Novel Human \u3cem\u3eABCC9/SUR2\u3c/em\u3e Brain-Expressed Transcripts and an eQTL Relevant to Hippocampal Sclerosis of Aging

ABCC9 genetic polymorphisms are associated with increased risk for various human diseases including hippocampal sclerosis of aging. The main goals of this study were 1 \u3e to detect the ABCC9 variants and define the specific 3′ untranslated region (3′UTR) for each variant in human brain, and 2 \u3e to determine whether a polymorphism (rs704180) associated with risk for hippocampal sclerosis of aging pathology is also associated with variation in ABCC9 transcript expression and/or splicing. Rapid amplification of ABCC9 cDNA ends (3′RACE) provided evidence of novel 3′ UTR portions of ABCC9 in human brain. In silico and experimental studies were performed focusing on the single nucleotide polymorphism, rs704180. Analyses from multiple databases, focusing on rs704180 only, indicated that this risk allele is a local expression quantitative trait locus (eQTL). Analyses of RNA from human brains showed increased ABCC9 transcript levels in individuals with the risk genotype, corresponding with enrichment for a shorter 3′ UTR which may be more stable than variants with the longer 3′ UTR. MicroRNA transfection experiments yielded results compatible with the hypothesis that miR‐30c causes down‐regulation of SUR2 transcripts with the longer 3′ UTR. Thus we report evidence of complex ABCC9 genetic regulation in brain, which may be of direct relevance to human disease

Current-driven magnetization dynamics and their correlation with magnetization configurations in perpendicularly magnetized tunnel junctions

We study spin-transfer-torque driven magnetization dynamics of a perpendicular magnetic tunnel junction (MTJ) nanopillar. Based on the combination of spin-torque ferromagnetic resonance and microwave spectroscopy techniques, we demonstrate that the free layer (FL) and the weak pinned reference layer (RL) exhibit distinct dynamic behaviors with opposite frequency vs. field dispersion relations. The FL can support a single coherent spin-wave (SW) mode for both parallel and antiparallel configurations, while the RL exhibits spin-wave excitation only for the antiparallel state. These two SW modes corresponding to the FL and RL coexist at an antiparallel state and exhibit a crossover phenomenon of oscillation frequency with increasing the external magnetic field, which could be helpful in the mutual synchronization of auto-oscillations for SW-based neuromorphic computing.Comment: 13 pages, 5 figure

Examination of the enterotoxigenic Escherichia coli population structure during human infection

Enterotoxigenic E. coli (ETEC) can cause severe diarrhea and death in children in developing countries; however, bacterial diversity in natural infection is uncharacterized. In this study, we explored the natural population variation of ETEC from individuals with cholera-like diarrhea. Genomic sequencing and comparative analysis of multiple ETEC isolates from twelve cases of severe diarrhea demonstrated clonal populations in the majority of subjects (10/12). In contrast, a minority of individuals (2/12) yielded phylogenomically divergent ETEC isolates. Detailed examination revealed that isolates also differed in virulence factor content. These genomic data suggest that severe, cholera-like ETEC infections are largely caused by a clonal population of organisms within individual patients. Additionally, the isolation of similar clones from geographically and temporally dispersed cases with similar clinical presentations suggests that some isolates are particularly suited for virulence. The identification of multiple genomically diverse isolates with variable virulence factor profiles from a single subject highlights the dynamic nature of ETEC, as well as a potential weakness in the examination of cultures obtained from a single colony in clinical settings. These findings have implications for vaccine design and provide a framework for the study of population variation in other human pathogens

Identification and Characterization of the Lamprey High-Mobility Group Box 1 Gene

High-mobility group box 1 (HMGB1), a highly conserved DNA-binding protein, plays an important role in maintaining nucleosome structures, transcription, and inflammation. We identified a homolog of HMGB1 in the Japanese lamprey (Lampetra japonica). The Lampetra japonica HMGB1 gene (Lj-HMGB1) has over 70% sequence identity with its homologs in jawed vertebrates. Despite the reasonably high sequence identity with other HMGB1 proteins, Lj-HMGB1 did not group together with these proteins in a phylogenetic analysis. We examined Lj-HMGB1 expression in lymphocyte-like cells, and the kidneys, heart, gills, and intestines of lampreys before and after the animals were challenged with lipopolysaccharide (LPS) and concanavalin A (ConA). Lj-HMGB1 was initially expressed at a higher level in the heart, but after treatment with LPS and ConA only the gills demonstrated a significant up-regulation of expression. The recombinant Lj-HMGB1 (rLj-HMGB1) protein bound double-stranded DNA and induced the proliferation of human adenocarcinoma cells to a similar extent as human HMGB1. We further revealed that Lj-HMGB1 was able to induce the production of tumor necrosis factor-α (TNF-α), a pro-inflammatory mediator, in activated human acute monocytic leukemia cells. These results suggest that lampreys use HMGB1 to activate their innate immunity for the purpose of pathogen defense

Numerical modelling of nonlinear extreme waves in the presence of wind

A numerical wave flume with fully nonlinear free surface boundary conditions is adopted to investigate the temporal characteristics of extreme waves in the presence of wind at various speeds. Incident wave trains are numerically generated by a piston-type wave maker, and the wind-excited pressure is introduced into dynamic boundary conditions using a pressure distribution over steep crests, as defined by Jeffreys’ sheltering mechanism. A boundary value problem is solved by a higher-order boundary element method (HOBEM) and a mixed Eulerian-Lagrangian time marching scheme. The proposed model is validated through comparison with published experimental data from a focused wave group. The influence of wind on extreme wave properties, including maximum extreme wave crest, focal position shift, and spectrum evolution, is also studied. To consider the effects of the wind-driven currents on a wave evolution, the simulations assume a uniform current over varying water depth. The results show that wind causes weak increases in the extreme wave crest, and makes the nonlinear energy transfer non-reversible in the focusing and defocusing processes. The numerical results also provide a comparison to demonstrate the shifts at focal points, considering the combined effects of the winds and the wind-driven currents