Replication and exploratory analysis of 24 candidate risk polymorphisms for neural tube defects.

BackgroundNeural tube defects (NTDs), which are among the most common congenital malformations, are influenced by environmental and genetic factors. Low maternal folate is the strongest known contributing factor, making variants in genes in the folate metabolic pathway attractive candidates for NTD risk. Multiple studies have identified nominally significant allelic associations with NTDs. We tested whether associations detected in a large Irish cohort could be replicated in an independent population.MethodsReplication tests of 24 nominally significant NTD associations were performed in racially/ethnically matched populations. Family-based tests of fifteen nominally significant single nucleotide polymorphisms (SNPs) were repeated in a cohort of NTD trios (530 cases and their parents) from the United Kingdom, and case-control tests of nine nominally significant SNPs were repeated in a cohort (190 cases, 941 controls) from New York State (NYS). Secondary hypotheses involved evaluating the latter set of nine SNPs for NTD association using alternate case-control models and NTD groupings in white, African American and Hispanic cohorts from NYS.ResultsOf the 24 SNPs tested for replication, ADA rs452159 and MTR rs10925260 were significantly associated with isolated NTDs. Of the secondary tests performed, ARID1A rs11247593 was associated with NTDs in whites, and ALDH1A2 rs7169289 was associated with isolated NTDs in African Americans.ConclusionsWe report a number of associations between SNP genotypes and neural tube defects. These associations were nominally significant before correction for multiple hypothesis testing. These corrections are highly conservative for association studies of untested hypotheses, and may be too conservative for replication studies. We therefore believe the true effect of these four nominally significant SNPs on NTD risk will be more definitively determined by further study in other populations, and eventual meta-analysis

Crossreactive T Cells Spotlight the Germline Rules for αβ T Cell-Receptor Interactions with MHC Molecules

SummaryTo test whether highly crossreactive αβ T cell receptors (TCRs) produced during limited negative selection best illustrate evolutionarily conserved interactions between TCR and major histocompatibility complex (MHC) molecules, we solved the structures of three TCRs bound to the same MHC II peptide (IAb-3K). The TCRs had similar affinities for IAb-3K but varied from noncrossreactive to extremely crossreactive with other peptides and MHCs. Crossreactivity correlated with a shrinking, increasingly hydrophobic TCR-ligand interface, involving fewer TCR amino acids. A few CDR1 and CDR2 amino acids dominated the most crossreactive TCR interface with MHC, including Vβ8 48Y and 54E and Vα4 29Y, arranged to impose the familiar diagonal orientation of TCR on MHC. These interactions contribute to MHC binding by other TCRs using related V regions, but not usually so dominantly. These data show that crossreactive TCRs can spotlight the evolutionarily conserved features of TCR-MHC interactions and that these interactions impose the diagonal docking of TCRs on MHC

Changing the Environment Based on Empowerment as Intrinsic Motivation

This is an open access article distributed under the Creative Commons Attribution License CC BY 3.0 which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.One aspect of intelligence is the ability to restructure your own environment so that the world you live in becomes more beneficial to you. In this paper we investigate how the information-theoretic measure of agent empowerment can provide a task-independent, intrinsic motivation to restructure the world. We show how changes in embodiment and in the environment change the resulting behaviour of the agent and the artefacts left in the world. For this purpose, we introduce an approximation of the established empowerment formalism based on sparse sampling, which is simpler and significantly faster to compute for deterministic dynamics. Sparse sampling also introduces a degree of randomness into the decision making process, which turns out to beneficial for some cases. We then utilize the measure to generate agent behaviour for different agent embodiments in a Minecraft-inspired three dimensional block world. The paradigmatic results demonstrate that empowerment can be used as a suitable generic intrinsic motivation to not only generate actions in given static environments, as shown in the past, but also to modify existing environmental conditions. In doing so, the emerging strategies to modify an agent’s environment turn out to be meaningful to the specific agent capabilities, i.e., de facto to its embodiment.Peer reviewedFinal Published versio

A minimal binding footprint on CD1d-glycolipid is a basis for selection of the unique human NKT TCR

Although it has been established how CD1 binds a variety of lipid antigens (Ag), data are only now emerging that show how αβ T cell receptors (TCRs) interact with CD1-Ag. Using the structure of the human semiinvariant NKT TCR–CD1d–α-galactosylceramide (α-GalCer) complex as a guide, we undertook an alanine scanning mutagenesis approach to define the energetic basis of this interaction between the NKT TCR and CD1d. Moreover, we explored how analogues of α-GalCer affected this interaction. The data revealed that an identical energetic footprint underpinned the human and mouse NKT TCR–CD1d–α-GalCer cross-reactivity. Some, but not all, of the contact residues within the Jα18-encoded invariant CDR3α loop and Vβ11-encoded CDR2β loop were critical for recognizing CD1d. The residues within the Vα24-encoded CDR1α and CDR3α loops that contacted the glycolipid Ag played a smaller energetic role compared with the NKT TCR residues that contacted CD1d. Collectively, our data reveal that the region distant to the protruding Ag and directly above the F′ pocket of CD1d was the principal factor in the interaction with the NKT TCR. Accordingly, although the structural footprint at the NKT TCR–CD1d–α-GalCer is small, the energetic footprint is smaller still, and reveals the minimal requirements for CD1d restriction

Crying and feeding problems in infancy and cognitive outcome in preschool children born at risk : a prospective population study

Objective: To investigate whether regulatory problems, i.e., crying and feeding problems in infants > 3 months of age, predict cognitive outcome in preschool children born at risk even when controlled for confounding factors. Methods: A prospective longitudinal study of children born in a geographically defined area in Germany. N = 4427 children of 6705 eligible survivors (66%) participated at all four assessment points (neonatal, 5, 20, and 56 months of age). Excessive crying and feeding problems were measured at 5 months. Mental development was assessed with the Griffiths Scale at 20 months, and cognitive assessments were conducted at 56 months. Neonatal complications, neurological, and psychosocial factors were controlled as confounders in structural equation modeling and analyses of variance. Results: One in five infants suffered from single crying or feeding problems, and 2% had multiple regulatory problems, i.e., combined crying and feeding problems at 5 months. In girls, regulatory problems were directly predictive of lower cognition at 56 months, even when controlled for confounders, whereas in boys, the influence on cognition at 56 months was mediated by low mental development at 20 months. Both in boys and girls, shortened gestational age, neonatal neurological complications, and poor parent-infant relationship were predictive of regulatory problems at 5 months and lower cognition at 56 months. Conclusion: Regulatory problems in infancy have a small but significant adverse effect on cognitive development

TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells

TET proteins oxidize 5-methylcytosine in DNA to 5-hydroxymethylcytosine and other oxidation products. We found that simultaneous deletion of Tet2 and Tet3 in mouse CD4+CD8+ double-positive thymocytes resulted in dysregulated development and proliferation of invariant natural killer T cells (iNKT cells). Tet2-Tet3 double-knockout (DKO) iNKT cells displayed pronounced skewing toward the NKT17 lineage, with increased DNA methylation and impaired expression of genes encoding the key lineage-specifying factors T-bet and ThPOK. Transfer of purified Tet2-Tet3 DKO iNKT cells into immunocompetent recipient mice resulted in an uncontrolled expansion that was dependent on the nonclassical major histocompatibility complex (MHC) protein CD1d, which presents lipid antigens to iNKT cells. Our data indicate that TET proteins regulate iNKT cell fate by ensuring their proper development and maturation and by suppressing aberrant proliferation mediated by the T cell antigen receptor (TCR)

The immune cell landscape in kidneys of patients with lupus nephritis.

Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies

A gender perspective on entrepreneurial leadership:female leaders in Kazakhstan

The paper proposes a conceptual model to understand female entrepreneurial leadership through an exploration of the perceptions and experiences of women entrepreneurs within their leadership roles. The paper addresses an existing knowledge gap on entrepreneurial leadership by bringing together three key constructs of gender, leadership and entrepreneurship. We apply Stewart's model of role demands-constraints-choices (DCC) to women entrepreneurs in Kazakhstan in order to understand their perceptions of the demands, constraints and choices they experience within their leadership roles. The results of in-depth interviews with women entrepreneurs present deeper conceptualization of their leadership enactment as a co-developing, co-constructed relational activity between leaders and others in their wider business environments and context

Treg depletion licenses T cell-driven HEV neogenesis and promotes tumor destruction

T-cell infiltration into tumors represents a critical bottleneck for immune-mediated control of cancer. We previously showed that this bottleneck can be overcome by depleting immunosuppressive Foxp3+ regulatory T cells (Tregs), a process which can increase frequencies of tumor-infiltrating lymphocytes (TILs) through promoting development of specialized portals for lymphocyte entry, namely high endothelial venules (HEVs). In this paper, we used a carcinogen-induced tumor model, that allows for co-evolution of the tumor microenvironment and the immune response, to demonstrate that Treg depletion not only results in widespread disruption to HEV networks in lymph nodes (LNs) but activates CD8+ T cells, which then drive intratumoral HEV development. Formation of these vessels contrasts with ontogenic HEV development in LNs in that the process is dependent on TNF receptor and independent of lymphotoxin beta receptor-mediated signaling. These intratumoral HEVs do not express the chemokine CCL21, revealing a previously undescribed intratumoral blood vessel phenotype. We propose a model whereby Treg depletion enables a self-amplifying loop of T-cell activation, which promotes HEV development, T-cell infiltration, and ultimately, tumor destruction. The findings point to a need to test for HEV development as part of ongoing clinical studies in patients with cancer