Ontogeny of Recognition Specificity and Functionality for the Broadly Neutralizing Anti-HIV Antibody 4E10

The process of antibody ontogeny typically improves affinity, on-rate, and thermostability, narrows polyspecificity, and rigidifies the combining site to the conformer optimal for binding from the broader ensemble accessible to the precursor. However, many broadly-neutralizing anti-HIV antibodies incorporate unusual structural elements and recognition specificities or properties that often lead to autoreactivity. The ontogeny of 4E10, an autoreactive antibody with unexpected combining site flexibility, was delineated through structural and biophysical comparisons of the mature antibody with multiple potential precursors. 4E10 gained affinity primarily by off-rate enhancement through a small number of mutations to a highly conserved recognition surface. Controverting the conventional paradigm, the combining site gained flexibility and autoreactivity during ontogeny, while losing thermostability, though polyspecificity was unaffected. Details of the recognition mechanism, including inferred global effects due to 4E10 binding, suggest that neutralization by 4E10 may involve mechanisms beyond simply binding, also requiring the ability of the antibody to induce conformational changes distant from its binding site. 4E10 is, therefore, unlikely to be re-elicited by conventional vaccination strategies

Precompetitive data sharing as a catalyst to address unmet needs in Parkinson's disease

Parkinson's disease is a complex heterogeneous disorder with urgent need for disease-modifying therapies. Progress in successful therapeutic approaches for PD will require an unprecedented level of collaboration. At a workshop hosted by Parkinson's UK and co-organized by Critical Path Institute's (C-Path) Coalition Against Major Diseases (CAMD) Consortiums, investigators from industry, academia, government and regulatory agencies agreed on the need for sharing of data to enable future success. Government agencies included EMA, FDA, NINDS/NIH and IMI (Innovative Medicines Initiative). Emerging discoveries in new biomarkers and genetic endophenotypes are contributing to our understanding of the underlying pathophysiology of PD. In parallel there is growing recognition that early intervention will be key for successful treatments aimed at disease modification. At present, there is a lack of a comprehensive understanding of disease progression and the many factors that contribute to disease progression heterogeneity. Novel therapeutic targets and trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination are required. The integration of robust clinical data sets is viewed as a powerful approach to hasten medical discovery and therapies, as is being realized across diverse disease conditions employing big data analytics for healthcare. The application of lessons learned from parallel efforts is critical to identify barriers and enable a viable path forward. A roadmap is presented for a regulatory, academic, industry and advocacy driven integrated initiative that aims to facilitate and streamline new drug trials and registrations in Parkinson's disease

The impact of helminths on the response to immunization and on the incidence of infection and disease in childhood in Uganda: design of a randomized, double-blind, placebo-controlled, factorial trial of deworming interventions delivered in pregnancy and early childhood [ISRCTN32849447]

BACKGROUND: Helminths have profound effects on the immune response, allowing long-term survival of parasites with minimal damage to the host. Some of these effects "spill-over", altering responses to non-helminth antigens or allergens. It is suggested that this may lead to impaired responses to immunizations and infections, while conferring benefits against inflammatory responses in allergic and autoimmune disease. These effects might develop in utero, through exposure to maternal helminth infections, or through direct exposure in later life. PURPOSE: To determine the effects of helminths and their treatment in pregnancy and in young children on immunological and disease outcomes in childhood. METHODS: The trial has three randomized, double-blind, placebo-controlled interventions at two times, in two people: a pregnant woman and her child. Pregnant women are randomized to albendazole or placebo and praziquantel or placebo. At age 15 months their children are randomized to three-monthly albendazole or placebo, to continue to age five years. The proposed designation for this sequence of interventions is a 2 x 2(x2) factorial design. Children are immunized with BCG and against polio, Diphtheria, tetanus, Pertussis, Haemophilus, hepatitis B and measles. Primary immunological outcomes are responses to BCG antigens and tetanus toxoid in whole blood cytokine assays and antibody assays at one, three and five years of age. Primary disease outcomes are incidence of malaria, pneumonia, diarrhoea, tuberculosis, measles, vertical HIV transmission, and atopic disease episodes, measured at clinic visits and twice-monthly home visits. Effects on anaemia, growth and intellectual development are also assessed. CONCLUSION: This trial, with a novel design comprising related interventions in pregnant women and their offspring, is the first to examine effects of helminths and their treatment in pregnancy and early childhood on immunological, infectious disease and allergic disease outcomes. The results will enhance understanding of both detrimental and beneficial effects of helminth infection and inform policy

Population tobacco control interventions and their effects on social inequalities in smoking: placing an equity lens on existing systematic reviews

BACKGROUND: With smoking increasingly confined to lower socio-economic groups, the tobacco control community has been urged to identify which population-level tobacco control interventions work in order to help tackle smoking-related health inequalities. Systematic reviews have a crucial role to play in this task. This overview was therefore carried out in order to (i) summarise the evidence from existing systematic reviews of population-level tobacco control interventions, and (ii) assess the need for a new systematic review of primary studies, with the aim of assessing the differential effects of such interventions. METHODS: Systematic review methods were used to evaluate existing systematic reviews that assessed a population-level tobacco control intervention and which reported characteristics of included participants in terms of at least one socio-demographic or socio-economic factor. RESULTS: Nineteen systematic reviews were included. Four reviews assessed interventions aimed at the population level alone, whilst fifteen included at least one primary study that examined this type of intervention. Four reviews assessed youth access restrictions, one assessed the effects of increasing the unit price of tobacco, and six assessed smoking bans or restrictions. Of the eight remaining reviews, six assessed multi-component community based interventions, in which the population-level interventions were part of a wider tobacco control programme, and two assessed the impact of smoking bans or restrictions in reducing exposure to environmental tobacco smoke. We found tentative evidence that the effect of increasing the unit price of tobacco products may vary between ethnic and socio-economic groups, and between males and females. However, differences in the context and the results of different reviews made it difficult to draw any firm conclusions. Few identified reviews explicitly attempted to examine differences in intervention effects between socio-demographic groups. Therefore on the basis of these reviews the potential for smoking bans, and youth access restrictions to decrease social inequalities in smoking remains unknown. CONCLUSION: There is preliminary evidence that increases in the unit price of tobacco may have the potential to reduce smoking related health inequalities. There is a need for equity effects to be explicitly evaluated in future systematic reviews and in primary research assessing the effects of population tobacco control interventions

Somatic mutations affect key pathways in lung adenocarcinoma

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well- classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers - including NF1, APC, RB1 and ATM - and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.National Human Genome Research InstituteWe thank A. Lash, M.F. Zakowski, M.G. Kris and V. Rusch for intellectual contributions, and many members of the Baylor Human Genome Sequencing Center, the Broad Institute of Harvard and MIT, and the Genome Center at Washington University for support. This work was funded by grants from the National Human Genome Research Institute to E.S.L., R.A.G. and R.K.W.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62885/1/nature07423.pd

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

PSY 230 Developmental Psychology

The purpose of this course is to\ud provide an overview of Development from the fetal period through old age.\ud Dominant theories in the field will be introduced. From these, we will extract the\ud general principles that allow us to identify periods of stasis and change over the\ud course of human life

Early Vocabulary, Number Word Meaning, and the Analog Magnitude System

The purpose of this project is to investigate the unique contributions of early Vocabulary Size and the Analog Magnitude System (AMS) to children's performance in the Give-N Task. Although there is good test-retest reliability for children who score as non-knowers or Cardinal Principle-knowers on this task, there is evidence of a high level of variability for children between these two levels (subset-knowers). Of interest is whether this variability is uniquely explained by both children's highest level of AMS representations and their Vocabulary Size. In a model incorporating Age, Expressive Vocabulary, AMS acuity, and variability in a Number Estimation Task, Libertus (2016) found significant prediction to overall math ability only from Age and Estimation variability but not from Expressive Vocabulary or AMS acuity. No significant predictors were found for informal math ability (which included the Cardinality Principle). In another study, Gunderson et al. (2015) concluded that Number Word Meaning and understanding of the Cardinal Principle, while developing in parallel, are nevertheless independent. Of interest is the role of receptive Vocabulary Size in supporting Number Word Meaning through the mechanism of Number Word Vocabulary. In a meta-analysis of 344 research articles, the authors found an overall relation of r=.42 between vocabulary and mathematics (Peng et al., 2020) with the strength of the correlation varying across receptive, expressive, and receptive+expressive language measurement (rs = .44, .39, and .50, respectively). More recently, Silver and Libertus (2022) concluded that although there is prior work on how language and other environmental factors shape symbolic math skills in children and adults, there is limited work on how these factors are related to early number word acquisition. We propose that there is both a symbolic and a nonsymbolic route to the acquisition of Number Word Meaning such that both Vocabulary Size and the Analog Magnitude System uniquely and independently support the development of Number Word Meaning as measured in the Give-N Task (Wynn, 1990)