Novel strategies in antifungal lead discovery

There have been significant developments in fungal genomics over the past year. The recently released genome sequences of Aspergillus fumigatus and Cryptococcus neoformans have provided unprecedented opportunities for comparative genomics studies of many clinically relevant fungal pathogens. Emerging experimental analysis tools, such as fitness profiling and protein microarrays, have greatly enhanced our ability to conduct genome-wide functional studies.     

Yeast KRE genes provide evidence for a pathway of cell wall beta-glucan assembly

The Saccharomyces cerevisiae KRE1 gene encodes a Ser/Thr-rich protein, that is directed into the yeast secretory pathway, where it is highly modified, probably through addition of O-linked mannose residues. Gene disruption of the KRE1 locus leads to a 40% reduced level of cell wall (1----6)-beta-glucan. Structural analysis of the (1----6)-beta-glucan fraction, isolated from a strain with a krel disruption mutation, showed that it had an altered structure with a smaller average polymer size. Mutations in two other loci, KRE5 and KRE6 also lead to a defect in cell wall (1----6)-beta-glucan production and appear to be epistatic to KRE1. These findings outline a possible pathway of assembly of yeast cell wall (1----6)-beta-glucan.     

A novel harmony search-K means hybrid algorithm for clustering gene expression data

Recent progress in bioinformatics research has led to the accumulation of huge quantities of biological data at various data sources. The DNA microarray technology makes it possible to simultaneously analyze large number of genes across different samples. Clustering of microarray data can reveal the hidden gene expression patterns from large quantities of expression data that in turn offers tremendous possibilities in functional genomics, comparative genomics, disease diagnosis and drug development. The k- ¬means clustering algorithm is widely used for many practical applications. But the original k-¬means algorithm has several drawbacks. It is computationally expensive and generates locally optimal solutions based on the random choice of the initial centroids. Several methods have been proposed in the literature for improving the performance of the k-¬means algorithm. A meta-heuristic optimization algorithm named harmony search helps find out near-global optimal solutions by searching the entire solution space. Low clustering accuracy of the existing algorithms limits their use in many crucial applications of life sciences. In this paper we propose a novel Harmony Search-K means Hybrid (HSKH) algorithm for clustering the gene expression data. Experimental results show that the proposed algorithm produces clusters with better accuracy in comparison with the existing algorithms.     

Host-associated speciation in the coral barnacle Wanella milleporae (Cirripedia: Pyrgomatidae) inhabiting the Millepora coral

Speciation by host shift is a common phenomenon observed in many symbiotic animals. The symbiont–host interaction is highly dynamic, but it is poorly documented in the marine realm. In the present study, we examined the genetic and morphological differentiation of the coral barnacle Wanella milleporae (obligate to fire corals) collected from four different Millepora host species in Taiwan to investigate the host specificity of this barnacle. Phylogenetic analysis of mitochondrial COI gene for 241 individuals of Wanella revealed five distinct clades, whose sequence divergences are comparable to values between other cogeneric barnacle species. The five clades also differ in shell and opercular plate morphology and colour. Genetic and morphological differentiations together strongly suggest the presence of cryptic species. Although the five clades do not display species-level host specificity, they showed a significant difference in preference on host growth form. Clades 1 and 2 were predominantly found on encrusting Millepora exaesa and Millepora platyphylla , while clades 3, 4 and 5 live exclusively on branching-form fire corals Millepora dichotoma and Millepora tenella . Phylogeny inferred from the combined mitochondrial COI, 16S and 12S (2182 bp) analysis suggests the division of the five clades into two major lineages congruent with the morphology of the host coral. Multiple independent invasions to the same form of host and subsequent speciation are evident in the Red Sea and Taiwan. Our results indicate that ecological/sympatric speciation could occur in marine symbiotic invertebrates through host shift and specialization. It appears that, as in their terrestrial counterparts, host–symbiont radiations in the marine realm are more prevalent than we expected and thus warrant further investigation.     

Disentangling genetic and epigenetic determinants of ultrafast adaptation

A major rationale for the advocacy of epigenetically mediated adaptive responses is that they facilitate faster adaptation to environmental challenges. This motivated us to develop a theoretical–experimental framework for disclosing the presence of such adaptation‐speeding mechanisms in an experimental evolution setting circumventing the need for pursuing costly mutation–accumulation experiments. To this end, we exposed clonal populations of budding yeast to a whole range of stressors. By growth phenotyping, we found that almost complete adaptation to arsenic emerged after a few mitotic cell divisions without involving any phenotypic plasticity. Causative mutations were identified by deep sequencing of the arsenic‐adapted populations and reconstructed for validation. Mutation effects on growth phenotypes, and the associated mutational target sizes were quantified and embedded in data‐driven individual‐based evolutionary population models. We found that the experimentally observed homogeneity of adaptation speed and heterogeneity of molecular solutions could only be accounted for if the mutation rate had been near estimates of the basal mutation rate. The ultrafast adaptation could be fully explained by extensive positive pleiotropy such that all beneficial mutations dramatically enhanced multiple fitness components in concert. As our approach can be exploited across a range of model organisms exposed to a variety of environmental challenges, it may be used for determining the importance of epigenetic adaptation‐speeding mechanisms in general.     

Collecting morbidity data in general practice: the Somerset morbidity project.

OBJECTIVE--To collect a valid, complete, continuous, and representative database of morbidity presenting to primary care and to use the data to help commission services on the basis of local need and effectiveness. SETTING--Computerised general practices in Somerset. METHODS--Participating general practices were selected to be representative of the district health authority population for general practice and population characteristics. All conditions presented at face to face consultations were assigned a Read code and episode type and the data were regularly validated. Data were sent by modem from the practices via a third party to the health authority each week. MAIN OUTCOME MEASURES--Proportion of consultations coded and accuracy of coding. RESULTS--11 practices agreed to participate. Validations for completeness during April 1994 to March 1995 revealed that 96.4% of the records were coded; 94% of the 1090 records validated had appropriate episode types and 87% appropriate Read codes. The results have been used to help formulate the health authority''s purchasing plans and have enabled a change in the local contracts for surgery for glue ear. CONCLUSIONS--The project has shown the feasibility of establishing a network of practices recording and reporting the morbidity seen in primary care. Early indications are that the data can be useful in evidence based purchasing.