An in vitro screen of bacterial lipopolysaccharide biosynthetic enzymes identifies an inhibitor of ADP-heptose biosynthesis

The lipopolysaccharide (LPS)-rich outer membrane of gram-negative bacteria provides a protective barrier that insulates these organisms from the action of numerous antibiotics. Breach of the LPS layer can therefore provide access to the cell interior to otherwise impermeant toxic molecules and can expose vulnerable binding sites for immune system components such as complement. Inhibition of LPS biosynthesis, leading to a truncated LPS molecule, is an alternative strategy for antibacterial drug development in which this vital cellular structure is weakened. A significant challenge for in vitro screens of small molecules for inhibition of LPS biosynthesis is the difficulty in accessing the complex carbohydrate substrates. We have optimized an assay of the enzymes required for LPS heptose biosynthesis that simultaneously surveys five enzyme activities by using commercially available substrates and report its use in a small-molecule screen that identifies an inhibitor of heptose synthesis.

Holocene climate change, vegetation history and human impact in the Central Mediterranean: evidence from the Maltese Islands

Holocene climates and human impact in the Mediterranean basin have received much attention, but the Maltese Islands in the Central Mediterranean, although a pivotal area, have been little researched. Here, sedimentary and palynological data are presented for three cores from the Holocene coastal and shallowmarine
deposits of the Maltese Islands. These show deforestation from Pinus-Cupressaceae woodland in the early Neolithic, and then a long, but relatively stable history of agriculturally degraded environments to the present day. The major climate events which have affected the Italian and Balkan peninsulas to the
north, and Tunisia to the south, are not reflected in the pollen diagrams from the Maltese Islands because of the strong anthropogenic imprint on the Maltese vegetation from early in the Neolithic. Previous suggestions of environmentally-driven agricultural collapse at the end of the Neolithic appear, however,
to be substantiated and may be linked to regional aridification around 4300 cal. BP. Depopulation in early Medieval times is not supported by the current palynological evidence.

Photodynamic Antimicrobial Chemotherapy (PACT) in combination with antibiotics for treatment of Burkholderia cepacia complex infection

This study aimed to determine if Photodynamic Antimicrobial Chemotherapy (PACT) was effective in the treatment of Burkholderia cepacia complex infection and whether a synergistic effect was evident if PACT was used in combination with antibiotics. The susceptibility of both planktonic and biofilm cultures of B. cepacia complex strains to methylene blue (MB) and meso-tetra(n-methyl-4-pyridyl)porphine tetra-tosylate (TMP)-mediated PACT was determined alone and in combination with antibiotics used in the treatment of Cystic Fibrosis pulmonary infection caused by these bacteria. When B. cepacia complex strains were grown planktonically, high levels of kill of were achieved with both TMP and MB-mediated PACT with strain and photosensitizer specific differences apparent. When strains were grown in biofilm, antibiotic treatment alone was bactericidal in 17/36 (47%) strain/antibiotic combinations tested. When antibiotic treatment was combined with PACT, bactericidal activity was apparent for 33/36 (92%) strain/antibiotic combinations. No antagonism was detected between PACT and antibiotic treatment with the combination synergistic for 6/36 (17%) and indifferent for 30/36 (83%) strain/antibiotic combinations. PACT could be a viable treatment option, either alone or in combination with antibiotics for treatment of B. cepacia complex pulmonary infection.

Organised Criminals as 'Agents of Obligation': The Case of Ireland

Relying on Brown’s (2005a, b) thesis that contemporary shifts in penal policy are best understood as a reprisal of colonial rationality, so that offenders become ‘non-citizens’ or ‘agents of obligation’, this article argues that this framework finds support in developments in Irish criminal justice policy. Recent legislation aimed at offenders suspected of involvement in ‘organised crime’ is examined through this lens. These offenders have found themselves reconstituted as ‘agents of obligation’ with duties to furnish information about their property and movements, report to the police concerning their location and, importantly, refrain from criminal activity or face extraordinary sanctions. It is therefore argued that this paradigm is a useful heuristic device through which to understand recent developments in Irish criminal justice and elsewhere. In light of the trends observed in Ireland, certain refinements and extensions to Brown’s argument are put forward for consideration.

Intra-uterine growth restriction and increased risk of hypertension in adult life: A follow-up study of 50-year-olds

OBJECTIVE:

To compare blood pressure between 50-year-old adults who were born at term (37-42 weeks of gestation) with intra-uterine growth restriction (IUGR; birth weight <10th centile) and a control group of similar age born at term without IUGR (birth weight =10th centile).

STUDY DESIGN:

Controlled comparative study.

METHODS:

Participants included 232 men and women who were born at the Royal Maternity Hospital, Belfast, a large regional maternity hospital in Northern Ireland, between 1954 and 1956. One hundred and eight subjects who were born with IUGR were compared with 124 controls with normal birth weight for gestation. The main outcome measures were systolic and diastolic blood pressure at approximately 50 years of age, measured according to European recommendations.

RESULTS:

The IUGR group had higher systolic and diastolic blood pressure than the control group: 131.5 [95% confidence interval (CI) 127.9-135.1] vs 127.1 (95% CI 124.3-129.2) mmHg and 82.3 (95% CI 79.6-85.0) vs 79.0 (95% CI 77.0-81.0) mmHg, respectively. After adjustment for gender, the differences between the groups were statistically significant: systolic blood pressure 4.5 (95% CI 0.3-8.7) mmHg and diastolic blood pressure 3.4 (95% CI 0.2-6.5) mmHg (both P < 0.05). More participants in the IUGR group were receiving treatment for high blood pressure compared with the control group [16 (15%) vs 11 (9%)], although this was not statistically significant. The proportion of subjects with blood pressure >140/90 mmHg or currently receiving antihypertensive treatment was 45% (n = 49) for the IUGR group, and 31% (n = 38) for the control group (odds ratio 1.9, 95% CI 1.1-3.3). Adjustment for potential confounders made little difference.

CONCLUSIONS:

IUGR is associated with higher blood pressure at 50 years of age. Individuals born with IUGR should have regular blood pressure screening and early treatment as required. Hypertension remains underdiagnosed and undertreated in adult life.

A millennial record of environmental change in peat deposits from the Misten bog (East Belgium)

In this study, palaeoenvironmental changes recorded in the top metre of a peat profile (Misten bog, East Belgium) were investigated using a multiproxy approach. Proxies include bulk density, Ti and Si content, pollen, macrofossils, d13C on specific Sphagnum stems, and d13C–d18O on Sphagnum leaves. A high-resolution chronology was generated using 210Pb measurements and 22 14C AMS dates on carefully selected Sphagnum macrofossils. d13C only records large change in mire surface wetness. This is partly due to the fact that the core was taken from the edge of a hummock, which may make it difficult to track small isotopic changes. The d13C signal seems to be dependent upon the Sphagnum species composition. For example, a change between Sphagnum section Cuspidata towards Sphagnum imbricatum causes a significant drop in the d13C values. On the whole, the C and O isotopes record two shallow pool phases during the 8th–9th and the 13th centuries. Pollen and atmospheric soil dust (ASD) fluxes records increased human occupation in the area. There may be some climatic signals in the ASD flux, but they are difficult to decipher from the increasing human impact (land clearance, agriculture) during the last millennium. The variations in the proxies are not always synchronous, suggesting different triggering factors (temperature, wetness, windiness) for each proxy. This study also emphasizes that, compared to studies dealing with pollution using geochemical proxies, palaeoclimatic inferences from peat bogs need as many proxies as possible, together with highly accurate and precise age-models, in order to better understand climate variability and their consequences during the Holocene.

New susceptibility Loci associated with kidney disease in type 1 diabetes

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ~2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P?=?1.2×10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P?=?2.0×10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-ß1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P?=?2.1×10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

Using temporal analysis of products and flux response technology to determine diffusion coefficients in catalytic monoliths

The importance of accurately measuring gas diffusivity in porous materials has led to a number of methods being developed. In this study the Temporal Analysis of Products (TAP) reactor and Flux Response Technology (FRT) have been used to examine the diffusivity in the washcoat supported on cordierite monoliths. Herein, the molecular diffusion of propane within four monoliths with differently prepared alumina/CeZrOx washcoats was investigated as a function of temperature. Moment-based analysis of the observed TAP responses led to the calculation of the apparent intermediate gas constant, Kp, that characterises adsorption into the mesoporous network and apparent time delay, tapp, that characterises residence time in the mesoporous network. Additionally, FRT has been successfully adapted as an extensive in situ perturbation technique in measuring intraphase diffusion coefficients in the washcoats of the same four monolith samples. The diffusion coefficients obtained by moment-based analysis of TAP responses are larger than the coefficients determined by zero length column (ZLC) analysis of flux response profiles with measured values of the same monolith samples between 20 and 100 °C ranging from 2–5×10^-9 m² s^-1 to 4–8×10^-10 m² s^-1, respectively. The TAP and FRT data, therefore, provide a range of the lower and upper limits of diffusivity, respectively. The reported activation energies and diffusivities clearly correlate with the difference in the washcoat structure of different monolith samples.

A systematic review of systematic reviews to improve maternal mental health and well-being

Objective: to identify non-invasive interventions in the perinatal period that could enable midwives to offer effective support to women within the area of maternal mental health and well-being.

Methods: a total of 9 databases were searched: MEDLINE, PubMed, EBSCO (CINAHL/British Nursing Index), MIDIRS Online Database, Web of Science, The Cochrane library, CRD (NHS EED/DARE/HTA), Joanne Briggs Institute and EconLit. A systematic search strategy was formulated using key MeSH terms and related text words for midwifery, study aim, study design and mental health. Inclusion criteria were articles published from 1999 onwards, English language publications and articles originating from economically developed countries, indicated by membership of the Organisation for Economic Co-operation and Development (OECD). Data were independently extracted using a data collection form, which recorded data on the number of papers reviewed, time frame of the review, objectives, key findings and recommendations. Summary data tables were set up outlining key data for each study and findings were organised into related groups. The methodological quality of the reviews was assessed based on predefined quality assessment criteria for reviews.

Findings: 32 reviews were identified as examining interventions that could be used or co-ordinated by midwives in relation to some aspect of maternal mental health and well-being from the antenatal to the postnatal period and met the inclusion criteria. The review highlighted that based on current systematic review evidence it would be premature to consider introducing any of the identified interventions into midwifery training or practice. However there were a number of examples of possible interventions worthy of further research including midwifery led models of care in the prevention of postpartum depression, psychological and psychosocial interventions for treating postpartum depression and facilitation/co-ordination of parent-training programmes. No reviews were identified that supported a specific midwifery role in maternal mental health and well-being in pregnancy, and yet, this is the point of most intensive contact.

Key conclusions and implications for practice: This systematic review of systematic reviews provides a valuable overview of the current strengths and gaps in relation to maternal mental health interventions in the perinatal period. While there was little evidence identified to inform the current role of midwives in maternal mental health, the review provides the opportunity to reflect on what is achievable by midwives now and in the future and the need for high quality randomised controlled trials to inform a strategic approach to promoting maternal mental health in midwifery.

Corruption and subsidiary profitability: US MNC subsidiaries in the Asia Pacific region

Would multinational corporation (MNC) subsidiaries be more profitable in host countries where corruption is less severe? Would MNC subsidiaries be more profitable in less corrupt countries if they focus on local sales? This paper examines the impact of the level of corruption on the profitability of US MNCs in the Asia Pacific region. Using foreign direct investment (FDI) data archived by the US Bureau of Economic Analysis and corruption data reported by the World Bank, we find that MNC subsidiaries located in countries with a lower level of corruption are more profitable. In addition, MNC subsidiaries with a greater focus on local sales are more profitable when the corruption level is low. This study contributes to the literature by showing that when local sales are important to MNC subsidiaries, a lower level of corruption by host countries positively affects the profitability of the MNC subsidiaries.

Asymmetric information without common priors: an indirect evolutionary analysis of quantity competition

The common prior assumption justifies private beliefs as posterior probabilities when updating a common prior based on individual information. We dispose of the common prior assumption for a homogeneous oligopoly market with uncertain costs and firms entertaining arbitrary priors about other firms' cost-type. We show that true prior beliefs can not be evolutionarily stable when truly expected profit measures (reproductive) success.

Enhanced transfer of arsenic to grain for Bangladesh grown rice compared to US and EU

A field survey was conducted in arsenic impacted and non-impacted paddies of Bangladesh to assess how arsenic levels in rice (Oryza sativa L) grain are related to soil and shoot concentrations. Ten field sites from an arsenic contaminated tubewell irrigation region (Faridpur) were compared to 10 field sites from a non-affected region (Gazipur). Analysis of the overall data set found that both grain and shoot total arsenic concentrations were highly correlated (P

Diclofenac residues in carcasses of domestic ungulates available to vultures in India

Gyps vulture populations across the Indian subcontinent are declining rapidly and evidence indicates that veterinary use of the non-steroidal anti-inflammatory drug (NSAID) diclofenac is the major cause. Exposure of vultures to diclofenac is likely to arise from the consumption of livestock carcasses that have been treated shortly before death, however, detailed information regarding the prevalence and residual levels of diclofenac in carcasses available to vultures in India remains unreported. Here, we present data on diclofenac residues in 1848 liver samples taken from carcasses of dead livestock sampled at 67 sites in 12 states within India, between May 2004 and July 2005. Diclofenac residues were detected in carcasses in all states except Orisa, where only one site was sampled. The overall prevalence of detectable diclofenac (>10 microg kg(-1)) across all states was 10.1% and varied significantly among states, with up to 22.3% prevalence determined in Bihar. The geometric mean concentration of diclofenac found in samples in which the drug was detected was 352 microg kg(-1). The prevalence of carcasses containing diclofenac is similar to that previously proposed to be required to have caused the observed Gyps vulture declines in India. On the 11th of May 2006, the Drug Controller General (India) ordered the withdrawal of all licenses granted for the manufacture of diclofenac for veterinary use within India. However, if Gyps vultures are to be protected, potentially substantial existing stocks now need to be quickly and effectively removed from the Indian veterinary market.

Sulfated Zirconia Modified SBA-15 Catalysts for Cellobiose Hydrolysis

Zirconia modified SBA-15 becomes a very active catalyst for the selective hydrolysis of cellobiose to glucose after sulfation. Spectroscopic investigations indicate the presence of Bronsted acid sites with similar properties to those present in conventional sulfated zirconia. Indications are found that the sulfate groups attached to zirconia interact with silanol groups of SBA-15. The catalytic activity in cellobiose hydrolysis correlates well with results for temperature-programmed decomposition of i-propylamine for a range of sulfated ZrO2/SBA-15 catalysts. A glucose yield of 60% during cellobiose hydrolysis at a reaction time of 90 min at 160 degrees C is obtained.

Decontextualised Minds: Adolescents with Autism are Less Susceptible to the Conjunction Fallacy than Typically Developing Adolescents

The conjunction fallacy has been cited as a classic example of the automatic contextualisation of problems. In two experiments we compared the performance of autistic and typically developing adolescents on a set of conjunction fallacy tasks. Participants with autism were less susceptible to the conjunction fallacy. Experiment 2 also demonstrated that the difference between the groups did not result from increased sensitivity to the conjunction rule, or from impaired processing of social materials amongst the autistic participants. Although adolescents with autism showed less bias in their reasoning they were not more logical than the control group in a normative sense. The findings are discussed in the light of accounts which emphasise differences in contextual processing between typical and autistic populations.