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

Toward cognitively constrained models of language processing:A review

Language processing is not an isolated capacity, but is embedded in other aspects of our cognition. However, it is still largely unexplored to what extent and how language processing interacts with general cognitive resources. This question can be investigated with cognitively constrained computational models, which simulate the cognitive processes involved in language processing. The theoretical claims implemented in cognitive models interact with general architectural constraints such as memory limitations. This way, it generates new predictions that can be tested in experiments, thus generating new data that can give rise to new theoretical insights. This theory-model-experiment cycle is a promising method for investigating aspects of language processing that are difficult to investigate with more traditional experimental techniques. This review specifically examines the language processing models of Lewis and Vasishth (2005), Reitter et al. (2011), and Van Rij et al. (2010), all implemented in the cognitive architecture Adaptive Control of Thought—Rational (Anderson et al., 2004). These models are all limited by the assumptions about cognitive capacities provided by the cognitive architecture, but use different linguistic approaches. Because of this, their comparison provides insight into the extent to which assumptions about general cognitive resources influence concretely implemented models of linguistic competence. For example, the sheer speed and accuracy of human language processing is a current challenge in the field of cognitive modeling, as it does not seem to adhere to the same memory and processing capacities that have been found in other cognitive processes. Architecture-based cognitive models of language processing may be able to make explicit which language-specific resources are needed to acquire and process natural language. The review sheds light on cognitively constrained models of language processing from two angles: we discuss (1) whether currently adopted cognitive assumptions meet the requirements for language processing, and (2) how validated cognitive architectures can constrain linguistically motivated models, which, all other things being equal, will increase the cognitive plausibility of these models. Overall, the evaluation of cognitively constrained models of language processing will allow for a better understanding of the relation between data, linguistic theory, cognitive assumptions, and explanation

Addiction to Runx1 is partially attenuated by loss of p53 in the Eμ-Myc lymphoma model

The Runx genes function as dominant oncogenes that collaborate potently with Myc or loss of p53 to induce lymphoma when over-expressed. Here we examined the requirement for basal Runx1 activity for tumor maintenance in the Eµ-Myc model of Burkitt’s lymphoma. While normal Runx1fl/fl lymphoid cells permit mono-allelic deletion, primary Eµ-Myc lymphomas showed selection for retention of both alleles and attempts to enforce deletion in vivo led to compensatory expansion of p53null blasts retaining Runx1. Surprisingly, Runx1 could be excised completely from established Eµ- Myc lymphoma cell lines in vitro without obvious effects on cell phenotype. Established lines lacked functional p53, and were sensitive to death induced by introduction of a temperature-sensitive p53 (Val135) allele. Transcriptome analysis of Runx1-deleted cells revealed a gene signature associated with lymphoid proliferation, survival and differentiation, and included strong de-repression of recombination-activating (Rag) genes, an observation that was mirrored in a panel of human acute leukemias where RUNX1 and RAG1,2 mRNA expression were negatively correlated. Notably, despite their continued growth and tumorigenic potential, Runx1null lymphoma cells displayed impaired proliferation and markedly increased sensitivity to DNA damage and dexamethasone-induced apoptosis, validating Runx1 function as a potential therapeutic target in Myc-driven lymphomas regardless of their p53 status

Deep heat: a comparison of water temperature, anemone bleaching, anemonefish density and reproduction between shallow and mesophotic reefs

French Polynesia is experiencing increasing coral bleaching events in shallow waters triggered by thermal anomalies and marine heatwaves linked to climate change, a trend that is replicated worldwide. As sea surface thermal anomalies are assumed to lessen with depth, mesophotic deep reefs have been hypothesized to act as refuges from anthropogenic and natural disturbances, the ‘deep reef refugia hypothesis’ (DRRH). However, evidence supporting the DRRH is either inconclusive or conflicting. We address this by investigating four assumptions of the DRRH focusing on the symbiotic association between anemones and anemonefish. First, we compare long-term temperature conditions between shallow (8 m) and mesophotic sites (50 m) on the island of Moorea from 2011–2020. Second, we compare the densities of the orange-fin anemonefish, Amphiprion chrysopterus between shallow and mesophotic (down to 60 m) reefs across three archipelagos in French Polynesia. Finally, we compare the percentage of anemone bleaching, as well as anemonefish reproduction, between shallow and mesophotic reefs. We found that the water column was well mixed in the cooler austral winter months with only a 0.19 °C difference in temperature between depths, but in the warmer summer months mixing was reduced resulting in a 0.71–1.03 °C temperature difference. However, during thermal anomalies, despite a time lag in warm surface waters reaching mesophotic reefs, there was ultimately a 1.0 °C increase in water temperature at both 8 and 50 m, pushing temperatures over bleaching thresholds at both depths. As such, anemone bleaching was observed in mesophotic reefs during these thermal anomalies, but was buffered compared to the percentage of bleaching in shallower waters, which was nearly five times greater. Our large-scale sampling across French Polynesia found orange-fin anemonefish, A. chrysopterus, in mesophotic zones in two high islands and one atoll across two archipelagos, extending its bathymetric limit to 60 m; however, orange-fin anemonefish densities were either similar to, or 25–92 times lower than in shallower zones. Three spawning events were observed at 50 m, which occurred at a similar frequency to spawning on shallower reefs at the same date. Our findings of thermal anomalies and bleaching in mesophotic reefs, coupled with mainly lower densities of anemonefish in mesophotic populations, suggest that mesophotic reefs show only a limited ability to provide refugia from anthropogenic and natural disturbances

Perspectives and Forecasts

As the twenty-first century approaches it is accompanied by dramatic changes for the South. Southerners have been inundated with demographic, technological, and social developments which have exercised and will continue to effect dramatic changes in the traditional southern life-style. Once sleeping villages have become busy cities complete with shopping malls and burgeoning industry. All white public schools, businesses, and even churches have yielded to pressures for social equality and racial integration. An equable climate and multitudinous recreational and retirement opportunities have magnetized millions of Americans from the Northeast and Midwest, luring them to the Southland. All of these developments will, or at least should have far-reaching implications for southern archives and professional archivists for years to come

Investigating Genetic Determinants of Plasma Inositol Status in Adult Humans

BACKGROUND: Myo-inositol (MI) is incorporated into numerous biomolecules, including phosphoinositides and inositol phosphates. Disturbance of inositol availability or metabolism is associated with various disorders, including neurological conditions and cancers, while supplemental MI has therapeutic potential in conditions such as depression, polycystic ovary syndrome and congenital anomalies. Inositol status may be influenced by diet, synthesis, transport, utilisation and catabolism. OBJECTIVES: We aimed to investigate potential genetic regulation of circulating MI status and to evaluate correlation of MI concentration with other metabolites. METHODS: Gas chromatography mass spectrometry was used to determine plasma MI concentration of more than 2,000 healthy, young adults (aged 18-28 years) from the Trinity Student Study. Genotyping data was used to test association of plasma MI with SNPs in candidate genes, encoding inositol transporters and synthesising enzymes, and test for genome-wide association. We evaluated potential correlation of plasma MI with D-chiro inositol, glucose and other metabolites by Spearman's rank correlation. RESULTS: Mean plasma MI showed a small but significant difference between males and females (28.5 and 26.9 µM, respectively). Candidate gene analysis revealed several nominally significant associations with plasma MI, most notably for SLC5A11, encoding a sodium-coupled inositol transporter, also known as SMIT2 (sodium-dependent myo-inositol transporter 2). However, these did not survive correction for multiple testing. Subsequent testing for genome-wide association with plasma MI did not identify associations of genome-wide significance (p < 5 × 10-8). However, 8 SNPs exceeded the threshold for suggestive significant association with plasma MI concentration (p < 1 × 10-5), 3 of which were located within or close to genes: MTDH, LAPTM4B and ZP2. We found significant positive correlation of plasma MI concentration with concentration of D-chiro-inositol and several other biochemicals including glucose, methionine, betaine, sarcosine and tryptophan. CONCLUSION: Our findings suggest potential for modulation of plasma MI in young adults by variation in SLC5A11 which is worthy of further investigation

Synthesis, Characterization, and Crystal Structure of the (η5-C5Ph5)Cr(CO)3 Radical

The reaction between Cr(CO)6 and Na(C5Ph5 ) in refluxing diglyme yields [Na(diglyme)3/2][(C5Ph5)Cr(CO)3], 1. Metathesis of 1 with [Ph3P=N=PPh3 ]Cl in CH2Cl2 yields [Ph3P=N=PPh3][(C5Ph5)Cr(CO)3], 2. Oxidation of 1 by AgBF4 in cold THF under an argon atmosphere produces (C5Ph5)Cr(CO)3, 3. Complexes 2 and 3 form a redox pair connected by a quasireversible one-electron process, E0 = -0.69 V vs ferrocene in CH2Cl2, E0 = -0.50 V in CH3CN, ks = 0.12 cm/s. ESR spectra of (C5Ph5)Cr(CO)3 in toluene at 90 K gave a rhombic g-tensor with components 2.1366, 2.0224, and 1.9953, consistent with the expected low-spin d5 electronic configuration. The largest g-tensor component was significantly temperature dependent, suggesting an equilibrium between conformations with 2A´ and 2A˝ ground states. Crystal structures of [Ph3P=N=PPh3][(C5Ph5)Cr(CO)3] and (C5Ph5)Cr(CO)3 were obtained

Visually narrating post-colonial lives: ghosts of war and empire

This paper is about two journeys: the first through the memories of an old soldier captured by the Japanese in the Second World War; the second through the present life to which this past gave rise, in which the old soldier tends the graves of his fellow soldiers as part of his current navigation by bus and taxi of the post-colonial landscape of Hong Kong

Compressive Mechanical Characterization of Non-Human Primate Spinal Cord White Matter

The goal of developing computational models of spinal cord injury (SCI) is to better understand the human injury condition. However, finite element models of human SCI have used rodent spinal cord tissue properties due to a lack of experimental data. Central nervous system tissues in non human primates (NHP) closely resemble that of humans and therefore, it is expected that material constitutive models obtained from NHPs will increase the fidelity and the accuracy of human SCI models. Human SCI most often results from compressive loading and spinal cord white matter properties affect FE predicted patterns of injury; therefore, the objectives of this study were to characterize the unconfined compressive response of NHP spinal cord white matter and present an experimentally derived, finite element tractable constitutive model for the tissue. Cervical spinal cords were harvested from nine male adult NHPs (Macaca mulatta). White matter biopsy samples (3 mm in diameter) were taken from both lateral columns of the spinal cord and were divided into four strain rate groups for unconfined dynamic compression and stress relaxation (post-mortem &lt;1-hour). The NHP spinal cord white matter compressive response was sensitive to strain rate and showed substantial stress relaxation confirming the viscoelastic behavior of the material. An Ogden 1st order model best captured the non-linear behavior of NHP white matter in a quasi-linear viscoelastic material model with 4-term Prony series. This study is the first to characterize NHP spinal cord white matter at high (&gt;10/sec) strain rates typical of traumatic injury. The finite element derived material constitutive model of this study will increase the fidelity of SCI computational models and provide important insights for transferring pre-clinical findings to clinical treatments