Assembly and architecture of the EBV B cell entry triggering complex.

Epstein-Barr Virus (EBV) is an enveloped double-stranded DNA virus of the gammaherpesvirinae sub-family that predominantly infects humans through epithelial cells and B cells. Three EBV glycoproteins, gH, gL and gp42, form a complex that targets EBV infection of B cells. Human leukocyte antigen (HLA) class II molecules expressed on B cells serve as the receptor for gp42, triggering membrane fusion and virus entry. The mechanistic role of gHgL in herpesvirus entry has been largely unresolved, but it is thought to regulate the activation of the virally-encoded gB protein, which acts as the primary fusogen. Here we study the assembly and function of the reconstituted B cell entry complex comprised of gHgL, gp42 and HLA class II. The structure from negative-stain electron microscopy provides a detailed snapshot of an intermediate state in EBV entry and highlights the potential for the triggering complex to bring the two membrane bilayers into proximity. Furthermore, gHgL interacts with a previously identified, functionally important hydrophobic pocket on gp42, defining the overall architecture of the complex and playing a critical role in membrane fusion activation. We propose a macroscopic model of the initiating events in EBV B cell fusion centered on the formation of the triggering complex in the context of both viral and host membranes. This model suggests how the triggering complex may bridge the two membrane bilayers, orienting critical regions of the N- and C- terminal ends of gHgL to promote the activation of gB and efficient membrane fusion

Part II. high-dose methotrexate with leucovorin rescue for severe COVID-19: An immune stabilization strategy for SARS-CoV-2 induced \u27PANIC\u27 attack

Here, in Part II of a duology on the characterization and potential treatment for COVID-19, we characterize the application of an innovative treatment regimen for the prevention of the transition from mild to severe COVID-19, as well as detail an intensive immunotherapy intervention hypothesis. We propose as a putative randomized controlled trial that high-dose methotrexate with leucovorin (HDMTX-LR) rescue can abolish \u27PANIC\u27, thereby \u27left-shifting\u27 severe COVID-19 patients to the group majority of those infected with SARS-CoV-2, who are designated as having mild, even asymptomatic, disease. HDMTX-LR is endowed with broadly pleiotropic properties and is a repurposed, generic, inexpensive, and widely available agent which can be administered early in the course of severe COVID-19 thus rescuing the critical and irreplaceable gas-exchange alveoli. Further, we describe a preventative treatment intervention regimen for those designated as having mild to moderate COVID-19 disease, but who exhibit features which herald the transition to the severe variant of this disease. Both of our proposed hypothesis-driven questions should be urgently subjected to rigorous assessment in the context of randomized controlled trials, in order to confirm or refute the contention that the approaches characterized herein, are in fact capable of exerting mitigating, if not abolishing, effects upon SARS-CoV-2 triggered \u27PANIC Attack\u27. Confirmation of our immunotherapy hypothesis would have far-reaching ramifications for the current pandemic, along with yielding invaluable lessons which could be leveraged to more effectively prepare for the next challenge to global health

Father–toddler communication in low-income families: The role of paternal education and depressive symptoms

Using data from a racially and ethnically diverse sample of low-income fathers and their 2-year-old children who participated in the Early Head Start Research Evaluation Project (n = 80), the current study explored the association among paternal depressive symptoms and level of education, fathers’ language to their children, and children’s language skills. There were three main findings. First, there was large variability in the quality and quantity of language used during linguistic interactions between low-income fathers and their toddlers. Second, fathers with higher levels of education had children who spoke more (i.e. utterances) and had more diverse vocabularies (i.e. word types) than fathers with lower levels of education. However, fathers with more depressive symptoms had children with less grammatically complex language (i.e. smaller MLUs) than fathers with fewer depressive symptoms. Third, direct effects between fathers’ depressive symptoms and level of education and children’s language outcomes were partially mediated by fathers’ quantity and quality of language

W(h)ither Fossils? Studying Morphological Character Evolution in the Age of Molecular Sequences

A major challenge in the post-genomics era will be to integrate molecular sequence data from extant organisms with morphological data from fossil and extant taxa into a single, coherent picture of phylogenetic relationships; only then will these phylogenetic hypotheses be effectively applied to the study of morphological character evolution. At least two analytical approaches to solving this problem have been utilized: (1) simultaneous analysis of molecular sequence and morphological data with fossil taxa included as terminals in the analysis, and (2) the molecular scaffold approach, in which morphological data are analyzed over a molecular backbone (with constraints that force extant taxa into positions suggested by sequence data). The perceived obstacles to including fossil taxa directly in simultaneous analyses of morphological and molecular sequence data with extant taxa include: (1) that fossil taxa are missing the molecular sequence portion of the character data; (2) that morphological characters might be misleading due to convergence; and (3) character weighting, specifically how and whether to weight characters in the morphological partition relative to characters in the molecular sequence data partition. The molecular scaffold has been put forward as a potential solution to at least some of these problems. Using examples of simultaneous analyses from the literature, as well as new analyses of previously published morphological and molecular sequence data matrices for extant and fossil Chiroptera (bats), we argue that the simultaneous analysis approach is superior to the molecular scaffold approach, specifically addressing the problems to which the molecular scaffold has been suggested as a solution. Finally, the application of phylogenetic hypotheses including fossil taxa (whatever their derivation) to the study of morphological character evolution is discussed, with special emphasis on scenarios in which fossil taxa are likely to be most enlightening: (1) in determining the sequence of character evolution; (2) in determining the timing of character evolution; and (3) in making inferences about the presence or absence of characteristics in fossil taxa that may not be directly observable in the fossil record. Published By: Missouri Botanical Garde

Socioeconomic inequalities in pregnancy outcome associated with Down syndrome: a population-based study.

OBJECTIVE: To investigate socioeconomic inequalities in outcome of pregnancy associated with Down syndrome (DS) compared with other congenital anomalies screened for during pregnancy. DESIGN AND SETTING: Retrospective population-based registry study (East Midlands & South Yorkshire in England). PARTICIPANTS: All registered cases of DS and nine selected congenital anomalies with poor prognostic outcome (the UK Fetal Anomaly Screening Programme (FASP)9) with an end of pregnancy date between 1 January 1998 and 31 December 2007. MAIN OUTCOME MEASURES: Poisson regression models were used to explore outcome measures, including socioeconomic variation in rates of anomaly; antenatal detection; pregnancy outcome; live birth incidence and neonatal mortality. Deprivation was measured using the Index of Multiple Deprivation 2004 at super output area level. RESULTS: There were 1151 cases of DS and 1572 cases of the nine severe anomalies combined. The overall rate of antenatal detection was 57% for DS, which decreased with increasing deprivation (rate ratio comparing the most deprived tenth with the least deprived: 0.76 (0.60 to 0.97)). Antenatal detection rates were considerably higher for FASP9 anomalies (86%), with no evidence of a trend with deprivation (0.99 95% CI (0.84 to 1.17)). The termination of pregnancy rate following antenatal diagnosis was higher for DS (86%) than the FASP9 anomalies (70%). Both groups showed wide socioeconomic variation in the termination of pregnancy rate (rate ratio: DS: 0.76 (0.58 to 0.99); FASP9 anomalies: 0.80 (0.65 to 0.97)). Consequently, socioeconomic inequalities in live birth and neonatal mortality rates associated with these anomalies arise that were not observed in utero. CONCLUSIONS: Socioeconomic inequalities exist in the antenatal detection of DS, and subsequent termination rates are much higher for DS than other anomalies. Termination rates for all anomalies are lower in more deprived areas leading to wide socioeconomic inequalities in live born infants with a congenital anomaly, particularly DS, and subsequent neonatal mortality

Identifying the science and technology dimensions of emerging public policy issues through horizon scanning

Public policy requires public support, which in turn implies a need to enable the public not just to understand policy but also to be engaged in its development. Where complex science and technology issues are involved in policy making, this takes time, so it is important to identify emerging issues of this type and prepare engagement plans. In our horizon scanning exercise, we used a modified Delphi technique [1]. A wide group of people with interests in the science and policy interface (drawn from policy makers, policy adviser, practitioners, the private sector and academics) elicited a long list of emergent policy issues in which science and technology would feature strongly and which would also necessitate public engagement as policies are developed. This was then refined to a short list of top priorities for policy makers. Thirty issues were identified within broad areas of business and technology; energy and environment; government, politics and education; health, healthcare, population and aging; information, communication, infrastructure and transport; and public safety and national security.Public policy requires public support, which in turn implies a need to enable the public not just to understand policy but also to be engaged in its development. Where complex science and technology issues are involved in policy making, this takes time, so it is important to identify emerging issues of this type and prepare engagement plans. In our horizon scanning exercise, we used a modified Delphi technique [1]. A wide group of people with interests in the science and policy interface (drawn from policy makers, policy adviser, practitioners, the private sector and academics) elicited a long list of emergent policy issues in which science and technology would feature strongly and which would also necessitate public engagement as policies are developed. This was then refined to a short list of top priorities for policy makers. Thirty issues were identified within broad areas of business and technology; energy and environment; government, politics and education; health, healthcare, population and aging; information, communication, infrastructure and transport; and public safety and national security

Genetic Analysis of a Novel Human Adenovirus with a Serologically Unique Hexon and a Recombinant Fiber Gene

In February of 1996 a human adenovirus (formerly known as Ad-Cor-96-487) was isolated from the stool of an AIDS patient who presented with severe chronic diarrhea. To characterize this apparently novel pathogen of potential public health significance, the complete genome of this adenovirus was sequenced to elucidate its origin. Bioinformatic and phylogenetic analyses of this genome demonstrate that this virus, heretofore referred to as HAdV-D58, contains a novel hexon gene as well as a recombinant fiber gene. In addition, serological analysis demonstrated that HAdV-D58 has a different neutralization profile than all previously characterized HAdVs. Bootscan analysis of the HAdV-D58 fiber gene strongly suggests one recombination event