A novel mechanism for binding of galactose-terminated glycans by the C-type carbohydrate recognition domain in blood dendritic cell antigen 2

Blood dendritic cell antigen 2 (BDCA-2; also designated CLEC4C or CD303) is uniquely expressed on plasmacytoid dendritic cells. Stimulation of BDCA-2 with antibodies leads to an anti-inflammatory response in these cells, but the natural ligands for the receptor are not known. The C-type carbohydrate recognition domain in the extracellular portion of BDCA-2 contains a signature motif typical of C-type animal lectins that bind mannose, glucose, or GlcNAc, yet it has been reported that BDCA-2 binds selectively to galactose-terminated, biantennary N-linked glycans. A combination of glycan array analysis and binding competition studies with monosaccharides and natural and synthetic oligosaccharides have been used to define the binding epitope for BDCA-2 as the trisaccharide Galβ1–3/4GlcNAcβ1–2Man. X-ray crystallography and mutagenesis studies show that mannose is ligated to the conserved Ca2+ in the primary binding site that is characteristic of C-type carbohydrate recognition domains, and the GlcNAc and galactose residues make additional interactions in a wide, shallow groove adjacent to the primary binding site. As predicted from these studies, BDCA-2 binds to IgG, which bears galactose-terminated glycans that are not commonly found attached to other serum glycoproteins. Thus, BDCA-2 has the potential to serve as a previously unrecognized immunoglobulin Fc receptor

Common Polymorphisms in Human Langerin Change Specificity for Glycan Ligands

Langerin, a C-type lectin on Langerhans cells, mediates carbohydrate-dependent uptake of pathogens in the first step of antigen presentation to the adaptive immune system. Langerin binds a diverse range of carbohydrates including high mannose structures, fucosylated blood group antigens, and glycans with terminal 6-sulfated galactose. Mutagenesis and quantitative binding assays indicate that salt bridges between the sulfate group and two lysine residues compensate for the nonoptimal binding of galactose at the primary Ca(2+) site. A commonly occurring single nucleotide polymorphism (SNP) in human langerin results in change of one of these lysine residues, Lys-313, to isoleucine. Glycan array screening reveals that this amino acid change abolishes binding to oligosaccharides with terminal 6SO(4)-Gal and enhances binding to oligosaccharides with terminal GlcNAc residues. Structural analysis shows that enhanced binding to GlcNAc may result from Ile-313 packing against the N-acetyl group. The K313I polymorphism is tightly linked to another SNP that results in the change N288D, which reduces affinity for glycan ligands by destabilizing the Ca(2+)-binding site. Langerin with Asp-288 and Ile-313 shows no binding to 6SO(4)-Gal-terminated glycans and increased binding to GlcNAc-terminated structures, but overall decreased binding to glycans. Altered langerin function in individuals with the linked N288D and K313I polymorphisms may affect susceptibility to infection by microorganisms

Is Lamarckian evolution relevant to medicine?

BACKGROUND: 200 years have now passed since Darwin was born and scientists around the world are celebrating this important anniversary of the birth of an evolutionary visionary. However, the theories of his colleague Lamarck are treated with considerably less acclaim. These theories centre on the tendency for complexity to increase in organisms over time and the direct transmission of phenotypic traits from parents to offspring. DISCUSSION: Lamarckian concepts, long thought of no relevance to modern evolutionary theory, are enjoying a quiet resurgence with the increasing complexity of epigenetic theories of inheritance. There is evidence that epigenetic alterations, including DNA methylation and histone modifications, are transmitted transgenerationally, thus providing a potential mechanism for environmental influences to be passed from parents to offspring: Lamarckian evolution. Furthermore, evidence is accumulating that epigenetics plays an important role in many common medical conditions. SUMMARY: Epigenetics allows the peaceful co-existence of Darwinian and Lamarckian evolution. Further efforts should be exerted on studying the mechanisms by which this occurs so that public health measures can be undertaken to reverse or prevent epigenetic changes important in disease susceptibility. Perhaps in 2059 we will be celebrating the anniversary of both Darwin and Lamarck

Effectiveness of early intervention programs for parents of preterm infants: a meta-review of systematic reviews

Background: Various intervention programs exist for parents of preterm babies and some systematic reviews (SRs) have synthesised the evidence of their effectiveness. These reviews are, however, limited to specific interventions, components, or outcomes, and a comprehensive evidence base is lacking. The aim of this meta-review was to appraise and meta-synthesise the evidence from existing SRs to provide a comprehensive evidence base on the effectiveness of interventions for parents of preterm infants on parental and infant outcomes. Methods: We conducted a comprehensive search of the following databases to identify relevant SRs: Cochrane library, Web of science, EMBASE, CINAHL, British Nursing Index, PsycINFO, Medline, ScienceDirect, Scopus, IBSS, DOAJ, ERIC, EPPI-Centre, PROSPERO, WHO Library. Additional searches were conducted using authors’ institutional libraries, Google Scholar, and the reference lists of identified reviews. Identified articles were screened in two stages against an inclusion criteria with titles and abstracts screened first followed by full-text screening. Selected SRs were appraised using the AMSTAR tool. Extracted data using a predesigned tool were synthesised narratively examining the direction of impact on outcomes. Results: We found 11 SRs eligible for inclusion that synthesised a total of 343 quantitative primary studies. The average quality of the SRs was ‘medium’. Thirty four interventions were reported across the SRs with considerable heterogeneity in the structural framework and the targeted outcomes that included maternal-infant dyadic, maternal/parental, and infant outcomes. Among all interventions, Kangaroo Care (KC) showed the most frequent positive impact across outcomes (n = 19) followed by Mother Infant Transaction Program (MITP) (n = 14). Other interventions with most consistent positive impact on infant outcomes were Modified-Mother Infant Transaction Program (M-MITP) (n = 6), Infant Health and Development Program (IHDP) (n = 5) and Creating Opportunities for Parent Empowerment (COPE) (n = 5). Overall, interventions with both home and facility based components showed the most frequent positive impact across outcomes. Conclusions: Neonatal care policy and planning for preterm babies should consider the implementation of interventions with most positive impact on outcomes. The heterogeneity in interventions and outcomes calls for the development and implementation of an integrated program for parents of preterm infants with a clearly defined global set of parental and infant outcomes

Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort

Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene

Discrete approaches to quantum gravity in four dimensions

The construction of a consistent theory of quantum gravity is a problem in theoretical physics that has so far defied all attempts at resolution. One ansatz to try to obtain a non-trivial quantum theory proceeds via a discretization of space-time and the Einstein action. I review here three major areas of research: gauge-theoretic approaches, both in a path-integral and a Hamiltonian formulation, quantum Regge calculus, and the method of dynamical triangulations, confining attention to work that is strictly four-dimensional, strictly discrete, and strictly quantum in nature.Comment: 33 pages, invited contribution to Living Reviews in Relativity; the author welcomes any comments and suggestion

Pre-Clinical Drug Prioritization via Prognosis-Guided Genetic Interaction Networks

The high rates of failure in oncology drug clinical trials highlight the problems of using pre-clinical data to predict the clinical effects of drugs. Patient population heterogeneity and unpredictable physiology complicate pre-clinical cancer modeling efforts. We hypothesize that gene networks associated with cancer outcome in heterogeneous patient populations could serve as a reference for identifying drug effects. Here we propose a novel in vivo genetic interaction which we call ‘synergistic outcome determination’ (SOD), a concept similar to ‘Synthetic Lethality’. SOD is defined as the synergy of a gene pair with respect to cancer patients' outcome, whose correlation with outcome is due to cooperative, rather than independent, contributions of genes. The method combines microarray gene expression data with cancer prognostic information to identify synergistic gene-gene interactions that are then used to construct interaction networks based on gene modules (a group of genes which share similar function). In this way, we identified a cluster of important epigenetically regulated gene modules. By projecting drug sensitivity-associated genes on to the cancer-specific inter-module network, we defined a perturbation index for each drug based upon its characteristic perturbation pattern on the inter-module network. Finally, by calculating this index for compounds in the NCI Standard Agent Database, we significantly discriminated successful drugs from a broad set of test compounds, and further revealed the mechanisms of drug combinations. Thus, prognosis-guided synergistic gene-gene interaction networks could serve as an efficient in silico tool for pre-clinical drug prioritization and rational design of combinatorial therapies

Widespread Hypomethylation Occurs Early and Synergizes with Gene Amplification during Esophageal Carcinogenesis

Although a combination of genomic and epigenetic alterations are implicated in the multistep transformation of normal squamous esophageal epithelium to Barrett esophagus, dysplasia, and adenocarcinoma, the combinatorial effect of these changes is unknown. By integrating genome-wide DNA methylation, copy number, and transcriptomic datasets obtained from endoscopic biopsies of neoplastic progression within the same individual, we are uniquely able to define the molecular events associated progression of Barrett esophagus. We find that the previously reported global hypomethylation phenomenon in cancer has its origins at the earliest stages of epithelial carcinogenesis. Promoter hypomethylation synergizes with gene amplification and leads to significant upregulation of a chr4q21 chemokine cluster and other transcripts during Barrett neoplasia. In contrast, gene-specific hypermethylation is observed at a restricted number of loci and, in combination with hemi-allelic deletions, leads to downregulatation of selected transcripts during multistep progression. We also observe that epigenetic regulation during epithelial carcinogenesis is not restricted to traditionally defined “CpG islands,” but may also occur through a mechanism of differential methylation outside of these regions. Finally, validation of novel upregulated targets (CXCL1 and 3, GATA6, and DMBT1) in a larger independent panel of samples confirms the utility of integrative analysis in cancer biomarker discovery

The Early Positive Approaches to Support (E-PAtS) study: study protocol for a feasibility cluster randomised controlled trial of a group programme (E-PAtS) for family caregivers of young children with intellectual disability

Background: Children with intellectual disability have an IQ < 70, associated deficits in adaptive skills and are at increased risk of having clinically concerning levels of behaviour problems. In addition, parents of children with intellectual disability are likely to report high levels of mental health and other psychological problems. The Early Positive Approaches to Support (E-PAtS) programme for family caregivers of young children (5 years and under) with intellectual and developmental disabilities is a group-based intervention which aims to enhance parental psychosocial wellbeing and service access and support positive development for children. The aim of this study is to assess the feasibility of delivering E-PAtS to family caregivers of children with intellectual disability by community parenting support service provider organisations. The study will inform a potential, definitive RCT of the effectiveness and cost-effectiveness of E-PAtS. Methods: This study is a feasibility cluster randomised controlled trial, with embedded process evaluation. Up to 2 family caregivers will be recruited from 64 families with a child (18 months to 5 years) with intellectual disability at research sites in the UK. Participating families will be allocated to intervention: control on a 1:1 basis; intervention families will be offered the E-PAtS programme immediately, continuing to receive usual practice, and control participants will be offered the opportunity to attend the E-PAtS programme at the end of the follow-up period and will continue to receive usual practice. Data will be collected at baseline, 3 months post-randomisation and 12 months post-randomisation. The primary aim is to assess feasibility via the assessment of: recruitment of service provider organisations; participant recruitment; randomisation; retention; intervention adherence; intervention fidelity and the views of participants, intervention facilitators and service provider organisations regarding intervention delivery and study processes. The secondary aim is preliminary evaluation of a range of established outcome measures for individual family members, subsystem relationships and overall family functioning, plus additional health economic outcomes for inclusion in a future definitive trial. Discussion: The results of this study will inform a potential future definitive trial, to evaluate the effectiveness and cost-effectiveness of the E-PAtS intervention to improve parental psychosocial wellbeing. Such a trial would have significant scientific impact internationally in the intellectual disability field