to engage in condomless sex.

Soil microbial community response to corrinoids is shaped by a natural reservoir of vitamin B12.

Soil microbial communities perform critical ecosystem services through the collective metabolic activities of numerous individual organisms. Most microbes use corrinoids, a structurally diverse family of cofactors related to vitamin B12. Corrinoid structure influences the growth of individual microbes, yet how these growth responses scale to the community level remains unknown. Analysis of metagenome-assembled genomes suggests corrinoids are supplied to the community by members of the archaeal and bacterial phyla Thermoproteota, Actinobacteria, and Proteobacteria. Corrinoids were found largely adhered to the soil matrix in a grassland soil, at levels exceeding those required by cultured bacteria. Enrichment cultures and soil microcosms seeded with different corrinoids showed distinct shifts in bacterial community composition, supporting the hypothesis that corrinoid structure can shape communities. Environmental context influenced both community and taxon-specific responses to specific corrinoids. These results implicate corrinoids as key determinants of soil microbiome structure and suggest that environmental micronutrient reservoirs promote community stability.

Structural Determinants of Health and Markers of Immune Activation and Systemic Inflammation in Sexual Minority Men With and Without HIV.

Among sexual minority men (SMM), HIV and use of stimulants such as methamphetamine are linked with immune activation and systemic inflammation. Throughout the COVID-19 pandemic, SMM encountered financial challenges and structural obstacles that might have uniquely contributed to immune dysregulation and systemic inflammation, beyond the impacts of HIV and stimulant use. Between August 2020 and February 2022, 72 SMM with and without HIV residing in South Florida enrolled in a COVID-19 prospective cohort study. Multiple linear regression analyses examined unemployment, homelessness, and history of arrest as structural correlates of soluble markers of immune activation (i.e., sCD14 and sCD163) and inflammation (i.e., sTNF-α receptors I and II) at baseline after adjusting for HIV status, stimulant use, and recent SARS-CoV-2 infection. Enrolled participants were predominantly Latino (59%), gay-identified (85%), and with a mean age of 38 (SD, 12) years with approximately one-third (38%) of participants living with HIV. After adjusting for HIV status, SARS-CoV-2 infection, and recent stimulant use, unemployment independently predicted higher levels of sCD163 (β = 0.24, p = 0.04) and sTNF-α receptor I (β = 0.26, p = 0.02). Homelessness (β = 0.25, p = 0.02) and history of arrest (β = 0.24, p = 0.04) independently predicted higher levels of sCD14 after adjusting for HIV status, SARS-CoV-2 infection, and recent stimulant use. Independent associations exist between structural barriers and immune activation and systemic inflammation in SMM with and without HIV. Future longitudinal research should further elucidate complex bio-behavioral mechanisms linking structural factors with immune activation and inflammation.