Resorculins: hybrid polyketide macrolides from Streptomyces sp. MST-91080.

Fourteen-membered macrolides are a class of compounds with significant clinical value as antibacterial agents. As part of our ongoing investigation into the metabolites of Streptomyces sp. MST-91080, we report the discovery of resorculins A and B, unprecedented 3,5-dihydroxybenzoic acid (α-resorcylic acid)-containing 14-membered macrolides. We sequenced the genome of MST-91080 and identified the putative resorculin biosynthetic gene cluster (rsn BGC). The rsn BGC is hybrid of type I and type III polyketide synthases. Bioinformatic analysis revealed that the resorculins are relatives of known hybrid polyketides: kendomycin and venemycin. Resorculin A exhibited antibacterial activity against Bacillus subtilis (MIC 19.8 µg mL-1), while resorculin B showed cytotoxic activity against the NS-1 mouse myeloma cell line (IC50 3.6 µg mL-1).

The role of emotional sensitivity to probability in the decision to choose genetic testing.

While the availability of genetic testing is rapidly increasing, many opt out of testing. The decision to test or not is emotionally charged, and both clinical research and theoretical work in psychology show that in emotional decisions, people often struggle to interpret and utilize risk information. Clinical research on genetic testing uptake also shows that feeling overwhelmed by numeric information may be a deterrent to testing. However, recent psychological research indicates that some portion of the population has greater emotional sensitivity to probability, (i.e., the extent to which emotional reactions to risk depend on probabilities) than others. We hypothesize that participants high in emotional sensitivity to probability will be more interested in genetic testing as an opportunity to seek greater precision in risk estimates and that this relationship is moderated by the testing context itself. In an online survey of a nationally representative sample (not recruited as patients), participants were presented with a hypothetical scenario describing a suspected diagnosis with an option for genetic testing. The scenario experimentally varied the pre-test probability estimate of the diagnosis (low or high) and whether the test results would result in certainty (ruling in or ruling out the diagnosis), or reduced uncertainty (providing a more precise individual risk estimate). Results indicated that emotional sensitivity to probability was a strong predictor of intention to test, particularly when the test allowed participants to rule out a diagnosis, reducing an already low probability to zero. These results highlight the way patients' individual characteristics interact with the testing context to guide decision-making and provide important insight into the way patients integrate risk probability information into intensely emotional decisions.

Recently Discovered Secondary Metabolites from Streptomyces Species.

The Streptomyces genus has been a rich source of bioactive natural products, medicinal chemicals, and novel drug leads for three-quarters of a century. Yet studies suggest that the genus is capable of making some 150,000 more bioactive compounds than all Streptomyces secondary metabolites reported to date. Researchers around the world continue to explore this enormous potential using a range of strategies including modification of culture conditions, bioinformatics and genome mining, heterologous expression, and other approaches to cryptic biosynthetic gene cluster activation. Our survey of the recent literature, with a particular focus on the year 2020, brings together more than 70 novel secondary metabolites from Streptomyces species, which are discussed in this review. This diverse array includes cyclic and linear peptides, peptide derivatives, polyketides, terpenoids, polyaromatics, macrocycles, and furans, the isolation, chemical structures, and bioactivity of which are appraised. The discovery of these many different compounds demonstrates the continued potential of Streptomyces as a source of new and interesting natural products and contributes further important pieces to the mostly unfinished puzzle of Earth's myriad microbes and their multifaceted chemical output.

Biosynthesis of a New Benzazepine Alkaloid Nanangelenin A from Aspergillus nanangensis Involves an Unusual l-Kynurenine-Incorporating NRPS Catalyzing Regioselective Lactamization.

1-Benzazepine is a pharmaceutically important scaffold but is rare among natural products. Nanangelenin A (1), containing an unprecedented 3,4-dihydro-1-benzazepine-2,5-dione-N-prenyl-N-acetoxy-anthranilamide scaffold, was isolated from a novel species of Australian fungus, Aspergillus nanangensis. Genomic and retrobiosynthetic analyses identified a putative nonribosomal peptide synthetase (NRPS) gene cluster (nan). The detailed biosynthetic pathway to 1 was established by heterologous pathway reconstitution in A. nidulans, which led to biosynthesis of intermediates nanagelenin B-F (2-5 and 7). We demonstrated that the NRPS NanA incorporates anthranilic acid (Ant) and l-kynurenine (l-Kyn), which is supplied by a dedicated indoleamine-2,3-dioxygenase NanC encoded in the gene cluster. Using heterologous in vivo assays and mutagenesis, we demonstrated that the C-terminal condensation (CT) and thiolation (T3) domains of NanA are responsible for the regioselective cyclization of the tethered Ant-l-Kyn dipeptide to form the unusual benzazepine scaffold in 1. We also showed that NanA-CT catalyzes the regioselective cyclization of a surrogate synthetic substrate, Ant-l-Kyn-N-acetylcysteamine, to give the benzazepine scaffold, while spontaneous cyclization of the dipeptide yielded the alternative kinetically favored benzodiazepine scaffold. The discovery of 1 and the characterization of NanA have expanded the chemical and functional diversities of fungal NRPSs.

Comprehensive chemotaxonomic and genomic profiling of a biosynthetically talented Australian fungus, Aspergillus burnettii sp. nov.

Aspergillus burnettii is a new species belonging to the A. alliaceus clade in Aspergillus subgenus Circumdati section Flavi isolated from peanut-growing properties in southern Queensland, Australia. A. burnettii is a fast-growing, floccose fungus with distinctive brown conidia and is a talented producer of biomass-degrading enzymes and secondary metabolites. Chemical profiling of A. burnettii revealed the metabolites ochratoxin A, kotanins, isokotanins, asperlicin E, anominine and paspalinine, which are common to subgenus Circumdati, together with burnettiene A, burnettramic acids, burnettides, and high levels of 14α-hydroxypaspalinine and hirsutide. The genome of A. burnettii was sequenced and an annotated draft genome is presented. A. burnettii is rich in secondary metabolite biosynthetic gene clusters, containing 51 polyketide synthases, 28 non-ribosomal peptide synthetases and 19 genes related to terpene biosynthesis. Functional annotation of digestive enzymes of A. burnettii and A. alliaceus revealed overlapping carbon utilisation profiles, consistent with a close phylogenetic relationship.

Nanangenines: drimane sesquiterpenoids as the dominant metabolite cohort of a novel Australian fungus, Aspergillus nanangensis.

Chemical investigation of an undescribed Australian fungus, Aspergillus nanangensis, led to the identification of the nanangenines - a family of seven new and three previously reported drimane sesquiterpenoids. The structures of the nanangenines were elucidated by detailed spectroscopic analysis supported by single crystal X-ray diffraction studies. The compounds were assayed for in vitro activity against bacteria, fungi, mammalian cells and plants. Bioinformatics analysis, including comparative analysis with other acyl drimenol-producing Aspergilli, led to the identification of a putative nanangenine biosynthetic gene cluster that corresponds to the proposed biosynthetic pathway for nanangenines.

Influence of resampling techniques on Bayesian network performance in predicting increased algal activity.

Early warning of increased algal activity is important to mitigate potential impacts on aquatic life and human health. While many methods have been developed to predict increased algal activity, an ongoing issue is that severe algal blooms often occur with low frequency in water bodies. This results in imbalanced data sets available for model specification, leading to poor predictions of the frequency of increased algal activity. One approach to address this is to resample data sets of increased algal activity to increase the prevalence of higher than normal algal activity in calibration data and ultimately improve model predictions. This study aims to investigate the use of resampling techniques to address the imbalanced dataset and determine if such methods can improve the prediction of increased algal activity. Three techniques were investigated, Kmeans under-sampling (US_Kmeans), synthetic minority over-sampling technique (SMOTE), and 'SMOTE and cluster-based under-sampling technique' (SCUT). The resampling methods were applied to a Bayesian network (BN) model of Lake Burragorang in New South Wales, Australia. The model was developed to predict chlorophyll-a (chl-a) using a range of water quality parameters as predictors. The original data and each of the balanced datasets were used for BN structures and parameter learning. The results showed that the best graphical structure was obtained by adding synthetic data from SMOTE with the highest true positive rate (TPR) and area under the curve (AUC). When compared using a fixed graphical structure for the BN, all resampling techniques increased the ability of the BN to detect events with higher probability of increased algal activity. The resampling model results can also be used to better understand the most important influences on high chl-a concentrations and suggest future data collection and model development priorities.

Context Matters: Emotional Sensitivity to Probabilities and the Bias for Action in Cancer Treatment Decisions.

BACKGROUND: Past studies have shown a commission bias for cancer treatment, a tendency to choose active treatment even when watchful waiting is less risky. This bias suggests motivations for action beyond mortality statistics, but recent evidence suggests that individuals differ in their emotional sensitivity to probabilities (ESP), the tendency to calibrate emotional reactions to probability. The current study aims to examine the role of ESP in the commission bias, specifically whether those higher in ESP are more likely to choose watchful waiting when risk probabilities align with that choice. METHODS: Participants (N = 1,055) read a scenario describing a hypothetical cancer diagnosis and chose between surgery and watchful waiting, with random assignment between versions where the mortality rate was either lower for surgery or for watchful waiting. We modeled choice using the Possibility Probability Questionnaire (PPQ), a measure of ESP, and several other individual differences in a logistic regression. RESULTS: We observed a commission bias as in past studies with most participants choosing surgery both when surgery was optimal (71%) and when watchful waiting was optimal (58%). An ESP × Condition interaction indicated that the predictive role of ESP depended on condition. Those higher in ESP were more likely to choose surgery when probabilities favored surgery, ß = 0.57, P < 0.001, but when probabilities favored watchful waiting, ESP had a near-zero relationship with choice, ß = 0.05, P < 0.99. CONCLUSIONS: The role of ESP in decision making is context specific. Higher levels of ESP predict choosing action when that action is warranted but do not predict a shift away from surgery when watchful waiting offers better chances of survival. ESP does not overcome the commission bias. HIGHLIGHTS: Past studies have identified a "commission bias," a tendency to choose active treatment over watchful waiting, even when mortality rate is lower for waiting.Evaluation of risk probabilities is related to individual differences in emotional sensitivity to probabilities (ESP) and has been shown to predict reactions to and decisions about health risk situations.ESP appears to be selectively factored into decision making. ESP was a robust predictor of choosing surgery when probability information supported surgery but did not predict decisions when probability information supported watchful waiting.Those who are most emotionally attuned to probabilities are just as susceptible to the commission bias as those who are less attuned.

School Challenges and Services Related to Executive Functioning for Fully Included Middle Schoolers with Autism.

The educational services available for fully included middle schoolers with autism spectrum disorder (ASD) in the general education setting are not well known. Even less is known about how the executive functioning (EF) deficits of such youth are addressed in the classroom. The current study sought to identify the challenges, including EF, that middle schoolers with ASD face and the services that they receive on their Individualized Education Program (IEP), and also explore specific strategies used to build EF skills at school. A convenience data sample was obtained from focus groups with educational personnel (n = 15), and qualitative analyses of IEPs were conducted in middle schoolers with ASD with EF deficits (n = 23). Results confirmed that social communication and EF challenges are common. Multiple services and accommodations were identified, although EF challenges were rarely targeted on IEPs. Factors that may facilitate the success of EF strategies in the classroom are discussed.

Suertides A-C: selective antibacterial cyclic hexapeptides from Amycolatopsis sp. MST-135876v3.

Amycolatopsis sp. MST-135876 was isolated from soil collected from the riverbank of El Pont de Suert, Catalonia, Spain. Cultivation of MST-135876 on a range of media led to the discovery of a previously unreported dichlorinated cyclic hexapeptide, suertide A (D-Ser, 5-Cl-D-Trp, 6-Cl-D-Trp, L-Ile, D-Val, D-Glu), featuring an unprecedented pair of adjacent 5/6-chlorotryptophan residues. Supplementing the growth medium with KBr resulted in production of the mono- and dibrominated analogues suertides B and C, respectively. Suertides A-C displayed selective activity against Bacillus subtilis (MIC 1.6 µg ml-1) and Staphylococcus aureus (MIC 3.1, 6.3, and 12.5 µg ml-1, respectively), while suertides A and B showed appreciable activity against methicillin-resistant S. aureus (MIC 1.6 and 6.3 µg ml-1, respectively).

Yeppoonic acids A - D: 1,2,4-trisubstituted arene carboxylic acid co-metabolites of conglobatin from an Australian Streptomyces sp.

Streptomyces sp. MST-91080 was isolated from a soil sample collected in Queensland, Australia. From this strain, yeppoonic acids A - D were purified and spectroscopically characterised. The yeppoonic acids are a family of diene enecarboxylic acids on a 1,2,4-trisubstituted benzene scaffold, structurally related to other Streptomyces secondary metabolites MF-EA-705α/ß, NFAT-133 and the lorneic acids. Yeppoonic acids B and C show strong cytotoxicity against the NS-1 mouse myeloma cell line (IC50 2.3 µg ml-1 and 3.8 µg ml-1, respectively) and moderate activity against the DU 145 human prostate cancer cell line (IC50 32.8 µg ml-1 and 49.6 µg ml-1, respectively).

Compared to what? A joint evaluation method for assessing quality of life.

PURPOSE: This study tests whether a joint evaluation method for assessing quality of life can stabilize ratings by providing contextual information, thereby helping participants calibrate responses on a rating scale. We also use the method to test for scale recalibration between patients and non-patients. METHOD: In an Internet survey, participants (N = 1,865) rated a target health condition, either diabetes or obesity, on a 100-point rating scale. Participants either rated several other items on the same rating scale first (joint evaluation), or rated the target condition first (single evaluation). We compared target condition ratings for joint versus single evaluation, as well as the rank position of that item among the other items. We also compared ratings and rankings for patients versus non-patients. RESULTS: The method effectively picked up distinct patterns of scale usage, with evidence of scale recalibration for obesity ratings, but not for diabetes ratings. The stabilizing effects of the method were mixed. For both diabetes and obesity, the joint evaluation task helped stabilize the rank position of the target condition, but not the rating. CONCLUSIONS: Results do not conclusively support joint evaluation as a method for reducing noise in rating scale usage, but do support its use for detecting scale recalibration between patients and non-patients.

Achieving Independence and Mastery in School: An Open Trial in the Outpatient Setting.

Youth with autism spectrum disorders (ASD) without intellectual disability frequently experience academic problems, in part due to executive functioning (EF) deficits. There are currently no evidence-based interventions targeting academic EF skills (e.g., organization, prioritization, etc.) for middle school youth with ASD. The need is critical given increasing demands on these skills during the transition from elementary to middle school. An intervention targeting academic EF skills, Achieving Independence and Mastery in School (AIMS), was recently developed. This paper reports on an open trial of the AIMS-Outpatient intervention with 21 middle schoolers with ASD. Results suggest high feasibility/satisfaction, and improved EF, particularly in the domains of organization and materials management. These promising results support further intervention development work and suggest that academic EF skills are malleable in youth with ASD.

Conglobatins B-E: cytotoxic analogues of the C2-symmetric macrodiolide conglobatin.

Chemical investigation of a previously unreported indigenous Australian Streptomyces strain MST-91080 has identified six novel analogues related to the oxazole-pendanted macrodiolide, conglobatin. Phylogenetic analysis of the 16S rRNA gene sequence identified MST-91080 as a species of Streptomyces, distinct from reported conglobatin producer, Streptomyces conglobatus ATCC 31005. Conglobatins B-E diverge from conglobatin through differing patterns of methylation on the macrodiolide skeleton. The altered methyl positions suggest a deviation from the published biosynthetic pathway, which proposed three successive methylmalonyl-CoA extender unit additions to the conglobatin monomer. Conglobatins B1, C1 and C2 exhibited more potent cytotoxic activity selectively against the NS-1 myeloma cell line (IC50 0.084, 1.05 and 0.45 µg ml-1, respectively) compared with conglobatin (IC50 1.39 µg ml-1).

The development of abstract letter representations for reading: evidence for the role of context.

We review evidence that in the course of reading, the visual system computes abstract letter identities (ALIs): a representation of letters that encodes their identity but that abstracts away from their visual appearance. How could the visual system learn such a seemingly nonvisual representation? We propose that different forms of the same letter tend to appear in similar distributions of contexts (in the same words written in different ways) and that this environmental correlation interacts with correlation-based learning mechanisms in the brain to lead to the formation of ALIs. We review a neural network model that demonstrates the feasibility of this common contexts hypothesis and present two experiments confirming some novel predictions: (a) repeatedly presenting arbitrary visual stimuli in common contexts leads those stimuli to be confusable with each other, and (b) different forms of the same letter are more confusable with each other in word-like contexts than in nonword-like contexts. We then extend the model to use real pictures of letters as input and simulate some of the novel empirical findings from the experiments.

Discovery and Heterologous Biosynthesis of the Burnettramic Acids: Rare PKS-NRPS-Derived Bolaamphiphilic Pyrrolizidinediones from an Australian Fungus, Aspergillus burnettii.

The burnettramic acids are a new class of antibiotics from an Australian fungus Aspergillus burnettii. The rare bolaamphiphilic scaffold consists of ß-d-mannose linked to a pyrrolizidinedione unit via a 26-carbon chain. The most abundant metabolite displayed potent in vitro antifungal activity. Comparative genomics identified the hybrid PKS-NRPS bua gene cluster, which was verified by heterologous pathway reconstitution in Aspergillus nidulans.

Are they really that happy? Exploring scale recalibration in estimates of well-being.

OBJECTIVE: The authors addressed a lingering concern in research on hedonic adaptation to adverse circumstances. This research typically relies on self-report measures of well-being, which are subjective and depend on the standards that people use in making judgments. The authors employed a novel method to test for, and rule out, such scale recalibration in self-reports of well-being. DESIGN: The authors asked patients with chronic illness (either lung disease or diabetes) and nonpatients to evaluate quality of life (QoL) for the patients' disease. In addition, the authors also asked them to rank and rate the aversiveness of a diverse set of adverse circumstances, allowing examination of both the numerical ratings and ordering among items. MAIN OUTCOME MEASURES: The authors compared patients' and nonpatients' ratings and rankings for the patients' disease and other conditions. RESULTS AND CONCLUSION: The authors found that patients not only assigned higher numerical QoL ratings to their own disease than did nonpatients but also ranked it higher among the broad set of conditions. These results suggest that scale recalibration cannot account for discrepant QoL ratings between patients and nonpatients. More generally, this study presents a new approach for measuring well-being that is not subject to the problem of scale recalibration.

A study of the chemical diversity of macroalgae from South Eastern Australia.

Macroalgae are a rich source of biologically active chemical diversity for pharmaceutical and agrichemical discovery. However, the ability to understand the complexities of their chemical diversity will dictate whether these natural products have a place in modern discovery paradigms. In this study, we examined the relationship between secondary metabolite production and biological activity for a cohort of 127 macroalgae samples collected from various locations across South Eastern Australia. Approximately 20% of the macroalgae samples showed high levels of chemical diversity and productivity, which also correlated strongly with bioactivity. These "talented" species represent sustainable sources of metabolites that may be readily harvested for large-scale production. At a taxonomic level, significant differences in metabolite production and diversity were observed between Chlorophyta, Rhodophyta and Phaeophyta. For each talented species, the cometabolite pattern was unique to that species, with closely related species within the same genus displaying very different profiles. Despite over 50years of investigation, we estimate that more than two-thirds of the chemical diversity of macroalgae remains unknown to science. By understanding the physicochemical properties and distribution patterns of metabolites, it is possible to make reasoned judgements about sustainable sourcing of macroalgae for biodiscovery.