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Research on African American English (AAE) since 1998 has covered topics ranging from origins of the variety to formal semantic computations used to explain the different readings of ambiguous sentences. Much of the work on AAE during this period, especially that related to the origins debate, is in the variation theory framework. The focus of the descriptive research has been on syntactic and semantic patterns in AAE used by speakers in the adolescent to adult age group. While research on phonological patterns and formal semantics of constructions has lagged behind other areas, some noteworthy studies in these areas have appeared since 1998. As the discussion of AAE has broadened, it has been possible to compare data and approaches in different studies and raise questions that provide more insight into the linguistic variety. It is also possible to extend descriptive analyses of different constructions to use in illustrations of the systematic nature of language in introductory linguistics courses and in linguistics and education courses.

Purpose: The purpose of this study was to investigate the safety and tolerability of Zosuquidar.3HCl, a potent inhibitor of P-glycoprotein (Pgp), when administered p.o. alone and in combination with doxorubicin and to determine whether Zosuquidar.3HCl affects doxorubicin pharmacokinetics and inhibits Pgp function in peripheral blood natural killer lymphocytes. Experimental Design: Patients with advanced nonhematological malignancies were eligible for this Phase I trial. Zosuquidar.3HCl and doxorubicin were administered separately during the first cycle of therapy and then administered concurrently. Zosuquidar.3HCl was administered over 4 days, with doses escalated until the occurrence of dose-limiting toxicity. Subsequently, doxorubicin doses were increased from 45 to 75 mg/m 2 . Zosuquidar.3HCl, doxorubicin, and doxorubicinol pharmacokinetics were analyzed, and dual fluorescence cytometry was used to determine the effects of Zosuquidar.3HCl on Pgp function in natural killer cells. Results: A total of 38 patients were treated at nine dose levels. Neurotoxicity was dose-limiting for oral Zosuquidar.3HCl, characterized by cerebellar dysfunction, hallucinations, and palinopsia. The maximum-tolerated dose for oral Zosuquidar.3HCl administered every 12 h for 4 days is 300 mg/m 2 . Zosuquidar.3HCl did not affect doxorubicin myelosuppression or pharmacokinetics, and Zosuquidar.3HCl pharmacokinetics were similar in the absence and presence of doxorubicin. Higher plasma concentrations of Zosuquidar.3HCl were associated with greater Pgp inhibition in natural killer cells. Conclusion: Zosuquidar.3HCl can be coadministered with doxorubicin using a 4-day oral dosing schedule, with little effect on doxorubicin toxicity or pharmacokinetics. Further refinement in Zosuquidar.3HCl dosing and scheduling should be explored to optimize Pgp inhibition while minimizing cerebellar toxicity.

Very few topics related to African American English (AAE) have been the subject of debates as often as issues related to language use and the education of African American youth. This paper presents a linguistic description of some of the lexical, phonological, and syntactic/semantic patterns of AAE and discusses the educational importance of understanding that speakers adhere to well-defined rules when they use them. Linguistic descriptions of AAE are useful in discussing education-related issues such as the extent to which the use of AAE interferes with reading and other educational achievement. Further research on constructions in the different components of the AAE grammar will lead to more accurate descriptive analysis of the AAE system. Such analysis will be useful in considering AAE in terms of current linguistic theory, and it may also be applicable in areas of research in education.

This paper examines aspectual be–type constructions in African American English. These constructions receive a habitual interpretation, but they are distinguished from simple tense generics in that they are not ambiguous between generic/habitual and capacity readings. The analysis proposed to account for these constructions is one in which aspectual be neutralizes the distinction between stage- and individual-level predicates. Following Kratzer (1995), I assume that stage-level predicates have a separate event argument associated with them, but individual-level predicates do not. Aspectual be forces individual-level predicates to take an eventuality argument which coerces them into stage-level predicates. The logical representations of these constructions are given a tripartite structure in which a habitual operator binds variables ranging over eventualities.

LY303366 is a semisynthetic analog of the antifungal lipopeptide echinocandin B that inhibits (1,3)-β- d -glucan synthase and exhibits efficacy in animal models of human fungal infections. In this study, we utilized flow cytometric analysis of propidium iodide uptake, single-cell sorting, and standard microbiological plating methods to study the antifungal effect of LY303366 on Saccharomyces cerevisiae and Candida albicans . Our data indicate that an initial 5-min pulse treatment with LY303366 caused yeasts to take up propidium iodide and lose their ability to grow. Amphotericin B and cilofungin required longer exposure periods (30 and 180 min, respectively) and higher concentrations to elicit these fungicidal effects. These two measurements of fungicidal activity by LY303366 were highly correlated ( r > 0.99) in concentration response and time course experiments. As further validation, LY303366-treated yeasts that stained with propidium iodide were unable to grow in single-cell-sorted cultures. Our data indicate that LY303366 is potent and rapidly fungicidal for actively growing yeasts. The potency and rapid action of this new fungicidal compound suggest that LY303366 may be useful for antifungal therapy.

We propose that shared features (noncontrastive) between African American English (AAE) and Standard American English (SAE) may be more diagnostically salient than features not shared (contrastive) when identifying children of AAE language backgrounds with language disorders. The syntax of child speakers of AAE with language disorders (LD) and child speakers of AAE without language disorders (NLD) were compared. Syntactic features were transcribed from conversational language samples of seven LD and seven NLD children, and these features were classified according to their overlapping relationship with SAE. Shared features between AAE and SAE were designated as "noncontrastive" and features not shared as "contrastive". The production of several noncontrastive linguistic features were significantly different between groups, whereas group differences were nonsignificant for all contrastive features, with the exception of the past tense /ed/ morpheme.

This article presents a description of two classes of verbs, auxiliaries and aspectual markers, in African American English. The auxiliaries be, do, and have can bear negation, move to the front of the sentence in yes/no questions, and delete in yes/no questions. The aspectual markers be, BIN , done, and be done do not undergo such processes, but they assign aspectual meaning to the sentences in which they occur. The discussion of the verb classes in this article focuses on patterns of the auxiliary system as a whole, and highlights the generalization that speakers of the dialect make when they use this system. The description shows that the language system is rule governed, and it also presents some meaning differences between forms in African American English and Standard American English.

How do children acquire African American English? How do they develop the specific language patterns of their communities? Drawing on spontaneous speech samples and data from structured elicitation tasks, this book explains the developmental trends in the children's language. It examines topics such as the development of tense/aspect marking, negation and question formation, and addresses the link between intonational patterns and meaning. Lisa Green shows the impact that community input has on children's development of variation in the production of certain constructions such as possessive -s, third person singular verbal -s, and forms of copula and auxiliary be. She discusses the implications that the linguistic description has for practical applications, such as developing instructional materials for children in the early stages of their education.

Dawn: I don’t wanna be no doctor. I wanna be a mailman . Introduction This chapter considers negation marking in child AAE, with a focus on negative concord. One general pattern that AAE shares with some languages, such as Romance and Slavic languages, as well as other non-standard varieties of English, is the use of multiple negative elements within a clause to convey a single negative meaning. For instance, in the sentence They didn’t have no books , negation is indicated on the auxiliary didn’t as well as within the noun phrase no books ; however, the meaning of the sentence is the same as that of the corresponding single negation sentence with the negated auxiliary and polarity item any : They didn’t have any books . Thus the term for this type of multiple negation is generally known as negative concord given that the multiple negative elements are in agreement or concord with each other rather than each indicating separate negative meaning or each contributing further negative import to the sentence. Simply put, agreement or concord refers to the choice of a following negative element based on the preceding one. For instance, instead of no in They didn’t have no books canceling out the negative didn’t , resulting in the positive sentence They did have books , no occurs because there is a preceding negative ( didn’t ), not to add any negative meaning but to agree with the negative that is already present. Because multiple negative elements are used without changing the negative meaning of the sentence, negative concord has often been associated with emphatic interpretation, which would mean that the sentence in (1) is more emphatic than the one in (2): Bruce didn ’ t have no book. Bruce didn ’ t have a book. While the sentence in (1) can certainly be emphatic, it is not necessarily so, and (2) can be as emphatic as (1), especially with emphasis on a book . Although negative concord is a stigmatized pattern, it does not present the type of interpretation challenges for speakers who do not understand AAE patterns that constructions such as aspectual be sequences present. That is, American English speakers who do not speak varieties of English in which negative concord is acceptable generally do not have problems understanding it. Charles Yang (2006, p. 120) goes even farther and notes the following: “Third, it is possible that everyone in America spoke a fragment of African American English at one point. Many children learning English, regardless of demographics, make frequent use of double or multiple negatives: Daddy’s not being nothing. I don’t want no milk! He didn’t do nothing.

The p38 alpha mitogen-activated protein kinase (MAPK) is essential in controlling the production of many proinflammatory cytokines, and its specific inhibitor can effectively block their production for treating human diseases. To effectively identify highly specific p38 alpha inhibitors in vivo, we developed an ex vivo mouse blood cell-based assay by flow cytometry to measure the intracellular p38 alpha kinase activation. We first attempted to identify the individual blood cell population in which the p38 alpha kinase pathway is highly expressed and activated. Based on CD11b, combined with Ly-6G cell surface expression, we identified two distinct subsets of non-neutrophilic myeloid cells, CD11b(Med)Ly-6G(-) and CD11b(Lo)Ly-6G(-), and characterized them as monocytes and natural killer (NK) cells, respectively. Then, we demonstrated that only monocytes, not NK cells, expressed a high level of p38 alpha kinase, which was rapidly activated by anisomycin stimulation as evidenced by the phosphorylation of both p38 and its substrate, MAPKAP-K2 (MK2). Finally, the p38 alpha kinase pathway activation in monocytes was fully inhibited by a highly selective p38 alpha kinase inhibitor dose-dependently in vitro and in vivo. In conclusion, we demonstrated an effective method for separating blood monocytes from other cells and for detecting the expression level and activation of the p38 alpha kinase pathway in monocytes, which provided a new approach for the rapid identification of specific p38 alpha inhibitors.

Thrombin cleavages of selective proteinase-activated receptors (PAR) as well as PAR-activating peptide ligands can initiate the phosphoinositide 3-kinase (PI3K) signaling cascade in platelets. Downstream to this event, fibrinogen receptors on platelets undergo conformational changes that enhance fibrinogen binding. In our study, we used this phenomenon as a surrogate biomarker for assessing effects on PI3K activity. Our method, using flow cytometric measurement of fluorescent ligand and antibody binding, uncovered a 16- to 45-fold signal window after PAR-induced platelet activation. Pretreatment (in vitro) with the PI3K inhibitors wortmannin and LY294002 resulted in concentration-dependent inhibition at predicted potencies. In addition, platelets taken from mice treated with wortmannin were blocked from PAR-induced ex vivo activation concomitantly with a decrease in phosphorylation of AKT from excised tumor xenografts. This surrogate biomarker assay was successfully tested (in vitro) on blood specimens received from volunteer cancer patients. Our results indicate that measurement of platelet activation could serve as an effective drug activity biomarker during clinical evaluation of putative PI3K inhibitors. [Mol Cancer Ther 2007;6(9):2600–7]

Purpose: To evaluate the effects of the novel protein kinase C (PKC) inhibitor enzastaurin on intracellular phosphoprotein signaling using flow cytometry and to use this approach to measure enzastaurin effects on surrogate target cells taken from cancer patients that were orally dosed with this agent. Experimental Design: The activity of PKC was assayed in intact cells using a modification of published techniques. The U937 cell line and peripheral blood mononuclear cells were stimulated with phorbol ester, fixed, permeabilized, and reacted with an antibody specific for the phosphorylated forms of PKC substrates. The processed samples were quantitatively analyzed using flow cytometry. The assay was validated for selectivity, sensitivity, and reproducibility. Finally, blood was obtained from volunteer cancer patients before and after receiving once daily oral doses of enzastaurin. These samples were stimulated ex vivo with phorbol ester and were assayed for PKC activity using this approach. Results: Assay of U937 cells confirmed the selectivity of the antibody reagent and enzastaurin for PKC. Multiparametric analysis of peripheral blood mononuclear cells showed monocytes to be the preferred surrogate target cell. Day-to-day PKC activity in normal donors was reproducible. Initial results showed that five of six cancer patients had decreased PKC activity following enzastaurin administration. In a following study, a group of nine patients displayed a significant decrease in PKC activity after receiving once daily oral doses of enzastaurin. Conclusion: An inhibition of surrogate target cell PKC activity was observed both in vitro and ex vivo after exposure to the novel kinase inhibitor, enzastaurin.

Esophageal squamous cell carcinoma (ESCC) is a common cancer with a very poor prognosis. New methods are needed to screen high-risk populations and identify curable tumors and precursor lesions early. Molecular markers may be useful in such screening efforts. This study was designed to determine the prevalence of p16, MGMT, RARbeta2, CLDN3, CRBP and MT1G gene methylation in patients with ESCC to evaluate the variation of gene methylation across a spectrum of preneoplastic lesions, and assess the feasibility of using gene methylation in a primary screening test utilizing frozen esophageal cells collected by balloon cytology samplers. Samples were obtained from high-risk subjects from north central China. These samples included 11 foci of histologically normal mucosa, 8 foci of low-grade squamous dysplasia, 7 foci of high-grade squamous dysplasia, and 13 foci of ESCC from 6 fully embedded resection specimens; endoscopic biopsies from 6 individuals with no histological evidence of disease; and frozen esophageal balloon samples from 12 asymptomatic subjects. Promoter CpG site-specific hypermethylation status was determined for each gene using real-time methylation-specific PCR (qMS-PCR) based on Taqman chemistry. Of the 6 ESCC patients, 5 showed methylation of at least one gene. For most genes, methylation occurred with increasing frequency during neoplastic progression, with the largest increase found between low- and high-grade dysplasia. There was considerable variation in methylation patterns among different foci of the same histological grade, even within individual patients, but 16/20 (80%) of high-grade dysplastic and cancer foci had >or= 2 methylated genes, while 17/19 (89%) of normal and low-grade dysplastic foci had

An immortalized human prostate stromal cell line (PS30) was previously established using recombinant retrovirus encoding human papillomavirus 16 gene products. In this study, we further characterize this stromal cell line for its potential use in a stromal-epithelial coculture model for prostate cancer prevention. Using reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, and immunocytochemistry, we examined expression of androgen receptor (AR), vitamin D receptor (VDR), prostate-specific antigen (PSA), transforming growth factor-beta (TGF-beta), and insulin-like growth factors (IGF) families and their receptors, metalloproteinases (MMP) MMP-2 and MMP-9, as well as the cells' ability to respond to the synthetic androgen R1881. The PS30 stromal cells do not express PSA, confirming their stromal origin. They are positive for both AR messenger ribonucleic acid (mRNA) and protein; however, they do not respond to growth stimulation by the synthetic androgen R1881. The PS30 cells express mRNA for VDR, TGF-betas, IGFs and their receptors, as well as the MMPs. Moreover, they produce significant amounts of TGF-beta1, TGF-beta2, IGFBP-3, and MMP-2 proteins. Our observations confirm the use of PS30 for the study of stromal-epithelial interactions in the modulation of prostate carcinogenesis.

Adolescent and adult African American English (AAE) is characterized by well-defined tense and aspect patterns; however, the stages of development in which child AAE speakers acquire these patterns have not been identified. For instance, aspectual f be functions as a habitual marker in adolescent and adult AAE, but the extent to which child AAE speakers use it in this way has not been explained. This paper presents an overview of properties of aspectual be and describes the way the marker is distinguished from the copula and auxiliary be along syntactic and semantic lines. For example, the copula and auxiliary be occur in C° in questions and license V’-ellipsis, but aspectual be does not. In addition, verbs naming states do not generally occur in the progressive (with auxiliary y be), but state verbs in their -ing form can occur with aspectual be. In this account, predicates in aspectual be constructions are argued to take an eventuality argument. Data from comprehension and production experiments show that child AAE speakers distinguish auxiliary be and aspectual be semantically and syntactically. For instance, children as young as 4 years respond to auxiliary be and aspectual be scenarios as if they depict different types of activity, recognizing that aspectual be refers to habitual situations. In addition, AAE speaking children distinguish auxiliary be and aspectual be by using appropriate negation strategies for each form. The ability to negate aspectual be constructions appropriately using do insertion increases with age.

Loss of imprinting (LOI) of insulin-like growth factor-II (IGF-II) may be an inherited epigenetic trait that is polymorphic in the population, and its presence may predispose an individual to the development of colorectal cancer. We evaluated the association between LOI of IGF-II in normal colonic mucosal samples and adenomas in women participating in a colonoscopy screening study. Among 40 participants, 11 (27.5%) had LOI of IGF-II in their normal colonic mucosal tissue. After adjusting for body mass index and family history of colorectal cancer, LOI status was associated with a fivefold increased risk of adenoma formation (odds ratio = 5.2, 95% confidence interval = 1.0 to 26.7). On average, IGF-II expression was more than threefold higher among women with LOI of IGF-II than among women with normal imprinting status. Our findings support the hypothesis that LOI of IGF-II is an epigenetic trait polymorphic in the population and suggest that LOI of IGF-II may play a role in colorectal cancer. These findings are intriguing and need to be confirmed in larger studies.

Focal point For the most part, words in sentences in AAE are arranged in the same order as words in sentences in other varieties of English, but in AAE different combinations are allowed. For example, in AAE, the word order subject-auxiliary-main verb-object occurs in AAE I didn't see nothing just as in general American English I didn't see anything . The difference is that in AAE both the auxiliary and object can be negative. Also, AAE uses the same words that occur in other varieties of English, but these words can take on different meanings and functions. One case in point is that it can be used to indicate that something exists: It be just the right amount of decoration on those birthday cakes . When I rose this morning, I didn't have no doubt. [line from a song sung in African American church services] Introduction This chapter presents a description of patterns in the syntactic and morphological components of AAE. As in chapter 2, I will be concerned with the way words are combined to form sentences, and I will also consider morphology, that part of the system that deals with the function of smaller units of words such as suffixes. Oftentimes negative opinions are formed about AAE and the people who speak it based on the type of data that will be discussed in this chapter.

Focal point The literary representation of AAE in some authors' works is considered to be an accurate and rich representation of folk speech, while that of others is labeled stereotypical renditions of the shiftless Negro. By manipulating the spoken word, maneuvering the spelling of some and evoking symbolism and imagery, authors are able to mold characters into dialect speakers or make them appear to be dialect speakers. If we are to believe the majority of writers of Negro dialect and burnt-cork artists, Negro speech is a weird thing, full of ‘ams’ and ‘Ises.’ Fortunately, we don't have to believe them. We may go directly to the Negro and let him speak for himself. [Zora Neale Hurston, “Characteristics of Negro Expression”] Introduction Language in literature is used to achieve a number of goals: (1) to connect the character with a particular region, (2) to identify the character as a particular type (e.g., belongs to certain class) (3) to make the character more authentic and more developed, (4) to evoke some feeling within the reader. In addition, as Holloway (1978) notes in her discussion of Zora Neale Hurston's works, language use can indicate that a character is “communicating cultural understanding” (p. 118). By this Holloway means that the more deeply entrenched Hurston's characters are with their language, African American dialect, the more involved and in tune they are with each other.

Focal point In preceding chapters, general descriptions of constructions in the syntactic and phonological components of AAE were presented. These descriptions may have practical applications if they can be extended to the development of classroom strategies that are used in teaching mainstream English proficiency. Using linguistic descriptions of AAE to develop lessons does not in any way mean teaching AAE to school age children. Such descriptions are useful in substantiating the claim that AAE is rule-governed, but they are not always successful in combating negative attitudes toward the linguistic system. For example, questions about whether it is right or wrong to use markers such as aspectual be or resultant state dәn usually do not just make reference to right or wrong grammatical structure. The evaluations are connected to broader social issues, as the following passage by Walter Mercer suggests. Regardless of the “genuineness” of the dialect, regardless of how remarkably it may add flavor and soul to a poem or song or novel, regardless of the solidarity it may lend to a political rally, I say it is illogical, nonsensical, and harmful to teach an innocent black child that it's quite all right to say ‘I done gone to school.’ [Walter Mercer, from Brasch 1981]