Allostatic Load in Childhood, Adolescence, and Young Adulthood: Are Assumptions of Measurement Invariance Warranted?

OVERVIEW: Allostatic load represents the cumulative toll of chronic mobilization of the body's stress response systems, as indexed by biomarkers. Higher levels of stress and disadvantage predict higher levels of allostatic load, which, in turn, predict poorer physical and mental health outcomes. To maximize the efficacy of prevention efforts, screening for stress- and disadvantage-associated health conditions must occur before middle age-that is, during childhood, adolescence, and young adulthood. However, this requires that models of allostatic load display properties of measurement invariance across age groups. Because most research on allostatic load has featured older adults, it is unclear if these requirements can be met. METHODS: To address this question, we fit a series of exploratory and confirmatory analytic models to data on eight biomarkers using a nationally representative sample of N = 4260 children, adolescents, and young adults drawn from the National Health and Nutrition Examination Survey dataset. RESULTS: Exploratory and confirmatory models indicated that, consistent with allostatic load theory, a unidimensional model was a good fit to the data. However, this model did not display properties of measurement invariance; post-hoc analyses suggested that the biomarkers included in the final confirmatory model were most strongly intercorrelated among young adults and most weakly intercorrelated among adolescents. CONCLUSIONS: These results underscore the importance of testing assumptions about measurement invariance in allostatic load before drawing substantive conclusions about stress, disadvantage, and health by directly comparing levels of allostatic load across different stages of development, while underscoring the need to expand investigations of measurement invariance to samples of longitudinal data.

Black Young Adult Superwomen in the Face of Gendered Racial Microaggressions: Contextualizing Challenges With Acceptance and Avoidance and Emotional Eating.

BACKGROUND: Black young adult women (ages 18-35) are at disproportionate risk for obesity and emotional eating. Emotional eating interventions target psychological flexibility, such as reducing experiential avoidance and increasing acceptance of food-related thoughts. Yet Black women face gendered racism, and some endorse roles that reduce psychological flexibility, such as the superwoman schema role. Culturally centered stress and coping has often been overlooked, leading to an incomplete understanding of processes that engender emotional eating and the implications for appropriate and effective interventions for Black young adult women. PURPOSE: We investigated direct and indirect pathways of associations between stress from gendered racial microaggressions to emotional eating through the endorsement of superwoman schema and two aspects of psychological flexibility. METHODS: Black young adult women (N = 504; Mage = 24.72; 75.2% African American; 98.4% cisgender) participated in an online survey wherein they reported demographics, stress from gendered racial microaggressions, superwoman schema, experiential avoidance, acceptance of food-related thoughts, and emotional eating. Path analysis was conducted to examine direct and indirect effects. RESULTS: Results provided evidence for indirect associations between more stress from gendered racial microaggressions and more emotional eating. More stress was associated with greater endorsement of the superwoman schema which was associated with more experiential avoidance and less acceptance of food-related thoughts, which were each associated with more emotional eating. CONCLUSIONS: Endorsement of superwoman schema and concomitant avoidance and less acceptance may be one way that gendered racial stress propels emotional eating. Future research could test intervention components that disrupt this path.

Emotional eating is eating in order to alleviate negative emotions, like those from stress. Black young adult women face particular forms of stress from being mistreated at the intersection of their race and gender. This research was needed to better understand processes that engender emotional eating for Black young adult women so that appropriate and effective interventions can be developed for this group. In this correlational study, Black young adult women (ages 18­35) completed an online survey wherein they answered questions about their experiences, thoughts, and behaviors. The study results indicated that stress from mistreatment due to being a Black woman was associated with endorsing a need to be strong. This need to be strong was associated with avoiding experiences that may lead to negative emotional states and being less accepting of distressing thoughts about food. More avoidance and less acceptance were each associated with more emotional eating. Therefore, if emotional eating or obesity-related interventions already target acceptance and avoidance, but do not reference or contextualize them for Black young adult women­particularly in terms of stress from mistreatment as a Black woman and the need to be strong­such interventions may be less effective.

Ebola virus VP35 interacts non-covalently with ubiquitin chains to promote viral replication.

Ebolavirus (EBOV) belongs to a family of highly pathogenic viruses that cause severe hemorrhagic fever in humans. EBOV replication requires the activity of the viral polymerase complex, which includes the cofactor and Interferon antagonist VP35. We previously showed that the covalent ubiquitination of VP35 promotes virus replication by regulating interactions with the polymerase complex. In addition, VP35 can also interact non-covalently with ubiquitin (Ub); however, the function of this interaction is unknown. Here, we report that VP35 interacts with free (unanchored) K63-linked polyUb chains. Ectopic expression of Isopeptidase T (USP5), which is known to degrade unanchored polyUb chains, reduced VP35 association with Ub and correlated with diminished polymerase activity in a minigenome assay. Using computational methods, we modeled the VP35-Ub non-covalent interacting complex, identified the VP35-Ub interacting surface, and tested mutations to validate the interface. Docking simulations identified chemical compounds that can block VP35-Ub interactions leading to reduced viral polymerase activity. Treatment with the compounds reduced replication of infectious EBOV in cells and in vivo in a mouse model. In conclusion, we identified a novel role of unanchored polyUb in regulating Ebola virus polymerase function and discovered compounds that have promising anti-Ebola virus activity.

Overcoming a Radical Polarity Mismatch in Strain-Release Pentafluorosulfanylation of [1.1.0]Bicyclobutanes: An Entryway to Sulfone- and Carbonyl-Containing SF5-Cyclobutanes.

The first assortment of achiral pentafluorosulfanylated cyclobutanes (SF5-CBs) are now synthetically accessible through strain-release functionalization of [1.1.0]bicyclobutanes (BCBs) using SF5Cl. Methods for both chloropentafluorosulfanylation and hydropentafluorosulfanylation of sulfone-based BCBs are detailed herein, as well as proof-of-concept that the logic extends to tetrafluoro(aryl)sulfanylation, tetrafluoro(trifluoromethyl)sulfanylation, and three-component pentafluorosulfanylation reactions. The methods presented enable isolation of both syn and anti isomers of SF5-CBs, but we also demonstrate that this innate selectivity can be overridden in chloropentafluorosulfanylation; that is, an anti-stereoselective variant of SF5Cl addition across sulfone-based BCBs can be achieved by using inexpensive copper salt additives. Considering the SF5 group and CBs have been employed individually as nonclassical bioisosteres, structural aspects of these unique SF5-CB "hybrid isosteres" were then contextualized using SC-XRD. From a mechanistic standpoint, chloropentafluorosulfanylation ostensibly proceeds through a curious polarity mismatch addition of electrophilic SF5 radicals to the electrophilic sites of the BCBs. Upon examining carbonyl-containing BCBs, we also observed rare instances whereby radical addition to the 1-position of a BCB occurs. The nature of the key C(sp3)-SF5 bond formation step - among other mechanistic features of the methods we disclose - was investigated experimentally and with DFT calculations. Lastly, we demonstrate compatibility of SF5-CBs with various downstream functionalizations.

Ebola Virus VP35 Interacts Non-Covalently with Ubiquitin Chains to Promote Viral Replication Creating New Therapeutic Opportunities.

Ebolavirus (EBOV) belongs to a family of highly pathogenic viruses that cause severe hemorrhagic fever in humans. EBOV replication requires the activity of the viral polymerase complex, which includes the co-factor and Interferon antagonist VP35. We previously showed that the covalent ubiquitination of VP35 promotes virus replication by regulating interactions with the polymerase complex. In addition, VP35 can also interact non-covalently with ubiquitin (Ub); however, the function of this interaction is unknown. Here, we report that VP35 interacts with free (unanchored) K63-linked polyUb chains. Ectopic expression of Isopeptidase T (USP5), which is known to degrade unanchored polyUb chains, reduced VP35 association with Ub and correlated with diminished polymerase activity in a minigenome assay. Using computational methods, we modeled the VP35-Ub non-covalent interacting complex, identified the VP35-Ub interacting surface and tested mutations to validate the interface. Docking simulations identified chemical compounds that can block VP35-Ub interactions leading to reduced viral polymerase activity that correlated with reduced replication of infectious EBOV. In conclusion, we identified a novel role of unanchored polyUb in regulating Ebola virus polymerase function and discovered compounds that have promising anti-Ebola virus activity.

Same Goals, but Different Outcomes: Present-Focused versus Future-Focused Memory Beliefs Differentially Predict Young and Older Adults' Everyday Use of Memory Strategies.

OBJECTIVE: We investigated whether beliefs about the current versus future effectiveness of memory strategies predict young and older adults' everyday strategy use. METHOD: 103 young and 91 older adults reported their memory goals, beliefs about the current and future effectiveness of various strategies, and frequency of use of each strategy type. RESULTS: The two age groups equally valued current and future memory. Young adults' strategy selection related only to their beliefs about the strategies' current effectiveness; older adults utilized approaches they perceived as effective for improving both future and current memory. IMPLICATIONS: Findings highlight the importance of the temporal nature of memory strategy beliefs.

Strain-Release Pentafluorosulfanylation and Tetrafluoro(aryl)sulfanylation of [1.1.1]Propellane: Reactivity and Structural Insight.

We leveraged the recent increase in synthetic accessibility of SF5 Cl and Ar-SF4 Cl compounds to combine chemistry of the SF5 and SF4 Ar groups with strain-release functionalization. By effectively adding SF5 and SF4 Ar radicals across [1.1.1]propellane, we accessed structurally unique bicyclopentanes, bearing two distinct elements of bioisosterism. Upon evaluating these "hybrid isostere" motifs in the solid state, we measured exceptionally short transannular distances; in one case, the distance rivals the shortest nonbonding C⋅⋅⋅C contact reported to date. This prompted SC-XRD and DFT analyses that support the notion that a donor-acceptor interaction involving the "wing" C-C bonds is playing an important role in stabilization. Thus, these heretofore unknown structures expand the palette for highly coveted three-dimensional fluorinated building blocks and provide insight to a more general effect observed in bicyclopentanes.

Evidence for C-F Bond Formation through Formal Reductive Elimination from Tellurium(VI).

The fundamental challenge of C-F bond formation by reductive elimination has been met by compounds of select transition metals and fewer main group elements. The work detailed herein expands the list of main group elements known to be capable of reductively eliminating a C-F bond to include tellurium. Surprising and novel modes of both sp2 and sp3 C-F bond formation were observed alongside formation of TeIV cations during two separate attempts to synthesize/characterize fluorinated organotellurium(VI) cations in superacidic media (SbF5 /SO2 ClF). Following detailed low-temperature NMR experiments, the mechanisms of the two unique reductive elimination reactions were probed and investigated using density functional theory (DFT) calculations. Ultimately, we found that an "indirect" reductive elimination pathway is likely operative whereby Sb plays a key role in fluoride abstraction and C-F bond formation, as opposed to unimolecular reductive elimination from a discrete TeVI cation.

Ubiquitination of Ebola virus VP35 at lysine 309 regulates viral transcription and assembly.

Ebola virus (EBOV) VP35 is a polyfunctional protein involved in viral genome packaging, viral polymerase function, and host immune antagonism. The mechanisms regulating VP35's engagement in different functions are not well-understood. We previously showed that the host E3 ubiquitin ligase TRIM6 ubiquitinates VP35 at lysine 309 (K309) to facilitate virus replication. However, how K309 ubiquitination regulates the function of VP35 as the viral polymerase co-factor and the precise stage(s) of the EBOV replication cycle that require VP35 ubiquitination are not known. Here, we generated recombinant EBOVs encoding glycine (G) or arginine (R) mutations at VP35/K309 (rEBOV-VP35/K309G/-R) and show that both mutations prohibit VP35/K309 ubiquitination. The K309R mutant retains dsRNA binding and efficient type-I Interferon (IFN-I) antagonism due to the basic residue conservation. The rEBOV-VP35/K309G mutant loses the ability to efficiently antagonize the IFN-I response, while the rEBOV-VP35/K309R mutant's suppression is enhanced. The replication of both mutants was significantly attenuated in both IFN-competent and -deficient cells due to impaired interactions with the viral polymerase. The lack of ubiquitination on VP35/K309 or TRIM6 deficiency disrupts viral transcription with increasing severity along the transcriptional gradient. This disruption of the transcriptional gradient results in unbalanced viral protein production, including reduced synthesis of the viral transcription factor VP30. In addition, lack of ubiquitination on K309 results in enhanced interactions with the viral nucleoprotein and premature nucleocapsid packaging, leading to dysregulation of virus assembly. Overall, we identified a novel role of VP35 ubiquitination in coordinating viral transcription and assembly.

The RNA helicase DHX16 recognizes specific viral RNA to trigger RIG-I-dependent innate antiviral immunity.

Type I interferons (IFN-I) are essential to establish antiviral innate immunity. Unanchored (or free) polyubiquitin (poly-Ub) has been shown to regulate IFN-I responses. However, few unanchored poly-Ub interactors are known. To identify factors regulated by unanchored poly-Ub in a physiological setting, we developed an approach to isolate unanchored poly-Ub from lung tissue. We identified the RNA helicase DHX16 as a potential pattern recognition receptor (PRR). Silencing of DHX16 in cells and in vivo diminished IFN-I responses against influenza virus. These effects extended to members of other virus families, including Zika and SARS-CoV-2. DHX16-dependent IFN-I production requires RIG-I and unanchored K48-poly-Ub synthesized by the E3-Ub ligase TRIM6. DHX16 recognizes a signal in influenza RNA segments that undergo splicing and requires its RNA helicase motif for direct, high-affinity interactions with specific viral RNAs. Our study establishes DHX16 as a PRR that partners with RIG-I for optimal activation of antiviral immunity requiring unanchored poly-Ub.

Mother knows best or does she? Perceptions of the memory abilities of pediatric patients with epilepsy as reported by patients and their parents across time.

PURPOSE: This study compared the self-reported and parent-reported memory of children with epilepsy across time and explored the relationships between these measures of subjective memory and the children's actual performance on objective neuropsychological tests. METHOD: One-hundred and nineteen children with epilepsy who were surgical candidates underwent comprehensive neuropsychological testing that included the Everyday Verbal Memory Questionnaire (EVMQ). Each child's parent and 82 of the children themselves completed the appropriate version of this subjective memory measure. After 9 months, the children returned for a second neuropsychological evaluation with 71 parents and 39 children completing the same questionnaire. Approximately one-third of the children in the study underwent surgery between the two evaluations. Standardized regression-based norms were used to quantify change in cognitive abilities across assessments. RESULTS: Results revealed significant relationships between parent reports and child reports of the children's memory abilities. Parent reports, but not child reports, correlated with the children's objective test scores at baseline. In contrast, children were more attuned to changes in their memory across time. CONCLUSIONS: These findings demonstrate the importance of considering both parent and child perceptions of everyday cognitive functioning when evaluating cognition and cognitive changes over time in pediatric patients with epilepsy.

Epigenetics for the 21st-Century Biology Student.

Epigenetics, a rapidly emerging biological science, investigates changes in gene expression without any change to the primary DNA sequence. Epigenetics plays an important role in diverse areas, including nutritional sciences, psychology, and environmental sciences. In addition, epigenetic phenomena are closely implicated in various diseases, including cancer and neurological disorders. Even though the importance of epigenetics has been widely discussed in the literature, there is no quantitative assessment on the development of epigenetics. In this paper, we show our metadata analysis of PubMed to quantitatively measure the temporal development of epigenetics. Our analysis indicates that the publication volume of epigenetics will reach 20.7% of all genetics paper in 10 years (year 2029). Based on our analysis, we suggest that epigenetics be added to the biology undergraduate curriculum.

Percutaneous coronary intervention using a combination of robotics and telecommunications by an operator in a separate physical location from the patient: an early exploration into the feasibility of telestenting (the REMOTE-PCI study).

AIMS: The present study explores the feasibility of telestenting, wherein a physician operator performs stenting on a patient in a separate physical location using a combination of robotics and telecommunications. METHODS AND RESULTS: Patients undergoing robotic stenting were eligible for inclusion. All manipulations of guidewires, balloons, and stents were performed robotically by a physician operator located in an isolated separate room outside the procedure room housing the patient. Communication between the operating physician and laboratory personnel was via telecommunication devices providing real-time audio and video connectivity. Among 20 patients who consented to participate, technical success, defined as successful advancement and retraction of guidewires, balloons, and stents by the robotic system without conversion to manual operation, was achieved in 19 of 22 lesions (86.4%). Procedural success, defined as <30% residual stenosis upon completion of the procedure in the absence of death or repeat revascularisation prior to hospital discharge, was achieved in 19 of 20 patients (95.0%). There were no deaths or repeat revascularisations prior to hospital discharge. CONCLUSIONS: To the best of our knowledge, the present study is the first to explore the feasibility of telestenting. Additional studies are required to determine if future advancements in robotics will facilitate telestenting over greater geographic distances.

Evaluating Emergency Department Asthma Management Practices in Florida Hospitals.

OBJECTIVE: To assess gaps in emergency department (ED) asthma management at Florida hospitals. DESIGN: Survey instrument with open- and closed-ended questions. Topics included availability of specific asthma management modalities, compliance with national guidelines, employment of specialized asthma care personnel, and efforts toward performance improvement. SETTING: Emergency departments at 10 large hospitals in the state of Florida. PARTICIPANTS: Clinical care providers and health administrators from participating hospitals. MAIN OUTCOME MEASURES: Compliance with national asthma care guideline standards, provision of specific recommended treatment modalities and resources, employment of specialized asthma care personnel, and engagement in performance improvement efforts. RESULTS: Our results suggest inconsistency among sampled Florida hospitals' adherence to national standards for treatment of asthma in EDs. Several hospitals were refining their emergency care protocols to incorporate guideline recommendations. Despite a lack of formal ED protocols in some hospitals, adherence to national guidelines for emergency care nonetheless remained robust for patient education and medication prescribing, but it was weaker for formal care planning and medical follow-up. CONCLUSIONS: Identified deficiencies in emergency asthma care present a number of opportunities for strategic mitigation of identified gaps. We conclude with suggestions to help Florida hospitals achieve success with ED asthma care reform. Team-based learning activities may offer an optimal strategy for sharing and implementing best practices.

Child routines and parental adjustment as correlates of internalizing and externalizing symptoms in children diagnosed with ADHD.

Attention deficit hyperactivity disorder (ADHD) is one of the most common disorders of childhood, and the presence of comorbid externalizing and internalizing symptoms often result in severe negative long-term consequences. Multiple etiological factors contribute to the development of co-occurring symptoms. Family stability and consistency appear to be particularly important in effectively managing behavioral concerns. One important factor in producing consistency and stability is the use of routines. The current study examined how routines may be related to internalizing/externalizing symptoms in a clinical sample (N = 371) of children with ADHD (M age = 9.13, SD = 1.96; 77% male). After controlling for child age, gender, and parental adjustment, routines predicted both internalizing and externalizing symptoms. Specific subtypes of routines including Household, Discipline, and Homework Routines were found to significantly predict symptomatology. A positive relation was found between parental and child adjustment problems; however, support for routines moderating the relation between parent and child adjustment was not supported.

HIV insertions within and proximal to host cell genes are a common finding in tissues containing high levels of HIV DNA and macrophage-associated p24 antigen expression.

HIV integration within host cell genomic DNA is a requisite step of the viral infection cycle. Yet, characteristics of the sites of provirus integration within the host genome remain obscure. The authors present evidence that in diseased tissues showing a high level of HIV DNA and macrophage-associated HIV p24 antigen expression from end stage forms of HIV disease, HIV-1 integration sites were favored within genes and transcriptionally active host cell genomic loci. Using an inverse PCR (IPCR) technique that identified dominant integrated forms of HIV, clonal IPCR products were isolated from AIDS dementia, AIDS lymphoma, and angioimmunoblastic lymphadenopathy tissues. Thirty of 34 disease-associated HIV-1 insertions were identified within annotated and hypothetical genes, an unexpected but highly nonrandom genetic coding region association (p <.026). The 1% sensitivity thresholds used for HIV IPCR suggested some form of selective expansion of cells containing these HIV proviruses. Consistent with this interpretation were the HIV-1 insertion sites identified within introns of genes that encoded for factors associated with signal transduction, apoptosis, and transcription regulation. In addition, HIV-1 proviruses were frequently found proximal to genes that encoded for receptor-associated, signal transduction-associated, transcription-associated, and translation-associated proteins. HIV-1 integration within host cell genomic DNA potentially represents a significant insertional mutagenic event. In certain cases, provirus insertions may mediate the dysregulation of specific gene expression events, providing mechanisms contributing to the pathogenesis associated with certain AIDS-related diseases.

Coinfection of SCID-hu Thy/Liv mice with human herpesvirus 6 and human immunodeficiency virus type 1.

Human herpesvirus 6 (HHV-6) has been proposed as a potential cofactor in the progression of human immunodeficiency virus type 1 (HIV-1) disease. We used the SCID-hu Thy/Liv mouse model to evaluate the in vivo interactions between HHV-6 and HIV-1. Our results demonstrate that HHV-6 and HIV-1 can simultaneously replicate in the human thymus in vivo. In this model, however, the presence of one virus appears not to modify the replication or cytopathicity of the other.

Human immunodeficiency virus type 1 coreceptor preferences determine target T-cell depletion and cellular tropism in human lymphoid tissue.

The present study sought to determine how usage of coreceptors by human immunodeficiency virus type 1 dictates cell tropism and depletion of CD4(+) T cells in human lymphoid tissues cultured ex vivo. We found that coreceptor preferences control the marked, preferential depletion of coreceptor-expressing CD4(+) lymphocytes. In addition, there was a strong, but not absolute, preference shown by CXCR4-using strains for lymphocytes and by CCR5-using strains for macrophages.

Human herpesvirus 6 (HHV-6) causes severe thymocyte depletion in SCID-hu Thy/Liv mice.

Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that may act as a cofactor in the progression of AIDS. Here, we describe the first small animal model of HHV-6 infection. HHV-6 subgroup A, strain GS, efficiently infected the human thymic tissue implanted in SCID-hu Thy/Liv mice, leading to the destruction of the graft. Viral DNA was detected in Thy/Liv implants by quantitative polymerase chain reaction (PCR) as early as 4 d after inoculation and peaked at day 14. The productive nature of the infection was confirmed by electron microscopy and immunohistochemical staining. Atypical thymocytes with prominent nuclear inclusions were detected by histopathology. HHV-6 replication was associated with severe, progressive thymocyte depletion involving all major cellular subsets. However, intrathymic T progenitor cells (ITTPs) appeared to be more severely depleted than the other subpopulations, and a preferred tropism of HHV-6 for ITTPs was demonstrated by quantitative PCR on purified thymocyte subsets. These findings suggest that thymocyte depletion by HHV-6 may be due to infection and destruction of these immature T cell precursors. Similar results were obtained with strain PL-1, a primary isolate belonging to subgroup B. The severity of the lesions observed in this animal model underscores the possibility that HHV-6 may indeed be immunosuppressive in humans.