Activation of stress signalling pathways enhances tolerance of fungi to chemical fungicides and antifungal proteins

Fungal disease is an increasing problem in both agriculture and human health. Treatment of human fungal disease involves the use of chemical fungicides, which generally target the integrity of the fungal plasma membrane or cell wall. Chemical fungicides used for the treatment of plant disease, have more diverse mechanisms of action including inhibition of sterol biosynthesis, microtubule assembly and the mitochondrial respiratory chain. However, these treatments have limitations, including toxicity and the emergence of resistance. This has led to increased interest in the use of antimicrobial peptides for the treatment of fungal disease in both plants and humans. Antimicrobial peptides are a diverse group of molecules with differing mechanisms of action, many of which remain poorly understood. Furthermore, it is becoming increasingly apparent that stress response pathways are involved in the tolerance of fungi to both chemical fungicides and antimicrobial peptides. These signalling pathways such as the cell wall integrity and high-osmolarity glycerol pathway are triggered by stimuli, such as cell wall instability, changes in osmolarity and production of reactive oxygen species. Here we review stress signalling induced by treatment of fungi with chemical fungicides and antifungal peptides. Study of these pathways gives insight into how these molecules exert their antifungal effect and also into the mechanisms used by fungi to tolerate sub-lethal treatment by these molecules. Inactivation of stress response pathways represents a potential method of increasing the efficacy of antifungal molecules.     

Predicting bankruptcy using recursive partitioning and a realistically proportioned data set

Auditors must assess their clients' ability to function as a going concern for at least the year following the financial statement date. The audit profession has been severely criticized for failure to ‘blow the whistle’ in numerous highly visible bankruptcies that occurred shortly after unmodified audit opinions were issued. Financial distress indicators examined in this study are one mechanism for making such assessments. This study measures and compares the predictive accuracy of an easily implemented two‐variable bankruptcy model originally developed using recursive partitioning on an equally proportioned data set of 202 firms. In this study, we test the predictive accuracy of this model, as well as previously developed logit and neural network models, using a realistically proportioned set of 14,212 firms' financial data covering the period 1981–1990. The previously developed recursive partitioning model had an overall accuracy for all firms ranging from 95 to 97% which outperformed both the logit model at 93 to 94% and the neural network model at 86 to 91%. The recursive partitioning model predicted the bankrupt firms with 33–58% accuracy. A sensitivity analysis of recursive partitioning cutting points indicated that a newly specified model could achieve an all firm and a bankrupt firm predictive accuracy of approximately 85%. Auditors will be interested in the Type I and Type II error tradeoffs revealed in a detailed sensitivity table for this easily implemented model. Copyright © 2000 John Wiley & Sons, Ltd.     

Convergent evolution of defensin sequence,structure and function

Defensins are a well-characterised group of small, disulphide-rich, cationic peptides that are produced by essentially all eukaryotes and are highly diverse in their sequences and structures. Most display broad range antimicrobial activity at low micromolar concentrations, whereas others have other diverse roles, including cell signalling (e.g. immune cell recruitment, self/non-self-recognition), ion channel perturbation, toxic functions, and enzyme inhibition. The defensins consist of two superfamilies, each derived from an independent evolutionary origin, which have subsequently undergone extensive divergent evolution in their sequence, structure and function. Referred to as the cis- and trans-defensin superfamilies, they are classified based on their secondary structure orientation, cysteine motifs and disulphide bond connectivities, tertiary structure similarities and precursor gene sequence. The utility of displaying loops on a stable, compact, disulphide-rich core has been exploited by evolution on multiple occasions. The defensin superfamilies represent a case where the ensuing convergent evolution of sequence, structure and function has been particularly extreme. Here, we discuss the extent, causes and significance of these convergent features, drawing examples from across the eukaryotes.     

Circadian variation in urinary melatonin in clinically healthy women in Japan and the United States of America

Summary Urinary melatonin excretion is lower in East-Asian (Japanese) than in North-American (whites of mixed ethnic origin) women. Moreover, a statistically significant circadian rhythm is demonstrated by population-mean cosinor in the data pool from both groups of women. Furthermore, statistical significance characterizes interactions of effects from geographic differences (between ethnic groups) with temporal factors. Such spatio-temporal interactions await further scrutiny with a view inter alia of carcinogenesis as it is influenced by a spectrum of intermodulating rhythms.Supported by U.S. Public Health Service (5-K6-GM-13981-17), National Cancer Institute (1R01-CA-14445-05 and N01-CP-5-5702), National Institute of Occupational Safety and Health (OH-00631-01), National Institute of Aging (AG-00158), Environmental Protection Agency (R804513-01-0), Swedish Medical Research Council grant 3371 and the St Paul Ramsey Medical Research and Education Foundation. R.B. Sothern and Jung-Keun Lee, Scientists, Chronobiology Laboratories, University of Minnesota provided valuable help.     

Trichoptera and other macroinvertebrates in springs of the Great Basin: species composition, richness, and distribution

Detailed surveys of aquatic invertebrates in 28 springs along the western border of the Great Basin were made using pan traps, emergence traps, black lights, and benthic sampling devices from 1994 to 1998. Although all macroinvertebrate groups were collected, caddisflies (Insecta: Trichoptera) were sampled most intensively. Fifty-eight species of caddisflies were collected from the 28 springs, with up to 18 species from a single spring. Although several springs had very similar physicochemical characteristics, none had identical trichopteran species composition. Using Wards minimum variance clustering technique, and with all macroinvertebrates identified to the lowest possible level, we found 3 taxa assemblages. These assemblages occurred in springs with the following physical conditions: (1) warm water (15.9° C), low elevation (1794 m); (2) cold water (8.5° C), mid-elevation (2334 m); and (3) cold water (6.6° C), high elevation (1794 m). Although the warm water group had a distinct assemblage of invertebrates (amphipods, gastropods, Trichoptera), distinct assemblages did not separate the 2 cold water groups. Discriminant analysis indicated that temperature, conductivity, alkalinity, and elevation were most responsible for discriminating group 1 from groups 2 and 3; temperature and elevation distinguished the latter 2 groups. Spring permanence, lack of disturbance, and cold water temperatures were the factors most responsible for explaining higher species richness of Trichoptera.     

Whole-genome analysis informs breast cancer response to aromatase inhibition

To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.     

Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.     

Properties and mechanisms of action of naturally occurring antifungal peptides

Antimicrobial peptides are a vital component of the innate immune system of all eukaryotic organisms and many of these peptides have potent antifungal activity. They have potential application in the control of fungal pathogens that are a serious threat to both human health and food security. Development of antifungal peptides as therapeutics requires an understanding of their mechanism of action on fungal cells. To date, most research on antimicrobial peptides has focused on their activity against bacteria. Several antimicrobial peptides specifically target fungal cells and are not active against bacteria. Others with broader specificity often have different mechanisms of action against bacteria and fungi. This review focuses on the mechanism of action of naturally occurring antifungal peptides from a diverse range of sources including plants, mammals, amphibians, insects, crabs, spiders, and fungi. While antimicrobial peptides were originally proposed to act via membrane permeabilization, the mechanism of antifungal activity for these peptides is generally more complex and often involves entry of the peptide into the cell.