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Sequestration of Plasmodium parasites in the placental vasculature causes increased morbidity and mortality in pregnant compared to non-pregnant patients in malaria- endemic regions. In this study, outbred pregnant CD1 mice with semi allogeneic fetuses were infected with transgenic Plasmodium berghei or mock-inoculated by mosquito bite at either embryonic day (E) 6 (first trimester-equivalent) or 10 (second trimester- equivalent) and compared with non-pregnant females. P. berghei -infected mosquitoes had greater biting avidity for E10 dams than uninfected mosquitoes, which was not apparent for E6 dams nor non-pregnant females. Infected E10 dams had greater numbers of parasites than E6 dams in the uterus and spleen, but not in the blood or liver. While parasites were found in placentas, no parasites were present in fetuses. Maternal infection at E6 caused greater maternal morbidity, with greater rates of fetal reabsorption and stillbirths than at E10. Infection at E10 caused adverse offspring outcomes, including growth restriction. To identify possible mechanisms of adverse offspring outcomes, E10 dams were euthanized during peak parasitemia (8 days post infection), and outcomes were compared with mock-infected dams. P. berghei caused significant systemic maternal immune activation with elevated circulating lymphocytes, eosinophils, and neutrophils and splenic cytokine concentrations. P. berghei infection at E10 increased corticosterone and decreased progesterone concentrations, which could contribute to adverse perinatal outcomes through immunomodulation. There were limited changes in the maternal fecal microbiome after P. berghei infection. Mosquito bite infection of outbred dams with P. berghei causes placental malaria and provides a novel, tractable model to investigate therapeutic treatments.

Bullying is a persistent social and behavioral problem in the United States. Bullying victimization and perpetration are linked to a host of negative physical, social, and emotional outcomes. Research suggests that a key risk factor for bullying behaviors is adverse childhood experiences (ACEs). On the other hand, positive childhood experiences (PCEs) may counter some of the negative effects of ACEs. This study (a) assesses the independent effects of ACEs and PCEs on adolescent bullying victimization and perpetration, and (b) examines whether ACEs and PCEs interact to affect bullying victimization and perpetration.We use data from the 2020 to 2021 National Survey of Children's Health, a nationally representative survey of children ages 0 to 17 in the United States. The analytic sample was limited to children who were 6 years old or older at the time of the survey ( N  = 60,809). Using caregiver reports of bullying victimization and perpetration, we created a cumulative ACEs scale comprised of 10 items and a cumulative PCEs scale comprised of eight measures. We then estimated a set of logistic regression models to predict bullying behaviors. The results showed that ACEs are associated with a higher likelihood of both bullying victimization and perpetration. Although PCEs have a slight mitigating effect, ACEs and PCEs interact such that even in the presence of PCEs, children with many ACEs still have a higher likelihood of both bullying victimization and perpetration. This highlights the considerable impact of ACEs on bullying behaviors. These findings suggest that enhancing ACE-aware care and ACE prevention is important because even promoting PCEs is unlikely to decrease bullying levels on their own., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interests with respect to the authorship and/or publication of this article.

Recent research suggests that bullying victimization increases the risk of handgun carrying among adolescents. Yet, little to no research has considered whether different types of bullying victimization (i.e., physical, verbal, cyber) shape handgun-carrying behaviors among youth. Understanding these relationships can, however, inform intervention efforts addressing youths' access to and motives for carrying handguns. The purposes of this study are twofold. First, we establish whether there is a relationship between bullying victimization and youth handgun carrying. Second, we seek to determine whether certain types of bullying victimization are associated more strongly with handgun carrying than others, using data from the 2022 Florida Youth Substance Abuse Survey (FYSAS, n = 47,572), a statewide representative sample of Florida middle school and high school students. The results from multinomial regression models indicate that physical bullying and cyberbullying victimization were associated with an elevated risk of carrying a handgun in the past 12 months. Interventions that underscore the importance of comprehensive anti-bullying interventions that not only address traditional physical aggression among adolescents but also mitigate the evolving challenges posed by unsupervised digital spaces may reduce the risk of handgun carrying., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interests with respect to the authorship and/or publication of this article.

Background: Many studies have investigated the effects of adverse childhood experiences (ACEs) on the health, development, and well-being of children and adolescents. However, most studies have failed to examine whether childhood adversity and ecological factors interact to influence relevant health outcomes., Objective: We used pooled data from the 2018-19 National Survey of Children's Health (n = 24,817) to assess the relationship between ACEs, neighborhood quality, and three domains of adolescent health and well-being: mental health (i.e., symptoms of anxiety problems and depression), neurodevelopmental health, and behavioral problems., Methods: Nine types of ACEs were captured in the NSCH data. Logistic regression models were employed to explore the relationship between ACEs, neighborhood quality, and adolescent health and well-being., Results: Our results indicate that ACEs are associated with each of these domains, with higher ACE scores associated with a higher risk of detrimental outcomes. Neighborhood disorder is also associated with several outcomes. Consistent with our expectations, in the presence of neighborhood disorder the association between higher ACEs exposure and behavior/conduct problems or neurodevelopmental disorders is larger., Conclusions: Our results have important implications for understanding how individual and contextual factors may combine to influence child health and behaviors, as well as offering policy recommendations that might help children who experience traumatic events., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Lung tissue resident memory (TRM) cells are thought to play crucial roles in lung host defense. We have recently shown that immunization with the adjuvant LTA1 (derived from the A1 domain of E. coli heat labile toxin) admixed with OmpX from K. pneumoniae can elicit antigen specific lung Th17 TRM cells that provide serotype independent immunity to members of the Enterobacteriaceae family. However, the upstream requirements to generate these cells are unclear. Single-cell RNA-seq showed that vaccine-elicited Th17 TRM cells expressed high levels of IL-1R1, suggesting that IL-1 family members may be critical to generate these cells. Using a combination of genetic and antibody neutralization approaches, we show that Th17 TRM cells can be generated independent of caspase-1 but are compromised when IL-1α is neutralized. Moreover IL-1α could serve as a molecular adjuvant to generate lung Th17 TRM cells independent of LTA1. Taken together, these data suggest that IL-1α plays a major role in vaccine-mediated lung Th17 TRM generation., (© 2024. The Author(s).)

A large literature demonstrates that social capital has positive effects on outcomes for children, but we know little about whether social capital is durable, i.e., whether its effects persist long after its creation. We use two nationally representative data sets of U.S. high school students and structural equation modeling designed for binomial outcomes to examine the durability of returns to social capital created in the family on both college enrollment and college completion. Controlling for selected school characteristics, race, family, SES and other factors, results suggest that family social capital continues to have strong associations with outcomes increasingly distant from its creation. Family SES has a smaller but positive effect on both college enrollment and college completion. These findings suggest that social capital can be a durable good if formed in the family, and that family SES is also influential., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Dufur 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.)

Craniofacial and dentoalveolar abnormalities are present in all types of osteogenesis imperfecta (OI). Mouse models of the disorder are critical to understand these abnormalities and underlying OI pathogenesis. Previous studies on severely affected OI mice report a broad spectrum of craniofacial phenotypes, exhibiting some similarities to the human disorder. The Brtl/+ and G610c/+ are moderately severe and mild-type IV OI, respectively. Little is known about the aging effects on the craniofacial bones of these models and their homology to human OI. This study aimed to analyze the Brtl/+ and G610c/+ craniofacial morphometries during aging to establish suitability for further OI craniofacial bone intervention studies. We performed morphological measurements on the micro-CT-scanned heads of 3-wk-old, 3-mo-old, and 6-mo-old female Brtl/+ and G610c/+ mice. We observed that Brtl/+ skulls are shorter in length than WT ( P  < .05), whereas G610c/+ skulls are similar in length to their WT counterparts. The Brtl/+ mice exhibit alveolar bone with a porotic-like appearance that is not observed in G610c/+. As they age, Brtl/+ mice show severe bone resorption in both the maxilla and mandible ( P  < .05). By contrast, G610c/+ mice experience mandibular resorption consistently across all ages, but maxillary resorption is only evident at 6 mo ( P  < .05). Western blot shows high osteoclastic activities in the Brtl/+ maxilla. Both models exhibit delayed pre-functional eruptions of the third molars ( P  < .05), which are similar to those observed in some bisphosphonate-treated OI subjects. Our study shows that the Brtl/+ and G610c/+ mice display clear features found in type IV OI patients; both show age-related changes in the craniofacial growth phenotype. Therefore, understanding the craniofacial features of these models and how they age will allow us to select the most accurate mouse model, mouse age, and bone structure for the specific craniofacial bone treatment of differing OI groups., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Immune responses to antigens, including innocuous, self, tumor, microbial, and vaccine antigens, differ between males and females. The quest to uncover the mechanisms for biological sex differences in the immune system has intensified, with considerable literature pointing toward sex hormonal influences on immune cell function. Sex steroids, including estrogens, androgens, and progestins, have profound effects on immune function. As such, drastic changes in sex steroid concentrations that occur with aging (e.g., after puberty or during the menopause transition) or pregnancy impact immune responses and the pathogenesis of immune-related diseases. The effect of sex steroids on immunity involves both the concentration of the ligand and the density and distribution of genomic and nongenomic receptors that serve as transcriptional regulators of immune cellular responses to affect autoimmunity, allergy, infectious diseases, cancers, and responses to vaccines. The next frontier will be harnessing these effects of sex steroids to improve therapeutic outcomes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Adverse childhood experiences (ACEs) are associated with several negative health and behavioral outcomes during adolescence, but most of the extant research has employed ACEs scores at one or two time points. Studies have not assessed whether latent class ACEs trajectories affect adolescent problem behaviors and conditions., Objectives: We used longitudinal data from the Fragile Families and Child Wellbeing Study (FFCWS, n = 3444) to assess ACEs at several time points and empirically developed latent class trajectories. We then examined the sociodemographic characteristics of youth who belonged to each trajectory group. We next evaluated whether the ACEs trajectories during childhood were associated with delinquent behavior, substance use, and symptoms of anxiety or depression. Finally, we explored whether closeness to mother buffered the impact of ACEs on these outcomes., Methods: Eight types of ACEs were captured in the FFCWS data. ACE scores were assessed at year one, three, five, and nine, along with the outcomes during year 15. Trajectories were estimated with a semiparametric latent class models., Results: The analysis revealed three latent trajectories during childhood: a low/none ACEs group, a medium exposure group, and a high exposure group. Adolescents in the high exposure group manifested a heightened risk of involvement in delinquent behaviors and substance use. They also reported more symptoms of anxiety and depression than their peers in the low/none and medium exposure groups., Conclusions: Repeated exposure to ACEs during childhood can have serious negative repercussions in the lives of adolescents, but maternal closeness may buffer their effects. Scholars should continue to examine the dynamics of ACEs exposure during childhood by using empirical approaches appropriate for identifying age-graded trajectories., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

There is an urgent need for new treatment options for carbapenem-resistant Klebsiella pneumoniae (K. pneumoniae), which is a common cause of life-threatening hospital- and community-acquired infections. Prophylactic or therapeutic vaccination may offer an approach to control these infections, however, none has yet been approved for human use. Here, we report the chemical synthesis of an outer core tetra- and pentasaccharide derived from the lipopolysaccharide of K. pneumoniae. The oligosaccharides were equipped with an aminopentyl linker, which facilitated conjugation to the carrier proteins CRM 197 and BSA. Mice immunized with the glycoconjugate vaccine candidates elicited antibodies that recognized isolated LPS as well as various strains of K. pneumoniae. The successful preparation of the oligosaccharides relied on the selection of monosaccharide building blocks equipped with orthogonal hydroxyl and amino protecting groups. It allowed the differentiation of three types of amines of the target compounds and the installation of a crowded 4,5-branched Kdo moiety., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Here, we describe the continued synthetic molecular evolution of a lineage of host-compatible antimicrobial peptides (AMP) intended for the treatment of wounds infected with drug-resistant, biofilm-forming bacteria. The peptides tested are variants of an evolved AMP called d-amino acid CONsensus with Glycine Absent (d-CONGA), which has excellent antimicrobial activities in vitro and in vivo . In this newest generation of rational d-CONGA variants, we tested multiple sequence-structure-function hypotheses that had not been tested in previous generations. Many of the peptide variants have lower antibacterial activity against Gram-positive or Gram-negative pathogens, especially variants that have altered hydrophobicity, secondary structure potential, or spatial distribution of charged and hydrophobic residues. Thus, d-CONGA is generally well tuned for antimicrobial activity. However, we identified a variant, d-CONGA-Q7, with a polar glutamine inserted into the middle of the sequence, that has higher activity against both planktonic and biofilm-forming bacteria as well as lower cytotoxicity against human fibroblasts. Against clinical isolates of Klebsiella pneumoniae , innate resistance to d-CONGA was surprisingly common despite a lack of inducible resistance in Pseudomonas aeruginosa reported previously. Yet, these same isolates were susceptible to d-CONGA-Q7. d-CONGA-Q7 is much less vulnerable to AMP resistance in Gram-negative bacteria than its predecessor. Consistent with the spirit of synthetic molecular evolution, d-CONGA-Q7 achieved a critical gain-of-function and has a significantly better activity profile.

Alcohol-associated liver disease is accompanied by intestinal mycobiome dysbiosis, yet the impacts on liver disease are unclear. We demonstrate that Candida albicans-specific T helper 17 (Th17) cells are increased in circulation and present in the liver of patients with alcohol-associated liver disease. Chronic ethanol administration in mice causes migration of Candida albicans (C. albicans)-reactive Th17 cells from the intestine to the liver. The antifungal agent nystatin decreased C. albicans-specific Th17 cells in the liver and reduced ethanol-induced liver disease in mice. Transgenic mice expressing T cell receptors (TCRs) reactive to Candida antigens developed more severe ethanol-induced liver disease than transgene-negative littermates. Adoptively transferring Candida-specific TCR transgenic T cells or polyclonal C. albicans-primed T cells exacerbated ethanol-induced liver disease in wild-type mice. Interleukin-17 (IL-17) receptor A signaling in Kupffer cells was required for the effects of polyclonal C. albicans-primed T cells. Our findings indicate that ethanol increases C. albicans-specific Th17 cells, which contribute to alcohol-associated liver disease., Competing Interests: Declaration of interests B.S. has been consulting for Ambys Medicines, Ferring Research Institute, Gelesis, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell Therapeutics, Patara Pharmaceuticals, and Takeda. B.S.’s institution UC San Diego has received research support from Artizan Biosciences, Axial Biotherapeutics, BiomX, CymaBay Therapeutics, NGM Biopharmaceuticals, Prodigy Biotech, and Synlogic Operating Company. B.S. is the founder of Nterica Bio. UC San Diego has filed several patents with B.S. and Y.D. as inventors related to this work. P.S. received grant support from Gilead Sciences Belgium., (Published by Elsevier Inc.)

Background: Psychoactive substance use is a transient behavior among many adolescents and diminishes as they mature, but some engage in heavy forms of substance use, which increases their risk of health and behavioral challenges. A consistent predictor of substance use among youth is family structure, with adolescents living in single-parent, stepparent, or no-parent families at higher risk than others of several forms of substance use. The objective of this research was to investigate whether unstructured socializing mediated the association between family structure and heavy alcohol or substance use., Methods: Data from 30 nations ( n = 65,737) were used to test the hypothesis using a generalized structural equation model and tests of mediation., Results: The analysis furnished clear support for a mediation effect among adolescents living with a single parent but less support among those living with a stepparent or neither parent., Conclusion: The association between living in a single-parent household and heavy alcohol or other substance use was mediated largely by time spent outside the home with friends in unsupervised activities. Additional research that uses longitudinal data and more nuanced measures of family structure is needed to validate this finding.

The aim of this review is to assess empirical studies from the last 2 decades that have examined the association between cumulative stressors and adolescent substance use. Cumulative stressors were measured in these studies with adverse childhood experiences or adolescent stressful life events inventories. The 109 articles meeting the eligibility criteria that emerged from the review demonstrated a consistent, yet modest, association between cumulative stressors and adolescent substance use. Of note, several studies found that the associations were moderated or mediated by genetic factors related to cortisol regulation, intrapersonal factors such as low self-control, or interpersonal factors such as peer substance use. The review's findings thus suggest that efforts to reduce the effects of cumulative stressors on substance use could gainfully identify and target these risk moderators and mediators.

The rapid development of COVID-19 vaccines was the result of decades of research to establish flexible vaccine platforms and understand pathogens with pandemic potential, as well as several novel changes to the vaccine discovery and development processes that partnered industry and governments. And while vaccines offer the potential to drastically improve global health, low-and-middle-income countries around the world often experience reduced access to vaccines and reduced vaccine efficacy. Addressing these issues will require novel vaccine approaches and platforms, deeper insight how vaccines mediate protection, and innovative trial designs and models. On June 28-30, 2021, experts in vaccine research, development, manufacturing, and deployment met virtually for the Keystone eSymposium "Innovative Vaccine Approaches" to discuss advances in vaccine research and development., (© 2022 New York Academy of Sciences.)