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Competing Interests: Conflicts of interest Dr Tegge works on projects funded by Indivior. Drs Phillips and Prickett are investigators for Castle Biosciences. Drs Patel, Fagan, Quan, Johnson, Holliday, Grider, Rush, and Eikenberg have no conflicts of interest to declare.

Chimeric antigen receptor (CAR)-T cells have demonstrated clinical potential, but current receptors still need improvements to be successful against chronic HIV infection. In this study, we address some requirements of CAR motifs for strong surface expression of a novel anti-HIV CAR by evaluating important elements in the extracellular, hinge, and transmembrane (TM) domains. When combining a truncated CD4 extracellular domain and CD8α hinge/TM, the novel CAR did not express extracellularly but was detectable intracellularly. By shortening the CD8α hinge, CD4-CAR surface expression was partially recovered and addition of the LYC motif at the end of the CD8α TM fully recovered both intracellular and extracellular CAR expression. Mutation of LYC to TTA or TTC showed severe abrogation of CAR expression by flow cytometry and confocal microscopy. Additionally, we determined that CD4-CAR surface expression could be maximized by the removal of FQKAS motif at the junction of the extracellular domain and the hinge region. CD4-CAR surface expression also resulted in cytotoxic CAR T cell killing of HIV Env+ target cells. In this study, we identified elements that are crucial for optimal CAR surface expression, highlighting the need for structural analysis studies to establish fundamental guidelines of CAR designs., Competing Interests: The authors report no conflict of interest that may arise from this research., (Copyright: © 2024 Zenere et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Understanding the evolutionary forces that maintain phenotypic variation in ecologically relevant traits has long been one of the central goals of evolutionary ecology. While the maintenance of variation in plant defense is most often hypothesized to be due to trait trade-offs or spatiotemporal variation in herbivore abundance, the role that heterogeneous selective agents may play on the maintenance of variation in plant defense is less examined. Trichomes are hair-like appendages on plant surfaces that can defend against multiple damaging agents such as pathogens, herbivores, and UV radiation. It is currently unknown however if conflicting selection from such heterogeneous agents of damage may act to maintain the variation observed in trichome traits. Here, we assess whether trichomes serve as an herbicide resistance trait and how it coincides with the conventionally studied defensive strategy of herbivory resistance. In a series of experiments, we exposed the annual invasive velvetleaf (Abutilon theophrasti) to glyphosate (active ingredient in "Roundup") to investigate whether trichome traits (type and density) are linked to herbicide resistance and to test whether herbicide influences selection on plant trichomes. We found that an increased proportion of branched trichomes positively impacted herbicide resistance and chewing herbivory resistance. We also found evidence that glyphosate imposes positive selection on branched trichomes in velvetleaf. Overall, our results indicate that branched trichomes can contribute to both herbicide and herbivory resistance, serving a concordant rather than conflicting role to reduce plant injury. Our findings further suggest that novel anthropogenic agents of selection can alter the composition of plant defense traits, potentially impacting trait-mediated interactions among external stressors., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Society for the Study of Evolution (SSE). All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: On April 11th, 2023, the My Way Trading (MWT) recycling facility in Richmond, Indiana caught fire, mandating the evacuation of local residents and necessitating the U.S. Environmental Protection Agency (EPA) to conduct air monitoring. The EPA detected elevated levels of plastic combustion-related air pollutants, including hydrogen cyanide and benzene., Objective: We aimed to identify these and other volatile organic compounds (VOCs) present as well as to identify the potential hazard of each compound for various human health effects., Methods: To identify the VOCs, we conducted air monitoring at sites within and bordering the evacuation zone using proton transfer reaction mass spectrometry (PTR-MS) and non-targeted analysis (NTA). To facilitate risk assessment of the emitted VOCs, we used the EPA Hazard Comparison Dashboard., Results: We identified 46 VOCs, within and outside the evacuation zone, with average detection levels above local background levels measured in Middletown, OH. Levels of hydrogen cyanide and 4 other VOCs were at least 1.8-fold higher near the incidence site in comparison to background levels and displayed unique temporal and spatial patterns. The 46 VOCs identified had the highest hazardous potential for eye and skin irritation, with approximately 45% and 39%, respectively, of the VOCs classified as high and very high hazards for these endpoints. Notably, all detected VOC levels were below the hazard thresholds set for single VOC exposures; however, hazard thresholds for exposure to VOC mixtures are currently unclear., Impact: This study serves as a proof-of-concept that PTR-MS coupled with NTA can facilitate rapid identification and hazard assessment of VOCs emitted following anthropogenic disasters. Furthermore, it demonstrates that this approach may augment future disaster responses to quantify additional VOCs present in complex combustion mixtures., (© 2024. The Author(s).)

Purpose of Review: Recent advances in hematology-oncology have pioneered cell-mediated elimination of pathologic B-cell populations employing chimeric antigen receptor (CAR) T cells. In this review, we discuss recent adoption of CAR-T treatment for severe refractory autoimmune disease. We highlight unique aspects of the autoimmune model and review current clinical data regarding treatment of rheumatologic disease., Recent Findings: To date, several CAR-Ts are FDA approved for Multiple Myeloma and B-cell malignancies and have demonstrated extraordinary clinical responses in refractory disease. Realizing the central role of B-cells in certain autoimmune diseases, CAR-T is now being explored for achieving drug-free remission induction, and potentially cure, of several rheumatologic diseases. The largest experience to date in the field of autoimmunity, building off the University Hospital Erlangen groups' earlier success treating a single patient with CD19-CAR in severe refractory SLE, Mackensen et al. enrolled five patients in a compassionate use program. Following autologous CD19-CAR T infusion, they demonstrated drug-free clinical and laboratory remission for at least 12 months in all five patients, with reconstitution of B cells expressing a naïve phenotype., Summary: CAR-T treatment has shown striking drug-free responses in severe lupus and other autoimmune diseases, creating a need for further exploration and development., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Exposure to arsenic during childhood is associated with various adverse health conditions. However, little is known about the effect of arsenic exposure on vaccine-related humoral immunity in children. We analyzed data from the National Health and Nutrition Examination Survey (2003-2004 and 2009-2010) to study the relationship between urinary arsenic and measles antibody levels in 476 US children aged 6-11. Multivariable linear regression was used to evaluate the association, adjusting for cycle, age, race, body mass index (BMI), serum cotinine, poverty index ratio, and vitamin B12 and selenium intakes. Stratified analyses were conducted by sex and serum folate levels using the median as cutoff (18.7 ng/mL). The measles antibody concentrations in the 3rd and 4th quartiles were found to have significantly decreased by 28.5 % (95 % Confidence Interval (CI) -47.6, -2.28) and 36.8 % (95 % CI -50.2, -19.5), compared to the lowest quartile among boys with serum folate levels lower than 18.7 ng/ml. The serum measles antibody titers significantly decreased by 16.7 % (95 %CI -25.0, -7.61) for each doubling of creatinine-corrected urinary total inorganic arsenic concentrations in the same group. No associations were found in boys with high serum folate levels or in girls. Further prospective studies are needed to validate these findings and develop interventions to protect children from infectious diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Understanding how macroautophagy/autophagy contributes to tissue homeostasis is essential for understanding organismal health. The intestinal epithelium is an ideal model to define mechanisms that regulate tissue homeostasis because it houses well-defined populations of intestinal stem cells. Active intestinal stem cells (a-ISCs) are defined by their active cycling and self-renewal during homeostasis, which supports continual tissue turnover in vivo. In vitro, this is observed as long-term organoid formation capacity. A second population of stem cells, called "facultative intestinal stem cells" (f-ISCs), are defined by their ability to 1) survive tissue damage that depletes the injury-sensitive a-ISCs and 2) reenter the cell cycle to repopulate the a-ISC compartment and regenerate the epithelium. The prospective identification of f-ISCs has been challenging, as cells expressing markers of multiple differentiated lineages, particularly secretory lineages, appear to function as f-ISCs in diverse injury contexts. We evaluated cell age (defined as time elapsed after cell cycle exit) and autophagic state (marked by autophagic vesicle content) as molecular features that may be related to f-ISC capacity. We found that autophagic state, but not cell age, prospectively identifies f-ISCs within multiple lineages. As such, we describe autophagy as a lineage-agnostic marker of f-ISC capacity in the mammalian intestine.

On February 3, 2023, a train carrying numerous hazardous chemicals derailed in East Palestine, OH, spurring temporary evacuation of residents and a controlled burn of some of the hazardous cargo. Residents reported health symptoms, including headaches and respiratory, skin, and eye irritation. Initial data from U.S. Environmental Protection Agency (EPA) stationary air monitors indicated levels of potential concern for air toxics based on hazard quotient calculations. To provide complementary data, we conducted mobile air quality sampling on February 20 and 21 using proton transfer reaction-mass spectrometry. Measurements were taken at 1 s intervals along routes designed to sample both close to and farther from the derailment. Mobile air monitoring indicated that average concentrations of benzene, toluene, xylenes, and vinyl chloride were below minimal risk levels for intermediate and chronic exposures, similar to EPA stationary monitoring data. Levels of acrolein were high relative to those of other volatile organic compounds, with spatial analyses showing levels in East Palestine up to 6 times higher than the local rural background. Nontargeted analyses identified levels of additional unique compounds above background levels, some displaying spatiotemporal patterns similar to that of acrolein and others exhibiting distinct hot spots. These initial findings warrant follow-up mobile air quality monitoring to characterize longitudinal exposure and risk levels., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

The purpose of this study was to determine (1) whether pulmonary function is reduced, and airway reactivity is increased after recovery from COVID-19 in individuals who did not have severe illness, and (2) whether physical activity levels had any impact on pulmonary function or airway reactivity. An exploratory aim of the study was also to assess whether number of symptoms was associated with pulmonary function outcomes. The maximal flow volume loop was used to measure pulmonary function in individuals who had previously tested positive for COVID-19 (COV; n  = 20, 23.0 ± 5.4 years) and those who had not (CON; n  = 20, 23.7 ± 5.5 years) before and after a hypertonic saline challenge (HSC) designed to increase airway reactivity. Self-reported symptoms and physical activity levels (MET (min/week)) were collected to examine their correlation with pulmonary outcomes. There were no significant differences in any pulmonary function outcomes between the COV and CON groups before or after the HSC. There were also no associations between physical activity and pulmonary function outcomes. However, among participants who reported greater than four symptoms, there was a larger decline in forced expiratory volume in 1 s divided by forced vital capacity following HSC ( p  = 0.035). Pulmonary function and airway reactivity are not impacted after recovery from COVID-19 in young individuals; however, it appears that the number of symptoms reported may be associated with increased airway reactivity even after recovery in young adults who were not hospitalized with the virus.

Background: Dementia affects 6.5 million persons in the U.S., a number which is expected to double by 2060. More than half of persons with dementia die at home, creating an enormous burden for both patients and caregivers. However, there is a paucity of research on community-based palliative care interventions for advanced dementia., Objectives: The Indiana Palliative Excellence in Alzheimer's Care Efforts (IN-PEACE) study is a randomized trial to test the effectiveness of a collaborative predominantly telehealth home-based intervention for persons with advanced dementia residing in the community and their primary, informal caregivers. The primary aim is to determine if this palliative care focused supportive intervention is superior to usual care in reducing neuropsychiatric symptoms of dementia. Secondarily, intervention effects on other patient symptoms (e.g., pain), caregiver distress and depression, and emergency department (ED)/hospitalization events are examined., Methods: The study population consists of participant pairs comprising a person with dementia and their primary, informal caregiver. The person with dementia must be ≥65 years old, with a clinical diagnosis of moderate to severe dementia. A total of 201 demographically and socioeconomically diverse participant pairs have been randomized to the IN-PEACE care coordination intervention (n = 99) or usual care (n = 102). Outcome assessments are conducted at baseline, and quarterly for up to 2 years (3, 6, 9, 12, 15, 18, 21, and 24 months)., Discussion: IN-PEACE results will inform care for the large number of individuals with advanced dementia residing in the community and enable informal caregivers to provide effective home-based care., Trial Registration: clinicaltrials.gov Identifier: NCT03773757., Competing Interests: Declaration of Competing Interest None of the authors have any conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Chip-based, single-frequency and low phase-noise integrated photonic laser diodes emitting in the violet (412 nm) and blue (461 nm) regime are demonstrated. The GaN-based edge-emitting laser diodes were coupled to high-quality on-chip micro-resonators for optical feedback and mode selection resulting in laser self-injection locking with narrow emission linewidth. Multiple group III-nitride (III-N) based photonic integrated circuit chips with different waveguide designs including single-crystalline AlN, AlGaN, and GaN were developed and characterized. Single-frequency laser operation was demonstrated for all studied waveguide core materials. The best side-mode suppression ratio was determined to be ∼36 dB at 412 nm with a single-frequency laser emission linewidth of only 3.8 MHz at 461 nm. The performance metrics of this novel, to the best of our knowledge, type of laser suggest potential implementation in next-generation, portable quantum systems.

Background: Interactions between air pollution and infectious agents are increasingly recognized and critical to identify, especially to protect vulnerable populations. Pregnancy represents a vulnerable period for influenza infection and air pollution exposure, yet interactions during pregnancy remain unclear. Maternal exposure to ultrafine particles (UFPs, [Formula: see text] 100 nm diameter), a class of particulate matter ubiquitous in urban environments, elicits unique pulmonary immune responses. We hypothesized that UFP exposure during pregnancy would lead to aberrant immune responses to influenza enhancing infection severity., Results: Building from our well-characterized C57Bl/6N mouse model employing daily gestational UFP exposure from gestational day (GD) 0.5-13.5, we carried out a pilot study wherein pregnant dams were subsequently infected with Influenza A/Puerto Rico/8/1934 (PR8) on GD14.5. Findings indicate that PR8 infection caused decreased weight gain in filtered air (FA) and UFP-exposed groups. Co-exposure to UFPs and viral infection led to pronounced elevation in PR8 viral titer and reduced pulmonary inflammation, signifying potential suppression of innate and adaptive immune defenses. Pulmonary expression of the pro-viral factor sphingosine kinase 1 (Sphk1) and pro-inflammatory cytokine interleukin-1β (IL-1 [Formula: see text]) was significantly increased in pregnant mice exposed to UFPs and infected with PR8; expression correlated with higher viral titer., Conclusions: Results from our model provide initial insight into how maternal UFP exposure during pregnancy enhances respiratory viral infection risk. This model is an important first step in establishing future regulatory and clinical strategies for protecting pregnant women exposed to UFPs., (© 2023. The Author(s).)

Early COVID-19 pandemic data suggested racial/ethnic minority and low-income earning people bore the greatest burden of infection. Structural racism, the reinforcement of racial and ethnic discrimination via policy, provides a framework for understanding disparities in health outcomes like COVID-19 infection. Residential racial and economic segregation is one indicator of structural racism. Little attention has been paid to the relationship of infection to relative overall concentrations of risk (i.e., segregation of the most privileged from the most disadvantaged). We used ordinary least squares and geographically weighted regression models to evaluate the relationship between racial and economic segregation, measured by the Index of Concentration at the Extremes, and COVID-19 cases in Louisiana. We found a significant global association between racial segregation and cumulative COVID-19 case rate in Louisiana and variation across the state during the study period. The northwest and central regions exhibited a strong negative relationship indicating greater risk in areas with high concentrations of Black residents. On the other hand, the southeastern part of the state exhibited more neutral or positive relationships indicating greater risk in areas with high concentrations of White residents. Our findings that the relationship between racial segregation and COVID-19 cases varied within a state further support evidence that social and political determinants, not biological, drive racial disparities. Small area measures and measures of polarization provide localized information better suited to tailoring public health policy according to the dynamics of communities at the census tract level, which may lead to better health outcomes., (© 2022. W. Montague Cobb-NMA Health Institute.)

Background & Aims: Dyskeratosis congenita (DC) is a telomere biology disorder caused primarily by mutations in the DKC1 gene. Patients with DC and related telomeropathies resulting from premature telomere dysfunction experience multiorgan failure. In the liver, DC patients present with nodular hyperplasia, steatosis, inflammation, and cirrhosis. However, the mechanism responsible for telomere dysfunction-induced liver disease remains unclear., Methods: We used isogenic human induced pluripotent stem cells (iPSCs) harboring a causal DC mutation in DKC1 or a CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/Cas9)-corrected control allele to model DC liver pathologies. We differentiated these iPSCs into hepatocytes (HEPs) or hepatic stellate cells (HSCs) followed by generation of genotype-admixed hepatostellate organoids. Single-cell transcriptomics were applied to hepatostellate organoids to understand cell type-specific genotype-phenotype relationships., Results: Directed differentiation of iPSCs into HEPs and stellate cells and subsequent hepatostellate organoid formation revealed a dominant phenotype in the parenchyma, with DC HEPs becoming hyperplastic and also eliciting a pathogenic hyperplastic, proinflammatory response in stellate cells independent of stellate cell genotype. Pathogenic phenotypes in DKC1-mutant HEPs and hepatostellate organoids could be rescued via suppression of serine/threonine kinase AKT (protein kinase B) activity, a central regulator of MYC-driven hyperplasia downstream of DKC1 mutation., Conclusions: Isogenic iPSC-derived admixed hepatostellate organoids offer insight into the liver pathologies in telomeropathies and provide a framework for evaluating emerging therapies., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The intestinal epithelium exhibits a rapid and efficient regenerative response to injury. Emerging evidence supports a model where plasticity of differentiated cells, particularly those in the secretory lineages, contributes to epithelial regeneration upon ablation of injury-sensitive stem cells. However, such facultative stem cell activity is rare within secretory populations. Here, we ask whether specific functional properties predict facultative stem cell activity. We utilize in vivo labeling combined with ex vivo organoid formation assays to evaluate how cell age and autophagic state contribute to facultative stem cell activity within secretory lineages. Strikingly, we find that cell age (time elapsed since cell cycle exit) does not correlate with secretory cell plasticity. Instead, high autophagic vesicle content predicts plasticity and resistance to DNA damaging injury independently of cell lineage. Our findings indicate that autophagic status prior to injury serves as a lineage-agnostic marker for the prospective identification of facultative stem cells., (© 2022 The Authors.)

Linear porokeratosis is a rare variant of porokeratosis that is characterized by unilateral lesions along the lines of Blaschko. Like all variants of porokeratosis, linear porokeratosis is characterized by the histopathologic finding of cornoid lamellae bracketing the lesion. The underlying pathophysiology involves a two-hit post-zygotic knockdown of genes involved in mevalonate biosynthesis in embryonic keratinocytes. Although there is currently no standard or effective treatment, therapies targeted to rescue this pathway and restore keratinocyte cholesterol availability are promising. Presented here is a patient with a rare, extensive case of linear porokeratosis treated with compounded 2% lovastatin/2% cholesterol cream leading to partial resolution of the plaques.

Background: Behavioral, psychological, and physical symptoms are prevalent in advanced dementia, as well as major contributors to poor quality of life, health care costs, caregiver burden, and nursing home placement. Objectives: To determine the frequency and severity of symptoms in persons with advanced dementia living in the community, as well as the association between symptoms and satisfaction with care, and the identification of factors associated with symptom burden. Design: Baseline data from a clinical trial testing the effectiveness of collaborative care home-based management for patients with advanced dementia. Setting/Subjects: Two hundred and one patient-caregiver dyads from an urban area in the United States, who were still residing in the community. Measurements: Caregivers completed the Symptom Management in End-of-Life Dementia (SM-EOLD) and Satisfaction with Care in End-of-Life Dementia (SWC-EOLD) scales. Results: Patients' mean age was 83.1; 67.7% were women, and most were either White (50.2%) or African American (43.8%). Most (88.1%) had severe dementia (Functional Assessment Staging Tool [FAST] stage 6 or 7). SM-EOLD mean score was 29.3 (on 0-45 scale) and SWC-EOLD score was 32.6 (on 10-40 scale). Pain, agitation, anxiety, and resistiveness to care were present at least weekly in ≥40% of patients. Multivariable linear regression modeling showed that higher neuropsychiatric symptom severity (assessed by the Neuropsychiatric Inventory), increased caregiver strain, and higher medical comorbidity were all independently associated with increased symptom burden. Satisfaction with care was high and had only a modest correlation ( r  = 0.20) with symptom burden. Conclusions: Community-dwelling patients with advanced dementia and their caregivers may benefit from home-based palliative care interventions to identify and manage burdensome symptoms.

Exposure to particulate matter (PM) is associated with lower respiratory tract infections. The role of ultrafine particles (UFPs, ≤0.1 μm) in respiratory disease is not fully elucidated, especially in models of immunologically immature populations. To characterize the effects of maternal UFP exposure on neonatal infection, we exposed time-mated C57Bl/6n mice to filtered air or UFPs at a low dose (LD, ∼55 μg/m 3 ) and high dose (HD, ∼275 μg/m 3 ) throughout gestation. At 5 days of age, offspring were infected with a respiratory syncytial virus (RSV) strain known to mimic infant infection or sham control. Offspring body weights were significantly reduced in response to infection in the LD RSV group, particularly females. Pulmonary gene expression analysis demonstrated significantly increased levels of oxidative stress- and inflammation-related genes in HD-exposed male offspring in sham and RSV-infected groups. In males, the highest grade of inflammation was observed in the HD RSV group, whereas in females, the LD RSV group showed the most marked inflammation. Overall, findings highlight neonatal responses are dependent on offspring sex and maternal UFP dose. Importantly, infant RSV pathology may be enhanced following even low dose UFP exposure signifying the importance of preventing maternal exposure.

Background: The lack of publicly available and culturally relevant data sets on African American and bilingual/Spanish-speaking Hispanic adults' disease prevention and health promotion priorities presents a major challenge for researchers and developers who want to create and test personalized tools built on and aligned with those priorities. Personalization depends on prediction and performance data. A recommender system (RecSys) could predict the most culturally and personally relevant preventative health information and serve it to African American and Hispanic users via a novel smartphone app. However, early in a user's experience, a RecSys can face the "cold start problem" of serving untailored and irrelevant content before it learns user preferences. For underserved African American and Hispanic populations, who are consistently being served health content targeted toward the White majority, the cold start problem can become an example of algorithmic bias. To avoid this, a RecSys needs population-appropriate seed data aligned with the app's purposes. Crowdsourcing provides a means to generate population-appropriate seed data., Objective: Our objective was to identify and test a method to address the lack of culturally specific preventative personal health data and sidestep the type of algorithmic bias inherent in a RecSys not trained in the population of focus. We did this by collecting a large amount of data quickly and at low cost from members of the population of focus, thereby generating a novel data set based on prevention-focused, population-relevant health goals. We seeded our RecSys with data collected anonymously from self-identified Hispanic and self-identified non-Hispanic African American/Black adult respondents, using Amazon Mechanical Turk (MTurk)., Methods: MTurk provided the crowdsourcing platform for a web-based survey in which respondents completed a personal profile and a health information-seeking assessment, and provided data on family health history and personal health history. Respondents then selected their top 3 health goals related to preventable health conditions, and for each goal, reviewed and rated the top 3 information returns by importance, personal utility, whether the item should be added to their personal health library, and their satisfaction with the quality of the information returned. This paper reports the article ratings because our intent was to assess the benefits of crowdsourcing to seed a RecSys. The analysis of the data from health goals will be reported in future papers., Results: The MTurk crowdsourcing approach generated 985 valid responses from 485 (49%) self-identified Hispanic and 500 (51%) self-identified non-Hispanic African American adults over the course of only 64 days at a cost of US $6.74 per respondent. Respondents rated 92 unique articles to inform the RecSys., Conclusions: Researchers have options such as MTurk as a quick, low-cost means to avoid the cold start problem for algorithms and to sidestep bias and low relevance for an intended population of app users. Seeding a RecSys with responses from people like the intended users allows for the development of a digital health tool that can recommend information to users based on similar demography, health goals, and health history. This approach minimizes the potential, initial gaps in algorithm performance; allows for quicker algorithm refinement in use; and may deliver a better user experience to individuals seeking preventative health information to improve health and achieve health goals., (©Neil Jay Sehgal, Shuo Huang, Neil Mason Johnson, John Dickerson, Devlon Jackson, Cynthia Baur. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 21.06.2022.)

The sonic hedgehog (SHH) inhibitors vismodegib and sonidegib are the only 2 first-line systemic medications approved for the treatment of locally aggressive basal cell carcinoma (BCC). Vismodegib is the only SHH inhibitor approved for metastatic BCC. Cemiplimab, an immune checkpoint inhibitor (ICI), is now an approved second-line therapy for locally advanced or metastatic BCC. Efficacy and adverse effect profiles of vismodegib and sonidegib appear comparable, although head-to-head clinical trials have not been conducted. Despite the remarkable efficacy demonstrated by the 2 SHH inhibitors, adverse effects are common and often lead to treatment discontinuation. Alternative dosing schedules may help to manage these side effects, with recent approval of dose interruptions of up to 8 weeks. Given the high rate of recurrence and emerging concern regarding drug resistance, maintenance dosing regimens and potential synergism with other treatment modalities, such as radiotherapy or antifungal therapy, should be further explored. The use of SHH inhibitors in the neoadjuvant setting also is warranted, as it may allow for surgical management of previously inoperable cases of BCC.

Background: Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with adverse health effects in children. Valid exposure assessment methods with accurate spatial and temporal resolution across pregnancy is a critical need for advancing environmental health studies., Objective: The objective of this study was to quantify maternal PAH exposure in pregnant women residing in McAllen, Texas where the prematurity rate and childhood asthma prevalence rates are high. A secondary objective was to compare PAH levels in silicone wristbands deployed as passive samplers with concentrations measured using standardized active air-sampling techniques., Methods: Participants carried a backpack that contained air-sampling equipment (i.e., filter and XAD sorbent) and a silicone wristband (i.e., passive sampler) for three nonconsecutive 24-h periods. Filters, XAD tubes, and wristbands were analyzed for PAHs., Results: The median level of exposure for the sum of 16 PAHs measured via active sampling over 24 h was 5.54 ng/m 3 (filters) and 43.82 ng/m 3 (XADs). The median level measured in wristbands (WB) was 586.82 ng/band. Concentrations of the PAH compounds varied across sampling matrix type. Phenanthrene and fluorene were consistently measured for all participants and in all matrix types. Eight additional volatile PAHs were measured in XADs and WBs; the median level of exposure for the sum of these eight PAHs was 342.98 ng/m 3 (XADs) and 632.27 ng/band. The silicone wristbands (WB) and XAD sorbents bound 1-methynaphthalyne, 2-methylnaphthalene, biphenyl following similar patterns of detection., Significance: Since prior studies indicate linkages between PAH exposure and adverse health outcomes in children at the PAH levels detected in our study, further investigation on the associated health effects is needed. Data reflect the ability of silicone wristbands to bind smaller molecular weight, semivolatile PAHs similar to XAD resin. Application of wristbands as passive samplers may be useful in studies evaluating semivolatile PAHs., (© 2021. The Author(s).)

Exposure to ultrafine particles (UFPs, PM 0.1 ) during pregnancy triggers placental oxidative stress and inflammation, similar to fine PM (PM 2.5 ). The Nrf2 gene encodes a redox-sensitive transcription factor that is a major regulator of antioxidant and anti-inflammatory responses. Disruption of NRF2 is known to substantially enhance PM 2.5 -driven oxidant and inflammatory responses; however, specific responses to UFP exposure, especially during critical windows of susceptibility such as pregnancy, are not fully characterized; To investigate the role of NRF2 in regulating maternal antioxidant defenses and placental responses to UFP exposure, wildtype (WT) and Nrf2 -/ - pregnant mice were exposed to either low dose (LD, 100 µg/m 3 ) or high dose (HD, 500 µg/m 3 ) UFP mixture or filtered air (FA, control) throughout gestation; Nrf2 -/ - HD-exposed female offspring exhibited significantly reduced fetal and placental weights. Placental morphology changes appeared most pronounced in Nrf2 -/ - LD-exposed offspring of both sexes. Glutathione (GSH) redox analysis revealed significant increases in the GSH/GSSG ratio (reduced/oxidized) in WT female placental tissue exposed to HD in comparison with Nrf2 -/ - HD-exposed mice. The expression of inflammatory cytokine genes ( Il1β,   Tnfα ) was significantly increased in Nrf2 -/ - placentas from male and female offspring across all exposure groups. Genes related to bile acid metabolism and transport were differentially altered in Nrf2 -/ - mice across sex and exposure groups. Notably, the group with the most marked phenotypic effects ( Nrf2 -/ - HD-exposed females) corresponded to significantly higher placental Apoa1 and Apob expression suggesting a link between placental lipid transport and NRF2 in response to high dose UFP exposure; Disruption of NRF2 exacerbates adverse developmental outcomes in response to high dose UFP exposure in female offspring. Morphological effects in placenta from male and female offspring exposed to low dose UFPs also signify the importance of NRF2 in maternal-fetal response to UFPs.

Early life exposure to particulate matter (PM) air pollution negatively impacts neonatal health. The underlying mechanisms following prenatal exposure, particularly to ultrafine particles (UFP, diameter ≤ 0.1 μm), are not fully understood; To evaluate the role of Nrf2 in response to in utero UFP exposure, we exposed time-mated Nrf2 -deficient ( Nrf2 -/ - ) or wildtype (WT) mice to filtered air (FA) or 100 μg/m 3 ultrafine PM daily throughout pregnancy. Offspring were evaluated for pulmonary immunophenotypes and pulmonary/systemic oxidative stress on postnatal day 5, a timepoint at which we previously demonstrated viral respiratory infection susceptibility; Nrf2 -/ - offspring exposed to FA had significantly lower average body weights compared to FA-exposed WT pups. Moreover, PM-exposed Nrf2 -/ - offspring weighed significantly less than PM-exposed WT pups. Notably, PM-exposed Nrf2 -/ - offspring showed a decreased pulmonary Th1/Th2 ratio, indicating a Th2 bias. Th17 cells were increased in FA-exposed Nrf2 -/ - neonates yet decreased in PM-exposed Nrf2 -/ - neonates. Analysis of oxidative stress-related genes in lung and oxidative stress biomarkers in liver tissues did not vary significantly across exposure groups or genotypes. Collectively, these findings indicate that the lack of Nrf2 causes growth inhibitory effects in general and in response to gestational UFP exposure. Prenatal UFP exposure skews CD4+ T lymphocyte differentiation toward Th2 in neonates lacking Nrf2 , signifying its importance in maternal exposure and infant immune responses.

Lithium-ion batteries (LIBs) are being used in locations and applications never imagined when they were first conceived. To enable this broad range of applications, it has become necessary for LIBs to be stable to an ever broader range of conditions, including temperature and energy. Unfortunately, while negative electrodes have received a great deal of focus in electrolyte development, stabilization of positive electrodes remains an elusive target. Here, we report a novel additive that shows the ability to protect positive electrodes against elevated temperatures and voltages. This additive can be used in small quantities, and its targeted behavior allows it to remain functional in complex electrolyte packages. This can prove an effective approach to targeting specific aspects of cell performance.

Particulate matter (PM) causes adverse developmental outcomes following prenatal exposure, but the underlying biological mechanisms remain uncertain. Here we elucidate the effects of diesel exhaust ultrafine particle (UFP) exposure during pregnancy on placental and fetal development. Time-mated C57Bl/6n mice were gestationally exposed to UFPs at a low dose (LD, 100 µg/m3) or high dose (HD, 500 µg/m3) for 6 h daily. Phenotypic effects on fetuses and placental morphology at gestational day (GD) of 18.5 were evaluated, and RNA sequencing was characterized for transcriptomic changes in placental tissue from male and female offspring. A significant decrease in average placental weights and crown to rump lengths was observed in female offspring in the LD exposure group. Gestational UFP exposure altered placental morphology in a dose- and sex-specific manner. Average female decidua areas were significantly greater in the LD and HD groups. Maternal lacunae mean areas were increased in the female LD group, whereas fetal blood vessel mean areas were significantly greater in the male LD and HD groups. RNA sequencing indicated several disturbed cellular functions related to lipid metabolism, which were most pronounced in the LD group and especially in female placental tissue. Our findings demonstrate the vulnerability of offspring exposed to UFPs during pregnancy, highlighting sex-specific effects and emphasizing the importance of mitigating PM exposure to prevent adverse health outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Unprecedented inland precipitation and catastrophic flooding associated with Hurricane Harvey potentially redistributed contaminants from industrial sites and transportation infrastructure to recreational areas that make up networks of green infrastructure, creeks, and waterways used for flood control throughout the Greater Houston Area. Sediment samples were collected in parks located near the Buffalo Bayou watershed 1 week after Hurricane Harvey made landfall and again 7 weeks later. Total concentrations of the U.S. Environmental Protection Agency's (EPA's) 16 priority polycyclic aromatic hydrocarbons (PAHs) were measured in each sample at both time points. Diagnostic ratios were calculated to improve understanding of potential sources of PAHs after flooding. Diagnostic ratios suggest vehicular traffic to be a potential source for PAHs in parks. Although the concentrations of PAHs in all samples were below EPA actionable levels, given that no background values were available for comparison, it is difficult to quantify the impact flooding from Hurricane Harvey had on PAH concentrations in Houston parks. However, given the high frequency of flooding in Houston, and the concentration of industrial facilities and transportation infrastructure adjacent to recreation areas, these data demonstrate that PAHs were still present after unprecedented flooding. This study may also serve as a baseline for future efforts to understand the environmental health impacts of disasters., Competing Interests: No competing financial interests exist., (Copyright 2021, Mary Ann Liebert, Inc., publishers.)

Background: Particulate matter (PM), a major component of ambient air pollution, accounts for a substantial burden of diseases and fatality worldwide. Maternal exposure to PM during pregnancy is particularly harmful to children's health since this is a phase of rapid human growth and development., Method: In this review, we synthesize the scientific evidence on adverse health outcomes in children following prenatal exposure to the smallest toxic components, fine (PM 2.5 ) and ultrafine (PM 0.1 ) PM. We highlight the established and emerging findings from epidemiologic studies and experimental models., Results: Maternal exposure to fine and ultrafine PM directly and indirectly yields numerous adverse birth outcomes and impacts on children's respiratory systems, immune status, brain development, and cardiometabolic health. The biological mechanisms underlying adverse effects include direct placental translocation of ultrafine particles, placental and systemic maternal oxidative stress and inflammation elicited by both fine and ultrafine PM, epigenetic changes, and potential endocrine effects that influence long-term health., Conclusion: Policies to reduce maternal exposure and health consequences in children should be a high priority. PM 2.5 levels are regulated, yet it is recognized that minority and low socioeconomic status groups experience disproportionate exposures. Moreover, PM 0.1 levels are not routinely measured or currently regulated. Consequently, preventive strategies that inform neighborhood/regional planning and clinical/nutritional recommendations are needed to mitigate maternal exposure and ultimately protect children's health., (© 2021. The Author(s).)

Three gene therapy strategies have received US Food and Drug Administration (FDA) approval; one includes HIV-1-based lentiviral vectors. These vectors incorporate features to provide long-term gene transfer and expression while minimizing generation of a replication-competent virus or pathogenicity. Importantly, the coding regions of viral proteins were deleted, and the cis-acting regulatory elements were retained. With the use of representative vectors developed for clinical/commercial applications, we compared the vector backbone sequences to the initial sources of the HIV-1. All vectors included required elements: 5' long terminal repeat (LTR) through the Ψ packaging signal, central polypurine tract/chain termination sequence (cPPT/CTS), Rev responsive element (RRE), and 3' LTR, including a poly(A) signal. The Ψ signaling sequence demonstrated the greatest similarity between all vectors with only minor changes. The 3' LTR was the most divergent sequence with a range of deletions. The RRE length varied between vectors. Phylogenetic analysis of the cPPT/CTS indicated multiple sources, perhaps because of its later inclusion into lentiviral vector systems, whereas other regions revealed node clusters around the HIV-1 reference genomes HXB2 and NL4-3. We examine the function of each region in a lentiviral vector, the molecular differences between vectors, and where optimization may guide development of the lentiviral delivery systems., Competing Interests: The content is solely the responsibility of the authors and does not necessarily represent the official views of the supporting agencies. The authors declare no competing interests., (© 2021 The Author(s).)

Low birth weight is an important risk factor for many co-morbidities both in early life as well as in adulthood. Numerous studies report associations between prenatal exposure to particulate matter (PM) air pollution and low birth weight. Previous systematic reviews and meta-analyses report varying effect sizes and significant heterogeneity between studies, but did not systematically evaluate the quality of individual studies or the overall body of evidence. We conducted a new systematic review to determine how prenatal exposure to PM 2.5 , PM 10 , and coarse PM (PM 2.5-10 ) by trimester and across pregnancy affects infant birth weight. Using the Navigation Guide methodology, we developed and applied a systematic review protocol [CRD42017058805] that included a comprehensive search of the epidemiological literature, risk of bias (ROB) determination, meta-analysis, and evidence evaluation, all using pre-established criteria. In total, 53 studies met our inclusion criteria, which included evaluation of birth weight as a continuous variable. For PM 2.5 and PM 10 , we restricted meta-analyses to studies determined overall as "low" or "probably low" ROB; none of the studies evaluating coarse PM were rated as "low" or "probably low" risk of bias, so all studies were used. For PM 2.5 , we observed that for every 10 µg/m 3 increase in exposure to PM 2.5 in the 2nd or 3rd trimester, respectively, there was an associated 5.69 g decrease (I 2 : 68%, 95% CI: -10.58, -0.79) or 10.67 g decrease in birth weight (I 2 : 84%, 95% CI: -20.91, -0.43). Over the entire pregnancy, for every 10 µg/m 3 increase in PM 2.5 exposure, there was an associated 27.55 g decrease in birth weight (I 2 : 94%, 95% CI: -48.45, -6.65). However, the quality of evidence for PM 2.5 was rated as "low" due to imprecision and/or unexplained heterogeneity among different studies. For PM 10 , we observed that for every 10 µg/m 3 increase in exposure in the 3rd trimester or the entire pregnancy, there was a 6.57 g decrease (I 2 : 0%, 95% CI: -10.66, -2.48) or 8.65 g decrease in birth weight (I 2 : 84%, 95% CI: -16.83, -0.48), respectively. The quality of evidence for PM 10 was rated as "moderate," as heterogeneity was either absent or could be explained. The quality of evidence for coarse PM was rated as very low/low (for risk of bias and imprecision). Overall, while evidence for PM 2.5 and course PM was inadequate primarily due to heterogeneity and risk of bias, respectively, our results support the existence of an inverse association between prenatal PM 10 exposure and low birth weight., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

MTORC1 activity is critical for tissue regeneration in multiple organs and contexts. In this issue of Developmental Cell, Miao et al. describe upstream regulators of mTORC1 activity which promote paligenosis, a process where mature cells de-differentiate to acquire stem cell activity in the face of injury., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Treatment of verruca plana is often challenging, and multiple treatment modalities, both pharmacologic and destructive, are frequently necessary to clear lesions. We report a case of a 16-year-old girl with a 2-year history of extensive verruca plana of the forehead, temples, and upper periorbital skin, recalcitrant to monotherapy with topical tretinoin cream, that completely resolved following first dose of nonavalent human papillomavirus (HPV) immunization., (© 2020 Wiley Periodicals LLC.)

It is now clear that parental histories of drug use, toxicant exposure, and social stress all have a significant influence on the health and development of the next generation. However, the ability of epigenetic parental life memories to interact with subsequent gestational exposures and cumulatively modify the developmental trajectory of the offspring remains an unexplored perspective in toxicology. Studies from our laboratory have identified male-specific postnatal growth restriction in a mouse model of chronic, preconception paternal alcohol exposure. The goal of the current study was to determine if paternal alcohol use, before conception, could modify the susceptibility of the offspring to a completely separate exposure encountered by the mother during pregnancy. In independent experiments, we previously identified altered developmental programming and increased markers of severe asthma induced by gestational exposure to particulate air pollution. In this study, male mice were exposed to either the control or alcohol preconception treatments, then mated to naive females, which we subsequently exposed to an ultrafine mixture of particulate matter via inhalation. Individually, neither preconception paternal drinking nor gestational exposures to particulate air pollution impacted the postnatal growth of female offspring. However, when both exposures were combined, females displayed a 30% reduction in weight gain. Unexpectedly, this exposure paradigm resulted in a dramatic postnatal increase in litter loss due to maternal cannibalism, which prevented additional measures of offspring health. These preliminary studies provide evidence of a complex interplay between preconception life history and intrauterine environmental factors in the control of postnatal growth., (© The Author(s) 2020. Published by Oxford University Press.)

Solids in the interstellar medium consist of an intimate mixture of silicate and carbonaceous grains. Because 99% of silicates in meteorites were reprocessed at high temperatures in the inner regions of the Solar Nebula, we propose that similar levels of heating of carbonaceous materials in the oxygen-rich Solar Nebula would have converted nearly all carbon in dust and grain coatings to CO. We discuss catalytic experiments on a variety of grain surfaces that not only produce gas phase species such as CH 4 , C 2 H 6 , C 6 H 6 , C 6 H 5 OH, or CH 3 CN, but also produce carbonaceous solids and fibers that would be much more readily incorporated into growing planetesimals. CH 4 and other more volatile products of these surface-mediated reactions were likely transported outwards along with chondrule fragments and small Calcium Aluminum-rich Inclusions (CAIs) to enhance the organic content in the outer regions of the nebula where comets formed. Carbonaceous fibers formed on the surfaces of refractory oxides may have significantly improved the aggregation efficiency of chondrules and CAIs. Carbonaceous fibers incorporated into chondritic parent bodies might have served as the carbon source for the generation of more complex organic species during thermal or hydrous metamorphic processes on the evolving asteroid.

Adult mammalian wounds, with rare exception, heal with fibrotic scars that severely disrupt tissue architecture and function. Regenerative medicine seeks methods to avoid scar formation and restore the original tissue structures. We show in three adult mouse models that pharmacologic activation of the nociceptor TRPA1 on cutaneous sensory neurons reduces scar formation and can also promote tissue regeneration. Local activation of TRPA1 induces tissue regeneration on distant untreated areas of injury, demonstrating a systemic effect. Activated TRPA1 stimulates local production of interleukin-23 (IL-23) by dermal dendritic cells, leading to activation of circulating dermal IL-17-producing γδ T cells. Genetic ablation of TRPA1, IL-23, dermal dendritic cells, or γδ T cells prevents TRPA1-mediated tissue regeneration. These results reveal a cutaneous neuroimmune-regeneration cascade triggered by topical TRPA1 activators that promotes adult mammalian tissue regeneration, presenting a new avenue for research and development of therapies for wounds and scars., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)