ESAT-6 undergoes self-association at phagosomal pH and an ESAT-6-specific nanobody restricts M. tuberculosis growth in macrophages.

Mycobacterium tuberculosis (Mtb) is known to survive within macrophages by compromising the integrity of the phagosomal compartment in which it resides. This activity primarily relies on the ESX-1 secretion system, predominantly involving the protein duo ESAT-6 and CFP-10. CFP-10 likely acts as a chaperone, while ESAT-6 likely disrupts phagosomal membrane stability via a largely unknown mechanism. we employ a series of biochemical analyses, protein modeling techniques, and a novel ESAT-6-specific nanobody to gain insight into the ESAT-6's mode of action. First, we measure the binding kinetics of the tight 1:1 complex formed by ESAT-6 and CFP-10 at neutral pH. Subsequently, we demonstrate a rapid self-association of ESAT-6 into large complexes under acidic conditions, leading to the identification of a stable tetrameric ESAT-6 species. Using molecular dynamics simulations, we pinpoint the most probable interaction interface. Furthermore, we show that cytoplasmic expression of an anti-ESAT-6 nanobody blocks Mtb replication, thereby underlining the pivotal role of ESAT-6 in intracellular survival. Together, these data suggest that ESAT-6 acts by a pH-dependent mechanism to establish two-way communication between the cytoplasm and the Mtb-containing phagosome.

Correction: Remapping the foundations of morality: Well-fitting structural model of the Moral Foundations Questionnaire.

[This corrects the article DOI: 10.1371/journal.pone.0258910.].

Evaluating Humoral Immunity Elicited by XBB.1.5 Monovalent COVID-19 Vaccine.

Because novel SARS-CoV-2 variants continue to emerge, immunogenicity of XBB.1.5 monovalent vaccines against live clinical isolates needs to be evaluated. We report boosting of IgG (2.1×), IgA (1.5×), and total IgG/A/M (1.7×) targeting the spike receptor-binding domain and neutralizing titers against WA1 (2.2×), XBB.1.5 (7.4×), EG.5.1 (10.5×), and JN.1 (4.7×) variants.

Humoral Immunity Elicited by the XBB.1.5 Monovalent COVID-19 Vaccine.

As novel SARS-CoV-2 variants continue to emerge, the updated XBB.1.5 monovalent vaccines remain to be evaluated in terms of immunogenicity against live clinical isolates. We report boosting of IgG(2.1X), IgA(1.5X), and total IgG/A/M(1.7X) antibodies targeting the spike receptor-binding domain and neutralizing titers against WA1(2.2X), XBB.1.5(7.4X), EG.5.1(10.5X), and JN.1(4.7X) variants.

Childhood Reading Ability and Pain in Childhood Through to Midlife.

Dyslexia and pain have recently been shown to correlate on a genetic level, but there has been little exploration of this association on the phenotypic level despite reports of increased pain in Attention Deficit Hyperactivity Disorder, which commonly co-occurs with dyslexia. In this study we test for an association between reading ability, which is the primary feature of dyslexia, and pain both in childhood and adulthood. Logistic regression modeling was used to test associations between reading ability in childhood and pain from childhood to midlife in a large UK birth cohort; the 1958 National Child Development Study. Associations were found between poor childhood reading ability and increased headache and abdominal pain in childhood, and between poor childhood reading ability and headache, eye pain, back pain, and rheumatism in adulthood. Mediation analyses indicated that socioeconomic status (defined by employment) fully mediated the association between poor reading ability in childhood and back pain at age 42. By contrast, the association between reading ability and eye pain acted independently of socioeconomic status. Different mechanisms were thus indicated for the association of reading with different pain types, including manual labor and a potential shared biological pathway. PERSPECTIVE: This study found a relationship between poor reading ability in childhood and pain in childhood and adulthood. Those with reading difficulties should be monitored for pain symptoms. Future research may uncover shared biological mechanisms, increasing our understanding of pain and potential treatments.

ESAT-6 undergoes self-association at phagosomal pH and an ESAT-6 specific nanobody restricts M. tuberculosis growth in macrophages.

Mycobacterium tuberculosis (Mtb) is known to survive within macrophages by compromising the integrity of the phagosomal compartment in which it resides. This activity primarily relies on the ESX-1 secretion system, predominantly involving the protein duo ESAT-6 and CFP-10. CFP-10 likely acts as a chaperone, while ESAT-6 likely disrupts phagosomal membrane stability via a largely unknown mechanism. we employ a series of biochemical analyses, protein modeling techniques, and a novel ESAT-6-specific nanobody to gain insight into the ESAT-6's mode of action. First, we measure the binding kinetics of the tight 1:1 complex formed by ESAT-6 and CFP-10 at neutral pH. Subsequently, we demonstrate a rapid self-association of ESAT-6 into large complexes under acidic conditions, leading to the identification of a stable tetrameric ESAT-6 species. Using molecular dynamics simulations, we pinpoint the most probable interaction interface. Furthermore, we show that cytoplasmic expression of an anti-ESAT-6 nanobody blocks Mtb replication, thereby underlining the pivotal role of ESAT-6 in intracellular survival. Together, these data suggest that ESAT-6 acts by a pH dependent mechanism to establish two-way communication between the cytoplasm and the Mtb-containing phagosome.

Diverging Maternal and Cord Antibody Functions From SARS-CoV-2 Infection and Vaccination in Pregnancy.

Maternal immunity impacts the infant, but how is unclear. To understand the implications of the immune exposures of vaccination and infection in pregnancy for neonatal immunity, we evaluated antibody functions in paired peripheral maternal and cord blood. We compared those who in pregnancy received mRNA coronavirus disease 2019 (COVID-19) vaccine, were infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the combination. We found that vaccination enriched a subset of neutralizing activities and Fc effector functions that was driven by IgG1 and was minimally impacted by antibody glycosylation in maternal blood. In paired cord blood, maternal vaccination also enhanced IgG1. However, Fc effector functions compared to neutralizing activities were preferentially transferred. Moreover, changes in IgG posttranslational glycosylation contributed more to cord than peripheral maternal blood antibody functional potency. These differences were enhanced with the combination of vaccination and infection as compared to either alone. Thus, Fc effector functions and antibody glycosylation highlight underexplored maternal opportunities to safeguard newborns.

Relational models theory: Validation and replication for four fundamental relationships.

Relational models theory predicts that social relationships are formed from four underlying psychological models: communal sharing, authority ranking, equality matching, and market pricing. Here, in four studies, we test this four-factor model using the 33-item Modes of Relationships Questionnaire (MORQ). In Study 1, we administered the MORQ to N = 347 subjects. A parallel analysis supported the four-factor structure, but several items failed to load on their predicted target factors. In Study 2 (N = 617), we developed a well-fitting four-factor model of the MORQ with a total of 20 items (five items retained for each factor). This model replicated across multiple relationships reported by each subject. In Study 3, we replicated the model in an independent dataset (N = 615). A general factor associated with relationship type was required in both Study 2 and Study 3. In Study 4, we tested the nature of this general factor, finding that it was associated with the closeness of the relationship. The results support the Relational Models four-factor structure of social relationships. Given the mature theory and applications in a wide range of disciplines, from social to organisational psychology, we hope that this compact, valid, and interpretable instrument leads to increased usage of the scale.

Diverging maternal and infant cord antibody functions from SARS-CoV-2 infection and vaccination in pregnancy.

Immunization in pregnancy is a critical tool that can be leveraged to protect the infant with an immature immune system but how vaccine-induced antibodies transfer to the placenta and protect the maternal-fetal dyad remains unclear. Here, we compare matched maternal-infant cord blood from individuals who in pregnancy received mRNA COVID-19 vaccine, were infected by SARS-CoV-2, or had the combination of these two immune exposures. We find that some but not all antibody neutralizing activities and Fc effector functions are enriched with vaccination compared to infection. Preferential transport to the fetus of Fc functions and not neutralization is observed. Immunization compared to infection enriches IgG1-mediated antibody functions with changes in antibody post-translational sialylation and fucosylation that impact fetal more than maternal antibody functional potency. Thus, vaccine enhanced antibody functional magnitude, potency and breadth in the fetus are driven more by antibody glycosylation and Fc effector functions compared to maternal responses, highlighting prenatal opportunities to safeguard newborns as SARS-CoV-2 becomes endemic.

Longitudinal Reading Measures and Genome Imputation in the National Child Development Study: Prospects for Future Reading Research.

Reading difficulties are prevalent worldwide, including in economically developed countries, and are associated with low academic achievement and unemployment. Longitudinal studies have identified several early childhood predictors of reading ability, but studies frequently lack genotype data that would enable testing of predictors with heritable influences. The National Child Development Study (NCDS) is a UK birth cohort study containing direct reading skill variables at every data collection wave from age 7 years through to adulthood with a subsample (final n = 6431) for whom modern genotype data are available. It is one of the longest running UK cohort studies for which genotyped data are currently available and is a rich dataset with excellent potential for future phenotypic and gene-by-environment interaction studies in reading. Here, we carry out imputation of the genotype data to the Haplotype Reference Panel, an updated reference panel that offers greater imputation quality. Guiding phenotype choice, we report a principal components analysis of nine reading variables, yielding a composite measure of reading ability in the genotyped sample. We include recommendations for use of composite scores and the most reliable variables for use during childhood when conducting longitudinal, genetically sensitive analyses of reading ability.

An extended interval between vaccination and infection enhances hybrid immunity against SARS-CoV-2 variants.

As the COVID-19 pandemic continues, long-term immunity against SARS-CoV-2 will be important globally. Official weekly cases have not dropped below 2 million since September of 2020, and continued emergence of novel variants has created a moving target for our immune systems and public health alike. The temporal aspects of COVID-19 immunity, particularly from repeated vaccination and infection, are less well understood than short-term vaccine efficacy. In this study, we explored the effect of combined vaccination and infection, also known as hybrid immunity, and the timing thereof on the quality and quantity of antibodies elicited in a cohort of 96 health care workers. We found robust neutralizing antibody responses among those with hybrid immunity; these hybrid immune responses neutralized all variants, including BA.2. Neutralizing titers were significantly improved for those with longer vaccine-infection intervals of up to 400 days compared with those with shorter intervals. These results indicate that anti-SARS-CoV-2 antibody responses undergo continual maturation following primary exposure by either vaccination or infection for at least 400 days after last antigen exposure. We show that neutralizing antibody responses improved upon secondary boosting, with greater potency seen after extended intervals. Our findings may also extend to booster vaccine doses, a critical consideration in future vaccine campaign strategies.

The time between vaccination and infection impacts immunity against SARS-CoV-2 variants.

As the COVID-19 pandemic continues, long-term immunity against SARS-CoV-2 will be globally important. Official weekly cases have not dropped below 2 million since September of 2020, and continued emergence of novel variants have created a moving target for our immune systems and public health alike. The temporal aspects of COVID-19 immunity, particularly from repeated vaccination and infection, are less well understood than short-term vaccine efficacy. In this study, we explore the impact of combined vaccination and infection, also known as hybrid immunity, and the timing thereof on the quality and quantity of antibodies produced by a cohort of 96 health care workers. We find robust neutralizing antibody responses among those with hybrid immunity against all variants, including Omicron BA.2, and we further found significantly improved neutralizing titers with longer vaccine-infection intervals up to 400 days. These results indicate that anti-SARS-CoV-2 antibody responses undergo continual maturation following primary exposure by either vaccination or infection for at least 400 days after last antigen exposure. We show that neutralizing antibody responses improved upon secondary boosting with greater impact seen after extended intervals. Our findings may also extend to booster vaccine doses, a critical consideration in future vaccine campaign strategies.

Discovery of 42 genome-wide significant loci associated with dyslexia.

Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia.

BNT162b2-induced neutralizing and non-neutralizing antibody functions against SARS-CoV-2 diminish with age.

Each severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant renews concerns about decreased vaccine neutralization weakening efficacy. However, while prevention of infection varies, protection from disease remains and implicates immunity beyond neutralization in vaccine efficacy. Polyclonal antibodies function through Fab domains that neutralize virus and Fc domains that induce non-neutralizing responses via engagement of Fc receptors on immune cells. To understand how vaccines promote protection, we leverage sera from 51 SARS-CoV-2 uninfected individuals after two doses of the BNT162b2 mRNA vaccine. We show that neutralizing activities against clinical isolates of wild-type and five SARS-CoV-2 variants, including Omicron BA.2, link to FcγRIIIa/CD16 non-neutralizing effector functions. This is associated with post-translational afucosylation and sialylation of vaccine-specific antibodies. Further, polyfunctional neutralizing and non-neutralizing breadth, magnitude, and coordination diminish with age. Thus, studying Fc functions in addition to Fab-mediated neutralization provides greater insight into vaccine efficacy for vulnerable populations, such as the elderly, against SARS-CoV-2 and novel variants.

Personal Care Aides: Assessing Self-Care Needs And Worker Shortages In Rural Areas.

Previous research has documented shortages of personal care aides who provide Medicaid home and community-based services, but there are few detailed geographic data to determine the areas of greatest need and assess the availability of personal care aides nationwide. Using 2013-17 data from the American Community Survey and the Office of Management and Budget, we analyzed potential need for personal care aide services among adults and the supply of aides across the US. Areas with the highest percentages of adults with self-care disability were mainly in the South, and the gap between the potential need for personal care aide services and the aide supply was greatest in southern states. Within states, there were fewer personal care aides per 1,000 adults with self-care disability in the more rural and most rural areas than in the least rural areas. Wage and benefit increases, improved training and career opportunities, increased flexibility in state Medicaid policies on paid family caregiving, incentives and compensation for travel, and increased data collection and government tracking of workforce data could help boost the supply of personal care aides in rural America.

Omicron neutralizing antibody response following booster vaccination compared with breakthrough infection.

BACKGROUND: The spread of the vaccine-resistant Omicron severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens unvaccinated and fully vaccinated individuals, and accelerated booster vaccination campaigns are underway to mitigate the ongoing wave of Omicron cases. The immunity provided by standard vaccine regimens, boosted regimens, and immune responses elicited by vaccination plus natural infection remain incompletely understood. The magnitude, quality, and durability of serological responses, and the likelihood of protection against future SARS-CoV-2 variants following these modes of exposure, are poorly characterized but are critical to the future trajectory of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Ninety-nine individuals were semi-randomly selected from a larger vaccination cohort following vaccination and, in some cases, breakthrough infection. We analyzed spike receptor-binding domain-specific immunoglobulin G (IgG), IgA, and IgM by enzyme-linked immunosorbent assay, neutralizing antibody titers against live SARS-CoV-2 variants, and antibody-dependent cell-mediated phagocytosis. FINDINGS: In 99 vaccinated adults, compared with responses after two doses of an mRNA regimen, the immune responses 3 months after a third vaccine dose and 1 month after breakthrough infection due to prior variants show dramatic increases in magnitude, potency, and breadth, including increased antibody-dependent cellular phagocytosis and robust neutralization of the currently circulating Omicron BA.2 variant. CONCLUSIONS: Boosters and natural infection substantially boost immune responses. As the number of Omicron sub-variant cases rise and as global vaccination and booster campaigns continue, an increasing proportion of the world's population will acquire potent immune responses that may be protective against future SARS-CoV-2 variants. FUNDING: This work was funded by the M. J. Murdock Charitable Trust, the OHSU Foundation, the NIH (T32HL083808), and OHSU Innovative IDEA.

Evolving the blank slate.

We support Uchiyama et al. in the value of genetics, sample diversification, and context measurement. Against the example of vitamins, we highlight the intransigence of many phenotypes. We caution that while culture can mask genetic differences, the dependence of behaviour on genetics is reinvented and unmasked by novel challenges across generations.

Practice patterns of postgraduate trained dentists in the United States.

OBJECTIVE: Postgraduate dental (PGD) primary care training has grown significantly. This study examines the individual, educational, community, and policy factors that predict practice patterns of PGD-trained dentists. STUDY DESIGN: Individual dentist records from the 2017 American Dental Association Masterfile, with indicators of Medicaid participation and practice in a Federally Qualified Health Center (FQHC), were linked to postdoctoral training, community/practice location, and state policy factors. Generalized logistic models, adjusted for these factors, were used to predict PGD-trained dentists: (1a) serving Medicaid children, (1b) accepting new Medicaid patients, and (2) working in an FQHC. RESULTS: Individual attributes that predicted serving Medicaid children included all race/gender combinations (vs. White females), and foreign-trained dentists and contractors/employees/associates (vs. practice owners). Black women are most likely to work in an FQHC. Residency attributes that predicted serving Medicaid children and working in an FQHC were Health Resources and Services Administration postdoctoral funding and being community based. Dentists practicing in rural or high-poverty communities were more likely to serve Medicaid children and work at FQHCs. States with higher levels of graduate medical education investment, higher Medicaid rates, and more generous adult dental Medicaid benefits increased the likelihood of serving Medicaid children, while states with more expansive adult dental Medicaid benefits increased the likelihood of working in an FQHC. CONCLUSION: Federal training investment in PGD education combined with Medicaid payment and coverage policies can strongly impact access to dental care for vulnerable populations. Yet, oral health equity cannot be achieved without increasing dentist workforce diversity.

Trends in postgraduate dental training in the United States.

OBJECTIVE: This study examines the individual, educational, and policy factors that predict dentists pursuing postgraduate dental (PGD) training. METHODS: Individual dentist records from the 2017 American Dental Association Masterfile were linked with pre-doctoral training attributes and state-level dental policy factors. Generalized logistic models, adjusted for individual, educational, and policy factors, were used to predict: (1) attending any PGD program, and (2) primary (i.e., advanced general practice, pediatrics, or dental public health, per the Health Resources and Services Administration [HRSA]) versus specialty care. RESULTS: The majority of new PGD residency slots (77%) were in primary care. Women held 56% of primary care slots; men held 62% of specialty slots. Individual characteristics that predicted PGD primary care training included being Black, Hispanic, Asian, or other race; being male or older age reduced the odds. Pre-doctoral school characteristics that predicted PGD primary care training included having a pre-doctoral HRSA grant, affiliation with an academic medical center, and being a historically Black college/university; being a private school or in a small metro area lowered the odds. At the policy level, the strongest predictors of attending PGD primary care training are a residency requirement in the state you currently practice in and federal graduate medical education (GME) investment per residency slot. CONCLUSION: Pursuing PGD training is variable based on the race/ethnicity/gender of the dentist. Federal investments in pre-doctoral dental education and GME can drive equity, as they significantly increase the odds that dentists will go on to PGD training, as do state licensure requirements.