Co-production and adaptation of a prison-based problem-solving workbook to support the mental health of patients housed within a medium- and low-secure forensic service.

INTRODUCTION: Problem-solving skills (PSS) help to provide a systematic approach to dealing with and managing complex problems. The overall aim of this study was to assess the acceptability and feasibility of developing and adapting a prison-based PSS  workbook for adults within a medium- and low-secure hospital. METHOD: We used the Medical Research Council framework in our participatory mixed methods study incorporating an adapted survey (to identify what types of problems people experience in secure hospitals), a series of three interactive workshops (to co-produce two case study examples for a workbook) and we gathered feedback from patients and hospital staff on the acceptability and feasibility of the workbook. Data from the survey were used to inform the case study examples, and the feedback from patients and hospital staff was descriptively summarised and the results consolidated. RESULTS: In total, 82 (51%) patients took part in the survey; 22 patients and 49 hospital staff provided feedback on the workbook. The survey results indicated that patients regularly experience problems while in the hospital. Patients reported problems relating to restrictions of freedom and boredom. The workshops produced two case studies for the workbooks, with mainly positive patient and staff feedback. More work is required to improve the visual representation of the characters in the case studies, the amount and content of the language and the mechanism of the intervention delivery. CONCLUSION: The adaptation process proved acceptable and feasible to both patients and staff. The co-production methodology for the workbook and feedback from patients and staff was an effective way of iteratively refining the materials to ensure that they were both meaningful and acceptable to staff and patients. Subsequent work is required to develop the workbook and evaluate the feasibility of the intervention delivery, recruitment rates, uptake and adherence to the PSS using a randomised controlled trial. PATIENT OR PUBLIC CONTRIBUTION: At each stage of the project consultation with patients and/or hospital staff was involved.

It's not just a phase; ubiquitination in cytosolic protein quality control.

The accumulation of misfolded proteins is associated with numerous degenerative conditions, cancers and genetic diseases. These pathological imbalances in protein homeostasis (termed proteostasis), result from the improper triage and disposal of damaged and defective proteins from the cell. The ubiquitin-proteasome system is a key pathway for the molecular control of misfolded cytosolic proteins, co-opting a cascade of ubiquitin ligases to direct terminally damaged proteins to the proteasome via modification with chains of the small protein, ubiquitin. Despite the evidence for ubiquitination in this critical pathway, the precise complement of ubiquitin ligases and deubiquitinases that modulate this process remains under investigation. Whilst chaperones act as the first line of defence against protein misfolding, the ubiquitination machinery has a pivotal role in targeting terminally defunct cytosolic proteins for destruction. Recent work points to a complex assemblage of chaperones, ubiquitination machinery and subcellular quarantine as components of the cellular arsenal against proteinopathies. In this review, we examine the contribution of these pathways and cellular compartments to the maintenance of the cytosolic proteome. Here we will particularly focus on the ubiquitin code and the critical enzymes which regulate misfolded proteins in the cytosol, the molecular point of origin for many neurodegenerative and genetic diseases.

Inhibition of JNK signaling in the Asian malaria vector Anopheles stephensi extends mosquito longevity and improves resistance to Plasmodium falciparum infection.

Malaria is a global health concern caused by infection with Plasmodium parasites. With rising insecticide and drug resistance, there is a critical need to develop novel control strategies, including strategies to block parasite sporogony in key mosquito vector species. MAPK signaling pathways regulated by extracellular signal-regulated kinases (ERKs) and the stress-activated protein kinases (SAPKs) c-Jun N-terminal kinases (JNKs) and p38 MAPKs are highly conserved across eukaryotes, including mosquito vectors of the human malaria parasite Plasmodium falciparum. Some of these pathways in mosquitoes have been investigated in detail, but the mechanisms of integration of parasite development and mosquito fitness by JNK signaling have not been elucidated. To this end, we engineered midgut-specific overexpression of MAPK phosphatase 4 (MKP4), which targets the SAPKs, and used two potent and specific JNK small molecule inhibitors (SMIs) to assess the effects of JNK signaling manipulations on Anopheles stephensi fecundity, lifespan, intermediary metabolism, and P. falciparum development. MKP4 overexpression and SMI treatment reduced the proportion of P. falciparum-infected mosquitoes and decreased oocyst loads relative to controls. SMI-treated mosquitoes exhibited no difference in lifespan compared to controls, whereas genetically manipulated mosquitoes exhibited extended longevity. Metabolomics analyses of SMI-treated mosquitoes revealed insights into putative resistance mechanisms and the physiology behind lifespan extension, suggesting for the first time that P. falciparum-induced JNK signaling reduces mosquito longevity and increases susceptibility to infection, in contrast to previously published reports, likely via a critical interplay between the invertebrate host and parasite for nutrients that play essential roles during sporogonic development.

Staphylococcal enterotoxin-like X (SElX) is a unique superantigen with functional features of two major families of staphylococcal virulence factors.

Staphylococcus aureus is an opportunistic pathogen that produces many virulence factors. Two major families of which are the staphylococcal superantigens (SAgs) and the Staphylococcal Superantigen-Like (SSL) exoproteins. The former are immunomodulatory toxins that induce a Vß-specific activation of T cells, while the latter are immune evasion molecules that interfere with a wide range of innate immune defences. The superantigenic properties of Staphylococcal enterotoxin-like X (SElX) have recently been established. We now reveal that SElX also possesses functional characteristics of the SSLs. A region of SElX displays high homology to the sialyl-lactosamine (sLacNac)-specific binding site present in a sub-family of SSLs. By analysing the interaction of SElX with sLacNac-containing glycans we show that SElX has an equivalent specificity and host cell binding range to the SSLs. Mutation of key amino acids in this conserved region affects the ability of SElX to bind to cells of myeloid origin and significantly reduces its ability to protect S. aureus from destruction in a whole blood killing (WBK) assay. Like the SSLs, SElX is up-regulated early during infection and is under the control of the S. aureus exotoxin expression (Sae) two component gene regulatory system. Additionally, the structure of SElX in complex with the sLacNac-containing tetrasaccharide sialyl Lewis X (sLeX) reveals that SElX is a unique single-domain SAg. In summary, SElX is an 'SSL-like' SAg.

Elongation of the Poly-γ-glutamate Tail of F420 Requires Both Domains of the F420:γ-Glutamyl Ligase (FbiB) of Mycobacterium tuberculosis.

Cofactor F420is an electron carrier with a major role in the oxidoreductive reactions ofMycobacterium tuberculosis, the causative agent of tuberculosis. A γ-glutamyl ligase catalyzes the final steps of the F420biosynthesis pathway by successive additions ofl-glutamate residues to F420-0, producing a poly-γ-glutamate tail. The enzyme responsible for this reaction in archaea (CofE) comprises a single domain and produces F420-2 as the major species. The homologousM. tuberculosisenzyme, FbiB, is a two-domain protein and produces F420with predominantly 5-7l-glutamate residues in the poly-γ-glutamate tail. The N-terminal domain of FbiB is homologous to CofE with an annotated γ-glutamyl ligase activity, whereas the C-terminal domain has sequence similarity to an FMN-dependent family of nitroreductase enzymes. Here we demonstrate that full-length FbiB adds multiplel-glutamate residues to F420-0in vitroto produce F420-5 after 24 h; communication between the two domains is critical for full γ-glutamyl ligase activity. We also present crystal structures of the C-terminal domain of FbiB in apo-, F420-0-, and FMN-bound states, displaying distinct sites for F420-0 and FMN ligands that partially overlap. Finally, we discuss the features of a full-length structural model produced by small angle x-ray scattering and its implications for the role of N- and C-terminal domains in catalysis.

Structure activity relationships of human galactokinase inhibitors.

Classic Galactosemia is a rare inborn error of metabolism that is caused by deficiency of galactose-1-phosphate uridyltransferase (GALT), an enzyme within the Leloir pathway that is responsible for the conversion of galactose-1-phosphate (gal-1-p) and UDP-glucose to glucose-1-phosphate and UDP-galactose. This deficiency results in elevated intracellular concentrations of its substrate, gal-1-p, and this increased concentration is believed to be the major pathogenic mechanism in Classic Galactosemia. Galactokinase (GALK) is an upstream enzyme of GALT in the Leloir pathway and is responsible for conversion of galactose and ATP to gal-1-p and ADP. Therefore, it was hypothesized that the identification of a small-molecule inhibitor of human GALK would act to prevent the accumulation of gal-1-p and offer a novel entry therapy for this disorder. Herein we describe a quantitative high-throughput screening campaign that identified a single chemotype that was optimized and validated as a GALK inhibitor.

Demographic composition of National Institutes of Health Clinical and Translational Science Awards (CTSA) Program principal investigators, scholars, and trainees.

Little has been published on the demographic composition of the clinical and translational science research workforce within the Clinical and Translational Science Awards (CTSA) Program despite the well-documented need for greater diversity in the biomedical research workforce. Analyses of workforce demographic reveal that women and members of underrepresented groups remain persistently underrepresented in the CTSA hub and training components principal investigators. In contrast, in the CTSA Program career development and training programs, females have greater representation as participants, and non-Whites were better represented in training programs.

Removal of the C-terminal regulatory domain of α-isopropylmalate synthase disrupts functional substrate binding.

α-Isopropylmalate synthase (α-IPMS) catalyzes the metal-dependent aldol reaction between α-ketoisovalerate (α-KIV) and acetyl-coenzyme A (AcCoA) to give α-isopropylmalate (α-IPM). This reaction is the first committed step in the biosynthesis of leucine in bacteria. α-IPMS is homodimeric, with monomers consisting of (ß/α)(8) barrel catalytic domains fused to a C-terminal regulatory domain, responsible for binding leucine and providing feedback regulation for leucine biosynthesis. In these studies, we demonstrate that removal of the regulatory domain from the α-IPMS enzymes of both Neisseria meningitidis (NmeIPMS) and Mycobacterium tuberculosis (MtuIPMS) results in enzymes that are unable to catalyze the formation of α-IPM, although truncated NmeIPMS was still able to slowly hydrolyze AcCoA. The lack of catalytic activity of these truncation variants was confirmed by complementation studies with Escherichia coli cells lacking the α-IPMS gene, where transformation with the plasmids encoding the truncated α-IPMS enzymes was not able to rescue α-IPMS activity. X-ray crystal structures of both truncation variants reveal that both proteins are dimeric and that the catalytic sites of the proteins are intact, although the divalent metal ion that is thought to be responsible for activating substrate α-KIV is displaced slightly relative to its position in the substrate-bound, wild-type structure. Isothermal titration calorimetry and WaterLOGSY nuclear magnetic resonance experiments demonstrate that although these truncation variants are not able to catalyze the reaction between α-KIV and AcCoA, they are still able to bind the substrate α-KIV. It is proposed that the regulatory domain is crucial for ensuring protein dynamics necessary for competent catalysis.

Structural and functional properties of staphylococcal superantigen-like protein 4.

Staphylococcus aureus is a prevalent and significant human pathogen. Among the repertoire of virulence factors produced by this bacterium are the 14 staphylococcal superantigen-like (SSL) proteins. SSL protein 4 (SSL4) is one member of this family and contains a highly conserved carbohydrate binding site also found in SSL2, SSL3, SSL5, SSL6, and SSL11. Recombinant SSL4(t), comprising amino acids 109 to 309 of Newman strain SSL4 (SSL4-Newman), has been shown to bind and be internalized by human granulocytes and macrophages in a sialic-acid (Sia)-dependent manner. SSL4(t) can compete with itself for cell binding, indicating that binding is target specific. A 2.5-Å-resolution crystal structure of SSL4(t) complexed with sialyl Lewis X (sLe(x)) [sLe(x)-Neu5Acα2-3Galß1-4(Fucα1-3)GlcNAc] revealed a similar binding site to SSL5 and SSL11. These data, along with data on SSL4(t) binding to a glycan array and biosensor analysis of sLe(x) and sialyllactosamine (sLacNac) binding are compared with those for SSL11. Although these proteins show great similarity in their carbohydrate binding sites, with a root mean square (RMS) difference between main chain atom positions of only 0.34 Å, these proteins differ in detail in their affinity for sLe(x) and sLacNac, as well as their glycan preference. Together with cell binding data, this shows how S. aureus produces multiple related proteins that target myeloid cells through specific sialyllactosamine-containing glycoproteins.

Structure of phosphoserine aminotransferase from Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb), the causative agent of TB, remains a serious world health problem owing to limitations of the available drugs and the emergence of resistant strains. In this context, key biosynthetic enzymes from Mtb are attractive targets for the development of new therapeutic drugs. Here, the 1.5 Å resolution crystal structure of Mtb phosphoserine aminotransferase (MtbPSAT) in complex with its cofactor, pyridoxal 5'-phosphate (PLP), is reported. MtbPSAT is an essential enzyme in the biosynthesis of serine and in pathways of one-carbon metabolism. The structure shows that although the Mtb enzyme differs substantially in sequence from other PSAT enzymes, its fold is conserved and its PLP-binding site is virtually identical. Structural comparisons suggest that this site remains unchanged throughout the catalytic cycle. On the other hand, PSAT enzymes are obligate dimers in which the two active sites are located in the dimer interface and distinct differences in the MtbPSAT dimer are noted. These impact on the substrate-binding region and access channel and suggest options for the development of selective inhibitors.

A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants.

BACKGROUND: The recently approved anti-AIDS drug rilpivirine (TMC278, Edurant) is a nonnucleoside inhibitor (NNRTI) that binds to reverse transcriptase (RT) and allosterically blocks the chemical step of DNA synthesis. In contrast to earlier NNRTIs, rilpivirine retains potency against well-characterized, clinically relevant RT mutants. Many structural analogues of rilpivirine are described in the patent literature, but detailed analyses of their antiviral activities have not been published. This work addresses the ability of several of these analogues to inhibit the replication of wild-type (WT) and drug-resistant HIV-1. RESULTS: We used a combination of structure activity relationships and X-ray crystallography to examine NNRTIs that are structurally related to rilpivirine to determine their ability to inhibit WT RT and several clinically relevant RT mutants. Several analogues showed broad activity with only modest losses of potency when challenged with drug-resistant viruses. Structural analyses (crystallography or modeling) of several analogues whose potencies were reduced by RT mutations provide insight into why these compounds were less effective. CONCLUSIONS: Subtle variations between compounds can lead to profound differences in their activities and resistance profiles. Compounds with larger substitutions replacing the pyrimidine and benzonitrile groups of rilpivirine, which reorient pocket residues, tend to lose more activity against the mutants we tested. These results provide a deeper understanding of how rilpivirine and related compounds interact with the NNRTI binding pocket and should facilitate development of novel inhibitors.

A structural perspective on lactoferrin function.

The 3-D structure of human lactoferrin was first solved in atomic detail in 1987. Since that time, a variety of proven and postulated activities have been added to the original annotation of lactoferrin as an iron-binding protein. Structural studies have also expanded to include iron-bound and iron-free (apo) forms, mutants, and the lactoferrins of different species. In this review, we take the current information on both structure and function and show that the 3-D structure provides a useful framework for understanding some activities and also points to productive research directions that could help elucidate other reported functions. Some functions relate to iron binding where the role of lactoferrin is to scavenge and retain iron across a wide pH range. We specifically focus on functions that depend on the surface structure of the molecule, identifying features that may determine the many other protective properties of this multifunctional protein.

Are there symptom differences in patients with coronary artery disease presenting to the ED ultimately diagnosed with or without ACS?

OBJECTIVES: Symptoms are compared among patients with coronary artery disease (CAD) admitted to the emergency department with or without acute coronary syndrome (ACS). Sex and age are also assessed. METHODS: A secondary analysis from the PROMOTION (Patient Response tO Myocardial Infarction fOllowing a Teaching Intervention Offered by Nurses) trial, an multicenter randomized controlled trial, was conducted. RESULTS: Of 3522 patients with CAD, at 2 years, 565 (16%) presented to the emergency department, 234 (41%) with non-ACS and 331 (59%) with ACS. Shortness of breath (33% vs 25%, P = .028) or dizziness (11% vs 3%, P = .001) were more common in non-ACS. Chest pain (65% vs 77%, P = .002) or arm pain (9% vs 21%, P = .001) were more common in ACS. In men without ACS, dizziness was more common (11% vs 2%; P = .001). Men with ACS were more likely to have chest pain (78% vs 64%; P = .003); both men and women with ACS more often had arm pain (men, 19% vs 10% [P = .019]; women, 26% vs 13% [P = .023]). In multivariate analysis, patients with shortness of breath (odds ratio [OR], 0.617 [confidence interval [CI], 0.410-0.929]; P = .021) or dizziness (OR, .0311 [CI, 0.136-0.708]; P = .005) were more likely to have non-ACS. Patients with prior percutaneous coronary intervention (OR, 1.592 [CI, 1.087-2.332]; P = .017), chest pain (OR, 1.579 [CI, 1.051-2.375]; P = .028), or arm pain (OR, 1.751 [CI, 1.013-3.025]; P <.042) were more likely to have ACS. CONCLUSIONS: In patients with CAD, shortness of breath and dizziness are more common in non-ACS, whereas prior percutaneous coronary intervention and chest or arm pain are important factors to include during ACS triage.

An analysis of the Clinical and Translational Science Award pilot project portfolio using data from Research Performance Progress Reports.

Introduction: Pilot projects ("pilots") are important for testing hypotheses in advance of investing more funds for full research studies. For some programs, such as Clinical and Translational Science Awards (CTSAs) supported by the National Center for Translational Sciences, pilots also make up a significant proportion of the research projects conducted with direct CTSA support. Unfortunately, administrative data on pilots are not typically captured in accessible databases. Though data on pilots are included in Research Performance Progress Reports, it is often difficult to extract, especially for large programs like the CTSAs where more than 600 pilots may be reported across all awardees annually. Data extraction challenges preclude analyses that could provide valuable information about pilots to researchers and administrators. Methods: To address those challenges, we describe a script that partially automates extraction of pilot data from CTSA research progress reports. After extraction of the pilot data, we use an established machine learning (ML) model to determine the scientific content of pilots for subsequent analysis. Analysis of ML-assigned scientific categories reveals the scientific diversity of the CTSA pilot portfolio and relationships among individual pilots and institutions. Results: The CTSA pilots are widely distributed across a number of scientific areas. Content analysis identifies similar projects and the degree of overlap for scientific interests among hubs. Conclusion: Our results demonstrate that pilot data remain challenging to extract but can provide useful information for communicating with stakeholders, administering pilot portfolios, and facilitating collaboration among researchers and hubs.

Cyan fluorescent proteins derived from mNeonGreen.

mNeonGreen, an engineered green fluorescent protein (GFP) derived from lancelet, is one of the most brightly fluorescent homologs of Aequorea victoria jellyfish GFP (avGFP) yet reported. In this work, we investigated whether this bright fluorescence might be retained in homologs of mNeonGreen with modified chromophore structures and altered fluorescent hues. We found mNeonGreen to be generally less tolerant than avGFP to chromophore modification by substitution of the key chromophore-forming tyrosine residue with other aromatic amino acids. However, we were ultimately successful in creating a variant, designated as NeonCyan1, with a tryptophan-derived cyan fluorescent protein (CFP)-type chromophore, and two additional mutants with distinct spectral hues. Structural, computational, and photophysical characterization of NeonCyan1 and its variants provided insight into the factors that control the fluorescence emission color. Though not recommended as replacements for contemporary CFP variants, we demonstrate that NeonCyan1 variants are potentially suitable for live cell imaging applications.

KL2 scholars' perceptions of factors contributing to sustained translational science career success.

Introduction: Identifying the most effective ways to support career development of early stage investigators in clinical and translational science should yield benefits for the biomedical research community. Institutions with Clinical and Translational Science Awards (CTSA) offer KL2 programs to facilitate career development; however, the sustained impact has not been widely assessed. Methods: A survey comprised of quantitative and qualitative questions was sent to 2144 individuals that had previously received support through CTSA KL2 mechanisms. The 547 responses were analyzed with identifying information redacted. Results: Respondents held MD (47%), PhD (36%), and MD/PhD (13%) degrees. After KL2 support was completed, physicians' time was divided 50% to research and 30% to patient care, whereas PhD respondents devoted 70% time to research. Funded research effort averaged 60% for the cohort. Respondents were satisfied with their career progression. More than 95% thought their current job was meaningful. Two-thirds felt confident or very confident in their ability to sustain a career in clinical and translational research. Factors cited as contributing to career success included protected time, mentoring, and collaborations. Conclusion: This first large systematic survey of KL2 alumni provides valuable insight into the group's perceptions of the program and outcome information. Former scholars are largely satisfied with their career choice and direction, national recognition of their expertise, and impact of their work. Importantly, they identified training activities that contributed to success. Our results and future analysis of the survey data should inform the framework for developing platforms to launch sustaining careers of translational scientists.

Synergistic allostery, a sophisticated regulatory network for the control of aromatic amino acid biosynthesis in Mycobacterium tuberculosis.

The shikimate pathway, responsible for aromatic amino acid biosynthesis, is required for the growth of Mycobacterium tuberculosis and is a potential drug target. The first reaction is catalyzed by 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAH7PS). Feedback regulation of DAH7PS activity by aromatic amino acids controls shikimate pathway flux. Whereas Mycobacterium tuberculosis DAH7PS (MtuDAH7PS) is not inhibited by the addition of Phe, Tyr, or Trp alone, combinations cause significant loss of enzyme activity. In the presence of 200 µm Phe, only 2.4 µm Trp is required to reduce enzymic activity to 50%. Reaction kinetics were analyzed in the presence of inhibitory concentrations of Trp/Phe or Trp/Tyr. In the absence of inhibitors, the enzyme follows Michaelis-Menten kinetics with respect to substrate erythrose 4-phosphate (E4P), whereas the addition of inhibitor combinations caused significant homotropic cooperativity with respect to E4P, with Hill coefficients of 3.3 (Trp/Phe) and 2.8 (Trp/Tyr). Structures of MtuDAH7PS/Trp/Phe, MtuDAH7PS/Trp, and MtuDAH7PS/Phe complexes were determined. The MtuDAH7PS/Trp/Phe homotetramer binds four Trp and six Phe molecules. Binding sites for both aromatic amino acids are formed by accessory elements to the core DAH7PS (ß/α)(8) barrel that are unique to the type II DAH7PS family and contribute to the tight dimer and tetramer interfaces. A comparison of the liganded and unliganded MtuDAH7PS structures reveals changes in the interface areas associated with inhibitor binding and a small displacement of the E4P binding loop. These studies uncover a previously unrecognized mode of control for the branched pathways of aromatic amino acid biosynthesis involving synergistic inhibition by specific pairs of pathway end products.

Relationship of persistent symptoms of anxiety to morbidity and mortality outcomes in patients with coronary heart disease.

OBJECTIVE: To examine the association of symptoms of persistent anxiety with the development of acute cardiac events in patients with coronary heart disease (CHD) followed for 2 years. The prevalence of symptoms of anxiety is high in patients with CHD, but their effect on cardiac events and mortality has not been well characterized. METHODS: Of 3522 patients with confirmed CHD enrolled, data on symptoms of anxiety were available at two time points in 3048 patients who were then followed up for detection of the composite end point of hospitalization for myocardial infarction, unstable or stable angina, other cardiac causes, or all-cause mortality. A composite anxiety symptoms score composed of baseline and 3-month anxiety data, in which the continuous-level scores were used, was tested using Cox proportional hazards regression model. Groups (persistent anxiety [anxiety at both time points] versus nonanxious [no anxiety at either time point] versus not persistently anxious [anxiety only at one time point]) were also compared. RESULTS: Symptoms of persistent anxiety, whether considered as a continuous- or categorical-level variable, were associated with shorter time to event. Persistent anxiety remained as an independent predictor of the end point after controlling for multiple variables (persistent anxiety as a summary score [hazard ratio = 1.27, 95% confidence interval = 1.067-1.514] and persistent anxiety as a categorical variable [hazard ratio = 1.52, 95% confidence interval = 1.149-2.015]). CONCLUSIONS: By measuring anxiety symptoms at more than one time point and controlling for relevant sociodemographic, comorbidity, risk factor, and psychological covariates, we illustrate that symptoms of persistent anxiety are a strong, independent predictor of cardiac event-free survival.

Neopetrosiquinones A and B, sesquiterpene benzoquinones isolated from the deep-water sponge Neopetrosia cf. proxima.

Two new marine-derived sesquiterpene benzoquinones which we designate as neopetrosiquinones A (1) and B (2), have been isolated from a deep-water sponge of the family Petrosiidae. The structures were elucidated on the basis of their spectroscopic data. Compounds 1 and 2 inhibit the in vitro proliferation of the DLD-1 human colorectal adenocarcinoma cell line with IC(50) values of 3.7 and 9.8 µM, respectively, and the PANC-1 human pancreatic carcinoma cell line with IC(50) values of 6.1 and 13.8 µM, respectively. Neopetrosiquinone A (1) also inhibited the in vitro proliferation of the AsPC-1 human pancreatic carcinoma cell line with an IC(50) value of 6.1 µM. The compounds are structurally related to alisiaquinone A, cyclozonarone, and xestoquinone.

Mirabamides E-H, HIV-inhibitory depsipeptides from the sponge Stelletta clavosa.

Four new depsipeptides, mirabamides E-H (1-4), and the known depsipeptide mirabamide C (5) have been isolated from the sponge Stelletta clavosa, collected from the Torres Strait. The planar structures were determined on the basis of extensive 1D and 2D NMR and HRESIMS. The absolute configurations were established by the advanced Marfey's method, NMR, and GC-MS. The four new compounds all showed strong inhibition of HIV-1 in a neutralization assay with IC(50) values of 121, 62, 68, and 41 nM, respectively.