Haplotype analysis of APOE intragenic SNPs

BACKGROUND: APOE epsilon4 allele is most common genetic risk factor for Alzheimer\u27s disease (AD) and cognitive decline. However, it remains poorly understood why only some carriers of APOE epsilon4 develop AD and how ethnic variabilities in APOE locus contribute to AD risk. Here, to address the role of APOE haplotypes, we reassessed the diversity of APOE locus in major ethnic groups and in Alzheimer\u27s Disease Neuroimaging Initiative (ADNI) dataset on patients with AD, and subjects with mild cognitive impairment (MCI), and control non-demented individuals. RESULTS: We performed APOE gene haplotype analysis for a short block of five SNPs across the gene using the ADNI whole genome sequencing dataset. The compilation of ADNI data with 1000 Genomes identified the APOE epsilon4 linked haplotypes, which appeared to be distant for the Asian, African and European populations. The common European epsilon4-bearing haplotype is associated with AD but not with MCI, and the Africans lack this haplotype. Haplotypic inference revealed alleles that may confer protection against AD. By assessing the DNA methylation profile of the APOE haplotypes, we found that the AD-associated haplotype features elevated APOE CpG content, implying that this locus can also be regulated by genetic-epigenetic interactions. CONCLUSIONS: We showed that SNP frequency profiles within APOE locus are highly skewed to population-specific haplotypes, suggesting that the ancestral background within different sites at APOE gene may shape the disease phenotype. We propose that our results can be utilized for more specific risk assessment based on population descent of the individuals and on higher specificity of five site haplotypes associated with AD

Association of Polymorphisms of Serotonin Transporter (5HTTLPR) and 5-HT2C Receptor Genes with Criminal Behavior in Russian Criminal Offenders

Background: Human aggression is a heterogeneous behavior with biological, psychological, and social backgrounds. As the biological mechanisms that regulate aggression are components of both reward-seeking and adversity-fleeing behavior, these phenomena are difficult to disentangle into separate neurochemical processes. Nevertheless, evidence exists linking some forms of ag

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.Peer reviewe

2-kV thyristor triggered in impact-ionization wave mode by a solid-state spiral generator

Impact-ionization wave triggering of a thyristor enables it to switch significantly higher currents with much faster rise times (d I /d t ) than through conventional triggering; indeed tests on commercial components demonstrate that both current and d I /d t can be increased an order of magnitude over their specified datasheet values by utilizing impact ionization. However, creating an impact ionization wave places stringent requirements on the generator used to trigger the thyristor—particularly the trigger pulse must have a voltage rise rate (d V /d t ) of more than 1 kV/ns and an amplitude over twice the thyristors static breakdown voltage. Given the capacitance of a thyristor is relatively large, often hundreds of pF, this is difficult to achieve with many common triggering methods. In this study, we present a bespoke, cost-effective, trigger generator that has been developed based on spiral/vector inversion techniques coupled to an optimized sharpening circuit. Using this generator, both a 2-kV single thyristor and a 4-kV stack of two thyristors in series were triggered in the impact-ionization mode. The thyristors had a wafer diameter of 32 mm and capacitances of 370 pF. With a single thyristor 100 shots were performed with it switching a peak current of 1.25 kA and an associated d I /d t of 12 kA/ μ s. With two thyristors, peak currents of 2.6 kA and with d I /d t of 25 kA/ μ s were achieved. In all experiments no degradation of the semiconductor structure was observed. The work opens the way for developing very powerful, but still compact, solid-state trigger generators and larger pulsers for a wide range of pulsed power applications. </p

Off-the-shelf diodes as high-voltage opening switches

A semiconductor opening switch (SOS) (also known as SOS diode) is a solid-state nanosecond switch of gigawatt power level. Due to its high pulse repetition rate, long lifetime, and maintenance-free capability, the SOS diodes are becoming increasingly attractive for use in solid-state pulsed power generators. However, the lack of SOS diode manufacturers prevents the widespread use of this technology. This work demonstrates the ability of off-the-shelf diodes to operate in the SOS mode. A wide range of off-the-shelf diodes including rectifier, fast recovery, avalanche, and transient-voltage-suppression (TVS) diodes have been tested as high-voltage opening switches. An experimental arrangement based on a saturating pulse transformer (PT) was developed to test off-the-shelf diodes in the SOS mode. The results obtained were compared with the existent top of the range SOS diodes, used as reference. Two versions of the experimental setup with the initially stored energy of 25 mJ and 10 J were used. The following pulse parameters were obtained using off-the-shelf diodes: 1) peak voltage impulse of 3 kV and rise time of 10 ns with a 110 Ω load (for the 25 mJ setup) and 2) peak voltage impulse of 80 kV and rise time of 20 ns with a 1 k Ω load (for the 10 J setup). Based on the parameters obtained, the door is opened for a future use of off-the-shelf diodes as opening switches in a wide range of solid-state-based pulsed power systems. </p

A Saturable Pulse Transformer Based on Nanocrystalline Magnetic Cores for an Adjustable Nanosecond High-Voltage Generator

This article is devoted to saturable pulse transformers (SPTs), combining the functions of a pulse transformer and a magnetic switch. Two nanocrystalline magnetic cores are investigated in the SPT of an inductive energy storage (IES) pulsed power system based on a semiconductor opening switch (SOS). The first magnetic core has a square hysteresis loop (Br/Bsat $>$ 90%), while the second core has a flat hysteresis loop (Br/Bsat $\sim$ 4%). A test bench with an initially stored energy of 10 J is developed. The circuit design is discussed, and the magnetic materials are compared. Based on the features of the hysteresis loops, two nanosecond high-voltage (HV) SOS generators are tested, with the output voltage adjusted by tuning the input voltage and controlling the bias magnetic field. The influence of the optimal core saturation on the operation of the SOS diode is studied. An adjustable output voltage impulse of more than 200 kV amplitude with a 16 ns rise time is demonstrated on a $1 \text {k}\Omega$ resistive load

Iron metabolic pathways in the processes of sponge plasticity.

The ability to regulate oxygen consumption evolved in ancestral animals and is intrinsically linked to iron metabolism. The iron pathways have been intensively studied in mammals, whereas data on distant invertebrates are limited. Sea sponges represent the oldest animal phylum and have unique structural plasticity and capacity to reaggregate after complete dissociation. We studied iron metabolic factors and their expression during reaggregation in the White Sea cold-water sponges Halichondria panicea and Halisarca dujardini. De novo transcriptomes were assembled using RNA-Seq data, and evolutionary trends were analyzed with bioinformatic tools. Differential expression during reaggregation was studied for H. dujardini. Enzymes of the heme biosynthesis pathway and transport globins, neuroglobin (NGB) and androglobin (ADGB), were identified in sponges. The globins mutate at higher evolutionary rates than the heme synthesis enzymes. Highly conserved iron-regulatory protein 1 (IRP1) presumably interacts with the iron-responsive elements (IREs) found in mRNAs of ferritin (FTH1) and a putative transferrin receptor NAALAD2. The reaggregation process is accompanied by increased expression of IRP1, the antiapoptotic factor BCL2, the inflammation factor NFκB (p65), FTH1 and NGB, as well as by an increase in mitochondrial density. Our data indicate a complex mechanism of iron regulation in sponge structural plasticity and help to better understand general mechanisms of morphogenetic processes in multicellular species

Split Hole Resonator: A Nanoscale UV Light Source

Because of strong light absorption by metals, it is believed that plasmonic nanostructures cannot be used for generating intensive radiation harmonics in the ultraviolet (UV) spectral range. This work presents results of investigation of nonlinear optical interaction with a single gold nanostructure, the split-hole resonator (SHR) under the state-of-the-art experimentally realized conditions. To realize interaction with all spectral components of a 6 fs laser pulse several multipole plasmon resonances were simultaneously excited in the SHR nanostructure. To the best of our knowledge, this paper reports for the first time a strong nonlinear optical interaction at the frequencies of these resonances that leads to (i) the second harmonic generation, (ii) the third harmonic generation (THG), and (iii) the light generation at mixed frequencies. The THG near field amplitude reaches 0.6% of the fundamental frequency field amplitude, which enables the creation of UV radiation sources with a record high intensity. The UV THG may find many important applications including biomedical ones (such as cancer therapy)

Association of Polymorphisms of Serotonin Transporter (5HTTLPR) and 5-HT2C Receptor Genes with Criminal Behavior in Russian Criminal Offenders

BACKGROUND: Human aggression is a heterogeneous behavior with biological, psychological, and social backgrounds. As the biological mechanisms that regulate aggression are components of both reward-seeking and adversity-fleeing behavior, these phenomena are difficult to disentangle into separate neurochemical processes. Nevertheless, evidence exists linking some forms of aggression to aberrant serotonergic neurotransmission. We determined possible associations between 6 serotonergic neurotransmission-related gene variants and severe criminal offenses. METHODS: Male Russian prisoners who were convicted for murder (n = 117) or theft (n = 77) were genotyped for variants of the serotonin transporter (5HTTLPR), tryptophan hydroxylase, tryptophan-2,3-dioxygenase, or type 2C (5-HT2C) receptor genes and compared with general-population male controls (n = 161). Prisoners were psychologically phenotyped using the Buss-Durkee Hostility Inventory and the Beck Depression Inventory. RESULTS: No differences were found between murderers and thieves either concerning genotypes or concerning psychological measures. Comparison of polymorphism distribution between groups of prisoners and controls revealed highly significant associations of 5HTTLPR and 5-HTR2C (rs6318) gene polymorphisms with being convicted for criminal behavior. CONCLUSIONS: The lack of biological differences between the 2 groups of prisoners indicates that the studied 5HT-related genes do not differentiate between the types of crimes committed