Practical considerations for using low-cost sensors to assess wildfire smoke exposure in school and childcare settings.

BACKGROUND: More frequent and intense wildfires will increase concentrations of smoke in schools and childcare settings. Low-cost sensors can assess fine particulate matter (PM2.5) concentrations with high spatial and temporal resolution. OBJECTIVE: We sought to optimize the use of sensors for decision-making in schools and childcare settings during wildfire smoke to reduce children's exposure to PM2.5. METHODS: We measured PM2.5 concentrations indoors and outdoors at four schools in Washington State during wildfire smoke in 2020-2021 using low-cost sensors and gravimetric samplers. We randomly sampled 5-min segments of low-cost sensor data to create simulations of brief portable handheld measurements. RESULTS: During wildfire smoke episodes (lasting 4-19 days), median hourly PM2.5 concentrations at different locations inside a single facility varied by up to 49.6 µg/m3 (maximum difference) during school hours. Median hourly indoor/outdoor ratios across schools ranged from 0.22 to 0.91. Within-school differences in concentrations indicated that it is important to collect measurements throughout a facility. Simulation results suggested that making handheld measurements more often and over multiple days better approximates indoor/outdoor ratios for wildfire smoke. During a period of unstable air quality, PM2.5 over the next hour indoors was more highly correlated with the last 10-min of data (mean R2 = 0.94) compared with the last 3-h (mean R2 = 0.60), indicating that higher temporal resolution data is most informative for decisions about near-term activities indoors. IMPACT STATEMENT: As wildfires continue to increase in frequency and severity, staff at schools and childcare facilities are increasingly faced with decisions around youth activities, building use, and air filtration needs during wildfire smoke episodes. Staff are increasingly using low-cost sensors for localized outdoor and indoor PM2.5 measurements, but guidance in using and interpreting low-cost sensor data is lacking. This paper provides relevant information applicable for guidance in using low-cost sensors for wildfire smoke response.

Cumulative housing cost burden exposures and disadvantages to children's well-being and health.

Housing affordability is a growing challenge for households in the United States and other developed countries. Prolonged exposure to housing cost burden can have damaging effects on households, and, in particular, children. These burdens can exacerbate parental stress, reduce investments in children and expose households to greater neighborhood disadvantage. In this study, we use national survey data to assess whether cumulative housing cost burden exposure is associated with disadvantages to children's well-being and health. We observe that long-term exposures are linked to lower achievement in math and reading standardized test scores, as well as higher levels of behavior problems. Moreover, we identify that three mechanisms--caregiver distress, economic strain, and neighborhood disadvantage--operate as mediating pathways for these disadvantages to different degrees between these three outcomes. Overall, our study highlights how the dimension of time is increasingly important to our understanding of the challenges that families face related to housing affordability.

Structural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy.

The high potential of siRNAs to silence oncogenic drivers remains largely untapped due to the challenges of tumor cell delivery. Here, divalent lipid-conjugated siRNAs are optimized for in situ binding to albumin to improve pharmacokinetics and tumor delivery. Systematic variation of the siRNA conjugate structure reveals that the location of the linker branching site dictates tendency toward albumin association versus self-assembly, while the lipid hydrophobicity and reversibility of albumin binding also contribute to siRNA intracellular delivery. The lead structure increases tumor siRNA accumulation 12-fold in orthotopic triple negative breast cancer (TNBC) tumors over the parent siRNA. This structure achieves approximately 80% silencing of the anti-apoptotic oncogene MCL1 and yields better survival outcomes in three TNBC models than an MCL-1 small molecule inhibitor. These studies provide new structure-function insights on siRNA-lipid conjugate structures that are intravenously injected, associate in situ with serum albumin, and improve pharmacokinetics and tumor treatment efficacy.

Engineering self-deliverable ribonucleoproteins for genome editing in the brain.

The delivery of CRISPR ribonucleoproteins (RNPs) for genome editing in vitro and in vivo has important advantages over other delivery methods, including reduced off-target and immunogenic effects. However, effective delivery of RNPs remains challenging in certain cell types due to low efficiency and cell toxicity. To address these issues, we engineer self-deliverable RNPs that can promote efficient cellular uptake and carry out robust genome editing without the need for helper materials or biomolecules. Screening of cell-penetrating peptides (CPPs) fused to CRISPR-Cas9 protein identifies potent constructs capable of efficient genome editing of neural progenitor cells. Further engineering of these fusion proteins establishes a C-terminal Cas9 fusion with three copies of A22p, a peptide derived from human semaphorin-3a, that exhibits substantially improved editing efficacy compared to other constructs. We find that self-deliverable Cas9 RNPs generate robust genome edits in clinically relevant genes when injected directly into the mouse striatum. Overall, self-deliverable Cas9 proteins provide a facile and effective platform for genome editing in vitro and in vivo.

Application of an Ultra-Low-Cost Passive Sampler for Light-Absorbing Carbon in Mongolia.

Low-cost, long-term measures of air pollution concentrations are often needed for epidemiological studies and policy analyses of household air pollution. The Washington passive sampler (WPS), an ultra-low-cost method for measuring the long-term average levels of light-absorbing carbon (LAC) air pollution, uses digital images to measure the changes in the reflectance of a passively exposed paper filter. A prior publication on WPS reported high precision and reproducibility. Here, we deployed three methods to each of 10 households in Ulaanbaatar, Mongolia: one PurpleAir for PM2.5; two ultrasonic personal aerosol samplers (UPAS) with quartz filters for the thermal-optical analysis of elemental carbon (EC); and two WPS for LAC. We compared multiple rounds of 4-week-average measurements. The analyses calibrating the LAC to the elemental carbon measurement suggest that 1 µg of EC/m3 corresponds to 62 PI/month (R2 = 0.83). The EC-LAC calibration curve indicates an accuracy (root-mean-square error) of 3.1 µg of EC/m3, or ~21% of the average elemental carbon concentration. The RMSE values observed here for the WPS are comparable to the reported accuracy levels for other methods, including reference methods. Based on the precision and accuracy results shown here, as well as the increased simplicity of deployment, the WPS may merit further consideration for studying air quality in homes that use solid fuels.

Engineering self-deliverable ribonucleoproteins for genome editing in the brain.

The delivery of CRISPR ribonucleoproteins (RNPs) for genome editing in vitro and in vivo has important advantages over other delivery methods, including reduced off-target and immunogenic effects 1 . However, effective delivery of RNPs remains challenging in certain cell types due to low efficiency and cell toxicity. To address these issues, we engineered self-deliverable RNPs that can promote efficient cellular uptake and carry out robust genome editing without the need for helper materials or biomolecules. Screening of cell-penetrating peptides (CPPs) fused to CRISPR-Cas9 protein identified potent constructs capable of efficient genome editing of neural progenitor cells. Further engineering of these fusion proteins identified a C-terminal Cas9 fusion with three copies of A22p, a peptide derived from human semaphorin-3a, that exhibited substantially improved editing efficacy compared to other constructs. We found that self-deliverable Cas9 RNPs generated robust genome edits in clinically relevant genes when injected directly into the mouse striatum. Overall, self-deliverable Cas9 proteins provide a facile and effective platform for genome editing in vitro and in vivo .

Deriving Novel Quaternary Ammonium Compound Disinfectant Scaffolds from a Natural Product: Mechanistic Insights of the Quaternization of Ianthelliformisamine C.

In the search for novel quaternary ammonium compound (QAC) disinfectants that can evade bacterial resistance, we turned to natural products as a source of inspiration. Herein we used natural product ianthelliformisamine C as a scaffold to design a small library of QACs. We first synthesized ianthelliformisamine C via an amide coupling that allowed for facile purification without the need for protecting groups. We then alkylated and quaternized the internal amines to yield four novel QACs, but all but one demonstrated no antibacterial activity against the tested strains. Using a combination of membrane depolarization and permeabilization assays, we were able to demonstrate that ianthelliformisamine C and the active QAC analog enact cell death via membrane permeabilization, contrary to prior reports on ianthelliformisamine C's mechanism of action.

Genome editing in the mouse brain with minimally immunogenic Cas9 RNPs.

Transient delivery of CRISPR-Cas9 ribonucleoproteins (RNPs) into the central nervous system (CNS) for therapeutic genome editing could avoid limitations of viral vector-based delivery including cargo capacity, immunogenicity, and cost. Here, we tested the ability of cell-penetrant Cas9 RNPs to edit the mouse striatum when introduced using a convection-enhanced delivery system. These transient Cas9 RNPs showed comparable editing of neurons and reduced adaptive immune responses relative to one formulation of Cas9 delivered using AAV serotype 9. The production of ultra-low endotoxin Cas9 protein manufactured at scale further improved innate immunity. We conclude that injection-based delivery of minimally immunogenic CRISPR genome editing RNPs into the CNS provides a valuable alternative to virus-mediated genome editing.

An updated systematic review and meta-analysis on portable air cleaners and blood pressure: Recommendations for users and manufacturers.

Fine particulate matter (PM2.5) air pollution is a leading contributor to the global burden of cardiovascular disease (CVD). One important underlying mechanism is an increase in blood pressure (BP). A growing number of studies have reported a beneficial effect of portable air cleaners (PACs) on systolic and diastolic BP; SBP and DBP. We conducted an updated systematic review and meta-analysis of studies using true versus sham mode filtration reporting the effects on BP. Of 214 articles identified up to February 5, 2023, seventeen (from China, USA, Canada, South Korea and Denmark) enrolling approximately 880 participants (484 female) met the inclusion criteria for meta-analyses. Aside from studies conducted in China, research on PACs and BP has been conducted in relatively low pollution settings. Mean indoor PM2.5 concentrations during the active and sham mode purification were 15.9 and 41.2 µg/m3, respectively. The mean efficiency of PACs against indoor PM2.5 was 59.8 % (ranging from 23 % to 82 %). True mode filtration was associated with a pooled mean difference of - 2.35 mmHg (95 % confidence interval [CI]: - 4.5, - 0.2) and - 0.81 mmHg (95 % CI: - 1.86, 0.24) in SBP and DBP, respectively. After removing the studies with high risk of bias, the magnitude of the pooled benefits on SBP and DBP increased to - 3.62 mmHg (95 % CI: - 6.69, - 0.56) and - 1.35 mmHg (95 % CI: - 2.29, - 0.41), respectively. However, there are several barriers to the use of PACs, specifically in low- and middle-income countries (LMICs), such as the initial purchase cost and filter replacements. There may be several avenues to help overcome these economic burdens and improve cost effectiveness, such as implementing government or other subsidized programs to distribute PACs targeting vulnerable and higher-risk individuals. We propose that environmental health researchers and healthcare providers should be better trained to educate the public regarding the use of PACs to reduce the impacts of PM2.5 on cardiometabolic diseases globally.

Total Synthesis and Biological Investigation of Mindapyrroles A and B.

In the search for antibacterial compounds that can overcome drug resistant species, molecules that enact novel or polypharmacological mechanisms of action (MoA) are needed. As a preliminary foray into molecules of this background, the total synthesis of mindapyrroles A and B was undertaken leveraging a biomimetic approach. Following their synthesis, they and their monomer pyoluteorin were tested against a range of pathogenic bacteria in minimum inhibitory concentration assays to confirm their activity. These molecules were then tested for their ability to disrupt membrane potential in S. aureus. Our findings indicate that pyoluteorin acts as a protonophore but the mindapyrroles do not. This work encapsulates the first total synthesis of mindapyrrole B and the second total synthesis of mindapyrrole A in 11 % and 30 % overall yields, respectively. It also provides insights into the antibacterial properties and different MoAs between the monomer and dimers.

Who benefits most from a prenatal HEPA filter air cleaner intervention on childhood cognitive development? The UGAAR randomized controlled trial.

BACKGROUND: Air pollution exposure during pregnancy affects children's brain function. Maternal stress and nutrition, socioeconomic status, and the child's sex may modify this relationship. OBJECTIVE: To identify characteristics of children with the largest increases in full-scale IQ (FSIQ) after their mothers used HEPA filter air cleaners during pregnancy. METHODS: In this randomized controlled trial we randomly assigned women to receive 1-2 air cleaners or no air cleaners during pregnancy. We analyzed maternal hair samples for cortisol and dehydroepiandrosterone (DHEA). When the children were 48 months old, we measured FSIQ with the Wechsler Preschool and Primary Scale of Intelligence. We evaluated ten potential modifiers of the intervention-FSIQ relationship using interaction terms in separate regression models. To account for correlations between modifiers, we also used a single regression model containing main effects and intervention x modifier terms for all potential modifiers. RESULTS: Among 242 mother-child dyads with complete data, the intervention was associated with a 2.3-point increase (95% CI: -1.5, 6.0 points) in mean FSIQ. The intervention improved mean FSIQ among children of mothers in the bottom (5.4 points; 95% CI: -0.8, 11.5) and top (6.1 points; 95% CI: 0.5, 11.8) cortisol tertiles, but not among those whose mothers were in the middle tertile. The largest between-group difference in the intervention's effect was a 7.5-point (95% CI: -0.7, 15.7) larger increase in mean FSIQ among children whose mothers did not take vitamins than among children whose mothers did take vitamins (interaction p-value = 0.07). We also observed larger benefits among children whose mothers did not complete university, and those with lower hair DHEA concentrations, hair cortisol concentrations outside the middle tertile, or more perceived stress. CONCLUSION: The benefits of reducing air pollution during pregnancy on brain development may be greatest for children whose mothers who do not take vitamins, experience more stress, or have less education.

Structural Optimization of siRNA Conjugates for Albumin Binding Achieves Effective MCL1-Targeted Cancer Therapy.

The high potential for therapeutic application of siRNAs to silence traditionally undruggable oncogenic drivers remains largely untapped due to the challenges of tumor cell delivery. Here, siRNAs were optimized for in situ binding to albumin through C18 lipid modifications to improve pharmacokinetics and tumor delivery. Systematic variation of siRNA conjugates revealed a lead structure with divalent C18 lipids each linked through three repeats of hexaethylene glycol connected by phosphorothioate bonds. Importantly, we discovered that locating the branch site of the divalent lipid structure proximally (adjacent to the RNA) rather than at a more distal site (after the linker segment) promotes association with albumin, while minimizing self-assembly and lipoprotein association. Comparison to higher albumin affinity (diacid) lipid variants and siRNA directly conjugated to albumin underscored the importance of conjugate hydrophobicity and reversibility of albumin binding for siRNA delivery and bioactivity in tumors. The lead conjugate increased tumor siRNA accumulation 12-fold in orthotopic mouse models of triple negative breast cancer over the parent siRNA. When applied for silencing of the anti-apoptotic oncogene MCL-1, this structure achieved approximately 80% MCL1 silencing in orthotopic breast tumors. Furthermore, application of the lead conjugate structure to target MCL1 yielded better survival outcomes in three independent, orthotopic, triple negative breast cancer models than an MCL1 small molecule inhibitor. These studies provide new structure-function insights on optimally leveraging siRNA-lipid conjugate structures that associate in situ with plasma albumin for molecular-targeted cancer therapy.

Recovery and Resilience in the Canal Community: Economic Impacts and Solutions During the COVID-19 Pandemic.

BACKGROUND: Public health pandemics, such as COVID-19, not only impact the physical health and wellbeing of communities but also often have far-reaching effects on their social, psychological, environmental, and economic welfare. The coronavirus pandemic has highlighted the significant inequities experienced among those who are Black, Indigenous, and People of Color (BIPOC), especially in the areas of housing instability, unemployment, and debt accrual. This study investigates the socioeconomic impacts of COVID-19 on residents of the Canal neighborhood ("The Canal"), a low-income Latinx community in Marin County, California. This study also uplifts mitigation strategies already underway to facilitate post-pandemic recovery efforts. METHODS: This study utilized a mixed-methods, community participatory approach in which community leaders from a local nonprofit, Canal Alliance, administered a survey assessing the impact of COVID-19 on Canal residents. Additionally, community stakeholders including nonprofits, small businesses, and public officials were interviewed, and their field notes were analyzed through exploratory open coding. RESULTS: On a macro level, the data showed that Canal residents were severely impacted by COVID-19 in the form of massive job loss (61.2% of respondents were unemployed or underemployed) as well as financial stress related to eviction, housing instability, and debt accrual (78.8% of respondents struggled to cover rent and often had to borrow money from friends and family). CONCLUSIONS: In spite of the severe socioeconomic impacts of COVID-19 on The Canal, there is a significant opportunity for recovery and growth because of an overwhelming investment by residents, community-based organizations, and public officials to support those who have been financially impacted by the pandemic. Some key areas of policy focus include expansion of affordable housing, pandemic-resistant workforce development, and restructuring of social services to increase accessibility. This report will explore recommendations related to strategic funding of community-based programs as well as short-term and long-term solutions for economic recovery.

Using Latent Profile Analysis to Identify Associations Between Gestational Chemical Mixtures and Child Neurodevelopment.

BACKGROUND: Unsupervised machine learning techniques have become increasingly popular for studying associations between gestational exposure mixtures and human health. Latent profile analysis is one method that has not been fully explored. METHODS: We estimated associations between gestational chemical mixtures and child neurodevelopment using latent profile analysis. Using data from the Maternal-Infant Research on Environmental Chemicals (MIREC) research platform, a longitudinal cohort of pregnant Canadian women and their children, we generated latent profiles from 27 gestational exposure biomarkers. We then examined the associations between these profiles and child Verbal IQ, Performance IQ, and Full-Scale IQ, measured with the Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III). We validated our findings using k-means clustering. RESULTS: Latent profile analysis detected five latent profiles of exposure: a reference profile containing 61% of the study participants, a high monoethyl phthalate (MEP) profile with moderately low persistent organic pollutants (POPs) containing 26%, a high POP profile containing 6%, a low POP profile containing 4%, and a smoking chemicals profile containing 3%. We observed negative associations between both the smoking chemicals and high MEP profiles and all IQ scores and between the high POP profile and Full-Scale and Verbal IQ scores. We also found a positive association between the low POP profile and Full-Scale and Performance IQ scores. All associations had wide 95% confidence intervals. CONCLUSIONS: Latent profile analysis is a promising technique for identifying patterns of chemical exposure and is worthy of further study for its use in examining complicated exposure mixtures.

Immigrant Legal Status among Essential Frontline Workers in the United States during the COVID-19 Pandemic Era.

Emerging evidence suggests that the COVID-19 pandemic has extracted a substantial toll on immigrant communities in the United States, due in part to increased potential risk of exposure for immigrants to COVID-19 in the workplace. In this article, we use federal guidance on which industries in the United States were designated essential during the COVID-19 pandemic, information about the ability to work remotely, and data from the 2019 American Community Survey to estimate the distribution of essential frontline workers by nativity and immigrant legal status. Central to our analysis is a proxy measure of working in the primary or secondary sector of the segmented labor market. Our results indicate that a larger proportion of foreign-born workers are essential frontline workers compared to native-born workers and that 70 percent of unauthorized immigrant workers are essential frontline workers. Disparities in essential frontline worker status are most pronounced for unauthorized immigrant workers and native-born workers in the secondary sector of the labor market. These results suggest that larger proportions of foreign-born workers, and especially unauthorized immigrant workers, face greater risk of potential exposure to COVID-19 in the workplace than native-born workers. Social determinants of health such as lack of access to health insurance and living in overcrowded housing indicate that unauthorized immigrant essential frontline workers may be more vulnerable to poor health outcomes related to COVID-19 than other groups of essential frontline workers. These findings help to provide a plausible explanation for why COVID-19 mortality rates for immigrants are higher than mortality rates for native-born residents.

Sensitivity analysis for live birth bias in the Ulaanbaatar Gestation and Air Pollution Research study.

The Ulaanbaatar Gestation and Air Pollution Research (UGAAR) study is a randomized controlled trial of the effects of portable high efficiency particulate air (HEPA) filter air cleaner use during pregnancy on fetal growth and child health outcomes. A challenge with the study is that the outcome variables cannot be measured in the absence of a live birth. Thus pregnancy loss is a competing event for the outcome variables that can obscure the intervention-outcome relationship. This phenomenon is called "live birth bias" in the epidemiological literature, and it is an example of selection bias due to adjustment for variables affected by previous exposure. Methods: In this investigation, we reanalyzed data from the UGAAR study and examined the impacts of the intervention on three health outcomes: preterm birth (PTB), birth weight, and full-scale IQ (FSIQ) measured with the Wechsler Preschool and Primary Scale of Intelligence III when children were four years old, while accounting for live birth bias. Specifically, we used a novel multiple imputation approach to simulate scenarios in which pregnancy losses had instead been born alive and experienced a range of health outcomes. Results: After accounting for live birth bias, the association between the intervention and PTB diminished. Additionally, the magnitude of intervention effect on birth weight and FSIQ increased. FSIQ was less sensitive to live birth bias than birth weight. Conclusion: We introduced a novel analysis approach to examine the role of live birth bias, and the findings will be useful in environmental epidemiology studies of birth cohorts.

LDL delivery of microbial small RNAs drives atherosclerosis through macrophage TLR8.

Macrophages present a spectrum of phenotypes that mediate both the pathogenesis and resolution of atherosclerotic lesions. Inflammatory macrophage phenotypes are pro-atherogenic, but the stimulatory factors that promote these phenotypes remain incompletely defined. Here we demonstrate that microbial small RNAs (msRNA) are enriched on low-density lipoprotein (LDL) and drive pro-inflammatory macrophage polarization and cytokine secretion via activation of the RNA sensor toll-like receptor 8 (TLR8). Removal of msRNA cargo during LDL re-constitution yields particles that readily promote sterol loading but fail to stimulate inflammatory activation. Competitive antagonism of TLR8 with non-targeting locked nucleic acids was found to prevent native LDL-induced macrophage polarization in vitro, and re-organize lesion macrophage phenotypes in vivo, as determined by single-cell RNA sequencing. Critically, this was associated with reduced disease burden in distinct mouse models of atherosclerosis. These results identify LDL-msRNA as instigators of atherosclerosis-associated inflammation and support alternative functions of LDL beyond cholesterol transport.

Energy cascades in donor-acceptor exciton-polaritons observed by ultrafast two-dimensional white-light spectroscopy.

Exciton-polaritons are hybrid states formed when molecular excitons are strongly coupled to photons trapped in an optical cavity. These systems exhibit many interesting, but not fully understood, phenomena. Here, we utilize ultrafast two-dimensional white-light spectroscopy to study donor-acceptor microcavities made from two different layers of semiconducting carbon nanotubes. We observe the delayed growth of a cross peak between the upper- and lower-polariton bands that is oftentimes obscured by Rabi contraction. We simulate the spectra and use Redfield theory to learn that energy cascades down a manifold of new electronic states created by intermolecular coupling and the two distinct bandgaps of the donor and acceptor. Energy most effectively enters the manifold when light-matter coupling is commensurate with the energy distribution of the manifold, contributing to long-range energy transfer. Our results broaden the understanding of energy transfer dynamics in exciton-polariton systems and provide evidence that long-range energy transfer benefits from moderately-coupled cavities.

Racial disparity in exposure to housing cost burden in the United States: 1980-2017.

This paper uses the Panel Study of Income Dynamics to analyze Black-White differences in housing cost burden exposure among renter households in the United States from 1980 to 2017, expanding understanding of this phenomenon in two respects. Specifically, we document how much this racial disparity changed among renters over almost four decades and identify how much factors associated with income or housing costs explain Black-White inequality in exposure to housing cost burden. For White households, the net contribution of household, neighborhood, and metropolitan covariates accounts for much of the change in the probability of housing cost burden over time. For Black households, however, the probability of experiencing housing cost burden continued to rise throughout the period of this study, even after controlling for household, neighborhood, and metropolitan covariates. This suggests that unobserved variables like racial discrimination, social networks or employment quality might explain the increasing disparity in cost burden among for Black and White households in the U.S.