Genomic insights into the origin of parasitism in the emerging plant pathogen Bursaphelenchus xylophilus.

Bursaphelenchus xylophilus is the nematode responsible for a devastating epidemic of pine wilt disease in Asia and Europe, and represents a recent, independent origin of plant parasitism in nematodes, ecologically and taxonomically distinct from other nematodes for which genomic data is available. As well as being an important pathogen, the B. xylophilus genome thus provides a unique opportunity to study the evolution and mechanism of plant parasitism. Here, we present a high-quality draft genome sequence from an inbred line of B. xylophilus, and use this to investigate the biological basis of its complex ecology which combines fungal feeding, plant parasitic and insect-associated stages. We focus particularly on putative parasitism genes as well as those linked to other key biological processes and demonstrate that B. xylophilus is well endowed with RNA interference effectors, peptidergic neurotransmitters (including the first description of ins genes in a parasite) stress response and developmental genes and has a contracted set of chemosensory receptors. B. xylophilus has the largest number of digestive proteases known for any nematode and displays expanded families of lysosome pathway genes, ABC transporters and cytochrome P450 pathway genes. This expansion in digestive and detoxification proteins may reflect the unusual diversity in foods it exploits and environments it encounters during its life cycle. In addition, B. xylophilus possesses a unique complement of plant cell wall modifying proteins acquired by horizontal gene transfer, underscoring the impact of this process on the evolution of plant parasitism by nematodes. Together with the lack of proteins homologous to effectors from other plant parasitic nematodes, this confirms the distinctive molecular basis of plant parasitism in the Bursaphelenchus lineage. The genome sequence of B. xylophilus adds to the diversity of genomic data for nematodes, and will be an important resource in understanding the biology of this unusual parasite.

Two distinct but interchangeable mechanisms for flipping of lipid-linked oligosaccharides

Translocation of lipid-linked oligosaccharide (LLO) intermediates across membranes is an essential but poorly understood process in eukaryotic and bacterial glycosylation pathways. Membrane proteins defined as translocases or flippases are implicated to mediate the translocation reaction. The membrane protein Wzx has been proposed to mediate the translocation across the plasma membrane of lipopolysaccharide (LPS) O antigen subunits, which are assembled on an undecaprenyl pyrophosphate lipid carrier. Similarly, PglK (formerly WlaB) is a Campylobacter jejuni-encoded ABC-type transporter proposed to mediate the translocation of the undecaprenylpyrophosphate-linked heptasaccharide intermediate involved in the recently identified bacterial N-linked protein glycosylation pathway. A combination of genetic and carbohydrate structural analyses defined and characterized flippase activities in the C. jejuni N-linked protein glycosylation and the Escherichia coli LPS O antigen biosynthesis. PglK displayed relaxed substrate specificity with respect to the oligosaccharide structure of the LLO intermediate and complemented a wzx deficiency in E. coli O-antigen biosynthesis. Our experiments provide strong genetic evidence that LLO translocation across membranes can be catalyzed by two distinct proteins that do not share any sequence similarity.

An amino acid substitution in Fasciola hepatica P-glycoprotein from triclabendazole-resistant and triclabendazole-susceptible populations

Control of fasciolosis is threatened by the development of anthelmintic resistance. Enhanced triclabendazole (TCBZ) efflux by ABC transporters such as P-glycoprotein (Pgp) has been implicated in this process. A putative full length cDNA coding for a Pgp expressed in adult Fasciola hepatica has been constructed and used to design a primer set capable of amplifying a region encoding part of the second nucleotide binding domain of Pgp when genomic DNA was used as a template. Application of this primer set to genomic DNA from TCBZ-resistant and -susceptible field populations has shown a significant difference in the alleles present. Analysis of an allele occurring at a three-fold higher frequency in the "resistant" population revealed that it was characterised by a serine to arginine substitution at residue 1144. Homology modelling studies have been used to locate this site in the Pgp structure and hence assess its potential to modify functional activity. © 2012 Elsevier B.V.

Sensory-motor problems in Autism

Despite being largely characterised as a social and cognitive disorder, strong evidence indicates the presence of significant sensory-motor problems in Autism Spectrum Disorder (ASD). This paper outlines our progression from initial, broad assessment using the Movement Assessment Battery for Children (M-ABC) to subsequent targeted kinematic assessment. In particular, pronounced ASD impairment seen in the broad categories of manual dexterity and ball skills was found to be routed in specific difficulties on isolated tasks, which were translated into focused experimental assessment. Kinematic results from both subsequent studies highlight impaired use of perception-action coupling to guide, adapt and tailor movement to task demands, resulting in inflexible and rigid motor profiles. In particular difficulties with the use of temporal adaption are shown, with "hyperdexterity" witnessed in ballistic movement profiles, often at the cost of spatial accuracy and task performance. By linearly progressing from the use of a standardised assessment tool to targeted kinematic assessment, clear and defined links are drawn between measureable difficulties and underlying sensory-motor assessment. Results are specifically viewed in-light of perception-action coupling and its role in early infant development suggesting that rather than being 'secondary' level impairment, sensory-motor problems may be fundamental in the progression of ASD. This logical and systematic process thus allows a further understanding into the potential route of observable motor problems in ASD; a vital step if underlying motor problems are to be considered a fundamental aspect of autism and allow a route of non-invasive preliminary diagnosis.

Newly Acquired Fear of Falling Leads to Altered Eye Movement Patterns and Reduced Stepping Safety: A Case Study

This opportune case study describes visual and stepping behaviours of an 87 year old female (P8), both prior to, and following two falls. Before falling, when asked to walk along a path containing two stepping guides positioned before and after an obstacle, P8 generally visually fixated the first stepping guide until after foot contact inside it. However, after falling P8 consistently looked away from the stepping guide before completing the step into it in order to fixate the upcoming obstacle in her path. The timing of gaze redirection away from the target (in relation to foot contact inside it) correlated with absolute stepping error. No differences in eyesight, cognitive function, or balance were found between pre- and post-fall recordings. However, P8 did report large increases in fall-related anxiety and reduced balance confidence, supporting previously suggested links between anxiety/increased fear or falling and maladaptive visual/stepping behaviours. The results represent a novel insight into how psychological and related behavioural factors can change in older adults following a fall, and provide a possible partial rationalisation for why recent fallers are more likely to fall again in the following 12 months. These findings highlight novel possibilities for falls prevention and rehabilitation.

Successful balance training is associated with improved multisensory function in fall-prone older adults

Balance maintenance relies on a complex interplay between many different sensory modalities. Although optimal multisensory processing is thought to decline with ageing, inefficient integration is particularly associated with falls in older adults. We investigated whether improved balance control, following a novel balance training intervention, was associated with more efficient multisensory integration in older adults, particularly those who have fallen in the past. Specifically, 76 healthy and fall-prone older adults were allocated to either a balance training programme conducted over 5 weeks or to a passive control condition. Balance training involved a VR display in which the on-screen position of a target object was controlled by shifts in postural balance on a Wii balance board. Susceptibility to the sound-induced flash illusion, before and after the intervention (or control condition), was used as a measure of multisensory function. Whilst balance and postural control improved for all participants assigned to the Intervention group, improved functional balance was correlated with more efficient multisensory processing in the fall-prone older adults only. Our findings add to growing evidence suggesting important links between balance control and multisensory interactions in the ageing brain and have implications for the development of interventions designed to reduce the risk of falls.

Unique mitochondrial DNA lineages in Irish stickleback populations: cryptic refugium or rapid recolonization?

Repeated recolonization of freshwater environments following Pleistocene glaciations has played a major role in the evolution and adaptation of anadromous taxa. Located at the western fringe of Europe, Ireland and Britain were likely recolonized rapidly by anadromous fishes from the North Atlantic following the last glacial maximum (LGM). While the presence of unique mitochondrial haplotypes in Ireland suggests that a cryptic northern refugium may have played a role in recolonization, no explicit test of this hypothesis has been conducted. The three-spined stickleback is native and ubiquitous to aquatic ecosystems throughout Ireland, making it an excellent model species with which to examine the biogeographical history of anadromous fishes in the region. We used mitochondrial and microsatellite markers to examine the presence of divergent evolutionary lineages and to assess broad-scale patterns of geographical clustering among postglacially isolated populations. Our results confirm that Ireland is a region of secondary contact for divergent mitochondrial lineages and that endemic haplotypes occur in populations in Central and Southern Ireland. To test whether a putative Irish lineage arose from a cryptic Irish refugium, we used approximate Bayesian computation (ABC). However, we found no support for this hypothesis. Instead, the Irish lineage likely diverged from the European lineage as a result of postglacial isolation of freshwater populations by rising sea levels. These findings emphasize the need to rigorously test biogeographical hypothesis and contribute further evidence that postglacial processes may have shaped genetic diversity in temperate fauna.

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce apoptosis in multi-drug-resistant cancer cells

PURPOSE: The development of multi-drug resistance (MDR) due to the expression of members of the ATP binding cassette (ABC) transporter family is a major obstacle in cancer treatment. The broad range of substrate specificities associated with these transporters leads to the efflux of many anti-cancer drugs from tumour cells. Therefore, the development of new chemotherapeutic agents that are not substrates of these transporters is important. We have recently demonstrated that some members of a novel series of pyrrolo-1,5-benzoxazepine (PBOX) compounds are microtubule-depolymerising agents that potently induce apoptosis in several cancer cell lines and impair growth of mouse breast tumours. The aim of this current study was to establish whether PBOXs were capable of inducing apoptosis in cancer cells expressing either P-glycoprotein or breast cancer resistance protein (BCRP), two of the main ABC transporters associated with MDR.

METHODS: We performed in vitro studies to assess the effects of PBOXs on cell proliferation, cell cycle and apoptosis in human cancer cell lines and their drug-resistant substrains expressing either P-glycoprotein or BCRP. In addition, we performed a preliminary molecular docking study to examine interactions between PBOXs and P-glycoprotein.

RESULTS: We established that three representative PBOXs, PBOX-6, -15 and -16 were capable of inducing apoptosis in drug-resistant HL60-MDR1 cells (expressing P-glycoprotein) and HL60-ABCG2 cells (expressing BCRP) with similar potencies as in parental human promyelocytic leukaemia HL60 cells. Likewise, resistance to PBOX-6 and -16 was not evident in P-glycoprotein-expressing A2780-ADR cells in comparison with parent human ovarian carcinoma A2780 cells. Finally, we deduced by molecular docking that PBOX-6 is not likely to form favourable interactions with the substrate binding site of P-glycoprotein.

CONCLUSION: Our results suggest that pro-apoptotic PBOX compounds may be potential candidates for the treatment of P-glycoprotein- or BCRP-associated MDR cancers.

A Hybrid Swarm Based Approach in Addressing University Timetabling Problems

This paper is concerned with the application of an automated hybrid approach in addressing the university timetabling problem. The approach described is based on the nature-inspired artificial bee colony (ABC) algorithm. An ABC algorithm is a biologically-inspired optimization approach, which has been widely implemented in solving a range of optimization problems in recent years such as job shop scheduling and machine timetabling problems. Although the approach has proven to be robust across a range of problems, it is acknowledged within the literature that there currently exist a number of inefficiencies regarding the exploration and exploitation abilities. These inefficiencies can often lead to a slow convergence speed within the search process. Hence, this paper introduces a variant of the algorithm which utilizes a global best model inspired from particle swarm optimization to enhance the global exploration ability while hybridizing with the great deluge (GD) algorithm in order to improve the local exploitation ability. Using this approach, an effective balance between exploration and exploitation is attained. In addition, a traditional local search approach is incorporated within the GD algorithm with the aim of further enhancing the performance of the overall hybrid method. To evaluate the performance of the proposed approach, two diverse university timetabling datasets are investigated, i.e., Carter's examination timetabling and Socha course timetabling datasets. It should be noted that both problems have differing complexity and different solution landscapes. Experimental results demonstrate that the proposed method is capable of producing high quality solutions across both these benchmark problems, showing a good degree of generality in the approach. Moreover, the proposed method produces best results on some instances as compared with other approaches presented in the literature.

A Hybrid Imperialist Approach in Solving University Timetabling Problems. Information Sciences. Vol. 283, 1-21

Generating timetables for an institution is a challenging and time consuming task due to different demands on the overall structure of the timetable. In this paper, a new hybrid method which is a combination of a great deluge and artificial bee colony algorithm (INMGD-ABC) is proposed to address the university timetabling problem. Artificial bee colony algorithm (ABC) is a population based method that has been introduced in recent years and has proven successful in solving various optimization problems effectively. However, as with many search based approaches, there exist weaknesses in the exploration and exploitation abilities which tend to induce slow convergence of the overall search process. Therefore, hybridization is proposed to compensate for the identified weaknesses of the ABC. Also, inspired from imperialist competitive algorithms, an assimilation policy is implemented in order to improve the global exploration ability of the ABC algorithm. In addition, Nelder–Mead simplex search method is incorporated within the great deluge algorithm (NMGD) with the aim of enhancing the exploitation ability of the hybrid method in fine-tuning the problem search region. The proposed method is tested on two differing benchmark datasets i.e. examination and course timetabling datasets. A statistical analysis t-test has been conducted and shows the performance of the proposed approach as significantly better than basic ABC algorithm. Finally, the experimental results are compared against state-of-the art methods in the literature, with results obtained that are competitive and in certain cases achieving some of the current best results to those in the literature.

Contributos para a implementação do TDABC numa empresa de serviços:consequências organizacionais e comportamentais

Dissertação, Mestrado, Contabilidade e Finanças, Instituto Politécnico de Santarém, Escola Superior de Gestão e Tecnologia, 2013

Modelo de contabilidade de gestão aplicado às piscinas municipais de Olhão

Este trabalho tem como objetivo desenhar e simular um modelo de apoio à gestão, baseado na técnica contemporânea designada de custeio baseado nas atividades (ABC), de aplicação aos complexos de piscinas. A informação e os dados necessários à concessão do desenho e à sua simulação, foram recolhidos através de entrevistas aos responsáveis de alguns dos complexos existentes no Algarve. Após a elaboração do modelo teórico, simulou-se o modelo ao caso concreto da exploração do Complexo de Piscina Municipais de Olhão, estrutura cujo funcionamento também inspirou o desenho do modelo, dado compreender um conjunto de atividades que são comuns à generalidade dos complexos desportivos e de lazer deste tipo.

The role of hypoxia in the regulation of membrane transporters

ATP binding cassette (ABC) and solute carrier (SLC) transporters are responsible for the majority of the transcellular movement of various substrates, including drugs, among epithelial cells. Despite the well characterized regulation of influx (SLC) and efflux (ABC) transporters by endogenous mediators, such as inflammatory cytokines, little is known about how changes in oxygen levels may affect expression of these transporters. In this study we showed that the expression of SLC22A4, SLC22A5, SLC22A1, SLC02B1, SLC10A2, ABCC2 and ABCC3 transporters is upregulated by hypoxia in HT29 colon carcinoma cells, but not in HepG2 hepatocarcinoma cells. Moreover, OCTN1 (SLC22A4), OCT1 (SLC22A1) and OATP-B (SLC02B1) transporter expression is also induced by inflammatory cytokines but in a smaller extent than in hypoxia. Furthermore our experiments indicate that there is no cross talk between HIF-1 and NF-κB pathways in HT-29 cells, but these two pathways act simultaneously activating common genes, such as, some SLC and ABC transporters. Our preliminary results from studies with an in vivo murine model of colitis, suggest that HIF-1is stabilized and OCTN1 is strongly induced during severe inflammation, which can be relevant for a recovery from the inflammatory process. We have also been interested in the distribution of HIF-1α variants among different ethnic groups as well as their contribution for cancer risk. Thus, we have demonstrated that there is an ethnicity-related variation in the frequency of the C1772T (P582S) single nucleotide polymorphism (SNP) in the HIF-1α gene. Furthermore, we performed a case-control study in a breast cancer population and our results suggest that there is no association between this SNP or the rare G1790A (A588T) SNP and the incidence of breast cancer. Taken together, the results obtained in this study contribute to a better knowledge of drug influx and efflux during hypoxia and inflammation as well as to the understanding of the pharmacogenetic variability of the HIF-1.