Twists, knots, and rings in proteins: Structural definition of the cyclotide framework

In recent years an increasing number of miniproteins containing an amide-cyclized backbone have been discovered. The cyclotide family is the largest group of such proteins and is characterized by a circular protein backbone and six conserved cysteine residues linked by disulfide bonds in a tight core of the molecule. These form a cystine knot in which an embedded ring formed by two of the disulfide bonds and the connecting backbone segment is threaded by a third disulfide bond. In the current study we have undertaken high resolution structural analysis of two prototypic cyclotides, kalata B1 and cycloviolacin O1, to define the role of the conserved residues in the sequence. We provide the first comprehensive analysis of the topological features in this unique family of proteins, namely rings (a circular backbone), twists (a cis-peptide bond in the Mobius cyclotides) and knots (a knotted arrangement of the disulfide bonds).

Towards definition of the global biotechnology value chain using cases from Australian biotechnology SMEs

The generic pharmaceutical value chain model has been employed to describe both the global pharmaceutical and biotechnology industries till now. This research investigates the organisational value chain in Australian biotechnology companies in order to assess the appropriateness of the pharmaceutical value chain to small-and medium-sized biotechnology companies. The main theme of the research is: Can a generic model of the organisational value chain be defined for the biotechnology industry? Emanating from the literature, two research propositions were developed. RP1: there are eight major definable elements/activities of the organisational value chain for the biotechnology industry. RP2: Coverage of the elements in the biotechnology value chain ranges from focused to broad. A multiple case study methodology was used to explore these propositions. To develop a number of case studies, data was collected from senior managers of small and medium Australian biotechnology companies using an interview instrument, as well as from publicly available documentation and through observation. The results were analysed using cross-case comparisons. The results showed that an aggregation of the value chains of each organisation can be reduced to these eight definable elements that constitute the biotechnology value chain: basic research, applied research, development, verification and validation, prototype development, clinical trials, manufacturing and marketing. However, the findings also indicate that these major elements of the value chain need to be further reduced into sub-activities or sub-tasks to cater for the unique differences between biotechnology companies. Generally, the findings were consistent with the literature. However, a wider sampling, including international biotechnology organisations should be studied. The major contribution of this research is in the development of a value chain model, including general sub-tasks, for the Australian biotechnology industry.

HBV core sequence: definition of genotype-specific variability and correlation with geographical origin

There are eight genotypes and nine subtypes of HBV. Small differences in geographical origin are associated with sequence changes in the surface gene. Here, we compared core gene sequences from different genotypes and geographical regions. Specific combinations of 24 amino acid substitutions at nine residues allowed allocation of a sequence to a subtype. Six of these nine residues were located in different T cell epitopes depending on HBV geographical area and/or genotype. Thirty-seven nucleotide changes were associated uniquely with specific genotypes and subtypes. Unique amino acid and nucleotide variants were found in a majority of sequences from specific countries as well as within subtype ayw2 and adr. Specific nucleotide motifs were defined for Korean, Indian, Chinese, Italian and Pacific region isolates. Finally, we observed amino acid motifs that were common to either South-east Asian or Western populations, irrespective of subtype. We believe that HBV strains spread within constrained ethnic groups, result in selection pressures that define sequence variability within each subtype. It suggests that particular T cell epitopes are specific for geographical regions, and thus ethnic groups; this may affect the design of immunomodulatory therapies.

Spatial and temporal definition of Ochlerotatus camptorhynchus (Thomson) (Diptera : Culicidae) in the Gippsland Lakes system of eastern Victoria

The confirmed vector of Ross River virus, Ochlerotatus camptorhynchus (Thomson), is the dominant mosquito species inhabiting saline marshes in coastal Victoria. This paper re-examines previously published data on Oc. camptorhynchus, plus additional data collected since that time, and provides greater spatial and temporal definition of Oc. camptorhynchus numbers at seven sites across the Gippsland Lakes system of eastern Victoria. A total of 357 672 Oc. camptorhynchus was captured from 1188 trap-nights across the seven trap sites during trapping seasons from 1990 to 2001. The dominance of Oc. camptorhynchus across the seven sites averaged 75%, with significant differences in mean abundance of Oc. camptorhynchus found between all trap sites. Significant differences in monthly abundance of Oc. camptorhynchus were observed for Wellington Shire. Increase in populations of Oc. camptorhynchus was associated with increases in rainfall at all trap sites, higher minimum temperatures at two of the seven trap sites, and wind speed at one trap site. Prioritisation of mosquito control may be applied based on spatial and temporal factors according to the findings of this study.

Minimal disease activity for rheumatoid arthritis: A preliminary definition

Agreement on response criteria in rheumatoid arthritis (RA) has allowed better standardization and interpretation of clinical trial reports. With recent advances in therapy, the proportion of patients achieving a satisfactory state of minimal disease activity (MDA) is becoming a more important measure with which to compare different treatment strategies. The threshold for MDA is between high disease activity and remission and, by definition, anyone in remission will also be in MDA. True remission is still rare in RA; in addition, the American College of Rheumatology definition is difficult to apply in the context of trials. Participants at OMERACT 6 in 2002 agreed on a conceptual definition of minimal disease activity (MDA): "that state of disease activity deemed a useful target of treatment by both the patient and the physician, given current treatment possibilities and limitations." To prepare for a preliminary operational definition of MDA for use in clinical trials, we asked rheumatologists to assess 60 patient profiles describing real RA patients seen in routine clinical practice. Based on their responses, several candidate definitions for MDA were designed and discussed at the OMERACT 7 in 2004. Feedback from participants and additional on-site analyses in a cross-sectional database allowed the formulation of 2 preliminary, equivalent definitions of MDA: one based on the Disease Activity Score 28 (DAS28) index, and one based on meeting cutpoints in 5 out the 7 WHO/ILAR core set measures. Researchers applying these definitions first need to choose whether to use the DAS28 or the core set definition, because although each selects a similar proportion in a population, these are not always the same patients. In both MDA definitions, an initial decision node places all patients in MDA who have a tender joint count of 0 and a swollen joint count of 0, and an erythrocyte sedimentation rate (ESR) no greater than 10 mm. If this condition is not met: center dot The DAS28 definition places patients in MDA when DAS28

Increasing uncertainty: A definition

We present a definition of increasing uncertainty, in which an elementary increase in the uncertainty of any act corresponds to the addition of an 'elementary bet' that increases consumption by a fixed amount in (relatively) 'good' states and decreases consumption by a fixed (and possibly different) amount in (relatively) 'bad' states. This definition naturally gives rise to a dual definition of comparative aversion to uncertainty. We characterize this definition for a popular class of generalized models of choice under uncertainty.

Definition and spatial annotation of the dynamic secretome during early kidney development

The term secretome has been defined as a set of secreted proteins (Grimmond et al. [2003] Genome Res 13:1350-1359). The term secreted protein encompasses all proteins exported from the cell including growth factors, extracellular proteinases, morphogens, and extracellular matrix molecules. Defining the genes encoding secreted proteins that change in expression during organogenesis, the dynamic secretome, is likely to point to key drivers of morphogenesis. Such secreted proteins are involved in the reciprocal interactions between the ureteric bud (UB) and the metanephric mesenchyme (AM) that occur during organogenesis of the metanephros. Some key metanephric secreted proteins have been identified, but many remain to be determined. In this study, microarray expression profiling of E10.5, E11.5, and E13.5 kidney and consensus bioinformatic analysis were used to define a dynamic secretome of early metanephric development. In situ hybridisation was used to confirm microarray results and clarify spatial expression patterns for these genes. Forty-one secreted factors were dynamically expressed between the E10.5 and E13.5 timeframe profiled, and 25 of these factors had not previously been implicated in kidney development. A text-based anatomical ontology was used to spatially annotate the expression pattern of these genes in cultured metanephric explants.