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Nodulocystic basal cell carcinoma (BCC) is a cystic variant of BCC, which can easily be misdiagnosed. We report a case of a 52-year-old man with a nodulocystic BCC that appeared at the site of a previously excised BCC 9 years prior. It examined as a benign cyst with a radiological signature of a vascular malformation. It was histologically confirmed on fine needle aspirate (FNA) and excisional biopsy to be a nodulocystic BCC. BCC is one of the most common paraneoplastic neoplasms affecting photo-exposed areas and displaying many variants. Nodulocystic BCC is a rarer variant that may have more than one dermoscopic face and can appear macroscopically benign. Given its malignant potential, it is imperative that it is accurately diagnosed. We highlighted that nodular cystic BCC can easily be misdiagnosed. Careful history and FNA are key differentiators to establish the correct diagnosis.

To evaluate the national trends in minimally invasive surgical therapies (MIST) for overactive bladder (OAB) in Australia over the past decade.Annual MIST data were extracted using the Australian Medicare Benefit Schedule (MBS) on intravesical botulinum toxin (BTX), sacral nerve modulators (SNM) and percutaneous tibial nerve stimulators (PTNS) performed between 2010 and 2021. Population-adjusted rates of these procedures were compared in relation to individual states and against the introduction of various OAB drugs during the intervening years.The overall national utilization of MIST for OAB has increased over the last decade. The data reflect a rapid uptake in PTNS over the last 2 years following its introduction compared to the relatively steady increase in BTX and SNM over the past decade. There was minimal difference in SNM lead and generator placement, suggesting perhaps the conversion of trial SNM to permanent SNM has been relatively stable across the years. In contrast, there was an increase in PTNS maintenance in the following years following the initial rise in the PTNS treatment initiation. The introduction of various OAB drugs in the market did not seem to significantly affect the pattern of MIST uptake.Despite the introduction of various OAB drugs, the overall MIST has increased steadily over the last decade, especially with PTNS. Further exploration into the motivators for specific MIST and cost-benefit analysis of these MIST for OAB is warranted.

Non-profit social enterprises address social problems with business models. This paper examines the founding years of an early non-profit social enterprise in the United States to highlight the rol...

This thesis was scanned from the print manuscript for digital preservation and is copyright the author. Researchers can access this thesis by asking their local university, institution or public library to make a request on their behalf. Monash staff and postgraduate students can use the link in the References field.

This document contains supplementary material for the journal articles to be published, titled "Conceptual Range Estimation for Total Cost of Ownership of Modular Process-Intensified Chemical Plants" and "Natural Gas Processing Case Study: Economic Analysis of Modular Chemical Process Intensification vs. Conventional Stick-Built Approaches"

This document contains supplementary material for the journal articles to be published, titled "Conceptual Range Estimation for Total Cost of Ownership of Modular Process-Intensified Chemical Plants" and "Natural Gas Processing Case Study: Economic Analysis of Modular Chemical Process Intensification vs. Conventional Stick-Built Approaches"

This document contains supplementary material for the journal articles to be published, titled "Conceptual Range Estimation for Total Cost of Ownership of Modular Process-Intensified Chemical Plants" and "Natural Gas Processing Case Study: Economic Analysis of Modular Chemical Process Intensification vs. Conventional Stick-Built Approaches"

This document contains supplementary material for the journal articles to be published, titled "Conceptual Range Estimation for Total Cost of Ownership of Modular Process-Intensified Chemical Plants" and "Natural Gas Processing Case Study: Economic Analysis of Modular Chemical Process Intensification vs. Conventional Stick-Built Approaches"

Dentistry has evolved from its origin to the present day, becoming almost entirely digitized and supervised. The digitalized dental laboratory saves time due to computer-aided design and computer-aided manufacture (CAD/CAM) technology, which will capture and display clients' tooth or teeth and gums on a 3D image on a computer screen sent to the lab. It enables a dental lab technician to work faster and get the perfect design of the digital dental restoration. The main advantage of digitalization includes faster and improved efficiency on the turn-around time of devices, like crowns and bridges, and improved accuracy of procedures and manufactured gadgets. Digitalization Dental Laboratory (DDL) is the first to offer a digital dental lab in the city of Bacolod. The service allows laboratories to design the prosthesis digitally from in-house CAD software and email the design data provider or download the data file into a proprietary web host or server. The lab will cater to the digital needs of dental patients of the Multi-Specialty Dental Center (a sister company of DDL) and other dental clients.

Calls for higher fuel efficiency in the United States and Europe are driving the need for waste heat recovery in automotive markets. While conventional heat exchangers can be designed to meet the heat duty requirement, the resulting volume, weight, and thermal mass are too large for rapid transient response and packaging of the device. The lightweight, compact form factor of microchannel heat exchangers with submillimeter flow passages is attractive for automotive applications. However, the industrial use of microchannel heat exchangers continues to be inhibited by high manufacturing costs. The objective of this paper is to develop a microchannel heat exchanger concept capable of meeting the cost and performance goals for an automotive application. So-called printed-circuit microchannel heat exchangers are produced using a stacked-lamina approach in which individual metal laminae are photochemically machined and diffusion bonded. Here, the conceptual design of a microchannel heat exchanger produced using more conventional stamping and joining technologies is discussed for an automotive application. The device is sized to provide waste heat recovery from an exhaust stream to engine coolant for a representative passenger vehicle with acceptable pressure loss. Using the specified design, a process-based cost model is presented showing cost modeling efforts to date including the capital investment and cost-of-goods-sold as a function of annual production volume. The initial results show a pathway for the cost effective integration of compact microchannel heat exchangers into advanced vehicle thermal management systems.

As they assemble organizations from different economic sectors, intersectoral collaborations are co-constituted by institutional pluralism. However, the intimacy and inequality of these arrangements also constrain an organization’s ability to respond strategically to the concomitant institutional pluralism. Members of the organization experience pluralism as a tension I call moral ambivalence, that is, they simultaneously hold opposing judgments about their actions or the situations in which they find themselves. Moral ambivalence leads actors to engage in institutional work, pragmatic compromises directed toward coping with the competing institutional rules they face. This institutional work produces hybrid actions that, in turn, help the organization maintain internal cohesion and prevent negative outcomes. The article traces the sources of institutional pluralism to organizational imprinting from for-profit partners and institutional pressures from other members of the field. Data come from an ethnography of a single nonprofit organization that collaborates with several large for-profit organizations.

Objectives To compare the cost-effectiveness (CE) of the National Institute for Health and Care Excellence (NICE) 2015 and the WHO 2013 diagnostic thresholds for gestational diabetes mellitus (GDM). Setting The analysis was from the perspective of the National Health Service in England and Wales. Participants 6221 patients from four of the Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) study centres (two UK, two Australian), 6308 patients from the Atlantic Diabetes in Pregnancy study and 12 755 patients from UK clinical practice. Primary and secondary outcome measures planned The incremental cost per quality-adjusted life year (QALY), net monetary benefit (NMB) and the probability of being cost-effective at CE thresholds of £20 000 and £30 000 per QALY. Results In a population of pregnant women from the four HAPO study centres and using NICE-defined risk factors for GDM, diagnosing GDM using NICE 2015 criteria had an NMB of £239 902 (relative to no treatment) at a CE threshold of £30 000 per QALY compared with WHO 2013 criteria, which had an NMB of £186 675. NICE 2015 criteria had a 51.5% probability of being cost-effective compared with the WHO 2013 diagnostic criteria, which had a 27.6% probability of being cost-effective (no treatment had a 21.0% probability of being cost-effective). For women without NICE risk factors in this population, the NMBs for NICE 2015 and WHO 2013 criteria were both negative relative to no treatment and no treatment had a 78.1% probability of being cost-effective. Conclusion The NICE 2015 diagnostic criteria for GDM can be considered cost-effective relative to the WHO 2013 alternative at a CE threshold of £30 000 per QALY. Universal screening for GDM was not found to be cost-effective relative to screening based on NICE risk factors.

This paper reports on the attitudes of 340 government primary principals from New South Wales, Australia, towards the inclusion of students with disruptive behaviours in schools. Principals’ attitudes were examined using the Principals and Behaviour Survey (PABS), a new composite measure built upon a foundation of existing validated surveys on attitudes towards the inclusion of students with disabilities. Principal component analysis identified 3 components that were used as variables for correlations with a range of demographic characteristics, such as age, qualifications, experience, school size and location. School size and the number of students with a diagnosed mental health condition in the school had a small relationship with principals’ attitudes. From the analysis of data from the emotional response scale, it was found that principals’ emotions about inclusion were less positive towards students with disruptive behaviour than towards students with sensory, physical or intellectual disabilities. Overall, principals appeared to hold dichotomous positions in regard to the benefits of inclusion, viewing it as beneficial for students with disruptive behaviour but not for their peers. However, principals who held more positive views were consistently more positive across all measures.

Both central and peripheral cannabinoid receptor type 1 (CB1R) have been considered to be among the key targets for obesity treatment. First generation CB1R antagonists/inverse agonists such as rimonabant and taranabant exhibited severe CNS side effects such as anxiety and depression, which are considered to be related to the compounds' ability to access central CB1R. Recently, several compounds have been developed as second generation antagonists with a profile of restriction to peripheral CB1R. We evaluated the distribution of TM38837, a second generation CB1R antagonist, using brain and whole body PET in three cynomolgus monkeys, and established the relationship between CB1R occupancy and dose/plasma concentration of TM38837 in comparison with rimonabant. A brain PET study was performed using [(11) C]MePPEP, a PET radioligand for CB1R, to evaluate the brain CB1R occupancy of TM38837 at various plasma concentrations in comparison with rimonabant at known efficacious plasma concentrations. A whole body PET study was performed to investigate the change of peripheral distribution of [(11) C]MePPEP by TM38837 administration, which indirectly estimated the effects to the peripheral CB1R by TM38837. CB1R occupancy by both TM38837 and rimonabant increased in a dose/plasma concentration-dependent manner. However, in vivo affinity by plasma level was more than 100 times lower for TM38837. Peripherally, [(11) C]MePPEP accumulation decreased in gall bladder and brown adipose tissue by TM38837 administration. TM38837 showed rather lower CB1R occupancy than rimonabant at the expected therapeutic plasma level, which is expected to reduce CNS side effects in clinical situations. Further clinical development of TM38837 is warranted.

Fields are contested social arenas. By examining the case of a single organization, in this case a social enterprise, the author shows how organizations respond to legitimacy challenges from members of the field and how such responses shape the organization's form and practices. At times, organizations endogenize, that is, incorporate practices from the field. Findings indicate that responses reflect strategies under constraint. Endogenizing institutionalized practices constrains managers’ ability to exercise agency. Endogenizing contested practices afford agency by allowing managers to translate those practices to accord with local exigencies. This article extends literature on impression management and institutional theory by showing how organizations respond to diffuse threats to legitimacy. In doing so, this article advances the study of organizational field dynamics and contention.

Aim Cannabinoid receptor type 1 (CB1) antagonists show central side effects, whereas beneficial effects are most likely peripherally mediated. In this study, the peripherally selective CB1 antagonist TM38837 was studied in humans. Methods This was a double-blind, randomized, placebo-controlled, crossover study. On occasions 1–4, 24 healthy subjects received 5 × 4 mg THC with TM38837 100 mg, 500 mg or placebo, or placebos only. During occasion 5, subjects received placebo TM38837 + THC with rimonabant 60 mg or placebo in parallel groups. Blood collections and pharmacodynamic (PD) effects were assessed frequently. Pharmacokinetics (PK) and PD were quantified using population PK−PD modelling. Results The TM38837 plasma concentration profile was relatively flat compared with rimonabant. TM38837 showed an estimated terminal half-life of 771 h. THC induced effects on VAS feeling high, body sway and heart rate were partly antagonized by rimonabant 60 mg [−26.70% [90% confidence interval (CI) −40.9, −12.6%]; −7.10%, (90%CI −18.1, 5.3%); −7.30%, (90% CI −11.5%, −3.0%) respectively] and TM38837 500 mg [−22.10% (90% CI −34.9, −9.4%); −12.20% (90% CI −21.6%, −1.7%); −8.90% (90% CI −12.8%, −5.1%) respectively]. TM38837 100 mg had no measurable feeling high or body sway effects and limited heart rate effects. Conclusions Rimonabant showed larger effects than TM38837, but the heart rate effects were similar. TM38837 100 mg had no impact on CNS effects, suggesting that this dose does not penetrate the brain. This TM38837 dose is predicted to be at least equipotent to rimonabant with regard to metabolic disorders in rodent models. These results provide support for further development of TM38837 as a peripherally selective CB1 antagonist for indications such as metabolic disorders, with a reduced propensity for psychiatric side effects.

This article discusses the results from an initial quantitative analysis of survey data collected from the Principals and Behaviour Survey (PABS) conducted in New South Wales, Australia. PABS was built upon a foundation of existing validated studies measuring principals' attitudes to the inclusion of students with disabilities in mainstream schools. Principal component analysis as an exploratory procedure indicated that whilst many similarities exist, the geographical context of the school impacts on a principal's skills and confidence, how they use their skills, and their attitudes towards the resources and supports required to support students with disruptive behaviour. Implications for the wide-scale implementation of approaches to managing disruptive behaviour across contexts are discussed alongside continuing dichotomies between the pragmatics of school practice and benefits of inclusive practice.

*† Although scholars have examined the different pathways to participation in social movements, far less research has looked at the endurance of activists once they mobilize. This article specifically explores the relationship between the pathways to mobilization and retention. Our data show that both social ties and individual motivations play a role in mobilizing participants of social movements. Contrary to what one might expect, we find that those activists who were mobilized with personal connections were less likely to be working for the organization a year later versus those who came to the organization as strangers. We find instead that self-starters— those canvassers who entered the canvass through their own volition—stayed on longer. Although those canvassers who came to the job through network ties were less likely to be working for the organization a year later, they were more likely to be engaged in other civic and political groups and they were more likely to be leaders of these groups. How do we understand social movement retention and in what ways is retention related to the pathways through which activists mobilize? Using data on a cohort of activists at one social movement organization, we assess the relationship between these two important and interrelated aspects of social movements. As will be spelled out in more detail in the sections that follow, although much research has explored the role of social ties in mobilization, very little research has looked at the role of social ties in the retention of activists (but see McAdam 1989; Downton and Wehr 1997; Sandell 1999). In addition, scholars have yet to study the ways that social ties, along with other pathways to mobilization, are related to the endurance of activists once they mobilize. Accordingly, this article explores how the pathways through which people become mobilized shape retention and ongoing involvement. Building on previous research, we identify and summarize two main pathways to mobilization: personal and/or organizational ties and selfstarters. Then, drawing on the limited scholarship on the relationship between mobilization and retention, we develop three propositions to clarify our expectations about how pathways shape retention and ongoing involvement. Our analysis is based on data collected from a cohort of young activists who worked as canvassers recruiting new members and renewing existing memberships for a number of progressive groups during the summer of 2003. The canvassers worked for one organization that is hired by these groups to raise money and awareness for them (see Fisher 2006a, 2006b). In the analysis, we explore the relationship between the ways the canvassers mobilized and their endurance at the organization. For those who left the canvass, we look at how their pathways to mobilization are related to their levels of civic engagement more broadly. In conclusion, we discuss how our results provide a more nuanced understanding of the relationship between how activists mobilize and their retention.

As an introduction to Nova Religio's special issue on ET-inspired (UFO) religions, this article maintains that despite less media attention since the furor surrounding the Heaven's Gate suicides, ET-inspired religions are still active. Moreover, increasing speculation linking extraterrestrials to 2012 apocalyptic scenarios, coupled with a significant percentage of the population who believe in extraterrestrial visitation, seems to indicate that purveyors of ET-inspired religious perspectives will continue to have a market. Rather than focusing upon the "strange" and seemingly "bizarre" nature of these religious groups, the articles in this special issue endeavor to demonstrate how members of ET-inspired religions appropriate materials and theological ideas from widely-accepted mainstream religious traditions. This article maintains that the value of such an approach lies in bridging the gulf between normalized religious perspectives and the marginalized religious "other."

By utilizing the textual products of extraterrestrial-inspired religious thinkers like George Van Tassel, Raël, and Patricia Cori, as well as related materials by Erich von Däniken and Zecharia Sitchin, this article explores the concept of revisionism in ET-inspired religions. The authors examined in this article reread ancient religious texts, especially the Bible, as containing evidence of extraterrestrial influence in the course of human history. The anatomy of this "drive to revise" human history is explored, including an examination of how an improvisational millenarianism combines with a cultic milieu suspicious of authority and hegemonic narratives, and the conspiratorial intellectual maverick willing to work with "stigmatized" knowledge to produce narratives that are highly critical and suspicious of established intellectual authorities and procedures.

This essay analyzes the carved footprints in the Iron Age temple at ‘Ain Dara, Syria from a broadly comparative perspective. This methodology is necessitated by the fact that footprint iconography is very rare in ancient Near Eastern art. The diverse examples utilized in this paper to help explicate the footprints at ‘Ain Dara range from the Footprints of the Buddha (Buddhapadas) to the sullied feet of Jesus. Through analysis of footprint iconography in other religious contexts, I have drawn conclusions concerning the form and function of the temple footprints at ‘Ain Dara that have escaped other scholars of the ancient Near East.

Despite the centrality of fields as a concept in organizational research, the processes by which fields form and change have not been studied in great depth. By situating action in time and space, field-configuring events (FCEs) offer valuable settings for researchers seeking insight into such processes. This paper develops a theory of accounts as a way to understand a mechanism by which institutional entrepreneurs seek to shape fields and influence the institutions that govern them. Actors produce and distribute justified accounts – narratives that describe the way work in the field ought to be done – and attempt to persuade powerful actors in the field to adopt them as conventions. FCEs can thus be understood as loci for conventionalizing accounts. The theory of accounts and field-level change is illustrated with a case study of a turning point FCE during which competing institutional entrepreneurs in the field of ‘non-profit technology assistance providers’ present alternative accounts. Successful institutional entrepreneurship comes from recognizing political opportunities to align one's account with the dominant orders of worth in the field, thereby convincing powerful actors to accept one's account as convention.

Genetic engineering has been applied to reprogramme non-ribosomal peptide synthetases (NRPSs) to produce novel antibiotics, but little is known about what determines the efficiency of production. We explored module exchanges at nucleotide sequences encoding interpeptide linkers in dptD, a gene encoding a di-modular NRPS subunit that incorporates 3-methylglutamic acid (3mGlu(12)) and kynurenine (Kyn(13)) into daptomycin. Mutations causing amino acid substitutions, deletions or insertions in the inter-module linker had no negative effects on lipopeptide yields. Hybrid DptD subunits were generated by fusing the 3mGlu(12) module to terminal modules from calcium-dependent antibiotic (CDA) or A54145 NRPSs, and recombinants produced daptomycin analogues with Trp(13) or Ile(13) at high efficiencies. A recombinant expressing DptD with a hybrid Kyn(13) module containing a di-domain from a d-Asn module caused the production of a new daptomycin analogue containing Asn(13).

Many technologies in our everyday lives are expressions of deliberate and protracted political struggles among interested groups. While some technologies are inherently political, other technologies become politicized through competition among different groups and organizations. How do seemingly apolitical technologies become politicized? In this article, the author examines the case of the “circuit riders,” a progressive technology movement in the United States that promotes information technology use among nonprofit and grassroots organizations, to show how a particular technology is politicized through field-level interactions. Applying and contributing to actor—network theory, the author finds that translation takes place as an organizational process by which actors associate the ideals of the technology in question with their political ideals and then attempt to enroll other actors to accept the resultant associations. Successful association depends on both discursive and organizational practices.

Daptomycin, a cyclic lipopeptide produced by Streptomyces roseosporus , is the active ingredient of Cubicin (daptomycin-for-injection), a first-in-class antibiotic approved for treatment of skin and skin-structure infections caused by Gram-positive pathogens and bacteremia and endocarditis caused by Staphylococcus aureus , including methicillin-resistant strains. Genetic engineering of the nonribosomal peptide synthetase (NRPS) in the daptomycin biosynthetic pathway was exploited for the biosynthesis of novel active antibiotics. λ-Red-mediated recombination was used to exchange single or multiple modules in the DptBC subunit of the NRPS to modify the daptomycin cyclic peptide core. We combined module exchanges, NRPS subunit exchanges, inactivation of the tailoring enzyme glutamic acid 3-methyltransferase, and natural variations of the lipid tail to generate a library of novel lipopeptides, some of which were as active as daptomycin against Gram-positive bacteria. One compound was more potent against an Escherichia coli imp mutant that has increased outer membrane permeability. This study established a robust combinatorial biosynthesis platform to produce novel peptide antibiotics in sufficient quantities for antimicrobial screening and drug development.

SummaryDaptomycin is a lipopeptide antibiotic produced by a nonribosomal peptide synthetase (NRPS) in Streptomyces roseosporus. The holoenzyme is composed of three subunits, encoded by the dptA, dptBC, and dptD genes, each responsible for incorporating particular amino acids into the peptide. We introduced expression plasmids carrying dptD or NRPS genes encoding subunits from two related lipopeptide biosynthetic pathways into a daptomycin nonproducing strain of S. roseosporus harboring a deletion of dptD. All constructs successfully complemented the deletion in trans, generating three peptide cores related to daptomycin. When these were coupled with incomplete methylation of 1 amino acid and natural variation in the lipid side chain, 18 lipopeptides were generated. Substantial amounts of nine of these compounds were readily obtained by fermentation, and all displayed antibacterial activity against gram-positive pathogens.

SAR explorations of the eastern and western parts of recently disclosed 2-aminoquinoline MCH1R-antagonists are reported. Eastern part investigations confirmed a high degree of structural freedom, and a number of additional single digit nanomolar antagonists were identified. Investigations of the western part also confirmed the initial SAR analysis, requiring a para-substituted phenyl ring spaced from the 6-amide by two connecting atoms. The exploration led to the discovery of a novel sub-series with a 4-biphenylcarboxamide western part, also exhibiting single digit nanomolar affinity.

In New South Wales (NSW), as in many other parts of the world, there is a growing anxiety about disruptive student behaviour in schools. As such, behaviour remains a dominant discourse adding to the complexity of schools. At the same time, policy attention has turned to school leadership as a solution to raising educational standards (Wilkinson & Eacott, 2013b). In particular, attention continues to be directed to the role that leadership of, and by, the principal plays in creating effective schools. At the centre of calls for effective leadership and greater use of evidence-based practices in managing disruption sits the school principal who is charged with the responsibility to make schools safe and orderly in order to promote learning. This thesis explores the ways school principals construct knowledge that is supportive (or not) of students with disruptive behaviour in NSW government primary schools. The study employs mixed methods and uses quantitative data from 341 NSW principals collected through the Principals and Behaviour Survey (PABS) alongside qualitative data collected through three case studies of primary principals nominated as effective in supporting students with disruptive behaviour. Analysed through a critical lens, the thesis challenges the linear rational view of knowledge as simply the translation of theory into practice. Employing Bourdieu's 'thinking tools' of field, capital and habitus, the study develops a theory of knowledge as practice, of and by the principal, who embodies and is embedded within dominant discourses of behaviour, educational leadership and the 'good school'. The thesis contends that principals' practice can be both reproductive and transformative. In schools, dominant discourses 'collide and collude' and reproduce practices that lead to rising exclusions of students with disruptive behaviour, often misrecognising exclusion as a result of different definitions of inclusion. Uncovering reproduction enables transformation to occur by identifying the moments where a principal's habitus can disrupt dominant ways of thinking and create conditions that challenge exclusions.

Daptomycin and the A21978C antibiotic complex are lipopeptides produced by Streptomyces roseosporus and also in recombinant Streptomyces lividans TK23 and TK64 strains, when a 128 kbp region of cloned S. roseosporus DNA containing the daptomycin gene cluster is inserted site-specifically in the phiC31 attB site. A21978C fermentation yields were initially much lower in S. lividans than in S. roseosporus, and detection was complicated by the production of host metabolites. However A21978C production in S. lividans was improved by deletion of genes encoding the production of actinorhodin and by medium optimization to control the chemical form of the calcium dependent antibiotic (CDA). This latter compound has not previously been chemically characterized as a S. lividans product. Adding phosphate to a defined fermentation medium resulted in formation of only the phosphorylated forms of CDA, which were well separated from A21978C on chromatographic analysis. Adjusting the level of phosphate in the medium led to an improvement in A21978C yield from 20 to 55 mg/l.

Daptomycin is a cyclic lipopeptide antibiotic produced by Streptomyces roseosporus. Cubicin (daptomycin-for-injection) was approved in 2003 by the FDA to treat skin and skin structure infections caused by Gram-positive pathogens. Daptomycin is particularly significant in that it represents the first new natural product antibacterial structural class approved for clinical use in three decades. The daptomycin gene cluster contains three very large genes (dptA, dptBC, and dptD) that encode the nonribosomal peptide synthetase (NRPS). The related cyclic lipopeptide A54145 has four NRPS genes (lptA, lptB, lptC, and lptD), and calcium dependent antibiotic (CDA) has three (cdaPS1, cdaPS2, and cdaPS3). Mutants of S. roseosporus containing deletions of one or more of the NRPS genes have been trans-complemented with dptA, dptBC, and dptD by inserting these genes under the control of the ermEp* promoter into separate conjugal cloning vectors containing phiC31 or IS117 attachment (attP int) sites; delivering the plasmids into S. roseosporus by conjugation from Escherichia coli; and inserting the plasmids site-specifically into the chromosome at the corresponding attB sites. This trans-complementation system was used to generate subunit exchanges with lptD and cdaPS3 and the recombinants produced novel hybrid molecules. Module exchanges at positions D: -Ala(8) and D: -Ser(11) in the peptide have produced additional novel derivatives of daptomycin. The approaches of subunit exchanges and module exchanges were combined with amino acid modifications of Glu at position 12 and natural variations in lipid side chain starter units to generate a combinatorial library of antibiotics related to daptomycin. Many of the engineered strains produced levels of novel molecules amenable to isolation and antimicrobial testing, and most of the compounds displayed antibacterial activities.

Daptomycin is a 13 amino acid, cyclic lipopeptide produced by a non-ribosomal peptide synthetase (NRPS) mechanism inStreptomyces roseosporus. A 128 kb region ofS. roseosporusDNA was cloned and verified by heterologous expression inStreptomyces lividansto contain the daptomycin biosynthetic gene cluster (dpt). The cloned region was completely sequenced and three genes (dptA,dptBC,dptD) encoding the three subunits of an NRPS were identified. The catalytic domains in the subunits, predicted to couple five, six or two amino acids, respectively, included a novel activation domain and amino-acid-binding pocket for incorporating the unusual amino acidl-kynurenine (Kyn), three types of condensation domains and an extra epimerase domain (E-domain) in the second module. Novel genes (dptE,dptF) whose products likely work in conjunction with a unique condensation domain to acylate the first amino acid, as well as other genes (dptI,dptJ) probably involved in supply of the non-proteinogenic amino acidsl-3-methylglutamic acid and Kyn, were located next to the NRPS genes. The unexpected E-domain suggested that daptomycin would haved-Asn, rather thanl-Asn, as originally assigned, and this was confirmed by comparing stereospecific synthetic peptides and the natural product both chemically and microbiologically.

A growing body of research has emerged on “mixed-form” markets—markets for goods and services in which for-profit, nonprofit, and government providers coexist. This article seeks to understand the dynamics between nonprofit and for-profit organizations operating within the same market. The authors propose a five-step theoretical framework that includes both nonprofit and for-profit actors to capture what is fundamentally a temporal process: market identification; market growth; increasing cost for goods/services; increasing price for goods/services; and cross-sector competition. The authors use data from extended qualitative investigations in distinct service markets to analyze the unique contributions and capacities of each organizational form, and the transformation of market structure over time. The authors conclude that the dynamic interplay between nonprofit and for-profit forms within markets produces three possible outcomes: stratified, displaced, and defended markets.

A convergent total synthesis of phorboxazole A (1a), from the C(3–19), C(20–27) and C(33–46) fragments 5, 4 and 91, respectively, concentrating on stereocontrolled formation of the bonds at C(2–3), C(19–20) and C(27–28), is described. Although a coupling reaction between a macrolide ketone and the side chain substituted sulfone, at C(27–28) was not successful, a Wadsworth–Emmons olefination involving the oxane methyl ketone 4 and an oxazole produced the oxane 90 which was next coupled to 91 leading to the C(20–46) unit 100. A further coupling of 100 to 71c at C(19–20) then led to 105, ultimately, and the synthesis was completed by a macrocyclisation reaction from 105, at the C(2–3) alkene bond, followed by deprotection of 106.