A popular species for food and sport, the European catfish (Silurus glanis) is well-studied in its native range, but little studied in its introduced range. Silurus glanis is the largestbodied freshwater fish of Europe and is historically known to take a wide range of food items including human remains. As a result of its piscivorous diet, S. glanis is assumed to be an invasive fish species presenting a risk to native species and ecosystems. To assess the potential risks of S. glanis introductions, published and 'grey' literature on the species' environmental biology (but not aquaculture) was extensively reviewed. Silurus glanis appears well adapted to, and sufficiently robust for, translocation and introduction outside its native range. A nest-guarding species, S. glanis is long-lived, rather sedentary and produces relatively fewer eggs per body mass than many fish species. It appears to establish relatively easily, although more so in warmer (i.e. Mediterranean) than in northern countries (e.g. Belgium, UK). Telemetry data suggest that dispersal is linked to flooding/spates and human translation of the species. Potential impacts in its introduced European range include disease transmission, hybridization (in Greece with native endemic Aristotle's catfish [Silurus aristotelis]), predation on native species and possibly the modification of food web structure in some regions. However, S. glanis has also been reported (France, Spain, Turkmenistan) to prey intensively on other non-native species and in its native Germany to be a poor biomanipulation tool for top-down predation of zooplanktivorous fishes. As such, S. glanis is unlikely to exert trophic pressure on native fishes except in circumstances where other human impacts are already in force. In summary, virtually all aspects of the environmental biology of introduced S. glanis require further study to determine the potential risks of its introduction to novel environments.

The impact of the parasitic swimbladder nematode, Anguillicola crassus Kuwahara, Niimi & Itagaki, on European eel populations is assessed with reference to published research on its origin and rapid dissemination, life cycle and transmission dynamics, and its pathogenic effect. The parasite was originally endemic to East Asia, but has transferred from its native host, the Japanese eel, Anguilla japonica Temminck & Schlegel, to the European eel, Anguilla anguilla (L.) and American eel, Anguilla rostrata (Le Seur). Anguillicola crassus is a very successful colonizer and is now known to occur in four continents (Asia, Europe, Africa and America). The nematode can severely impair swimbladder function and has caused mortalities in both farmed and wild populations in the presence of other stressors. Anguillicola crassus may impair the capacity of European eels to complete the spawning migration, although direct evidence is not available to support this hypothesis. Areas for future research are recommended.K E Y W O R D S : Anguillicola crassus, eels parasite, nematode, pathology, swimbladder.

BRAF is a serine-threonine-specific protein kinase that is mutated in 2% of human cancers. Oncogenic BRAF is a validated therapeutic target that constitutively activates mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling, driving tumor cell proliferation and survival. Drugs designed to target BRAF have been developed, but it is difficult to prove that they mediate their antitumor effects by inhibiting BRAF rather than by working through off-target effects. We generated drug-resistant versions of oncogenic BRAF by mutating the gatekeeper residue. Signaling by the mutant proteins was resistant to the small-molecule inhibitor sorafenib, but sorafenib still inhibited the growth of tumors driven by the mutant protein. In contrast, both BRAF signaling and tumor growth were resistant to another RAF drug, PLX4720. These data provide unequivocal evidence that sorafenib mediates its antitumor effects in a manner that is independent of its ability to target oncogenic BRAF, whereas PLX4720 inhibits tumor growth by targeting oncogenic BRAF directly.

BRAF is a serine/threonine kinase that is mutated in a range of cancers, including 50-70% of melanomas, and has been validated as a therapeutic target. We have designed and synthesized mutant BRAF inhibitors containing pyridoimidazolone as a new hinge-binding scaffold. Compounds have been obtained which have low nanomolar potency for mutant BRAF (12 nM for compound 5i) and low micromolar cellular potency against a mutant BRAF melanoma cell line, WM266.4. The series benefits from very low metabolism, and pharmacokinetics (PK) that can be modulated by methylation of the NH groups of the imidazolone, resulting in compounds with fewer H-donors and a better PK profile. These compounds have great potential in the treatment of mutant BRAF melanomas.

Protein kinases C (PKCs) and extracellular signal-regulated kinases (ERKs) are evolutionary conserved cell signalling enzymes that coordinate cell function. Here we have employed biochemical approaches using ‘smart’ antibodies and functional screening to unravel the importance of these enzymes to Schistosoma mansoni physiology. Various PKC and ERK isotypes were detected, and were differentially phosphorylated (activated) throughout the various S. mansoni life stages, suggesting isotype-specific roles and differences in signalling complexity during parasite development. Functional kinase mapping in adult worms revealed that activated PKC and ERK were particularly associated with the adult male tegument, musculature and oesophagus and occasionally with the oesophageal gland; other structures possessing detectable activated PKC and/or ERK included the Mehlis' gland, ootype, lumen of the vitellaria, seminal receptacle and excretory ducts. Pharmacological modulation of PKC and ERK activity in adult worms using GF109203X, U0126, or PMA, resulted in significant physiological disturbance commensurate with these proteins occupying a central position in signalling pathways associated with schistosome muscular activity, neuromuscular coordination, reproductive function, attachment and pairing. Increased activation of ERK and PKC was also detected in worms following praziquantel treatment, with increased signalling associated with the tegument and excretory system and activated ERK localizing to previously unseen structures, including the cephalic ganglia. These findings support roles for PKC and ERK in S. mansoni homeostasis, and identify these kinase groups as potential targets for chemotherapeutic treatments against human schistosomiasis, a neglected tropical disease of enormous public health significance.

BRAF, a serine/threonine specific protein kinase that is part of the MAPK pathway and acts as a downstream effector of RAS, is a potential therapeutic target in melanoma. We have developed a series of small-molecule BRAF inhibitors based on a 1H-imidazo[4,5-b]pyridine-2(3H)-one scaffold (ring A) as the hinge binding moiety and a number of substituted phenyl rings C that interact with the allosteric binding site. The introduction of various groups on the central phenyl ring B combined with appropriate A- and C-ring modifications afford very potent compounds that inhibit (V600E)BRAF kinase activity in vitro and oncogenic BRAF signaling in melanoma cells. Substitution on the central phenyl ring of a 3-fluoro, a naphthyl, or a 3-thiomethyl group improves activity to yield compounds with an IC(50) of 1 nM for purified (V600E)BRAF and nanomolar activity in cells.

The effect of salinity on hatching, larval survival and infectivity of Anguillicola crassus was studied under experimental conditions using eggs obtained from naturally infected eels. Egg hatching rate, second-stage larval survival and larval infectivity were maximal in fresh water and declined with increase in salinity. Larvae survived up to 100 d in fresh water, 70 d in 50% sea water and 40 d in 100% sea water. Infectivity experiments demonstrated that salinity influenced transmission success throughout the life cycle by decreasing total infectivity of the larval population in utero within female A , crassus and when larvae were free-living in the aquatic environment. Infectivity was agedependent in relation to salinity. Larvae were infective to intermediate and paratenic hosts for up to 80 d in fresh water, 21 d in 50% sea water and up to 8 d in 100% sea water. The data confirm field observations that infection levels decrease with an increase in salinity. The study contributes to experimental verification of the colonization abilities of A. crassus and supports the hypothesis that A. crassus can be disseminated and transmitted in brackish water. The importance of regular monitoring and stringent hygiene practices in the transportation of eels is emphasised.

The study aims were to quantify the survivorship of Anguillicola crassus in eels in seawater and investigate transmission in estuarine (50% seawater) and marine (100% seawater) simulated conditions. Most A. crassus were able to survive and reproduce in 50% and 100% seawater eels for up to 6 months and therefore could survive during the spawning migration of eels to the Sargasso Sea. Up to 10% of the parasite metapopulation were damaged after long-term exposure to 50% or 100% seawater. Transmission of A. crassus was completed in 50% and 100% seawater in the laboratory, although infection levels in 100% seawater hosts were always lower. Transmission in estuaries is ecologically possible since the copepod Eurytemora affinis is susceptible to infection and is the dominant autochthonous species in most tidal estuaries in the Northern hemisphere. Transmission at sea is unlikely due to lack of suitable intermediate hosts. The data support the suggestion that dissemination of A. crassus has been facilitated by natural movement of eels in coastal waters. It is possible that A. crassus could impair the success of the eel spawning migration to the Sargasso Sea, although there is no direct evidence to support this.