Phytophthora species blight potatoes and tomatoes, devastate soybean, rot cacao, and are the cause of sudden oak death. Understanding this versatile genus will be key to its control Phytophthora ramorum, it took less than four years to produce a draft sequence of its genome, one of the fastest-ever discovery-to-sequence stories for a complex pathogen. This achievement was a United States initiative, facilitated by the injection of federal and state funding into Phytophthora research. But the US is not alone in the battle against this genus. Phytophthora species cause thousands of millions of dollars of damage to the world's commercial crops every year: they blight potatoes and tomatoes, devastate the lucrative soybean, and rot cacao, threatening the world's supply of chocolate  in tens of thousands of oak trees across the coastal counties of California, is now present in at least three other US states and is threatening to take on the native flora of the entire North American continent. It is also lurking in Europe, although apparently with less devastating consequences.The most infamous of the Phytophthora. This year, the US federal government will channel US$7,400,000 toward research into SOD. A major focus of this funding is genomics. Sequencing the genomes of several Phytophthora will help clarify the phylogeny and evolution of these enigmatic organisms , it's about twice the size of the Arabidopsis genome. His latest research, published in the Journal ofBiological Chemistry (P. infestans protease inhibitor—extracellular protease inhibitor 1 (EPI1)—that could be one of a unique class of suppressor proteins that Phytophthora deploy to infect and counteract host defences. The pathogen seems to upregulate the epi1 gene during colonisation of its host. EPI1 inhibits plant apoplastic proteases—extracellular enzymes that are part of the host's defensive armoury that have evolved to prevent foreign proteins entering cells.The hemistry , describP. infestans colonisation of host apoplast,’ Kamoun and his colleagues report  and the US Department of Energy's Joint Genome Project based in Walnut Creek, California. The focus here is the soybean pathogen P. sojae and the SOD pathogen P. ramorum, for which draft sequences are now complete (www.jgi.doe.gov/). The genomes are much smaller than that of the 250-Mb P. infestans—P. sojae is about 90 Mb and P. ramorum is just 55 Mb. This, in part, explains the comparative speed of these sequencing efforts. But another factor is undeniably the fear of the unknown P. ramorum, which in 2002 netted the Virginia–California initiative US$3,800,000 in federal funding to describe its genome. Ultimately, however, the sequence of one species will help to inform on the sequence of other related species.Even more advanced than the P. sojae to infect its host. He agrees with Kamoun that understanding this machinery is the way to devise new control measures that could give plants the upper hand in the evolutionary arms race against their Phytophthora pests. At present, most strategies to limit the damage caused by species like P. infestans and P. sojae rely on developing resistant cultivars by selective breeding of varieties with major resistance genes—single genes that can block a pathogen. However, Phytophthora seem able to find ways to overcome these efforts. ‘P. infestans is absolutely notorious for its ability to genetically change in response to a major resistance gene,’ says Tyler. ‘Typically major resistance genes in potato barely last a single season.’Brett Tyler, Research Professor at the Virginia Bioinformatics Institute, is focusing on the molecular tools used by P. sojae for five to ten years. However, this resistance is starting to break down, and breeders are running out of major resistance genes with which to conjure new varieties. The alternative, says Tyler, is quantitative or multigenic resistance, which relies on getting plants to express several resistance genes at once, each of which makes a small contribution to the plant's overall resistance. It should be much harder for P. sojae to evolve a new attack against this kind of robust defence. The search is also on for new genes that could be used to encourage quantitative resistance to host species. One particularly promising approach is to pit pathogen against host to see which genes are switched on. The host should upregulate genes that defend it against infection and the pathogen should upregulate genes that it needs to attack. The discovery that plants produce proteases and that Phytophthora have responded by secreting protease inhibitors to disable them is important if long-lasting solutions are to be found. ‘We just need to find a way to introduce new protein-degrading enzymes into the plant that the pathogen doesn't know how to block,’ says Tyler. ‘With these genomic tools we can really accelerate the pace at which we can evaluate different possible protective measures.’Things look better for the soybean. New cultivars containing major resistance genes show resilience to Phytophthora can be mistaken for a fungus, so DNA profiling of isolates is crucial if species and strains of species are to be identified correctly so that action appropriate to each infection can be taken. Since 2000, Matteo Garbelotto, Adjunct Professor of Mycology and Forest Pathology at the University of California at Berkeley , has spent a significant part of his working life tracking the spread of P. ramorum, the Phytophthora that has killed off vast tracts of oak trees in native Californian forest  and viburnum (Viburnum spp.), which seem to act as carriers for the pathogen. ‘What we're seeing is a parallel to what has been happening throughout Europe, where the infection has basically moved using the commercial routes of the ornamental plant industry,’ Garbelotto says.DNA analysis has been crucial to confirm suspected cases of P. ramorum does not appear to have the same devastating consequences in Europe as it does in the US—at least not yet. It's not entirely clear why, but it could have something to do with the structure of the bark of different host species, suggests Garbelotto. ‘We normally see more infection where we have more corrugation, and that's because water accumulates in the fissures … where the zoospores have a chance to infect the bark.’ However, he notes, European beech (Fagus sylvatica) appears to be extremely susceptible to P. ramorum. ‘If it reaches areas where there are a lot of beeches, it could potentially mirror what's happening in California,’ he warns.P. ramorum infection were first described on rhododendrons in The Netherlands in 1993. Once this was confirmed to be the same species as the pathogen responsible for Californian SOD, there was speculation that P. ramorum had either been introduced to the US from Europe or vice versa. However, in December 2002, it emerged that these two populations are of different mating types—A1 in Europe and A2 in the US. The latest research from Garbelotto and his colleagues, due to be published in Mycological Research (Camellia spp.) and rhododendrons in a nursery in Washington state showed that the A1 and A2 strains were living side by side. ‘That was a big surprise for us,’ recalls Garbelotto. ‘We had no knowledge at that point that both the European and the North American type could be present in the same nursery.’In Europe, symptoms characteristic of Research , supportPhytophthora can produce a new species with different properties from those of either parent. One of the best cases comes from Europe, where a new Phytophthora emerged in 1993 that began to attack alder trees (Alnus spp.). Research carried out by scientists in the United Kingdom demonstrated that the alder Phytophthora was a product of a hybridisation event between P. cambivora and an unknown species similar to P. fragariae, neither of which attacks alder.Hybridisation between different species of Phytophthora species to hybridise and new phenotypes to emerge, there is legitimate concern that sexual recombination between the A1 and A2 mating types could produce something more devastating than either form. Within the controlled confines of his laboratory, Garbelotto has been exploring whether the two types of P. ramorum can get it together. Initial findings are that oospores—the product of sexual recombination—are being produced, although most of them abort before they reach maturity. However, 30% progress further, and  look like they could be functional. ‘They'll germinate,’ he predicts.Given this propensity for Phytophthora was isolated from two sites in England. Although the new species—currently referred to as Phytophthora taxon C sp. nov. (P. taxon C)— appears to cause relatively mild damage to its beech and rhododendron hosts, the UK's Department for Environment, Food and Rural Affairs (DEFRA) acknowledges that hybridisation of P. taxon C with P. ramorum could have serious consequences. ‘The potential for the pathogen to adapt further to its putative new environment intrinsically or via hybridisation is not known,’ note the authors of a DEFRA report on the mystery species (www.defra.gov.uk/planth/pra/forest.pdf). ‘Long-distance spread could easily occur through the movement of infected stock of rhododendron or beech and possibly other (as yet unknown) hosts,’ they warn.The threat that hybridisation could create a novel strain with a different host range is a concern that the UK is also taking seriously. In December 2003, an entirely new P. taxon C and P. ramorum are only distantly related, making hybridisation unlikely, says Joan Webber, Head of Pathology at the UK government's Forestry Commission. The closest known relative of P. taxon C is P. boehmeriae, a pathogen that has been recorded on several species of tree in China and Australia, and on cotton in China and Greece, suggesting possible origins for the newly described species. But, says Webber, the sequence match between P. taxon C and P. boehmeriae is only 92%—not especially close. Much more evidence is needed to build a strong case for the origin of this new Phytophthora, she says.DEFRA is monitoring the situation closely . HoweverP. infestans strain that caused the Irish potato famine. Jean Beagle Ristaino of North Carolina State University  is due to publish in Mycological Research an analysis of DNA extracted from diseased potato plants preserved from the nineteenth-century Irish epidemic  and forest dieback (P. cinnamomi), the chlamydospores play a crucial role, allowing the pathogen to survive from season to season. The formation of sexual structures is relatively rare, but oospores—the product of sexual recombination—occur in many species  and the true oaks coast live oak (Quercus agrifolia), California black oak (Quercus kellogii) and Shreve's oak (Quercus parvula var. shrevei). These species develop large wounds or cankers in their woody tissue, which disrupt physiology and in extreme cases lead to death in a matter of months.In 1995, trees in oak forests in the coastal counties of California started to show a range of alarming and lethal symptoms. Since then, the disease has reached epidemic proportions, with tens of thousands of trees dying along approximately 300 km of the central Californian coastline . By 2000P. ramorum does not appear to cause the same damage, leaving hosts like the Californian bay laurel  and rhododendrons (Rhododendron spp.) with the relatively mild symptoms of leaf blight and occasional branch dieback. However, these non-oak hosts probably act as reservoirs of disease and may even help it to spread. The sporangia and chlamydospores that are thought to be the main asexual propagules of the pathogen (In non-oak species, pathogen  are readP. ramorum was found at a large wholesale horticultural nursery in Los Angeles County. The California Department of Food and Agriculture, the US Department of Agriculture's Animal and Plant Health Inspection Service, and state agriculture departments around the country are tracing all plants shipped from this nursery over the past year in an effort to identify and destroy any infected material, and hence prevent any further spread of the disease. However, the rot has already set in at nurseries in three states outside California: Oregon, Washington, and Florida. A National SOD Nursery Survey is underway to try to assess how far the disease might have spread.In March 2004,


The exploitation of information extraction (IE), a technology aiming to provide instances of structured representations from free-form text, has been rapidly growing within the molecular biology (MB) research community to keep track of the latest results reported in literature. IE systems have traditionally used shallow syntactic patterns for matching facts in sentences but such approaches appear inadequate to achieve high accuracy in MB event extraction due to complex sentence structure. A consensus in the IE community is emerging on the necessity for exploiting deeper knowledge structures such as through the relations between a verb and its arguments shown by predicate-argument structure (PAS). PAS is of interest as structures typically correspond to events of interest and their participating entities. For this to be realized within IE a key knowledge component is the definition of PAS frames. PAS frames for non-technical domains such as newswire are already being constructed in several projects such as PropBank, VerbNet, and FrameNet. Knowledge from PAS should enable more accurate applications in several areas where sentence understanding is required like machine translation and text summarization. In this article, we explore the need to adapt PAS for the MB domain and specify PAS frames to support IE, as well as outlining the major issues that require consideration in their construction.PASBio by extending a model based on PropBank to the MB domain. The hypothesis we explore is that PAS holds the key for understanding relationships describing the roles of genes and gene products in mediating their biological functions. We chose predicates describing gene expression, molecular interactions and signal transduction events with the aim of covering a number of research areas in MB. Analysis was performed on sentences containing a set of verbal predicates from MEDLINE and full text journals. Results confirm the necessity to analyze PAS specifically for MB domain.We introduce PASBio contains the analyzed PAS of over 30 verbs, publicly available on the Internet for use in advanced applications. In the future we aim to expand the knowledge base to cover more verbs and the nominal form of each predicate.At present  We are now in an era where full genomes, data from high throughput experimental methods (e.g. micro-arrays) and electronic versions of scientific literature are easily available to every researcher over the Internet. These advances have made it possible to work on more than one gene at a time, ask complex questions and increase the pace of biological discovery. However, the progress made in scientific research until now has been recorded in the form of free-text articles readable only by humans and accessible by machine mostly through shallow keyword-based search engines. For improved methods of information access and knowledge discovery it is necessary to automatically map from the unstructured text representation into partially structured forms that provide discovered facts to databases.The large-scale data generated from the experiments in molecular biology needs to be assessed and integrated into the scientific communities' knowledge stores. This has created a need for various kinds of specialized databases. While some existing databases contain only molecular level information (e.g. PDB , SCOP 22) othersPrevious research in IE for biology has focused intensively on the recognition of named entities (NE) from scientific texts -9, i.e. catalyst and reaction being catalyzed in the case of the first and second arguments to the predicate catalyze. Alternatively, functional roles can be employed such as thematic relations that try to express some linguistically motivated aspect of the argument's behavior such as agent, location or experiencer.Predicate-argument structure (PAS) analysis seeks to formally describe 'frames' for predicates  and the roles of their arguments (parts of the sentence surrounding it). Such roles usually need to be specified according to several factors including meaning and obligation. Meaning can be determined in several ways such as a domain or predicate-specific fashion such as Traditional IE systems that use regular expressions based on shallow chunking at the phrase level (e.g. noun phrase, verb phrase, preposition phrase) capture weak notions of 'argument' for event predicates and their linear precedence. Such approaches seem to be inadequate to the goal of achieving high completeness and accuracy in event extraction. In recognition of this several major projects -24 have For PAS to be practically realized within IE three major knowledge components will be required: (1) a hierarchy of concept categories for objects of interest; (2) a definition of predicate-argument frames and the semantic labels of their arguments; and (3) the mapping rules that define how to transform the relevant parts of a surface sentence to the arguments in the PAS frame. Currently (1) is already quite advanced with several controlled vocabularies such as MeSH  or Gene In this work we introduce the concept of semantic analysis of argument roles in biological texts and propose the construction of PAS for molecular biology (PASBio). We have analyzed and annotated sentences from MEDLINE abstracts and full-text journal articles for building PASBio. The working scheme is similar to the PropBank project ,23. ResuIn this article we first give a short introduction to IE and PAS. Next, we describe the approach taken in the PropBank project. Then, we discuss and exemplify how the specification of predicate-argument frames needs to be extended to meet the requirements for extracting molecular events. The second half of the paper is devoted to explaining the methodology used to define the PAS and discussing results of our analysis and its comparison with those of PropBank. Finally, we describe how the PAS frames can be exploited by showing their place in the IE system for molecular biology and discussing existing IE systems used for event extraction in molecular biology.company outlook) then patterns such as "np (stock index) + vp (driven up) + integer (number %)" and "np (company) + vp (bid) + np (stock)" could be developed as a template. Sentences in documents which (1) contain a noun phrase (np) describing stock index, together with a verb phrase (vp) driven up, and followed by a number; or (2) contain a noun phrase representing a company name, followed by a verb phrase with bid, plus a noun phrase of stock index should be extracted. The difficulties are compounded because a single event can nearly always be written in a variety of syntactic forms due to linguistic processes such as passive voice, (pro-) nominalization, raising, etc.IE systems aim to provide instances of structured knowledge representations from unstructured free-form text. IE, based on the Message Understanding Conference (MUC) tradition of task segmentation  works fuspray alternation by Levin [spray may express its arguments in at least two different ways, i.e. (a) "Peter sprayed water on his flowers." and (b) "Peter sprayed his flowers with water." Thus, two syntax-based regular expressions plus some information about NE as "np (people) + vp (spray) + np (object1) + pp (on) + np (object2)" and "np (people) + vp (spray) + np (object2) + pp (on) + np (object1)" are required.The following simple example involves a linguistic phenomenon sometimes called locative alternation or by Levin . The verMsp1p" and "Dec1p" from a sentence "Msp1p is a component of the secretary vesicle docking complex whose function is closely associated with that of Dec1p.These findings suggest that ", because it conforms to the pattern "A associate with B" predefined within the system. In this respect we consider that deeper knowledge, describing the semantic relationship between verbs and their arguments, encoded in PAS are needed.Surface level extraction patterns can be hand built  or basedactivate, its participial modifier format would be activating or activated, and its nominal format would be activation. Beyond a verb, sentence constituents holding semantic roles to complete the meaning of an event indicated by the verb are called arguments. The semantic roles played by the set of arguments with respect to the particular verb are represented in the PAS frame of that verb.An event is described in a sentence by a composition of a verb and its arguments. A verb, which indicates a particular type of event conveyed by a sentence, can exist in its verbal form, its participial modifier format or its nominal form. For example, the normal form of a verb used to describe the event "making something active" would be sell and rent are proposed as two distinct structures in the case of PropBank and only a single structure for both verbs in the case of VerbNet and FrameNet . It often involves transformation, in the sense that something goes into a process and something different comes out of it. Examples of biological processes are cell growth and maintenance, signal transduction, metabolism and biosynthesis etc.According to the Gene Ontology (GO) , the terphosphorylation of a protein molecule by a protein kinase is a molecular event, which is a part of the cellular signalling process or transcription of a gene by a polymerase is a part of the gene expression process. Hence, by definition a molecular event or a disruption of it will have a local effect in terms of the process that it is a part of and an observable or phenotypic effect in terms of overall effect of disruption of the entire process. For example, a mutation in the coding region of a gene that introduces a stop codon into the open reading frame would lead to a pre-mature termination of transcription considered as the local effect and may be responsible for a disease state of an organism due to deficiency of that protein as the phenotypic effect. Different events are described by different verbs ; sentence (2) shows the passive form, without mention of A and C, for which a syntactic-based extraction pattern would be "B are eliminated" ; sentence (3) shows a form, using a different preposition compared to sentence (1) in order to mention C, for which the syntactic-based extraction pattern would be "A would eliminate B within C" (where A = a 3-bp in-frame deletion, B = an asparagines residue and C = a kinase domain of the product).The sentences (1)–(3) in Figure  MEDLINE  and EMBO MEDLINE  Journal express are shown as sentences (4)–(6). Information slots consist of A – entity expressed, B – physical property of the expressed entity, and C – location referring to organelle, cell or tissue. In sentence (4), (where A = the enzyme, B = two mRNA isoforms of 2.4 and 4.0 kb, C = brain) the information needed to describe the event with respect to slot B is marked by using a prepositional phrase, but in sentence (5),  using an appositive form, seemingly not playing an important role in the description of the event in which it participates. Sentence (6),  shows a different kind of problem that arises because biologists generally would not think of "T cells" as an agent in this context, perceiving it as information about location. On the other hand, without deep domain knowledge one may understand "T cells" as an agent of the express event instead of its intended role as a cell or tissue.Examples of sentences describing the event These examples show that using regular expressions around syntactic information of the surface texts would not be adequate for IE to make sense of the complex surface structure. PAS represents information describing verb arguments and the semantic roles these arguments play in conveying a certain event. Different surface forms describing the same event can be mapped into the same PAS.Peter sprayed water on his flowers." and (b) "Peter sprayed his flowers with water." Both sentences can be mapped into the PAS of a verb spray, which indicates the particular event "apply thin liquid to surface" with 3 required arguments (i.e. agent, liquid, surface). The sentence's constituent "Peter" in both sentences is perceived from its verb-specific semantic role to be an agent that does the action. "water", when it is either a direct object as in sentence (a) or an object of a preposition as in (b), is perceived as the liquid used in the event, and "his flowers" is perceived as the surface getting wet. Similarly, a surface text from molecular biological corpus such as "One exon is spliced out of the MLC3 nm transcript in smooth muscle to give an alternative product." could be conceptualized into PAS relationship as shown at the topmost level in Figure To illustrate this point we return to the example mentioned earlier, (a) "One exon", "is spliced out", "of the MLC3 nm transcript", "in smooth muscle", and "to give alternative product" have their syntactic categories as noun phrase, verb, prepositional phrase, prepositional phrase, and verb phrase respectively. At the syntactic relations level, "One exon" shows its role as the surface subject of the passive form verb "is spliced out" and other constituents play the role of complements.Figure One exon", "the MLC3 nm transcript", "smooth muscle" and "alternative product" constituents pertain to the domain concept classes of a gene product (RNA), tissue and alternative mRNA respectively. At the highest level of our scheme the representation contains the most abstract information. Semantic roles played by other constituents to the verb indicating the event are represented at this level. Thus, the process of removal of an exon from mRNA  is indicated by the verb splice out. Here, the verb arguments play the semantic roles of lost component ("One exon"), entity getting spliced ("the MLC3 nm transcript"), location referring to tissue ("smooth muscle"), and secondary predication – showing purpose or reason in this example . The semantic role secondary predication is assigned to the argument "to give an alternative product" because this by itself is capable of instantiating a PAS frame and is considered in our scheme to possibly be a core argument.Beyond the syntactic level of description, there are semantic levels including argument categories level and predicate-argument relations level. At the argument categories level "The semantics of a sentence relate in complex ways to the syntax of the sentence, as we can see from the illustration of semantic and syntactic levels in Figure In molecular biology, a gene and its products are at the center of the study, as a set of these molecular entities dictate, and their products carry out, different functions at the cellular level and the combined effects can be seen at the organism level. Hence, in the literature a gene or a gene product is possibly described as an agent participating in some events, with the help of various appropriate verbs indicating the specific events. Different molecular-level or phenotypic effects are described as the other arguments of such events. As described above, PAS is a representation of semantic relationships between arguments with specified roles and a verb relating to a particular event narrated in a sentence. Thus, PAS would be a natural choice for IE, especially event extraction in molecular biology.mutate. Arg X  is used for labeling the first type of core argument and ArgR is used for the second type. A mnemonic label is added after Arg X and ArgR in order to give a short description of the semantic role played by the argument. Biological function and usage of the argument are used to describe the semantic role in PAS. No attempt is made to ensure the consistency of mapping between argument labels (argument name) and the roles (the mnemonic labels) played by the arguments across verb frames, except Arg0. Arg0 is reserved for only the argument playing the semantic role of agent. In some cases, this agent argument is not found in the usage of some verbs. Thus, PAS frames of such verbs will contain the core argument from Arg1. See PAS frames for mutate  to define PAS for the molecular biology domain. To define PAS for any verb, a survey about the usages of the verb from a set of sample sentences in a representative corpus is made. Examining the usage of an individual verb will indicate if it needs to be divided into several senses. In PASBio, these senses are divided with the aim of obtaining fine-grained semantic senses using the WordNet  lexical e Figure -Frame 1,s Figure  and tran2 Figure -Frame 9 Arg X or ArgR, the sentence's constituents which do not play the role of core arguments but fall into three types, i.e. adverbial, negation and modality, are annotated with the tag ADV or MAN in the case of an adverbial, NEG in the case of negation, and MOD in the case of modality. At the current stage of this project, only adverbials in terms of adverbs are considered to be annotated as MAN (for a manner adverb) or ADV (for other types of adverbs). If any adverbials in terms of phrases or clauses are mandatory for expressing events indicated by particular predicates, these adverbials will be defined as core arguments within PAS frames. For example, an adverbial phrase playing the role of locative modifier is included in the set of core arguments in the frame for predicate initiate. (Refer to example sentence "Apparently HeLa cells either initiate transcription at multiple sites within RPS14 exon 1."). Moreover, we are interested in distinguishing only the adverb playing the roles of manner modifiers  from other adverbs. A manner adverb deserves special distinction from other adverb types because it shows how a certain action is performed which is very important to understand facts in a biological sentence. For example, "normally" in the sentence "Mice have previously been shown to develop normally" is necessary for IE in order to understand that there is no problem in the development of the mice. Other types of adverbs for example play the roles of aspectual modifiers that give information about whether some event or state of affairs is completed or is still going on, and so forth , adverbs playing roles as frequency modifiers that indicate the frequency of a certain type of event , adverbs playing roles as focusing modifiers that consist of the four words even, only, also, and too , and so on will be all tagged as ADV. In case of negation and modality, NEG and MOD are given directly to a negator word (i.e. not or n't) and a modal verb  respectively. Though negations (operating at the sentence level) and modality (operating at various levels) are not defined as core arguments (mandatory arguments) within any PASBio's PAS frames because linguistically both of them cannot even be considered as any types of predicate's arguments, they are all worth annotating from an IE perspective if they exist in the same clause where a focused predicate exists. Similarly, adverbials which are not mandatory enough to be core arguments are also considered worthy of being annotated when found in the text. We consider that they should not be ignored because they can significantly alter or even reverse the meaning of the sentence.In addition to annotating a sentence's constituents corresponding to core-arguments with the tag splice) or have a unique biological interpretation (e.g. express, translate, etc.), (2) verbs that have a similar meaning used in the newswire domain and biology domain but show different patterns of usage , and (3) verbs that are used with the same meaning and usage style in both domains (e.g. abolish, delete, etc.). The usage of different verbs in biology influence PAS for biological domain falls into four groups: A – same sense, more arguments; B – same sense, fewer arguments; C – same sense, same structure; D – different sense or does not occur. Table In this subsection, we show some examples of PASBio's PAS frames and discuss how each frame is defined by examples of sentences relevant to it. There are three important cases that we examine in comparison to PropBank: 1) verbs that are rarely used in general language (e.g.  verbs thVerbs in this group have been used in biology documents with the same semantic sense as in PropBank, but they required more core arguments in their structures.mutate is used to describe the changes in an entity (gene or gene product) and mutations can be natural or engineered. PropBank defines two arguments for this verb which are Arg0: agent and Arg1: entity undergoing mutation, but from analysis we propose four arguments for the PAS frame of the verb mutate. As mentioned in the Guidelines section, Arg0 is reserved only for the argument playing the semantic role of agent. From all the examples we observed, passive forms are used to describe mutate events which mean that the agent does exist in the event but it is unnecessary to be explicitly stated because it is commonly known by the domain experts. This results in PASBio's core arguments for mutate starting from Arg1 and we leave a position for agent which possibly could be mentioned in other biological sub-domains. The PASBio's Arg2 describing event participating entities (referred to as 'Name Entities') is analogous to PropBank's Arg1. Thus PASBio's Arg1, Arg3, and ArgR are extra arguments compared to PropBank. The arguments Arg1 and Arg3 are captured conforming to linguistic criterion [eat which denotes a type of food. Similarly, Figure Arg1 and Arg3 do not exist in all sentences 1.1 to 1.3, but are assigned as core arguments by their intuitive presence in the domain models of biologists. Noticeably, consequences of the event driven by verb mutate are often seen in examples. Apart from "changes at molecular level" assigned as Arg3, the consequence, "changes at phenotype level" is suggested as ArgR (explained below). Sentence 1.1, 1.2, and 1.3 support this explanation.Consider the event of mutation, one of the most important biological events and a general cause behind genetic diseases. The verb riterion  which coArgR:results/consequences is an argument giving information about consequences after the event denoted by the predicate occurs. For mutate, most of the example sentences describing this event contain an ArgR argument, revealing the necessity of it. The requirement of this argument from an observation perspective coincides with biologist's viewpoint, thus we consider this as a core argument (more precisely an IE core argument) and named as ArgR instead of Arg X (a core argument from a purely linguistic perspective). We make this distinction under the rule that Arg X has to play a role during the event but not after the event. This condition is depicted by a formula like "mutation event = (Arg X + mutation + Arg X) + ArgR". Empirically, we find that this result argument (ArgR) is used with verbs relating to an abnormal biological phenomenon. Examples of other verbs that need this argument are skip, delete, etc.The argument initiate also takes additional arguments as core arguments. As shown in Figure Arg2 (sentences 2.1 and 2.2) describes the point of transcription initiation and Arg3 provides information about the tissue/cell where the gene (or product) is expressed. In PropBank, the sentence's segments defined by the parser with functional tag as LOC (location) will be considered as non-required elements. However, the extraction of spatial information is very important from the perspective of biological description. Furthermore, another interesting point that can be seen from the examples in Figure HeLa cells" is syntactically the subject which seems to be the agent of an initiate event, but domain knowledge suggests that the agent can be only a protein  in this case. "HeLa cells" is annotated as Arg3:location as tissue or cell instead of Arg0:agent. In sentence 2.2, "I kappa B-epsilon translation" is also a subject as in the previous example, but it is "entity created" assigned as Arg1. Only in Sentence 2.3 , the subject of the sentence fills the semantic role "agent", so a subject "RTKs" can be annotated as Arg0. Additionally, the point to note is "the entity created" in sentence 2.3 is different from sentence 2.1 and 2.2 as it is a signaling event that is initiated, but not a transcription or translation event.Verb Verbs in this group have been used in biological texts with the same semantic sense as in PropBank, but they required fewer arguments in their structures in our PASblock both in biomedical texts and in business news texts has very similar semantics. However, an event described by verb block in the biomedical domain may not mention information about secondary predication and instrument most of the time. The semantic role secondary predication is assigned to the argument that is in itself capable of instantiating another PAS frame. The sentence " [JohnArg0] blocked [MaryArg1] from [completing her dissertationArg2] with [his constant pesteringArg3]." is annotated by PropBank's PAS frame. An argument Arg2-secondary predication is annotated for "completing her dissertation" because this contains in itself the PAS of the verb complete. From this PropBank example, the meaning of the event denoted by block cannot be completely understood if the sentence just states as " [JohnArg0] blocked [MaryArg1]." as it is necessary to mention the action being stopped. In contrast in the biology domain, by mentioning only the entity being stopped (Sentence 3.1–3.3), the expert reader can understand that the event which applies to that entity is being stopped without providing an explanation of the action being stopped at the position of secondary predication. Similarly, an instrument used to block is encoded in the nature of an agent or causer. The structure of block and its examples are given in Figure MAN is used to label "specifically" as this adverb plays the role of a manner modifier.Verb generate is similar to that of block. Only Arg0-agent and Arg1-entity created are expressed in all observed sentences from our biology corpus.In Figure Verbs in this group have been used in biological documents with the same semantic sense as in PropBank. Moreover, their usage in both the biology corpus and PropBank indicates that their PAS frames are identical. Specialization of domain does not seem to affect verbs in this group.confer and lead. In both biology and newswire corpora, confer is used with semantic "to give (as a property or characteristic) to someone or something" and lead to is used in the sense of "to tend toward or have a result".In Figure express and transform are presented in Figures Verbs in this group have been used in biology documents with a different semantic sense compared to PropBank, or PAS frames for them are not found in PropBank. More than one semantic sense is found in our corpus for some verbs. PAS frames for express is used in the biology domain with the meaning "to manifest the existence of a gene or gene product" (or detection of the same by the experimenter) unlike its normal usage with the meaning of "give an opinion or send quickly". The PAS of express is given as Figure The verb transform, two senses are used in biology papers: "to cause (a cell) to undergo genetic (or neoplasmic) transformation" as shown in Figure transform found in our corpus is similar to the sense of "change" found by PropBank, there is still a huge gap between them. In the biological literature, illustrated by examples in sentences 8.1–8.3, this genetic transformation mentions only the agent or causer, what entity is getting transformed, and what will be the effect after transformation. It will not mention the start state of the entity undergoing transformation because it is known from the expert reader's domain 'common sense' knowledge that the start state refers to a normal condition of that entity. Transform in the second sense always occurs in a sentence connected by preposition into, and in the passive voice form in which no mention is made with regard to the agent.In the case of In the discussion so far we have assumed that the predicate is the center of semantic information. Here we intend to show that the argument contents can change the event description specified by the predicate, by examining sentences that describe an 'alternative splicing' event. Alternative splicing is used to generate multiple transcripts from a single gene and hence is a helpful event for increasing the functional complexity of eukaryotic systems.express: (a) "Northern blot analysis with mRNA from eight different human tissues demonstrated that [the enzymeArg1] was expressed exclusively [in brainArg3], [with two mRNA isoforms of 2.4 and 4.0 kbArg2]." and (b) "[A complementary DNA cloneArg1] encoding the large subunit of the essential mammalian pre-messenger RNA splicing component 2 snRNP auxiliary factor(U2AF65) has been isolated and expressed [in vitroArg3]." Sentence (a) is considered as a sentence denoting the alternative splicing event but sentence (b) is considered as a negative  sentence, which talks about expression of an mRNA of a splicing factor.Consider the following example of a set of sentences that talk about the 'expression' of a single type of mature mRNA generated from 'splicing' of pre-mRNA and generation (and expression) of multiple mature mRNA transcripts with different properties from the single type of pre-mRNA. Sentences annotated follow PASBio's frame for It would be difficult, based on word contents or regular expression methods, to put these two examples into different 'bins' for alternative splicing events. But the discussion about the length of the two different transcripts in Arg2 (with two mRNA isoforms of 2.4 and 4.0 kb) in the first sentence can be helpful to understand it as a sentence discussing about alternative splicing. On the other hand, the later sentence contains all the interesting words (e.g., mRNA, express and splicing) but misses Arg2, hence describes just an expression event.Construction of PAS frames by expert introspection may be considered as a time-consuming process, however domain-specific PAS frame definitions have valuable uses in several applications as discussed below.Each PAS frame in PASBio provides a set of semantic relationships between arguments participating in an event and a verb conveying the event. Although we focus on applying PASBio for event extraction in the molecular biology domain, information processing applications that require semantic understanding of a sentence will be able to take advantage of this knowledge. For example, machine translation (MT) requires encoding a surface sentence of a source language into a language independent logical form of clause meaning, and then generating from this logical representation a surface sentence in a target language. PAS would be one practical choice to be used as such a logical representation in MT ,30. In tWith respect to our molecular event extraction system, as we discussed in the introduction, PASBio takes on the role of a reference source in the stage of corpus annotation for creating training examples for machine learning. The planned IE system is composed of 4 activities: (1) construction of PASBio semantic lexicon; (2) annotation of full-text journal in terms of semantic represented in PASBio's frames; (3) construction of the module for automatically transforming an unseen sentence into a logical form of semantic relationships drawn within each particular PASBio frame; (4) integration of the resultant automatic semantic interpretation module within the event extraction system. So far, manual annotation and machine learning have not been completed yet and will be reported elsewhere. For a description of an IE system that can make use of such an annotated corpus we refer readers to the work of for example Surdeanu et al.  who usesApart from our corpus-based semantic interpretation approach, several other research groups have proposed systems for event extraction from the biological literature, especially about the interaction information between genes and genes product. Related work so far can be summarized into two sets. The first set of methods use regular expressions and rely on syntactic patterns. These methods may use statistical models of the surface words ,13, ruleThe only work in the second set, that has taken into account a large number of linguistic and deeper semantic aspects is, that of Novichkova et al. . The appAs mentioned above, most of the approaches, whether a deep notion of predicate-argument relations is taken  or a shaRecently, another research group  reportedWith the explosion of molecular data, tools developed by computer scientists are gradually being applied and integrated in the domain of biology to aid in information access and knowledge discovery. Text data appearing as reports about biological discoveries demands automated IE methods for faster knowledge discovery. Traditional IE systems that use regular expressions based on shallow chunking at the phrase level (e.g. noun phrase, verb phrase, preposition phrase etc.) capture weak notions of 'argument' for event predicates and their linear precedence. Such approaches seem to be inadequate to the goal of achieving high accuracy in event extraction in molecular biology. PAS which is used as a representation of the semantic relationship between a verb and its arguments participating in the event has the potential to support deep knowledge acquisition from a sentence within the extended system framework that is now being proposed within the IE community.Due to the importance of PAS and the lack of a specific PAS frame resource for the domain of molecular biology, we have proposed the analysis of PAS for molecular biology in this article. We have analyzed sentences for 30 verbs (and different frames per senses of the verb) from MEDLINE abstracts and full-text journal articles where the sentences contain each verb in its verbal form and its participial modified form for building PASBio. Our analysis suggests in some cases a significant difference in the predicate frames compared to those obtained from analyzing news articles by the PropBank project. In addition to the significance of verb senses used in the molecular biology domain, syntactic constructions also differ markedly; such as the use of passives allowing the semantic subject to be omitted where they are part of the common-sense understanding in the domain. Human readers are required to have domain knowledge in order to understand the texts. Our result frames and examples are available to the wider research community as a knowledge base at PASBio's webpage.In the future, we intend to utilize knowledge from the PASBio frames for annotating a corpus to be used as training examples to achieve automatic annotation of PAS semantics into sentences. Furthermore, we aim to complete analyzing PAS for more verbs related to molecular events and afterwards to extend our analysis to sentences containing the nominal forms of verbs.The English language used in research articles of biological and biomedical sciences is a sublanguage of written natural language. While most of its vocabulary is similar to that of general English, some verbs are domain-specific in nature. Our main focus here is the verbs that are used for describing molecular events in biology. Various researchers have different areas of interest and new concepts are added in the literature continuously. However, the areas of cellular signaling, gene expression, regulation and disruption of expression events are very important for the larger community of investigators involved in basic biomedical research and those involved in high throughput analysis. They are discussed throughout different parts of papers as possible cause of normal and disease states of different organisms. Hence, ignoring the normal distribution (frequency) of different verbs in the literature we choose the verbs from those involved in the above-mentioned processes (events). Most of the verbs are shown in Figure Information extraction work is still largely carried out using PubMed abstracts. Using abstracts is advantageous because they contain the highest density of keywords compared to other section of research articles but our intuition is that bio-text mining should scale-up to analyze full journal articles where the most detailed results are contained along with supporting evidence, comparisons to others work and background information, etc.  Recent iSentences were carefully chosen to cover a broad usage of each verb under study from the MEDLINE and full text journal corpora as described before. We tried to choose equal numbers of sentences containing a particular verb in its verbal format and its participial modifier format. Before starting an analysis on each sentence, a sentence was parsed using Connexor Parser  that useThis work was directed by NC. TW carried out the analysis of the predicate-argument structures with technical support from NC and biological knowledge from PKS. PKS chose the predicates and the sentences analyzed from the MedLine corpus. Sentences from other corpuses were complemented by TW. TW prepared the figures (except fig


While the molecular pathway that mediates cellular intake of iron through the TfR is known, it was not clear just how TfR assists in iron release to the cell and how it binds HFE and transferrin. By introducing multiple mutations in human TfRs, Pamela Bjorkman and colleagues identified functional binding sites for transferrin in both its iron-loaded and iron-free (apo-Tf) forms and for HFE. From these data, the researchers mapped out a scenario of the dynamic interactions between receptor and ligands (the bound molecule) and worked out a structure-based model for the mechanism of TfR-assisted iron release from Fe-Tf.Iron is an essential nutrient for sustaining life-forms as diverse as plankton and humans. But too much iron, or too little, can spell trouble. Mammalian cells maintain the proper balance partly with the help of a specialized cell surface protein called the transferrin receptor (TfR). TfRs bind to the iron-carrying transferrin protein (Fe-Tf) and escort their cargo to the cell's interior.  that support Fe-Tf but not apo-Tf binding, confirming that the receptor binding footprints of the two metal-binding states of transferrin are indeed different. With a structural model showing By suggesting a mechanism through which TfR binding regulates iron release, this structural model of the transferrin–TfR complex will bolster efforts to elucidate the molecular details of this process. Confirmation that transferrin and HFE do indeed compete for docking privileges reveals a possible role for HFE in maintaining iron homeostasis and will provide valuable insights into the dysregulation that leads to the warehousing of iron and resulting tissue and organ damage associated with hemochromatosis.


XRCC1 Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln, and investigate their role as susceptibility markers for colorectal cancer.Recent studies relating to the association between DNA repair-gene polymorphisms and colorectal cancer risk would, to the best of our knowledge, appear to be very limited. This study was designed to examine the polymorphisms associated with three DNA repair genes, namely: XRCC1, XRCC3 and XPD) in the context of colorectal cancer risk for the Taiwanese population. Genomic DNA isolated from 10 ml whole blood was used to genotype XRCC1 Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis.We conducted a case-control study including 727 cases of cancer and 736 hospital-based age- and sex-matched healthy controls to examine the role of genetic polymorphisms of three DNA-repair genes , the XRCC3 241Thr/Thr genotype  or the XPD 751Gln allele , although individuals featuring a greater number of risk genotypes (genotype with OR greater than 1) did experience a higher risk for colorectal cancer when compared to those who didn't feature any risk genotypes (Trend test P = 0.03). Compared with those individuals who didn't express any putative risk genotypes, individuals featuring all of the putative risk genotypes did experience a significantly greater cancer risk (OR = 2.43, 95% CI = 1.21–4.90), particularly for individuals suffering tumors located in the rectum (OR = 3.18, 95% CI = 1.29–7.82) and diagnosed prior to the age of 60 years (OR = 4.90, 95% CI = 1.72–14.0).The risk for colorectal cancer did not appear to differ significantly amongst individuals featuring the Our results suggest that DNA-repair pathways may simultaneously modulate the risk of colorectal cancer for the Taiwanese population, and, particularly for rectal cancer and younger patients. These cA damage . The intA damage . Since tA damage -6, the pA damage -11.XPD gene encodes a helicase that is a component of the transcription factor TFIIH [XPD 751Gln/Gln did demonstrate suboptimal DNA-repair capacity (DRC) in regard to its ability to remove UV photoproducts when compared to the XPD 751Lys/Lys and Lys/Gln genotypes. The XRCC1 protein is a scaffolding protein directly associated with polymerase beta, DNA ligase III and poly (ADP-ribose) polymerase (PARP) and functions in a complex to facilitate the base-excision repair (BER) and single-strand break-repair processes [XRCC1 399Gln allele were associated, more significantly, with higher levels of both aflatoxin B1-DNA adducts and glycophorin A variants when compared to individuals who exhibited the Arg/Arg genotype [Amongst the known genetic polymorphisms of the DNA-repair genes , the xeror TFIIH , this faor TFIIH . In 2002or TFIIH  reportedrocesses -19. In 1genotype . XRCC3 pXRCC1 399Gln allele, compared to the XRCC1 399Arg/Arg genotype, was associated with an increased risk for developing colorectal cancer, especially amongst young urban residents, although in 2003, Mort et al. [XPD, XPF, XPG, ERCC1) or XRCC1. In the present paper, we conducted a hospital-based case-controlled study to examine the role of genetic polymorphisms of three DNA-repair genes (XRCC1, XRCC3 and XPD) in the context of colorectal cancer risk for the Taiwanese population.To the best of our knowledge, studies pertaining to these DNA-repair genes focusing on colorectal cancer risk would appear to be limited and controversial. In 2000, Abdel-Rahman et al.  observedt et al.  failed tn = 776) participating in this study were newly diagnosed and histologically confirmed. Patients suffering from familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, or inflammatory bowel disease and other related malignancies were excluded from study participation. Seven hundred and twenty-seven of the original 776 cases (94%) were finally included in this study. Seven hundred and forty-seven age (same age) and sex-matched controls were recruited from the Physical Check-Up Department during the same period. All the participating controls had received comprehensive health examinations including colonoscopies. After excluding individuals diagnosed with other colorectal diseases, a history of other cancers or the existence of a family history of colorectal cancer, 736 controls (98%, 736/747) were finally included in this study. With informed consent, the socio-demographic characteristics of study participants were ascertained by means of the application of a structured questionnaire, at which time 10 ml of venous blood was collected.Detailed descriptions of the specific characteristics of the study participants have been published previously . In brieXRCC1 Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. All of the PCR reactions were carried out by a Mastercycler gradient thermocycler (Eppendorf, Hamburg, Germany) in a final volume of 25 ul containing 200 ng of each primer, 50 ng genomic DNA, 1.5 mM MgCl2, 200 ul dNTPs and 1.0 unit of Taq DNA Polymerase in the buffer provided by the manufacturer. In addition, all laboratory genotyping personnel were blind to the case-control status of the samples.Genomic DNA isolated from 10 ml whole blood was used to genotype XRCC1 PCR products were amplified with the primers 5'-TTGTGCTTTCTCTGTGTCCA-3' (sense) and 5'-TCCTCCAGCCTTTTCTGATA-3' (antisense) and digested with MspI (New England BioLabs, Beverly, MA, USA). The Arg allele revealed 374 and 221 bp fragments following digestion and polyacrylamide gel electrophoresis, whilst the Gln allele was not digested by MspI [XRCC3 PCR products were amplified with the primers 5'-GCCTGGTGGTCATCGACTC-3' (sense) and 5'-ACAGGGCTCTGGAAGGCACTGCTCAGCTCACGCACC-3' (antisense) and digested with NcoI (New England BioLabs). The Met allele revealed 97 and 39 bp fragments following digestion and polyacrylamide gel electrophoresis, while the Thr allele was not digested by NcoI [XPD PCR products were amplified with the primers 5'-CCTCTCCCTTTCCTCTGTTC-3' (sense) and 5'-CAGGTGAGGGGGACATCT-3' (antisense) and digested with PstI (Takara, Japan). The Gln allele revealed 646 and 88 bp fragments following digestion and polyacrylamide gel electrophoresis, whilst the Lys allele was not able to be digested by PstI [The 615 bp  by NcoI . The 734 by PstI .t-test. Multivariate unconditional logistic regressions were used to examine the association between the XRCC1, XRCC3 and XPD genotypes and the risk for colorectal cancer. Since the differences in the estimated risks between conditional logistical regression and unconditional logistical regression were small, unconditional logistical regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) with the matching factors (age and gender) included in the model for estimation [Tests for Hardy-Weinberg equilibrium amongst controls were conducted using observed genotype frequencies and a chi-square test featuring one degree of freedom. Baseline sociodemographic characteristics between cases and controls were analyzed using the chi-square test and two-sample Students' timation . Other pXRCC1, XRCC3 and XPD genes on the risk for the colorectal cancer. Since the associations between polymorphisms of DNA-repair gene, cancer susceptibility and DNA repair capacity are inconsistent [Based on the multiplicative scale, the likelihood ratio test was further used to evaluate the interaction between nsistent , we defiMore men (56%) than women participated in this study Table . The meaXRCC1 399Gln, XRCC3 241Met and XPD 751Gln allele amongst the controls were, respectively, 0.27, 0.05 and 0.07, these genotype frequencies being in Hardy-Weinberg equilibrium. Due to the relatively low frequencies of variant alleles for these genes in the present study, any genotype featuring one or more variant alleles was combined for further analyses. The risk for colorectal cancer was not significantly different for individuals featuring the XRCC1 399Arg/Arg genotype , the XRCC3 241Thr/Thr genotype  or the XPD 751Gln allele .The genotypic distributions of the three DNA-repair genes for both cancer cases and controls are shown in Table P = 0.03). Subjects who demonstrated two or three of the putative risk genotypes did reveal a significantly greater risk for colorectal cancer  as compared to those individuals who did not feature any putative risk genotypes, although it appears that no gene-gene interactions arose amongst these three genes . When stratified by tumor site and age at diagnosis, these combined gene effects upon cancer risk were observed for individuals who revealed that their tumor was located in the rectum (Trend test P = 0.03) and those individuals for whom their tumor was diagnosed prior to their being 60 years of age . In 2003, Mort et al. [XRCC3 241Thr allele (OR = 1.52, 95% CI = 1.04–2.22) and only slightly increased for those individuals who revealed the XRCC1 399Gln and XPD 751Gln alleles. In 2001, Park et al. [XPD 751Gln/Gln genotype featured a poorer (positive) response rate to chemotherapy and also a shorter survival period compared with colorectal cancer-suffering individuals who belonged to either the 751Lys/Lys or the 751Lys/Gln group.Although we didn't find any significant independent associations between these DNA-repair genes and colorectal cancer risk, the risk appeared to be slightly increased for individuals who featured the  reports ,22, the k et al.  reportedXRCC1 399Gln, XRCC3 241Met and XPD 751Gln alleles amongst the healthy controls in this study (0.27, 0.05 and 0.07, respectively) were similar to the results for other studies conducted in Taiwan [XRCC1 399Gln, 0.45 for XRCC3 241Met and 0.36 for XPD 751Gln) for a British population. On the other hand, the XRCC1 399Gln allele frequency observed in the present study is greater than that observed by Abdel-Rahman et al. in 2000 (0.14 for XRCC1 399Gln) [XRCC1 399Gln allele [The apparent divergence between these studies and ours might be due to one of two reasons. Firstly, it may simply be that ethnic differences in allele frequency for the polymorphism might explain the controversial findings. The frequencies for the n Taiwan ,29 and Cn Taiwan ,31, but n Taiwan  (0.42 fo 399Gln) . Abdel-Rn allele . TherefoXRCC1 Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln genes in regard to colorectal cancer risk were observed in the present study. With the complexity of detail of environmental exposures to various carcinogens, it is plausible that the effective repair of DNA damaged by chemical mixtures necessitates multiple DNA-repair pathways (including BER, HRR and NER pathways). The failure of, or the presence of deficient DNA repair capacity for each specific DNA-repair pathway may contribute to an increase in cancer risk. Additive or multiplicative effects of combined genetic variants for different DNA-repair pathways have been previously reported for lung cancer [XRCC1 and XPD genes. Hu et al. [APE1 and XRCC1 genes that were present. It would therefore appear reasonable to hypothesize that genetic polymorphism(s) for DNA-repair genes may simultaneously contribute to colorectal cancer susceptibility.Combined effects of polymorphisms of the g cancer , melanomg cancer  and breag cancer . In 2003g cancer  found thu et al.  also obsXRCC1 399Gln allele appeared to be significantly associated with detectable DNA adducts in their blood mononuclear cells when compared to younger subjects who featured the 399Arg/Arg genotype. In 2001, Hemminki et al. [XPD 751Gln/Gln genotype exhibited a decreased DNA-repair rate for, specifically, UV-specific cyclobutane pyrimidine dimers in the skin. Therefore, it is possible that individuals who demonstrate a less-efficient DNA-repair capacity might develop tumors at a younger age than individuals who reveal an efficient DNA-repair capacity.In this study, we found that the combined effect of multiple DNA-repair genes upon colorectal cancer risk was significant for our younger age group, but not so for the older age group. This finding appears to be similar to the results of most of the previous studies pertaining to colorectal cancer , basal-ci et al.  also fouIn our study, we also found that the combined genetic effect of these three DNA-repair genes in regard to cancer risk was more pronounced for the rectum than for the colon. This difference may reflect certain etiological differences between colon and rectal carcinogenesis. In fact, different epidemiological characteristics, etiology, pathogenesis and clinical behavior have been reported for different anatomical sites of colorectal cancer ,50, thisXRCC1, XRCC3 and XPD polymorphisms in relation to the risk of colorectal cancer for the Taiwanese population. Our results suggest that genetic polymorphisms of the XRCC1, XRCC3 and XPD genes, particularly in combination, may be associated with an individual's susceptibility to colorectal cancer. Acknowledging the relatively limited sample size in the subgroups for the low allelic frequencies, further studies incorporating a larger sample size and/or another ethnic population are needed to confirm the genetic role of DNA-repair mechanisms as regards colorectal cancer susceptibility.To the best of our knowledge, this study is the first to report on Our results suggest that DNA-repair pathways may simultaneously modulate the risk of colorectal cancer for the Taiwanese population, and, particularly for rectal cancer and younger patients.The author(s) declare that they have no competing interests.CCY carried out the genotyping analysis, performed the statistical analysis and drafted the manuscript. FCS participated in the design of the study. RT and CRCC participated in the design of the study and provided clinical biospecimens. LLH conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Australia and New Zealand Health Policy is a new journal which aims to promote debate and understanding about contemporary health policy developments in Australia and New Zealand. Although there are other international journals focussing on health policy, there are no Australian or New Zealand journals with this focus.Australia and New Zealand Health Policy is to focus on contemporary critiques and contemporary developments. Accordingly an e-journal format is particularly appropriate. Australian and New Zealand Health Policy is an open access journal which means that all articles will be freely and universally accessible online which, amongst other things, means that all articles will be freely and universally accessible online without any barriers to access, which increases their visibility.One of the aims of  Australia and New Zealand Health Policy a new journal which aims to promote debate and understanding about contemporary health policy developments in Australia and New Zealand. Health policy is regularly in the media and is a high profile issue at election times. In Australia the health system has been characterised by conflicts over values and policy choices over the decades. So pervasive is this conflict that Sax entitled his 1984 book about health services, "A Strife of Interests" [Australia and New Zealand Health Policy aims to provide a prestigious venue for analysis and critique of health policy in the two countries.Welcome to terests" ,3. HealtAlthough there are other international journals focussing on health policy, there are no Australian or New Zealand journals with this focus. Other related-area local journals are medical, public health or hospital-related. Although the local journals publish occasional policy articles, this area is not their principal interest, nor are they necessarily the journals which policy-oriented academics or policy practitioners scan to keep abreast of developments.Australia and New Zealand Health Policy will address this by publishing annual reviews of policy developments.The absence of a health policy journal serving Australia and New Zealand has long-term consequences for the development of systematic analysis of and research into health policy. One consequence is that there is no forum where health policy developments are documented and tracked, a lacuna which precludes cumulative analyses of trends. Australia and New Zealand Health Policy is to focus on contemporary critiques and contemporary developments, an e-journal format is particularly appropriate. Debate will also be stimulated by providing for 'Comment' on published articles, in a way analogous to a letters column.As one of the aims of Australia and New Zealand Health Policy is a peer reviewed journal. In keeping with its policy-applied focus, articles will be refereed by two referees, preferably one with a strong practitioner background, such as currently or recently employed in a policy role in a health authority, and one from an academic background. At least one of the referees will have substantive content knowledge relating to the article. Articles published in Australia and New Zealand Health Policy will be listed in PubMed and permanently archived in PubMed Central as well as certain other national archives.Australia and New Zealand Health Policy contributes to understanding of health policy development and practice with a particular focus on Australia and New Zealand. It welcomes submissions which:• Review and critique contemporary health policy issues;• Identify major trends in health policy and emerging policy issues, including new evidence about the effect of policy changes;• Identify impacts of health services research on new policies;• Identify major public policy and governance trends and their application to health policy;• Analyse contemporary health policy themes which cut across a range of policy areas;• Report on international policy developments and new international comparisons of health policy involving Australia and/or New Zealand; or• Critique contemporary health policy developments.Australia and New Zealand Health Policy is an Open Access journal, which means:• All articles will be freely and universally accessible online without any barriers to access, which increases their visibility.BioMed Central copyright and license agreement.• You and your peers will be free to print out copies of your article, email it to colleagues, and post it on the web because of the Open access journals are funded by article processing charges rather than journal subscriptions. The costs are therefore borne by the authors, their institutions of from their grants. That is, all access to journals is free to readers via the web . Authors from institutional supporters are exempt from authorship charges. The institutional supporters pay a sliding scale based on the number of staff and postgraduate students in biomedical sciences.Institutional subscription has a number of benefits. In addition to the direct benefits in terms of waived author fees, there are public policy benefits in supporting an open access journal regime such as Biomed Central. Open access journals are one mechanism for putting pressure on regular journal publishers to moderate their price increases.Unfortunately there are no New Zealand institutional subscribers to BioMed Central at present, which means that New Zealand authors will face article processing charges, although no article processing charges will be payable on manuscripts submitted in the first six months following the launch of the journal. Article processing charges are also usually regarded as a legitimate charge against research grants. In the medium term, alternative arrangements, such as institutional support, should be encouraged, although after this time the editor-in-chief will be able to grant a limited number of discretionary processing charge waivers.Australia and New Zealand Health Policy commences its publication program with a series of articles which describe and evaluate health policy developments in Australia in 2003. Responses or commentaries on these articles would be welcome. It is the aim of the Editorial Board to encourage a cluster of articles at the start of each year about health policy developments in Australia and New Zealand in the previous calendar year. Authors who have an interest in reviewing contemporary developments are encouraged to submit manuscripts on these themes early in the New Year so that the articles can contribute in a timely way to health policy debate in the two countries.S.J.DuckettEditor-in-Chief


Many challenges emerged during completion of a study to examine radiation dose and acute leukemia among children in areas of the former Soviet Union. In an era of globalization, our experiences might benefit others involved in multinational investigations. This paper identifies the major challenges faced and the lessons learned in addressing them by the collaborative research groups involved in developing and conducting a large, multi-national case-control study of acute leukemia among children in areas of the former Soviet Union (FSU) that were most heavily exposed to radioactive fallout as a result of the April 1986 accident in reactor vessel #4 of the Chernobyl Nuclear Power Plant.131I), cesium (137Cs, 134Cs), and strontium (90Sr), were released from the damaged reactor vessel contaminating soil, vegetation, and groundwater [In this accident, a variety of radioisotopes including iodine 31I, cesiAcute external exposures to ionizing radiation have been etiologically linked with observed increases in the risk of all types of leukemia, except chronic lymphocytic leukemia; the risk is greatest for acute myeloid leukemia -12. The Collaborative studies are challenging at best; international consortia efforts are even more so. The study of border-crossing disasters such as that in Chernobyl need be investigated as a single scientific challenge to take advantage of standardizing the investigative process across national boundaries, and to afford adequate sample size and the associated statistical power to reach meaningful conclusions. This paper will not recount the events of the Chernobyl disaster or specific results of the investigation. Rather, it will share the lessons learned while conducting a collaborative, multinational study for the benefit of other investigators.One of our first challenges was to establish an understanding of and a presence in each of the affected areas of the FSU. Multinational/multi-site studies are labor intensive and difficult to coordinate from distant locations. Therefore, the identification of a strong, on-site research team is essential. Each group must be treated as a full-member of the larger study team and be fully engaged. The local team is primarily responsible for study implementation. It is imperative that local teams with relevant expertise be formed. Our teams employed physicians, epidemiologists, statisticians, and dosimetrists. Local teams participated in study design, as well as study management in the field and troubleshooting problems. This required teams that were extremely knowledgeable about geopolitical boundaries, location of cities/small villages, governmental structures, and the health care delivery system. The latter area was particularly important given that the entire study hinged on the identification of acute leukemias and pair matched healthy controls. The health care systems in Belarus, the Russian Federation, and Ukraine have been adapted from the FSU system. Each Oblast  has 1–2, and in rare cases 4, large cancer treatment and diagnostic facilities (termed oncodispensaries). There are separate facilities for childhood (i.e., <16 years of age at time of diagnosis) and adult patients. In addition to providing nearly all cancer-related medical treatment, oncodispensaries house records of all reported cancer patients within the Oblast. These treatment centers contained critical source records vital to the success of our study.On-site research teams knew how to identify cases (e.g., review of oncodispensary records), where to identify controls (e.g., polyclinics), and what agency permission was needed to obtain access to these data. This would have been impossible for an "outsider" to do. The identification of committed and skilled collaborators from each of the Republics facilitated project coordination and monitoring from outside the FSU. However, not surprisingly, there have been some difficulties related to language and culture. Although English language proficiency is progressing rapidly within the FSU, many of the individual researchers were unable to effectively communicate via English. Moreover, the collaborators based in the USA were even more limited in their Russian language fluency. This issue of language was addressed early in this collaboration through a consensus that English would be used as the common language, which was endorsed by our FSU collaborators. Certain investigators were well trained in English and the Consortium relied on simultaneous interpretation for initial meetings of collaborators, and then switched to having an interpreter present to provide general and personal assistance as needed. All printed materials, such as study protocols and survey instruments were produced in dual language versions (Russian and English) and verified via back translation.Since the late 1990s, key project staff members in the USA and each FSU Republic maintained frequent linkages through e-mail communications at intervals between site visits and periodic project reviews. However, it should be noted that prior to the late 1990s, e-mail was scarce in the FSU and somewhat unreliable. International communications were first established via facsimile transmissions then evolved to an electronic platform (e-mail) as Internet coverage in the FSU expanded.This study was supported by the International Consortium for Research on the Health Effects of Radiation (ICRHER), based in the United States.  Our reThe ICRHER was incorporated in June 1993. It was born of the insight and enthusiasm of one man, the late Admiral Elmo Zumwalt, Jr., United State Navy (retired), who was concerned about environmental exposures and cancer risk; particularly, how such exposures might affect military personnel. Admiral Zumwalt was also concerned about the humanitarian aspects of accidental exposure to toxic agents, including ionizing radiation. The Chernobyl reactor accident provided an opportunity to pursue both these interests.Initially, the ICRHER (the "Consortium") was comprised of collaborative groups at institutions in the United States of America (USA) and FSU republics, specifically, the Baylor College of Medicine, Houston, Texas; the Research Center for Radiation Medicine, Kiev, Ukraine; the Fred Hutchinson Cancer Research Center (FHCRC), Seattle, Washington; the National Center for Hematology, Moscow, Russia; Hadassah Medical Organization, Jerusalem and Haifa, Israel; and the National Marrow Donor Program, Minneapolis, Minnesota. The Bridgeport Hospital/Yale University and the Research Institute of Radiation Medicine and Endocrinology, Minsk, Belarus, joined the Consortium later. The final research team for the multinational Leukemia case-control study includes the FHCRC in collaboration with the Medical Radiological Research Center in Russia and two groups from the Roswell Park Cancer Institute .The Consortium helped to bring structure and organization in a variety of areas, from assembling the principal investigators to creating working groups to empanelling external advisory boards. A corporate entity or central office was formed to coordinate these activities, and to manage common logistic requirements, to draw up contracts for U.S. and Israeli institutions, to support the FSU collaborators, and to provide an administrative office of record. Satellite offices were established in Kiev, Minsk, Moscow, Obninsk, Bryansk and Jerusalem to provide administrative, communication and logistical support to the research activities in the FSU and Israel. FSU offices, as will be seen later, were critical to the success of this study.Given the changes in leadership and make up of the ICRHER since its inception, it was imperative to maintain flexibility and responsiveness to change. Modifications in research partners may occur for many reasons. Therefore, it is critical that some type of "corporate entity" exist to aid in these transitions through detailed documentation and to provide continuity at the executive/advisory level.Consortium investigators developed a pilot study to test the feasibility of initiating a full-scale epidemiologic investigation, and to determine whether needed collaborations could be established. The primary goals were to assess radiation dose, to identify individuals at risk for radiation-related illness (including émigrés to Israel), to develop data collection instruments and common study protocols, to elucidate mechanisms of radiation damage, and to establish core support through the central office. The original group invested considerable time in reviewing exposure data, the populations involved, and possible health outcomes. Following these critical discussions, a decision was made to launch a pilot investigation of acute leukemia. This study would prove challenging, but it was facilitated by the knowledge and experiences gleaned from the feasibility study.Based on the feasibility and pilot studies, a consensus decision was made to begin a multinational leukemia case-control study in Belarus, the Russian Federation, and the Ukraine, including the Israeli component (the Israeli studies concluded in August 2000). The focus has been on the most radiosensitive malignancy in the most radiosensitive at-risk age group: occurrence of acute leukemia in those 0 to <6 years at the time of the accident .Initially, the aim of the Consortium was to investigate the occurrence of acute leukemia among individuals who were 0 to age 20 years at the time of the Chernobyl accident. The original population was selected due to early indications of high radiation dose exposures and easily achievable sample size estimates based on power calculations. When doses were not found to be as high as predicted, the sample size requirements became exceedingly large. Therefore, the researchers decided to narrow their focus to individuals aged 0 to <6 years at the time of the accident, since they represented a much more radiosensitive subpopulation. Hence, there is the need for well-designed feasibility studies to provide critical information in study planning and decision-making.in utero to <6 years of age at the time of the Chernobyl accident in April 1986.The final study population included 421 confirmed cases of acute leukemia and 842 population controls pair-matched to cases on age, gender, and type of residence. All participants were Case identification was often difficult, particularly when compared to studies conducted in the U.S. that typically rely on either population-based cancer registries or hospital-based rapid case identification. Many regions studied did not have an up-to-date, population-based cancer registry. And, since nearly all medical records in the FSU exist in paper form, exhaustive manual reviews of hard copy records were often required. This task was somewhat simplified by the local custom of referring cancer cases to regional oncodispensaries, thereby, restricting record reviews to a finite number of facilities. Moreover, it was also necessary to review death files to ascertain cases not previously brought to medical attention. Trained physicians reviewed the records at the oncodispensaries in Belarus, the Russian Federation, and the Ukraine. Records were retrieved for all potential patients (i.e., date of birth, date of diagnosis, and residence location). After verifying eligibility, trained interviewers contacted parents of these patients and scheduled an interview.Control selection was equally vexing. In the US, researchers typically use neighborhood controls, random digit telephone dialing methods, and/or computerized databases -16. In tThe research teams visited the polyclinic and randomly selected 20 potential controls fitting the inclusion criteria. Interviews were generally scheduled and completed for the first two potential controls on the list. Other names on the list were contacted and scheduled for interviews as needed. Over 90% of potential controls contacted by the research teams agreed to participate. These high rates of case and control participation may be attributed to the dedication and resourcefulness and commitment of the research teams and the use of modest incentives (food baskets).As formidable as the above tasks were, they paled in comparison to actual data collection. During the feasibility study, investigator meetings were held in the US to develop common data collection instruments. These instruments were structured to address issues of cultural and language compatibility for use in the three Republics. While Russian was adopted as the standard language for data collection, study instruments contained both Russian and English text. Instruments were back translated into English to ensure accuracy of translation.Next, a team of interviewers needed to be recruited and trained. We relied almost exclusively on recruiting physicians who were familiar with the disease process, were credible representatives, were respected by study participants, and who could be depended on to provide accurate and verifiable data. The mix of urban areas and rural settlements presented logistical challenges in terms of tracking participants, arranging appointments, and completing face-to-face interviews. To overcome this challenge, some interviewers mailed letters to introduce the project, and to request that the participant contact the interviewer. Others traveled to local communities to personally discuss participation and to schedule interviews. Still others used local contacts to identify participant places of employment for either telephone or direct contact.Traveling to interview study participants was another challenge. In contrast to conducting research in the US where there are widespread and reliable telecommunication systems, well-developed highway systems, and accurate maps, FSU travel was more problematic. For example, not all roads to small villages in the FSU are paved and most are limited to a single lane in either direction. Roads can be particularly treacherous in the winter and rainy seasons. Maps do not always show the precise location of small villages. Villages have neither street signs nor house numbers. Further, the collapse of the Soviet Union resulted in changes in the names of many streets, settlements, and villages. This arduous process of locating and interviewing controls took considerable effort and time. Where interviewers in the U.S. are generally out and back in the same day, FSU colleagues were out in the field for days at a time and would be fortunate if they could complete a handful of interviews each day. These differences in operations must also be factored in to the overall cost of the study. Finally, local residents tended to be wary of strangers and special introductions were often necessary to gain entry.One cannot overstate the importance of having a well-trained and dedicated on-site research team that is familiar with cultural norms and local "maps". The two-hour, face-to-face interviews were generally completed with the mothers of cases and controls. Interview items were developed by US and FSU scientists and included sections addressing demographics, general health status, maternal and paternal occupational history, and a detailed questionnaire for obtaining information necessary for developing estimates of individualized internal and external radiation exposures, including questions regarding consumption of locally produced milk, meats, and vegetables; residence history and type of housing structure; use of protective measures immediately after the accident; and time spent outdoors.Those involved in multinational or multi-site investigations may consider the creation of Working Groups to monitor the various components of the study. As has been utilized in other international studies , the leaA common methodology to assess individual absorbed radiation doses and corresponding uncertainties was developed and tested by the dosimetry intercomparison working group (DIWG) for all subjects based on interview data and available exposure data. The interview collected detailed exposure data for each subject from the time of the Chernobyl accident until the reference date. It should be noted that interview data alone were not sufficient to determine individual dose estimations. For retrospective dose estimation specialized radioecological data were necessary. These resources provided information concerning local soil types, food contamination with different radionuclides, dates of radioactive cloud arrivals to each local community, etcetera. These data were collected by the members of DIWG based on information published within the FSU.Dosimetrists are a good example of the specialized personnel that need to be a full-time, on-site presence. They have critical knowledge of the local area as well as access to primary data essential in quantifying exposure. Individual dose estimates reflected local conditions (e.g., contamination levels, soil type, soil to milk transfer coefficients) at each location where a particular subject lived during the appropriate time interval. The subject's residence history and other important personal information, such as milk consumption and food sources, were collected during the standardized interviews by trained examiners. Fieldwork was performed jointly by physicians and dosimetrists.A Data Analysis Working Group was essential for oversight of the analytic phase. Composition included representatives from each site with a strong chair to maintain focus and momentum. Also, a Data Audit Working Group was established at study inception to conduct periodic reviews to assure adherence to study protocols. And finally, a centralized Data Coordination Office served as a repository of the common dataset and oversaw periodic computerized checks for quality and completeness.Our experiences in the organization and successful implementation of a multinational, retrospective study of acute leukemia in regions impacted by the Chernobyl disaster have been highlighted. Issues identified during the implementation of our multi-national epidemiology study, along with strategies for resolution are summarized in table The breakup of the former Soviet Union in 1991 created national autonomy in Belarus, the Russian Federation, and Ukraine. Although the study area for this project included selected regions of the FSU, the intent was to study acute leukemia without regard to specific national boundaries, while recognizing the requirement to bring together investigators from these three Republics in a common effort. Proprietary concerns and country-specific restrictions on the sharing of scientific information were thoroughly addressed to gain agreement and to facilitate the pooling of analytic information.The Consortium played an integral role in providing infrastructure support for this project through the appointment of project support administrators at each research site to oversee communications, equipment procurement/maintenance, and compensation. The fiscal aspects of supporting research are unique to each country. A careful examination of collaborating scientific institutions and the financial regulations of each participating country prior to setting up any support mechanisms is critical, and may result in country-specific arrangements. Essential computer, laboratory, and communication equipment was supplied. Computer software, which was compatible across the three research settings, was installed and upgraded periodically. Equipment was segregated and secured to insure exclusive use by project staff.It should be emphasized that this investigation represents the largest retrospective study examining the relationship between Chernobyl radiation exposures and risk of acute leukemia conducted to date and the only research effort to bring together data from the most exposed areas into a single study; results of the multinational case-control study are presented in a separate paper . The conFSU, former Soviet UnionUSSR, Union of Soviet Socialist RepublicsUSA, United States of AmericaICRHER, International Consortium for Research on the Health Effects of Radiation; the "Consortium"FHCRC, Fred Hutchinson Cancer Research CenterDIWG, dosimetry intercomparison working groupThe author(s) declare that they have no competing interests.MCM and AMM were responsible for the study concept. MCM and AMM drafted the manuscript; KMM, PLM, RCM, VFS and RWD provided critical review and input. MCM, KMM, PLM, RCM, VFS, RWD and AMM participated in interpretation, as well as in data acquisition efforts. All authors read and approved this manuscript.The pre-publication history for this paper can be accessed here: