ABSTRACT
Proteases are enzymes that cleave and hydrolyse the peptide bonds between two specific amino acid residues of target substrate proteins. Protease-controlled proteolysis plays a key role in the degradation and recycling of proteins, which is essential for various physiological processes. Thus, solving the substrate identification problem will have important implications for the precise understanding of functions and physiological roles of proteases, as well as for therapeutic target identification and pharmaceutical applicability. Consequently, there is a great demand for bioinformatics methods that can predict novel substrate cleavage events with high accuracy by utilizing both sequence and structural information. In this study, we present Procleave, a novel bioinformatics approach for predicting protease-specific substrates and specific cleavage sites by taking into account both their sequence and 3D structural information. Structural features of known cleavage sites were represented by discrete values using a LOWESS data-smoothing optimization method, which turned out to be critical for the performance of Procleave. The optimal approximations of all structural parameter values were encoded in a conditional random field (CRF) computational framework, alongside sequence and chemical group-based features. Here, we demonstrate the outstanding performance of Procleave through extensive benchmarking and independent tests. Procleave is capable of correctly identifying most cleavage sites in the case study. Importantly, when applied to the human structural proteome encompassing 17,628 protein structures, Procleave suggests a number of potential novel target substrates and their corresponding cleavage sites of different proteases. Procleave is implemented as a webserver and is freely accessible at http://procleave.erc.monash.edu/.
ABSTRACT
Global public health security is both a collective aspiration and a mutual responsibility that demands cooperative action at all levels. The expansion of the current H5N1 avian influenza enzootic and its incursion into human health presents a real and significant threat of an influenza pandemic. The world has for the first time an unprecedented opportunity for pandemic preparation. Current global efforts to tackle the H5N1 pandemic threat are centred around the framework of the International Health Regulations (2005) that requires countries to openly share disease intelligence including clinical samples, viruses and epidemiological information. Present international initiatives also seek to establish more equitable allocation and sharing mechanisms for developing countries, of therapeutic resources, public health interventions and other broad-based support in the event of a pandemic. To be sustainable, country preparatory efforts need to be integrated within wider national emergency preparedness frameworks and emphasise the strengthening of basic capacities in disease surveillance, outbreak response and health systems that can respond to a range of public health emergencies. Such capacity building represents permanent investments in health that will have enduring benefits beyond a pandemic. Preparations must also go beyond the health sector; greater promotion of intersectoral cooperation and an adoption of a whole-of-society approach to preparation is recommended. Broad collaboration is vital in addressing the complex challenge posed by influenza to our collective security.
Subject(s)
Animals , Humans , Birds , Communicable Disease Control , Methods , Global Health , Health Planning , Influenza A Virus, H5N1 Subtype , Influenza in Birds , Epidemiology , Virology , Public HealthABSTRACT
We conducted a randomized, double-blind comparison of 8% sevoflurane and propofol as induction agents for day-case cystoscopy in 102 patients. All patients received an i.v. cannula and breathed oxygen 5 litre min -1. Anaesthesia was induced with propofol i.v. or inhalation of 8% sevoflurane and 10% Intralipid [as a placebo] i.v., delivered by a blinded observer. Anaesthesia was maintained in all patients with 2% sevoflurane via a face mask. Induction of anaesthesia with sevoflurane was significantly slower compared with propofol [mean 84 [SD 24] s vs 57 [11] s], but was associated with a lower incidence of apnoea [16% vs 65%] and a shorter time to establish spontaneous ventilation [94 [34] s vs 126 [79] s]. Induction complications were uncommon in each group but the transition to maintenance was smoother with sevoflurane and was associated with less hypotension compared with propofol. Emergence from anaesthesia induced with sevoflurane occurred significantly earlier compared with propofol [5.2 [2.2] min vs 7.0 [3.2] min] and anaesthetic induction was also significantly cheaper with sevoflurane. According to a postoperative questionnaire, the majority of patients found both anaesthetic techniques acceptable. Nevertheless, significantly more patients [14%] rated induction with sevoflurane as unpleasant compared with propofol [0] and significantly more patients [24%] would not choose sevoflurane induction compared with propofol [6%]. This phenomenon may have been related to the particular patient population studied, however. Inhalation induction with 8% sevoflurane would appear to offer several objective advantages compared with induction with propofol in day-case patients, although a significant minority may dislike this technique. [Br. J. Anaesth.1997; 78: 356-361]