Coccidioides' most recent common ancestor underwent gene family expansions for proteases and keratinases, membrane biology genes, and toxin production, all likely utilized for survival in animal ...tissues and morphological changes; and a loss of genes associated with degradation of plant tissue, such as tannases, cellulases, and cutinases 1. Both Coccidioides species have similar biology, with a well-characterized asexual life cycle with distinct saprobic and parasitic stages, and only molecular evidence of a sexual cycle (Fig 1). ...analysis at a single 10-meter square area in Tucson, Arizona, revealed multiple genotypes present in a single environmental location 11.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Coccidioidomycosis, or valley fever, is a growing health concern endemic to the southwestern United States. Safer, more effective, and more easily administered drugs are needed especially for severe, ...chronic, or unresponsive infections. The novel fungal CYP51 inhibitor VT-1161 demonstrated in vitro antifungal activity, with MIC50 and MIC90 values of 1 and 2 μg/ml, respectively, against 52 Coccidioides clinical isolates. In the initial animal study, oral doses of 10 and 50 mg/kg VT-1161 significantly reduced fungal burdens and increased survival time in a lethal respiratory model in comparison with treatment with a placebo (P < 0.001). Oral doses of 25 and 50 mg/kg VT-1161 were similarly efficacious in the murine central nervous system (CNS) model compared to placebo treatment (P < 0.001). All comparisons with the positive-control drug, fluconazole at 50 mg/kg per day, demonstrated either statistical equivalence or superiority of VT-1161. VT-1161 treatment also prevented dissemination of infection from the original inoculation site to a greater extent than fluconazole. Many of these in vivo results can be explained by the long half-life of VT-1161 leading to sustained high plasma levels. Thus, the efficacy and pharmacokinetics of VT-1161 are attractive characteristics for long-term treatment of this serious fungal infection.
Urban histories of modern South Asia have centred on British Indian cities and the reign of colonial urbanism, with dependence on metropolitan imperatives and models regarded as givens. Focusing on ...Hyderabad, one of the subcontinent's five largest cities and capital of an autonomous princely state throughout the colonial era, this article establishes the analytical utility of princely urbanism as a framework for writing the history of South Asian cities. Characterized by state-directed planning, transnational urbanist networks and multiple overlapping property regimes, this mode of city development and its resonance points to hidden genealogies of modern urbanism.
It was the late Bishop Ithiel Conrad Clemmons, former minister of the First Church of God in Christ of Brooklyn, New York, who said of the late famed novelist/essayist James Baldwin that “he was ...America’s inside eye on the Black Holiness and Pentecostal Churches”. Though Baldwin admitted that the culture and ethos of the African-American Pentecostal church were “highly significant and indelibly imprinted upon him”, according to Baldwin, his faith community’s “naiveté about life appalled him and drove him away”. While Baldwin left behind the church of his youth, never to return, for the remainder of his writing career, the “backslidden” minister’s literary musings continued to be informed (in both style and content) by the formative religious tradition that he left behind. Though several studies have been undertaken that examine Baldwin’s significance to various aspects of the study of African-American religion and culture, precious little has been written regarding Baldwin’s continuing engagement of the idiom of African-American preaching, the idiom which cultural critic Michael Eric Dyson has nominated as the “jewel in the crown of Black Sacred Rhetoric”. While many studies of Baldwin include the fact that Baldwin was a preacher’s son and that Baldwin himself preached for a time during his youth, the account is yet to be given of how Baldwin’s writings continued to employ the rhythms, grammar, tones, and textures of the Black sacred rhetorical tradition, especially from beyond the borders of the African-American church. This essay seeks to expose not only how Baldwin self-consciously continued to stand in the rhetorical trajectory of the African-American preaching tradition, but the attempt is also to reveal how the writer secularizes the idiom, providing the Black Holiness preacher a hearing from beyond the church. Through a focus on Baldwin as a Black sacred rhetorician, sermonizing from beyond the church, this essay participates in the nearly 100-year-old conversation instigated by the early African-American literary and cultural critic James Weldon Johnson in God’s Trombones: Seven Negro Sermons in Verse (1927), regarding the neglected significance of the sermon and the preacher in African-American literature and Black expressive cultures. Baldwin’s sermonic is here examined as a highly distinctive mode of Black public theologizing.
The Gram-negative proteobacteria genus Burkholderia encompasses multiple bacterial species that are pathogenic to humans and other vertebrates. Two pathogenic species of interest within this genus ...are Burkholderia pseudomallei (Bpm) and the B. cepacia complex (Bcc); the former is the causative agent of melioidosis in humans and other mammals, and the latter is associated with pneumonia in immunocompromised patients. One understudied and shared characteristic of these two pathogenic groups is their ability to persist and establish chronic infection within the host. In this review, we will explore the depth of knowledge about chronic infections caused by persistent Bpm and Bcc. We examine the host risk factors and immune responses associated with more severe chronic infections. We also discuss host adaptation and phenotypes associated with persistent Burkholderia species. Lastly, we survey how other intracellular bacteria associated with chronic infections are combatted and explore possible future applications to target Burkholderia. Our goal is to highlight understudied areas that should be addressed for a more thorough understanding of chronic Burkholderia infections and how to combat them.
This work explores the depth of knowledge about chronic infections caused by persistent Burkholderia pseudomallei and B. cepacia complex.
Graphical Abstract Figure.
This work explores the depth of knowledge about chronic infections caused by persistent Burkholderia pseudomallei and B. cepacia complex.
Burkholderia pseudomallei (Bpm) is a saprophytic rod-shaped gram-negative bacterium and the causative agent of melioidosis. This disease has previously been described as endemic in areas such as ...northern Australia and Southeast Asia, but, more recently, a better understanding of the epidemiology of melioidosis indicated that the disease is distributed worldwide, including regions of the Americas and Africa. A 16S-23S rDNA internal transcribed spacer (ITS) typing system has been developed for Bpm and has revealed that ITS types C, E, and hybrid CE are mainly associated with Australia and Southeast Asia while type G strains are more associated with cases of melioidosis in the Western Hemisphere. The purpose of the current study was to determine the in vitro and in vivo virulence profiles of the understudied Bpm type G strains Ca2009, Ca2013a, Mx2013, and 724644 and compared such phenotypes to the commonly studied Bpm type C strain K96243. We evaluated virulence by measuring invasion/uptake and survival of these Bpm strains in murine respiratory epithelial LA-4 cells and alveolar macrophage MH-S cells using different multiplicity of infections (MOIs of 1 and 10). We also calculated the lethal dose 50 values (LD50) in BALB/c mice that were inoculated intranasally with either Ca2009, Ca2013a, or Mx2013. Overall, the virulence and lethality phenotypes of Bpm type G strains were similar to the Bpm type C strain K96243. Additional comparative analyses between the Bpm ITS types may lead to a better understanding of the contribution of the ITS type to the epidemiology and ecology of Bpm strains.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVETo assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis ...(RMS).
METHODSPatients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion.
RESULTSThe cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo (p < 0.001). Post hoc analysis (excluding weeks 1–4) estimated a ≥90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses ≥30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing.
CONCLUSIONImaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robustcumulative doses ≥30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells.
CLASSIFICATION OF EVIDENCEThis study provides Class I evidence that for patients with RMS, ofatumumab decreases the number of new MRI gadolinium-enhancing lesions 12 weeks after treatment initiation.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Borrelia hermsii, a spirochete and cause of relapsing fever, is notable for its immune evasion by multiphasic antigenic variation within its vertebrate host. This is based on a diverse repertoire of ...surface antigen genes, only one of which is expressed at a time. Another major surface protein, the Variable Tick Protein (Vtp), is expressed in the tick vector and is invariable at its genetic locus. Given the limited immune systems of ticks, the finding of considerable diversity among the Vtp proteins of different strains of B. hermsii was unexpected. We investigated one explanation for this diversity of Vtp proteins, namely expression of the protein in mammals and a consequent elicitation of a specific immune response. Mice were infected with B. hermsii of either the HS1 or CC1 strain, which have antigenically distinctive Vtp proteins but otherwise have similar repertoires of the variable surface antigens. Subsequently collected sera were examined for antibody reactivities against Vtp and other antigens using Western blot analysis, dot blot, and protein microarray. Week-6 sera of infected mice contained antibodies that were largely specific for the Vtp of the infecting strain and were not attributable to antibody cross-reactivities. The antibody responses of the mice infected with different strains were otherwise similar. Further evidence of in vivo expression of the vtp gene was from enumeration of cDNA sequence reads that mapped to a set of selected B. hermsii genes. This measure of transcription of the infecting strain's vtp gene was ~10% of that for the abundantly-expressed, serotype-defining variable antigen gene but similar to that of genes known for in vivo expression. The findings of Vtp expression in a vertebrate host and elicitation of a specific anti-Vtp antibody response support the view that balancing selection by host adaptive immunity accounts in part for the observed diversity of Vtp proteins.
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Improvisation and Social Aesthetics Georgina Born, Eric Lewis, Will Straw / Georgina Born, Eric Lewis, Will Straw
Duke University Press eBooks,
01/2017
eBook
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Addressing a wide range of improvised art and music forms—from jazz and cinema to dance and literature—this volume's contributors locate improvisation as a key site of mediation between the ...social and the aesthetic. As a catalyst for social experiment and political practice, improvisation aids in the creation, contestation, and codification of social realities and identities. Among other topics, the contributors discuss the social aesthetics of the Association for the Advancement of Creative Musicians, the Feminist Improvising Group, and contemporary Malian music, as well as the virtual sociality of interactive computer music, the significance of "uncreative" improvisation, responses to French New Wave cinema, and the work of figures ranging from bell hooks and Billy Strayhorn to Kenneth Goldsmith.
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