New Micropeptins with Anti-Neuroinflammatory Activity Isolated from a Cyanobacterial Bloom

Metabolite mining of environmentally collected aquatic and marine microbiomes offers a platform for the discovery of new therapeutic lead molecules. Combining a prefractionated chromatography library with liquid chromatography tandem mass spectrometry (LC-MS/MS)-based molecular networking and biological assays, we isolated and characterized two new micropeptins (1 and 2) along with the previously characterized micropeptin 996. These metabolites showed potency in anti-neuroinflammatory assays using BV-2 mouse microglial cells, showing a 50% reduction in inflammation in a range from 1 to 10 μM. These results show promise for cyanobacterial peptides in the therapeutic realm apart from their impact on environmental health and provide another example of the utility of large prefractionated natural product libraries for therapeutic hit and lead identification

Exploiting the UMLS Metathesaurus for extracting and categorizing concepts representing signs and symptoms to anatomically related organ systems

AbstractObjectiveTo develop a method to exploit the UMLS Metathesaurus for extracting and categorizing concepts found in clinical text representing signs and symptoms to anatomically related organ systems. The overarching goal is to classify patient reported symptoms to organ systems for population health and epidemiological analyses.Materials and methodsUsing the concepts’ semantic types and the inter-concept relationships as guidance, a selective portion of the concepts within the UMLS Metathesaurus was traversed starting from the concepts representing the highest level organ systems. The traversed concepts were chosen, filtered, and reviewed to obtain the concepts representing clinical signs and symptoms by blocking deviations, pruning superfluous concepts, and manual review. The mapping process was applied to signs and symptoms annotated in a corpus of 750 clinical notes.ResultsThe mapping process yielded a total of 91,000 UMLS concepts (with approximately 300,000 descriptions) possibly representing physical and mental signs and symptoms that were extracted and categorized to the anatomically related organ systems. Of 1864 distinct descriptions of signs and symptoms found in the 750 document corpus, 1635 of these (88%) were successfully mapped to the set of concepts extracted from the UMLS. Of 668 unique concepts mapped, 603 (90%) were correctly categorized to their organ systems.ConclusionWe present a process that facilitates mapping of signs and symptoms to their organ systems. By providing a smaller set of UMLS concepts to use for comparing and matching patient records, this method has the potential to increase efficiency of information extraction pipelines

Reproductive experiences and outcomes among a representative sample of women: the Second Australian Study of Health and Relationships

Objective: To enumerate pregnancy outcomes for a representative sample of women in Australia surveyed in 2012–2013 (primary aim) and compare these with women surveyed in 2001–2002 (secondary aim). Methods: Computer-assisted telephone interviews with over 10,000 women aged 16–69 years (participation rate 68.4%). Results are weighted for chance of selection and to reflect the population as a whole. Results: Of women with experience of vaginal intercourse, 75.1% had ever been pregnant, 18.4% reported difficulties getting pregnant and 10.0% had had fertility treatment. Of those who had been pregnant, 91.3% had ever had a live birth, 34.3% a miscarriage, 22.8% an abortion and 2.3% a stillbirth; 0.9% had relinquished a child for adoption. The proportion first pregnant in their 30s was 11% among women aged 60–69 and 26% among those aged 40–49. Fewer older women reported difficulties getting pregnant. Of the 21,882 pregnancies reported, 70% led to live births and 10% were terminated. Compared with our 2001–2002 survey, fewer women reported ever having been pregnant. Giving up newborns for adoption has become very rare. Conclusions: Falling fertility since the 1960s reflects greater access to contraception and abortion and higher opportunity costs of childbearing. Implications for public health: These findings on women's lifetime reproductive experiences complement routine annual data collections

Effect on genital warts in Australian female and heterosexual male individuals after introduction of the national human papillomavirus gender-neutral vaccination programme: an analysis of national sentinel surveillance data from 2004–18

Background: In Australia, the government-funded human papillomavirus (HPV) vaccination programme was introduced in April, 2007, for girls and young women, and in February, 2013, for boys. As of Dec 31, 2018, all Australian-born female individuals younger than 38 years and male individuals younger than 21 years have been eligible for the free quadrivalent or nonavalent HPV vaccine. We aimed to examine the trends in genital wart diagnoses among Australian-born female and heterosexual male individuals who attended sexual health clinics throughout Australia before and after the introduction of the gender-neutral HPV vaccination programme in February, 2013. Methods: We did a serial cross-sectional analysis of genital wart diagnoses among Australian-born female and heterosexual male individuals attending a national surveillance network of 35 clinics between Jan 1, 2004, and Dec 31, 2018. We calculated prevalence ratios of genital warts, using log-binomial regression models, for the female-only vaccination period (July 1, 2007, to Feb 28, 2013), gender-neutral vaccination period (March 1, 2013, to Dec 31, 2018), and the whole vaccination period (July 1, 2007, to Dec 31, 2018) compared with the pre-vaccination period (Jan 1, 2004, to June 30, 2007). Findings: We included 121 038 men and 116 341 women in the analysis. Overall, we observed a 58% reduction (prevalence ratio 0·42, 95% CI 0·40–0·44) in genital wart diagnoses in female individuals and a 45% reduction (0·55, 0·53–0·57) in genital wart diagnoses in heterosexual male individuals after the introduction of the vaccination programme in 2007. The largest reduction in genital warts was observed in younger individuals, and there was a decreasing magnitude of reduction with increasing age (80%, 72%, 61%, 41%, and 16% reductions in female individuals aged 15–20 years, 21–25 years, 26–30 years, 31–35 years, and ≥36 years, respectively; 70%, 61%, 49%, 37%, and 29% reductions in male individuals aged 15–20 years, 21–25 years, 26–30 years, 31–35 years, and ≥36 years, respectively). Significant reductions observed in female individuals (0·32, 0·28–0·36) and male individuals (0·51, 0·43–0·61) aged 15–20 years in the female-only vaccination period were followed by a more substantial reduction in female individuals (0·07, 0·06–0·09) and male individuals (0·11, 0·08–0·15) aged 15–20 years in the gender-neutral vaccination period. Interpretation: The national gender-neutral HPV vaccination programme has led to substantial and ongoing reduction in genital warts among Australian female and heterosexual male individuals, with a marked reduction in young individuals who received the vaccine at school. Funding: Seqirus Australia and the Australian Government Department of Health

Einstein-Weyl structures corresponding to diagonal K\"ahler Bianchi IX metrics

We analyse in a systematic way the four dimensionnal Einstein-Weyl spaces equipped with a diagonal K\"ahler Bianchi IX metric. In particular, we show that the subclass of Einstein-Weyl structures with a constant conformal scalar curvature is the one with a conformally scalar flat - but not necessarily scalar flat - metric ; we exhibit its 3-parameter distance and Weyl one-form. This extends previous analysis of Pedersen, Swann and Madsen , limited to the scalar flat, antiself-dual case. We also check that, in agreement with a theorem of Derdzinski, the most general conformally Einstein metric in the family of biaxial K\"ahler Bianchi IX metrics is an extremal metric of Calabi, conformal to Carter's metric, thanks to Chave and Valent's results.Comment: 15 pages, Latex file, minor modifications, to be published in Class. Quant. Gra

Germline polymorphisms in SIPA1 are associated with metastasis and other indicators of poor prognosis in breast cancer

INTRODUCTION: There is growing evidence that heritable genetic variation modulates metastatic efficiency. Our previous work using a mouse mammary tumor model has shown that metastatic efficiency is modulated by the GTPase-activating protein encoded by Sipa1 ('signal-induced proliferation-associated gene 1'). The aim of this study was to determine whether single nucleotide polymorphisms (SNPs) within the human SIPA1 gene are associated with metastasis and other disease characteristics in breast cancer. METHOD: The study population (n = 300) consisted of randomly selected non-Hispanic Caucasian breast cancer patients identified from a larger population-based series. Genomic DNA was extracted from peripheral leukocytes. Three previously described SNPs within SIPA1 (one within the promoter [-313G>A] and two exonic [545C>T and 2760G>A]) were characterized using SNP-specific PCR. RESULTS: The variant 2760G>A and the -313G>A allele were associated with lymph node involvement (P = 0.0062 and P = 0.0083, respectively), and the variant 545C>T was associated with estrogen receptor negative tumors (P = 0.0012) and with progesterone negative tumors (P = 0.0339). Associations were identified between haplotypes defined by the three SNPs and disease progression. Haplotype 3 defined by variants -313G>A and 2760G>A was associated with positive lymph node involvement (P = 0.0051), and haplotype 4 defined by variant 545C>T was associated with estrogen receptor and progesterone receptor negative status (P = 0.0053 and P = 0.0199, respectively). CONCLUSION: Our findings imply that SIPA1 germline polymorphisms are associated with aggressive disease behavior in the cohort examined. If these results hold true in other populations, then knowledge of SIPA1 SNP genotypes could potentially enhance current staging protocols

Diversity oriented biosynthesis via accelerated evolution of modular gene clusters.

Erythromycin, avermectin and rapamycin are clinically useful polyketide natural products produced on modular polyketide synthase multienzymes by an assembly-line process in which each module of enzymes in turn specifies attachment of a particular chemical unit. Although polyketide synthase encoding genes have been successfully engineered to produce novel analogues, the process can be relatively slow, inefficient, and frequently low-yielding. We now describe a method for rapidly recombining polyketide synthase gene clusters to replace, add or remove modules that, with high frequency, generates diverse and highly productive assembly lines. The method is exemplified in the rapamycin biosynthetic gene cluster where, in a single experiment, multiple strains were isolated producing new members of a rapamycin-related family of polyketides. The process mimics, but significantly accelerates, a plausible mechanism of natural evolution for modular polyketide synthases. Detailed sequence analysis of the recombinant genes provides unique insight into the design principles for constructing useful synthetic assembly-line multienzymes