The Xer activation factor of TLCΦ expands the possibilities for Xer recombination.

The chromosome dimer resolution machinery of bacteria is generally composed of two tyrosine recombinases, XerC and XerD. They resolve chromosome dimers by adding a crossover between sister copies of a specific site, dif. The reaction depends on a cell division protein, FtsK, which activates XerD by protein-protein interactions. The toxin-linked cryptic satellite phage (TLCΦ) of Vibrio cholerae, which participates in the emergence of cholera epidemic strains, carries a dif-like attachment site (attP). TLCΦ exploits the Xer machinery to integrate into the dif site of its host chromosomes. The TLCΦ integration reaction escapes the control of FtsK because TLCΦ encodes for its own XerD-activation factor, XafT. Additionally, TLCΦ attP is a poor substrate for XerD binding, in apparent contradiction with the high integration efficiency of the phage. Here, we present a sequencing-based methodology to analyse the integration and excision efficiency of thousands of synthetic mini-TLCΦ plasmids with differing attP sites in vivo. This methodology is applicable to the fine-grained analyses of DNA transactions on a wider scale. In addition, we compared the efficiency with which XafT and the XerD-activation domain of FtsK drive recombination reactions in vitro. Our results suggest that XafT not only activates XerD-catalysis but also helps form and/or stabilize synaptic complexes between imperfect Xer recombination sites.

Differences in cricket fast bowling kinematics between grass and artificial surface pitches.

Cricket fast bowling training and research are often conducted on artificial turf, while matches are played on natural grass. It is unknown if technique differs between the different surfaces; therefore, the aim of this study was to explore if fast bowling technique differed between surfaces. Shoe slip distance and kinematic and temporal parameters previously associated with ball release velocity and lumbar bone stress injury were determined for eight male sub-elite fast bowlers using three-dimensional motion analysis on grass and artificial surfaces. Paired t-test and statistical parametric mapping were used to identify differences in technique between surfaces. Significantly greater slip distance was observed during back and front foot contact on the artificial surface compared to bowling on the grass surface. No kinematic or temporal parameter significantly differed between surfaces, therefore fast bowling technique is likely similar between grass and artificial surfaces, and previous research utilising artificial surfaces in fast bowling research is likely to be valid.

Oxide Ion Conductivity, Proton Conductivity, and Phase Transitions in Perovskite-Derived Ba3-x Sr x YGa2O7.5 0 ≤ x ≤ 3 Materials.

We report the synthesis, structural characterization, and oxide ion and proton conductivities of the perovskite-related Ba3-x Sr x YGa2O7.5 family. Single-phase samples are prepared for 0 ≤ x ≤ 3 and show a complex structural evolution from P2/c to C2 space groups with an increase in x. For 1.0 ≲ x ≲ 2.4, average structures determined by X-ray and neutron powder diffraction show metrically orthorhombic unit cells, but HAADF-STEM imaging reveals this is caused by microstructural effects due to intergrowths of the Ba- and Sr-rich structure types. Variable-temperature powder diffraction studies suggest that 0 ≲ x ≲ 2.4 compositions undergo a phase transition upon being heated to space group Cmcm that involves disordering of the oxygen substructure. Thermal expansion coefficients are reported for the series. Complex impedance studies show that the Ba-rich samples are mixed proton and oxide ion conductors under moist atmospheres but are predominantly oxide ion conductors at high temperatures or under dry atmospheres. Sr-rich samples show significantly less water uptake and appear to be predominantly oxide ion conductors under the conditions studied.

Natural turf surfaces: the case for continued research.

It is well documented that health and social benefits can be attained through participation in sport and exercise. Participation, particularly in sports, benefits from appropriate surface provisions that are safe, affordable and high quality preferably across the recreational to elite continuum. Investment, construction and research into artificial sports surfaces have increased to meet this provision. However, not all sports (e.g. golf, rugby and cricket) are suited to training and match-play on artificial turf without compromising some playing characteristics of the games. Therefore, full sport surface provision cannot be met without the use of natural turf surfaces, which also have an important role as green spaces in the built environment. Furthermore, a significant number of people participate in outdoor sport on natural turf pitches, although this is a declining trend as the number of synthetic turf surfaces increases. Despite natural turf being a common playing surface for popular sports such as soccer, rugby and cricket, few biomechanical studies have been performed using natural turf conditions. It is proposed that if natural turf surfaces are to help meet the provision of sports surfaces, advancement in the construction and sustainability of natural turf surface design is required. The design of a natural turf surface should also be informed by knowledge of surface-related overuse injury risk factors. This article reviews biomechanical, engineering, soil mechanics, turfgrass science, sports medicine and injury-related literature with a view to proposing a multidisciplinary approach to engineering a more sustainable natural turf sport surface. The present article concludes that an integrated approach incorporating an engineering and biomechanical analysis of the effects of variations in natural turf media on human movement and the effects of variations in human movement on natural turf is primarily required to address the longer-term development of sustainable natural turf playing surfaces. It also recommends that the use of 'natural turf' as a catch-all categorization in injury studies masks the spatial and temporal variation within and among such surfaces, which could be important.

Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone: a potent, orally bioavailable human CB1/CB2 dual agonist with antihyperalgesic properties and restricted central nervous system penetration.

Selective activation of peripheral cannabinoid CB1 receptors has the potential to become a valuable therapy for chronic pain conditions as long as central nervous system effects are attenuated. A new class of cannabinoid ligands was rationally designed from known aminoalkylindole agonists and showed good binding and functional activities at human CB1 and CB2 receptors. This has led to the discovery of a novel CB1/CB2 dual agonist, naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (13), which displays good oral bioavailability, potent antihyperalgesic activity in animal models, and limited brain penetration.

Analysis of human Nav1.8 expressed in SH-SY5Y neuroblastoma cells.

The tetrodotoxin-resistant voltage-gated sodium channel alpha-subunit Nav1.8 is expressed in nociceptors and has been implicated in chronic pain. Difficulties of heterologous expression have so far precluded analysis of the pharmacological properties of human Nav1.8. To address this we have introduced human Nav1.8 in neuroblastoma SH-SY5Y cells. Voltage-clamp analysis showed that human Nav1.8 generated an inward tetrodotoxin-resistant sodium current with an activating threshold around -50 mV, half maximal activation at -11+/-3 mV and a reversal potential of 67+/-4 mV. These properties closely match those of the endogenous rat tetrodotoxin-resistant sodium current in dorsal root ganglia suggesting that the expressed human channel is in a near physiological conformation. Human Nav1.8 was resistant to tetrodotoxin and activated by the pyrethroid toxin deltamethrin. Both voltage-activated and deltamethrin-activated human Nav1.8 were inhibited by the sodium channel blockers BIII 890 CL, NW-1029, and mexiletine. Inhibition of Nav1.8 by these compounds may underlie their known analgesic effects in animal models.

Strategies to identify ion channel modulators: current and novel approaches to target neuropathic pain.

Modulation of ion channel function has been a successful area for drug development, with ion channel modulating drugs being used in the therapeutic treatment of epilepsy, hypertension, diabetes and chronic pain. Most of the ion channel-modulating drugs that are currently on the market were developed without extensive knowledge of the molecular structure of ion channels, or an understanding of the full complexity of ion channel subtypes or knowledge of how ion channel expression is regulated during pathology. As new information on the roles that different ion channel subtypes play in pathophysiological processes becomes available, drugs will be designed to target specific ion channel subtypes via mechanisms that involve either direct channel block or modulation of ion channel functional expression. Using neuropathic pain as an example, this article reviews current knowledge of the structure and function of ion channels and current technology and future opportunities for the identification of novel drugs that are capable of modulating ion channel function.

In vivo pharmacology of SDZ 249-665, a novel, non-pungent capsaicin analogue.

Capsaicin and analogues are valuable analgesic agents when administered to mammals, including humans. However, their pungency and the effects on the cardiovascular and respiratory systems through their general activation of small calibre (nociceptive) primary afferents severely limit their use. Recently, structure activity analysis revealed that the initial pungent and general excitatory effects can be prevented by structural modifications in such a way that the analgesic activity is retained. In this paper we present SDZ 249-665, a capsaicin analogue which produced analgesia in the mouse and anti-hyperalgesic effects in the rat and guinea pig. SDZ 249-665 was administered p.o., s.c. and i.v. in models of nociceptive pain, such as tail flick latency in response to a noxious thermal stimulus and acetic acid-induced writhing in mice, and in models of inflammatory mechanical hyperalgesia induced by turpentine or carrageenan in the rat and guinea pig, respectively. SDZ 249-665 was effective in the tail flick and the writhing assays and produced significant anti-hyperalgesic effects in the inflammatory models. The efficacy of SDZ 245-665 was similar to that of capsaicin, however, it was significantly more potent. SDZ 249-665 did not produce any irritancy in a nose wipe assay in guinea pigs or an eye irritancy assay in rats, while capsaicin was clearly irritant in both cases. Furthermore, unlike capsaicin, SDZ 249-665 did not produce unwanted side effects such as bronchoconstriction and blood pressure changes in the analgesic/anti-hyperalgesic dose range. Thus, a clear analgesic therapeutic window exists for SDZ 249-665. In summary, SDZ 249-665 is a potent orally active, analgesic/anti-hyperalgesic agent in mouse, rat and guinea pig. It lacks the excitatory effects associated with capsaicin and other close analogues, and therefore provides a clear therapeutic window for use in painful conditions. In addition to this favourable profile, no sign of tolerance was detected after a 5 day repeated dose treatment.

Association of lower limb injury with boot cleat design and playing surface in elite soccer.

Reducing external injury risk factors associated with the boot-surface interaction is important in reducing the incidence and severity of foot and ankle injury. A review of prospective football (soccer) injury epidemiology studies determined that the incidence of noncontact ankle sprain injury is relatively high. Research on the impact of cleat shape and configuration and boot design on the boot-surface interaction is providing new understanding of the impact on player biomechanics and injury risk but is not keeping pace with commercial advances in boot design and innovation in natural and synthetic turf surface technology.

The therapeutic and diagnostic potential of FKBPL; a novel anticancer protein.

The immunophilin family of proteins has a vast number of roles regulating a variety of biological processes through protein-protein interactions. A relatively new and divergent member of this family, FK506-binding protein like (FKBPL), is emerging as a key player in the DNA damage response, steroid receptor signalling and more recently, control of tumour growth where it regulates response to endocrine therapy in addition to acting as a novel antiangiogenic protein. As a new therapeutic peptide based on FKBPL approaches clinical trials, this article highlights a unique approach to targeting tumours that are resistant to current antiangiogenic therapies and supports the role of FKBPL as a novel prognostic and predictive biomarker, distinct from its other family members.

A model of greenhouse gas emissions from the management of turf on two golf courses.

An estimated 32,000 golf courses worldwide (approximately 25,600 km2), provide ecosystem goods and services and support an industry contributing over $124 billion globally. Golf courses can impact positively on local biodiversity however their role in the global carbon cycle is not clearly understood. To explore this relationship, the balance between plant­soil system sequestration and greenhouse gas emissions from turf management on golf courses was modelled. Input data were derived from published studies of emissions from agriculture and turfgrass management. Two UK case studies of golf course type were used, a Links course (coastal, medium intensity management, within coastal dune grasses) and a Parkland course (inland, high intensity management, within woodland).Playing surfaces of both golf courses were marginal net sources of greenhouse gas emissions due to maintenance (Links −2.2 ± 0.4 Mg CO2e ha(−1) y(−1); Parkland − 2.0 ± 0.4 Mg CO2e ha(−1) y(−1)). A significant proportion of emissions were from the use of nitrogen fertiliser, especially on tees and greens such that 3% of the golf course area contributed 16% of total greenhouse gas emissions. The area of trees on a golf course was important in determining whole-course emission balance. On the Parkland course, emissions from maintenance were offset by sequestration from turfgrass, and trees which comprised 48% of total area, resulting in a net balance of −5.4 ± 0.9 Mg CO2e ha(−1) y(−1). On the Links course, the proportion of trees was much lower (2%) and sequestration from links grassland resulted in a net balance of −1.6 ± 0.3 Mg CO2e ha(−1) y(−1). Recommendations for golf course management and design include the reduction of nitrogen fertiliser, improved operational efficiency when mowing, the inclusion of appropriate tree-planting and the scaling of component areas to maximise golf course sequestration capacity. The findings are transferrable to the management and design of urban parks and gardens, which range between fairways and greens in intensity of management.

A model of greenhouse gas emissions from the management of turf on two golf courses.

An estimated 32,000 golf courses worldwide (approximately 25,600 km(2)), provide ecosystem goods and services and support an industry contributing over $ 124 billion globally. Golf courses can impact positively on local biodiversity however their role in the global carbon cycle is not clearly understood. To explore this relationship, the balance between plant-soil system sequestration and greenhouse gas emissions from turf management on golf courses was modelled. Input data were derived from published studies of emissions from agriculture and turfgrass management. Two UK case studies of golf course type were used, a Links course (coastal, medium intensity management, within coastal dune grasses) and a Parkland course (inland, high intensity management, within woodland). Playing surfaces of both golf courses were marginal net sources of greenhouse gas emissions due to maintenance (Links 0.4 ± 0.1Mg CO(2)e ha(-1)y(-1); Parkland 0.7 ± 0.2Mg CO(2)e ha(-1)y(-1)). A significant proportion of emissions were from the use of nitrogen fertiliser, especially on tees and greens such that 3% of the golf course area contributed 16% of total greenhouse gas emissions. The area of trees on a golf course was important in determining whole-course emission balance. On the Parkland course, emissions from maintenance were offset by sequestration from trees which comprised 48% of total area, resulting in a net balance of -4.3 ± 0.9 Mg CO(2e) ha(-1)y(-1). On the Links course, the proportion of trees was much lower (2%) and sequestration from links grassland resulted in a net balance of 0.0 ± 0.2Mg CO(2e) ha(-1)y(-1). Recommendations for golf course management and design include the reduction of nitrogen fertiliser, improved operational efficiency when mowing, the inclusion of appropriate tree-planting and the scaling of component areas to maximise golf course sequestration capacity. The findings are transferrable to the management and design of urban parks and gardens, which range between fairways and greens in intensity of management.

Biomechanical response to changes in natural turf during running and turning.

Integrated biomechanical and engineering assessments were used to determine how humans responded to variations in turf during running and turning. Ground reaction force (AMTI, 960 Hz) and kinematic data (Vicon Peak Motus, 120 Hz) were collected from eight participants during running (3.83 m/s) and turning (10 trials per condition) on three natural turf surfaces in the laboratory. Surface hardness (Clegg hammer) and shear strength (cruciform shear vane) were measured before and after participant testing. Peak loading rate during running was significantly higher (p < .05) on the least hard surface (sandy; 101.48 BW/s ± 23.3) compared with clay (84.67 BW/s ± 22.9). There were no significant differences in running kinematics. Compared with the "medium" condition, fifth MTP impact velocities during turning were significantly (RM-ANOVA, p < .05) lower on clay (resultant: 2.30 m/s [± 0.68] compared with 2.64 m/s [± 0.70]), which was significantly (p < .05) harder "after" and had the greatest shear strength both "before" and "after" participant testing. This unique finding suggests that further study of foot impact velocities are important to increase understanding of overuse injury mechanisms.

FKBPL and peptide derivatives: novel biological agents that inhibit angiogenesis by a CD44-dependent mechanism.

PURPOSE: Antiangiogenic therapies can be an important adjunct to the management of many malignancies. Here we investigated a novel protein, FKBPL, and peptide derivative for their antiangiogenic activity and mechanism of action. EXPERIMENTAL DESIGN: Recombinant FKBPL (rFKBPL) and its peptide derivative were assessed in a range of human microvascular endothelial cell (HMEC-1) assays in vitro. Their ability to inhibit proliferation, migration, and Matrigel-dependent tubule formation was determined. They were further evaluated in an ex vivo rat model of neovascularization and in two in vivo mouse models of angiogenesis, that is, the sponge implantation and the intravital microscopy models. Antitumor efficacy was determined in two human tumor xenograft models grown in severe compromised immunodeficient (SCID) mice. Finally, the dependence of peptide on CD44 was determined using a CD44-targeted siRNA approach or in cell lines of differing CD44 status. RESULTS: rFKBPL inhibited endothelial cell migration, tubule formation, and microvessel formation in vitro and in vivo. The region responsible for FKBPL's antiangiogenic activity was identified, and a 24-amino acid peptide (AD-01) spanning this sequence was synthesized. It was potently antiangiogenic and inhibited growth in two human tumor xenograft models (DU145 and MDA-231) when administered systemically, either on its own or in combination with docetaxel. The antiangiogenic activity of FKBPL and AD-01 was dependent on the cell-surface receptor CD44, and signaling downstream of this receptor promoted an antimigratory phenotype. CONCLUSION: FKBPL and its peptide derivative AD-01 have potent antiangiogenic activity. Thus, these agents offer the potential of an attractive new approach to antiangiogenic therapy.

High prevalence of plasmid-mediated quinolone resistance determinants in commensal members of the Enterobacteriaceae in Ho Chi Minh City, Vietnam.

Antimicrobial-resistant pathogenic members of the Enterobacteriaceae are a well-defined global problem. We hypothesized that one of the main reservoirs of dissemination of antimicrobial resistance genes in Vietnam is non-pathogenic intestinal flora, and sought to isolate antimicrobial-resistant organisms from hospitalized patients and non-hospitalized healthy individuals in Ho Chi Minh City. The results identified substantial faecal carriage of gentamicin-, ceftazidime- and nalidixic acid-resistant members of the Enterobacteriaceae in both hospitalized patients and non-hospitalized healthy individuals. A high prevalence of quinolone resistance determinants was identified, particularly the qnrS gene, in both community- and hospital-associated strains. Furthermore, the results demonstrated that a combination of quinolone resistance determinants can confer resistance to nalidixic acid and ciprofloxacin, even in the apparent absence of additional chromosomal resistance mutations in wild-type strains and laboratory strains with transferred plasmids. These data suggest that intestinal commensal organisms are a significant reservoir for the dissemination of plasmid-mediated quinolone resistance in Ho Chi Minh City.

Synthesis and SAR of novel 2-arylthiazolidinones as selective analgesic N-type calcium channel blockers.

A series of new N-type (Ca(v)2.2) calcium channel blockers derived from the 'hit' structures 2-(3-bromo-4-fluorophenyl)-3-(2-pyridin-2-ylethyl)thiazolidin-4-one 9 and its 2-[4-(4-bromophenyl)pyridin-3-yl]-3-isobutyl analogue 10 is described. Extensive SAR studies using a range of synthetic approaches resulted in novel, patented compounds with IC50 values of up to 0.2 microM in an in vitro IMR32 assay, and selectivities for N/L of up to 30-fold. The new compounds described have potential in treatment of neuropathic pain.