Evaluating the spectral distinction between sibilant fricatives through a speaker-centered approach

This study was designed to examine the feasibility of using the spectral mean and/or spectral skewness to distinguish between alveolar and palato-alveolar fricatives produced by individual adult speakers of English. Five male and five female speaker participants produced 100 CVC words with an initial consonant /s/ or /ʃ/. The spectral mean and skewness were derived every 10 milliseconds throughout the fricative segments and plotted for all productions. Distinctions were examined for each speaker through visual inspection of these time history plots and statistical comparisons were completed for analysis windows centered 50 ms after the onset of the fricative segment. The results showed significant differences between the alveolar and palato-alveolar fricatives for both the mean and skewness values. However, there was considerable inter-speaker overlap, limiting the utility of the measures to evaluate the adequacy of the phonetic distinction. When the focus shifted to individual speakers rather than average group performance, only the spectral mean distinguished consistently between the two phonetic categories. The robustness of the distinction suggests that intra-speaker overlap in spectral mean between prevocalic /s/ and /ʃ/ targets may be indicative of abnormal fricative production and a useful measure for clinical applications

Applications of patching to quadratic forms and central simple algebras

This paper provides applications of patching to quadratic forms and central simple algebras over function fields of curves over henselian valued fields. In particular, we use a patching approach to reprove and generalize a recent result of Parimala and Suresh on the u-invariant of p-adic function fields, for p odd. The strategy relies on a local-global principle for homogeneous spaces for rational algebraic groups, combined with local computations.Comment: 48 pages; connectivity now required in the definition of rational group; beginning of Section 4 reorganized; other minor change

Identification and Analysis of the Active Phytochemicals from the Anti-Cancer Botanical Extract Bezielle

Bezielle is a botanical extract that has selective anti-tumor activity, and has shown a promising efficacy in the early phases of clinical testing. Bezielle inhibits mitochondrial respiration and induces reactive oxygen species (ROS) in mitochondria of tumor cells but not in non-transformed cells. The generation of high ROS in tumor cells leads to heavy DNA damage and hyper-activation of PARP, followed by the inhibition of glycolysis. Bezielle therefore belongs to a group of drugs that target tumor cell mitochondria, but its cytotoxicity involves inhibition of both cellular energy producing pathways. We found that the cytotoxic activity of the Bezielle extract in vitro co-purified with a defined fraction containing multiple flavonoids. We have isolated several of these Bezielle flavonoids, and examined their possible roles in the selective anti-tumor cytotoxicity of Bezielle. Our results support the hypothesis that a major Scutellaria flavonoid, scutellarein, possesses many if not all of the biologically relevant properties of the total extract. Like Bezielle, scutellarein induced increasing levels of ROS of mitochondrial origin, progressive DNA damage, protein oxidation, depletion of reduced glutathione and ATP, and suppression of both OXPHOS and glycolysis. Like Bezielle, scutellarein was selectively cytotoxic towards cancer cells. Carthamidin, a flavonone found in Bezielle, also induced DNA damage and oxidative cell death. Two well known plant flavonoids, apigenin and luteolin, had limited and not selective cytotoxicity that did not depend on their pro-oxidant activities. We also provide evidence that the cytotoxicity of scutellarein was increased when other Bezielle flavonoids, not necessarily highly cytotoxic or selective on their own, were present. This indicates that the activity of total Bezielle extract might depend on a combination of several different compounds present within it

Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1

The wogonin-containing herb Scutellaria baicalensis has successfully been used for curing various diseases in traditional Chinese medicine. Wogonin has been shown to induce apoptosis in different cancer cells and to suppress growth of human cancer xenografts in vivo. However, its direct targets remain unknown. In this study, we demonstrate for the first time that wogonin and structurally related natural flavones, for example, apigenin, chrysin and luteolin, are inhibitors of cyclin-dependent kinase 9 (CDK9) and block phosphorylation of the carboxy-terminal domain of RNA polymerase II at Ser2. This effect leads to reduced RNA synthesis and subsequently rapid downregulation of the short-lived anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1) resulting in apoptosis induction in cancer cells. We show that genetic inhibition of Mcl-1 or CDK9 expression by siRNA is sufficient to mimic flavone-induced apoptosis. Pull-down and in silico docking studies demonstrate that wogonin directly binds to CDK9, presumably to the ATP-binding pocket. In contrast, wogonin does not inhibit CDK2, CDK4 and CDK6 at doses that inhibit CDK9 activity. Furthermore, we show that wogonin preferentially inhibits CDK9 in malignant compared with normal lymphocytes. Thus, our study reveals a new mechanism of anti-cancer action of natural flavones and supports CDK9 as a therapeutic target in oncology

The Flavonoid Luteolin Inhibits Fcγ-Dependent Respiratory Burst in Granulocytes, but Not Skin Blistering in a New Model of Pemphigoid in Adult Mice

Bullous pemphigoid is an autoimmune blistering skin disease associated with autoantibodies against the dermal-epidermal junction. Passive transfer of antibodies against BP180/collagen (C) XVII, a major hemidesmosomal pemphigoid antigen, into neonatal mice results in dermal-epidermal separation upon applying gentle pressure to their skin, but not in spontaneous skin blistering. In addition, this neonatal mouse model precludes treatment and observation of diseased animals beyond 2–3 days. Therefore, in the present study we have developed a new disease model in mice reproducing the spontaneous blistering and the chronic course characteristic of the human condition. Adult mice were pre-immunized with rabbit IgG followed by injection of BP180/CXVII rabbit IgG. Mice pre-immunized against rabbit IgG and injected 6 times every second day with the BP180/CXVII-specific antibodies (n = 35) developed spontaneous sustained blistering of the skin, while mice pre-immunized and then treated with normal rabbit IgG (n = 5) did not. Blistering was associated with IgG and complement C3 deposits at the epidermal basement membrane and recruitment of inflammatory cells, and was partly dependent on Ly-6G-positive cells. We further used this new experimental model to investigate the therapeutic potential of luteolin, a plant flavonoid with potent anti-inflammatory and anti-oxidative properties and good safety profile, in experimental BP. Luteolin inhibited the Fcγ-dependent respiratory burst in immune complex-stimulated granulocytes and the autoantibody-induced dermal-epidermal separation in skin cryosections, but was not effective in suppressing the skin blistering in vivo. These studies establish a robust animal model that will be a useful tool for dissecting the mechanisms of blister formation and will facilitate the development of more effective therapeutic strategies for managing pemphigoid diseases

A Flavonoid, Luteolin, Cripples HIV-1 by Abrogation of Tat Function

Despite the effectiveness of combination antiretroviral treatment (cART) against HIV-1, evidence indicates that residual infection persists in different cell types. Intensification of cART does not decrease the residual viral load or immune activation. cART restricts the synthesis of infectious virus but does not curtail HIV-1 transcription and translation from either the integrated or unintegrated viral genomes in infected cells. All treated patients with full viral suppression actually have low-level viremia. More than 60% of treated individuals also develop minor HIV-1 –associated neurocognitive deficits (HAND) due to residual virus and immune activation. Thus, new therapeutic agents are needed to curtail HIV-1 transcription and residual virus. In this study, luteolin, a dietary supplement, profoundly reduced HIV-1 infection in reporter cells and primary lymphocytes. HIV-1inhibition by luteolin was independent of viral entry, as shown by the fact that wild-type and VSV–pseudotyped HIV-1 infections were similarly inhibited. Luteolin was unable to inhibit viral reverse transcription. Luteolin had antiviral activity in a latent HIV-1 reactivation model and effectively ablated both clade-B- and -C -Tat-driven LTR transactivation in reporter assays but had no effect on Tat expression and its sub-cellular localization. We conclude that luteolin confers anti–HIV-1 activity at the Tat functional level. Given its biosafety profile and ability to cross the blood-brain barrier, luteolin may serve as a base flavonoid to develop potent anti–HIV-1 derivatives to complement cART

“I\u27m right thereâ€: Central Appalachian women in public school leadership.

Despite a deluge of national attention to equity issues, public school administration is still the domain of men. Research attention to women in leadership has done little to close the gender gap in superintendents\u27 and secondary school principals\u27 offices, perhaps because of its focus on successful men rather than on the women who hold these positions. Qualitative interviews examine seven central Appalachian women school leaders in light of feminist standpoint theory, focusing on the way the women enter leadership, articulate a personal construction of the leadership role, and negotiate the borders between their own constructions and the prevailing ones. Profiles illustrate how the women have dealt with their invisibility as teachers and aspiring leaders, as well as the ways in which they have built woman-friendly environments within their schools and communities. Extended presence and unofficial leadership roles within their school systems (“being thereâ€) appear to contribute to their move into administration, but participants remain constrained by a lack of language to articulate their understanding of leadership. Bringing about equity in public school leadership will require more attention to the development and dissemination of the female voice in leadership studies

Partitions of finite vector spaces over GF(2) into subspaces of dimensions 2 and s

AbstractA vector space partition of a finite vector space V over the field of q elements is a collection of subspaces whose union is all of V and whose pairwise intersections are trivial. While a number of necessary conditions have been proved for certain types of vector space partitions to exist, the problem of the existence of partitions meeting these conditions is still open. In this note, we consider vector space partitions of a finite vector space over the field GF(2) into subspaces of dimensions 2 and s.While certain cases have been done previously (s=1, s=3, and s even), in our main theorem we build upon these general results to give a constructive proof for the existence of vector space partitions over GF(2) into subspaces of dimensions s and 2 of almost all types. In doing so, we introduce techniques that identify subsets of our vector space which can be viewed as the union of subspaces having trivial pairwise intersection in more than one way. These subsets are used to transform a given partition into another partition of a different type. This technique will also be useful in constructing further partitions of finite vector spaces