ASIC design of an IIR digital filter: Using Mentor Graphics DSP Station Tools

Automation in VLSI design is a powerful way to simplify the VLSI layout process and will allow for faster time to market for integrated circuit designs. One means of automation is VHDL, a hardware description language for integrated circuit designs. A structured VHDL description can be used to describe the hardware design at the logic-gate level, and automated software is available that will use this gate-level design to generate the VLSI layout. A more recent type of automation occurs at a level above this. The Mentor Graphics DSP Station tools use a high-level algorithmic description to generate the gate-level VHDL description. These tools are especially intended for applications in digital signal processing (DSP), providing simulation tools particularly geared toward DSP algorithms. One application of digital signal processing is an infinite impulse response (IIR) filter. With the use of the Mentor Graphics tools, a digital filter was designed from a set of original specifications down to the silicon level. N-well 1.2 micron CMOS technology with two metal layers and one polysilicon layer was used to implement the filter layout. Using the 1.2 micron CMOSN standard cell library, the final VLSI layout measured 7.315 mm x 7.213 mm, containing approximately 25,700 transistors

Utilization of Never-Medicated Bipolar Disorder Patients towards Development and Validation of a Peripheral Biomarker Profile

There are currently no biological tests that differentiate patients with bipolar disorder (BPD) from healthy controls. While there is evidence that peripheral gene expression differences between patients and controls can be utilized as biomarkers for psychiatric illness, it is unclear whether current use or residual effects of antipsychotic and mood stabilizer medication drives much of the differential transcription. We therefore tested whether expression changes in first-episode, never-medicated BPD patients, can contribute to a biological classifier that is less influenced by medication and could potentially form a practicable biomarker assay for BPD. We employed microarray technology to measure global leukocyte gene expression in first-episode (n=3) and currently medicated BPD patients (n=26), and matched healthy controls (n=25). Following an initial feature selection of the microarray data, we developed a cross-validated 10-gene model that was able to correctly predict the diagnostic group of the training sample (26 medicated patients and 12 controls), with 89% sensitivity and 75% specificity (p<0.001). The 10-gene predictor was further explored via testing on an independent cohort consisting of three pairs of monozygotic twins discordant for BPD, plus the original enrichment sample cohort (the three never-medicated BPD patients and 13 matched control subjects), and a sample of experimental replicates (n=34). 83% of the independent test sample was correctly predicted, with a sensitivity of 67% and specificity of 100% (although this result did not reach statistical significance). Additionally, 88% of sample diagnostic classes were classified correctly for both the enrichment (p=0.015) and the replicate samples (p<0.001). We have developed a peripheral gene expression biomarker profile, that can classify healthy controls from patients with BPD receiving antipsychotic or mood stabilizing medication, which has both high sensitivity and specificity. Moreover, assay of three first-episode patients who had never received such medications, to first enrich the expression dataset for disease-related genes independent of medication effects, and then to test the 10-gene predictor, validates the peripheral biomarker approach for BPD

Inhibition of Growth Factor-Mediated Tyrosine Phosphorylation in Vascular Smooth Muscle by PD 089828, a New Synthetic Protein Tyrosine Kinase Inhibitor

ABSTRACT PD 089828, a novel protein tyrosine kinase inhibitor of a new structural class, the 6-aryl-pyrido- [2,3-d]pyrimidines, was identified by screening a compound library with assays that measured protein tyrosine kinase activity. PD 089828 was found to inhibit human full-length fibroblast growth factor (FGF) receptor-1 (FGFR-1), platelet-derived growth factor (PDGF) receptor ␤ subunit (PDGFR-␤), Src nonreceptor tyrosine kinase (c-Src) and epidermal growth factor (EGF) receptor (EGFR) tyrosine kinases with half-maximal inhibitory potencies (IC 50 values) of 0.15 Ϯ 0.02 (n ϭ 4), 0.18 Ϯ 0.04 (n ϭ 3), 1.76 Ϯ 0.28 (n ϭ 4) and 5.47 Ϯ 0.78 (n ϭ 6) M, respectively. PD 089828 was further characterized as an ATP competitive inhibitor of the growth factor receptor tyrosine kinases (FGFR-1, PDGFR-␤ and EGFR) but a noncompetitive inhibitor of c-Src tyrosine kinase with respect to ATP. In addition, PD 089828 inhibited PDGF-and EGF-stimulated receptor autophosphorylation in vascular SMC (VSMC) and basic FGF-mediated tyrosine phosphorylation in A121 cells with IC 50 values similar to the potencies observed for inhibition of receptor tyrosine kinase activity. The inhibition of PDGF receptor autophosphorylation in VSMC by PD 089828 occurred rapidly, with maximal effects reached within 5 min of drug exposure. Inhibition after single exposure was long lasting but also rapidly reversible, occurring within 5 min after drug removal. The PDGF-induced association of downstream signaling proteins, including phosphoinositide-3-kinase (PI-3K), growth factor receptor binding protein-2 (GRB2), SH-2 domain and collagen like (Shc) and phospholipase C␥ (PLC␥), with VSMC PDGF receptors was also blocked as a result of the inhibition of PDGF-stimulated receptor autophosphorylation by PD 089828. PD 089828 also inhibited the PDGF-induced tyrosine phosphorylation of the 44-and 42-kDa mitogen-activated protein kinase isoforms. Moreover, the effects of PD 089828 were demonstrated in functional assays in which PDGF-stimulated DNA synthesis, PDGF-directed migration and serum-stimulated growth of VSMC were all inhibited to the same extent as PDGF receptor autophosphorylation (IC 50 ϭ 0.8, 4.5 and 1.8 M, respectively). These results highlight the biological characteristics of PD 089828 as a novel, broadly active protein tyrosine kinase inhibitor with long-lasting but reversible cellular effects. The potential therapeutic use of these broadly acting, nonselective inhibitors as antiproliferative and antimigratory agents could extend to such diseases as cancer, atherosclerosis and restenosis in which redundancies in growth-signaling pathways are known to exist

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Brain tumor-initiating cells (BTICs) have been identified as key contributors to therapy resistance, recurrence, and progression of diffuse gliomas, particularly glioblastoma (GBM). BTICs are elusive therapeutic targets that reside across the blood–brain barrier, underscoring the urgent need to develop novel therapeutic strategies. Additionally, intratumoral heterogeneity and adaptations to therapeutic pressure by BTICs impede the discovery of effective anti-BTIC therapies and limit the efficacy of individual gene targeting. Recent discoveries in the genetic and epigenetic determinants of BTIC tumorigenesis offer novel opportunities for RNAi-mediated targeting of BTICs. Here we show that BTIC growth arrest in vitro and in vivo is accomplished via concurrent siRNA knockdown of four transcription factors (SOX2, OLIG2, SALL2, and POU3F2) that drive the proneural BTIC phenotype delivered by multiplexed siRNA encapsulation in the lipopolymeric nanoparticle 7C1. Importantly, we demonstrate that 7C1 nano-encapsulation of multiplexed RNAi is a viable BTIC-targeting strategy when delivered directly in vivo in an established mouse brain tumor. Therapeutic potential was most evident via a convection-enhanced delivery method, which shows significant extension of median survival in two patient-derived BTIC xenograft mouse models of GBM. Our study suggests that there is potential advantage in multiplexed targeting strategies for BTICs and establishes a flexible nonviral gene therapy platform with the capacity to channel multiplexed RNAi schemes to address the challenges posed by tumor heterogeneity. Keywords: siRNA; lipopolymeric nanoparticle; glioblastoma transcription factor; brain tumor-initiating; cells; convection-enhanced deliver

Overshooting Americanisation. Accent stylisation in pop singing – acoustic properties of the bath and trap vowels in focus

The paper addresses the problem of overshoot involved in singing accent stylisation. Selected phonetic features indexed as “American” and “Cockney” are analysed in the singing and speaking styles of a British vocalist, Adele. Overshoot, understood as a greater frequency or an exaggerated quality of a given feature, is characteristic of staged performance (Bell and Gibson 2011; Coupland 2007). PRAAT is used to establish the acoustic properties (F1 and F2) of the BATH and TRAP vowels, as well as the presence or absence of the BATH-TRAP split. The results show that Americanisation regarding the BATH-TRAP split in singing is present and the Americanised vowel tokens are “overshot”, having higher F2 frequency compared with the regular British TRAP vowel

Pharmacologic Characterization of Cl-996, a New Angiotensin Receptor Antagonist

Mg II, angiotensin II; Cl-996, 4-[2-(1-oxo-2,2,2-trrnuoroethyl)-1H-pyrrol-1-yq-2-propyl-1-[(2&apos;-(1H-tetrazol-5-yl)biphen-4-yl)

Transcriptomic profiling of host-parasite interactions in the microsporidian <i>Trachipleistophora hominis</i>

BACKGROUND: Trachipleistophora hominis was isolated from an HIV/AIDS patient and is a member of a highly successful group of obligate intracellular parasites. METHODS: Here we have investigated the evolution of the parasite and the interplay between host and parasite gene expression using transcriptomics of T. hominis-infected rabbit kidney cells. RESULTS: T. hominis has about 30 % more genes than small-genome microsporidians. Highly expressed genes include those involved in growth, replication, defence against oxidative stress, and a large fraction of uncharacterised genes. Chaperones are also highly expressed and may buffer the deleterious effects of the large number of non-synonymous mutations observed in essential T. hominis genes. Host expression suggests a general cellular shutdown upon infection, but ATP, amino sugar and nucleotide sugar production appear enhanced, potentially providing the parasite with substrates it cannot make itself. Expression divergence of duplicated genes, including transporters used to acquire host metabolites, demonstrates ongoing functional diversification during microsporidian evolution. We identified overlapping transcription at more than 100 loci in the sparse T. hominis genome, demonstrating that this feature is not caused by genome compaction. The detection of additional transposons of insect origin strongly suggests that the natural host for T. hominis is an insect. CONCLUSIONS: Our results reveal that the evolution of contemporary microsporidian genomes is highly dynamic and innovative. Moreover, highly expressed T. hominis genes of unknown function include a cohort that are shared among all microsporidians, indicating that some strongly conserved features of the biology of these enormously successful parasites remain uncharacterised. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-1989-z) contains supplementary material, which is available to authorized users