Evidence of Differential Allelic Effects between Adolescents and Adults for Plasma High-Density Lipoprotein

A recent meta-analysis of genome-wide association (GWA) studies identified 95 loci that influence lipid traits in the adult population and found that collectively these explained about 25–30% of heritability for each trait. Little is known about how these loci affect lipid levels in early life, but there is evidence that genetic effects on HDL- and LDL-cholesterol (HDL-C, LDL-C) and triglycerides vary with age. We studied Australian adults (N = 10,151) and adolescents (N = 2,363) who participated in twin and family studies and for whom we have lipid phenotypes and genotype information for 91 of the 95 genetic variants. Heterogeneity tests between effect sizes in adult and adolescent cohorts showed an excess of heterogeneity for HDL-C (pHet<0.05 at 5 out of 37 loci), but no more than expected by chance for LDL-C (1 out of 14 loci), or trigycerides (0 out 24). There were 2 (out of 5) with opposite direction of effect in adolescents compared to adults for HDL-C, but none for LDL-C. The biggest difference in effect size was for LDL-C at rs6511720 near LDLR, adolescents (0.021±0.033 mmol/L) and adults (0.157±0.023 mmol/L), pHet = 0.013; followed by ZNF664 (pHet = 0.018) and PABPC4 (pHet = 0.034) for HDL-C. Our findings suggest that some of the previously identified variants associate differently with lipid traits in adolescents compared to adults, either because of developmental changes or because of greater interactions with environmental differences in adults

Lipopolysaccharide O1 Antigen Contributes to the Virulence in Klebsiella pneumoniae Causing Pyogenic Liver Abscess

Klebsiella pneumoniae is the common cause of a global emerging infectious disease, community-acquired pyogenic liver abscess (PLA). Capsular polysaccharide (CPS) and lipopolysaccharide (LPS) are critical for this microorganism's ability to spread through the blood and to cause sepsis. While CPS type K1 is an important virulence factor in K. pneumoniae causing PLA, the role of LPS in PLA is not clear. Here, we characterize the role of LPS O antigen in the pathogenesis of K. pneumoniae causing PLA. NTUH-K2044 is a LPS O1 clinical strain; the presence of the O antigen was shown via the presence of 1,3-galactan in the LPS, and of sequences that align with the wb gene cluster, known to produce O-antigen. Serologic analysis of K. pneumoniae clinical isolates demonstrated that the O1 serotype was more prevalent in PLA strains than that in non-tissue-invasive strains (38/42 vs. 9/32, P<0.0001). O1 serotype isolates had a higher frequency of serum resistance, and mutation of the O1 antigen changed serum resistance in K. pneumoniae. A PLA-causing strain of CPS capsular type K2 and LPS serotype O1 (i.e., O1:K2 PLA strain) deleted for the O1 synthesizing genes was profoundly attenuated in virulence, as demonstrated in separate mouse models of septicemia and liver abscess. Immunization of mice with the K2044 magA-mutant (K1− O1) against LPS O1 provided protection against infection with an O1:K2 PLA strain, but not against infection with an O1:K1 PLA strain. Our findings indicate that the O1 antigen of PLA-associated K. pneumoniae contributes to virulence by conveying resistance to serum killing, promoting bacterial dissemination to and colonization of internal organs after the onset of bacteremia, and could be a useful vaccine candidate against infection by an O1:K2 PLA strain

Diffusion of an e-learning programme among Danish General Practitioners: A nation-wide prospective survey

<p>Abstract</p> <p>Background</p> <p>We were unable to identify studies that have considered the diffusion of an e-learning programme among a large population of general practitioners. The aim of this study was to investigate the uptake of an e-learning programme introduced to General Practitioners as part of a nation-wide disseminated dementia guideline.</p> <p>Methods</p> <p>A prospective study among all 3632 Danish GPs. The GPs were followed from the launching of the e-learning programme in November 2006 and 6 months forward. Main outcome measures: Use of the e-learning programme. A logistic regression model (GEE) was used to identify predictors for use of the e-learning programme.</p> <p>Results</p> <p>In the study period, a total of 192 different GPs (5.3%) were identified as users, and 17% (32) had at least one re-logon. Among responders at first login most have learnt about the e-learning programme from written material (41%) or from the internet (44%). A total of 94% of the users described their ability of conducting a diagnostic evaluation as good or excellent. Most of the respondents used the e-learning programme due to general interest (90%). Predictors for using the e-learning programme were Males (OR = 1.4, 95% CI 1.1; 2.0) and members of Danish College of General Practice (OR = 2.2, 95% CI 1.5; 3.1), whereas age, experience and working place did not seem to be influential.</p> <p>Conclusion</p> <p>Only few Danish GPs used the e-learning programme in the first 6 months after the launching. Those using it were more often males and members of Danish College of General Practice. Based on this study we conclude, that an active implementation is needed, also when considering electronic formats of CME like e-learning.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier: NCT00392483.</p

BIM-Mediated AKT Phosphorylation Is a Key Modulator of Arsenic Trioxide-Induced Apoptosis in Cisplatin-Sensitive and -Resistant Ovarian Cancer Cells

Background: Chemo-resistance to cisplatin-centered cancer therapy is a major obstacle to the effective treatment of human ovarian cancer. Previous reports indicated that arsenic trioxide (ATO) induces cell apoptosis in both drug-sensitive and-resistant ovarian cancer cells. Principal Findings: In this study, we determined the molecular mechanism of ATO-induced apoptosis in ovarian cancer cells. Our data demonstrated that ATO induced cell apoptosis by decreasing levels of phosphorylated AKT (p-AKT) and activating caspase-3 and caspase-9. Importantly, BIM played a critical role in ATO-induced apoptosis. The inhibition of BIM expression prevented AKT dephosphorylation and inhibited caspase-3 activation during cell apoptosis. However, surprisingly, gene silencing of AKT or FOXO3A had little effect on BIM expression and phosphorylation. Moreover, the activation of caspase-3 by ATO treatment improved AKT dephosphorylation, not only by cleaving the regulatory A subunit of protein phosphatase 2A (PP2A), but also by increasing its activation. Furthermore, our data indicated that the c-Jun N-terminal kinases (JNK) pathway is involved in the regulation of BIM expression. Conclusions: We demonstrated the roles of BIM in ATO-induced apoptosis and the molecular mechanisms of BIM expression regulated by ATO during ovarian cancer cell apoptosis. Our findings suggest that BIM plays an important role in regulating p-AKT by activating caspase-3 and that BIM mediates the level of AKT phosphorylation to determine th

A prospective study of Helicobacter pylori in relation to the risk for pancreatic cancer

<p>Abstract</p> <p>Background</p> <p>The relationship between <it>Helicobacter pylori </it>infection and pancreatic cancer has been investigated in three previous studies with contradictory results. The aim of the present study was to investigate the association between <it>H. pylori </it>seropositivity and the risk for pancreatic cancer in a nested case-control study within a population based cohort.</p> <p>Methods</p> <p>Selected birth-year cohorts (born 1921–1949) of residents in Malmö, Sweden, were invited to a health screening investigation. A total of 33 346 subjects participated. Cases with pancreatic cancer (n = 87) were matched to controls (n = 263) using age, sex and time for baseline investigation as matching variables. <it>H. pylori </it>serology was analysed in stored serum samples using an enzyme-linked immunosorbent assay. Odds ratios (OR) for pancreatic cancer were calculated with 95% confidence intervals (CI) using logistic regression.</p> <p>Results</p> <p><it>H. pylori </it>seropositivity was not associated with pancreatic cancer in the total cohort (adjusted OR 1.25 (0.75–2.09)). However, a statistically significant association was found in never smokers (OR 3.81 (1.06–13.63) adjusted for alcohol consumption) and a borderline statistically significant association was found in subjects with low alcohol consumption (OR 2.13 (0.97–4.69) adjusted for smoking).</p> <p>Conclusion</p> <p>We conclude that no association between <it>H. pylori </it>infection and the risk for pancreatic cancer was found in the total cohort. However, in never smokers and in subjects with low risk alcohol consumption, a positive <it>H. pylori </it>serology was associated with an increased risk for pancreatic cancer. These findings should be interpreted cautiously due to the limited number of cases in these subgroups.</p

Functions of Some Capsular Polysaccharide Biosynthetic Genes in Klebsiella pneumoniae NTUH K-2044

The growing number of Klebsiella pneumoniae infections, commonly acquired in hospitals, has drawn great concern. It has been shown that the K1 and K2 capsular serotypes are the most detrimental strains, particularly to those with diabetes. The K1 cps (capsular polysaccharide) locus in the NTUH-2044 strain of the pyogenic liver abscess (PLA) K. pneumoniae has been identified recently, but little is known about the functions of the genes therein. Here we report characterization of a group of cps genes and their roles in the pathogenesis of K1 K. pneumoniae. By sequential gene deletion, the cps gene cluster was first re-delimited between genes galF and ugd, which serve as up- and down-stream ends, respectively. Eight gene products were characterized in vitro and in vivo to be involved in the syntheses of UDP-glucose, UDP-glucuronic acid and GDP-fucose building units. Twelve genes were identified as virulence factors based on the observation that their deletion mutants became avirulent or lost K1 antigenicity. Furthermore, deletion of kp3706, kp3709 or kp3712 (ΔwcaI, ΔwcaG or Δatf, respectively), which are all involved in fucose biosynthesis, led to a broad range of transcriptional suppression for 52 upstream genes. The genes suppressed include those coding for unknown regulatory membrane proteins and six multidrug efflux system proteins, as well as proteins required for the K1 CPS biosynthesis. In support of the suppression of multidrug efflux genes, we showed that these three mutants became more sensitive to antibiotics. Taken together, the results suggest that kp3706, kp3709 or kp3712 genes are strongly related to the pathogenesis of K. pneumoniae K1

Laying the Foundations for a Human-Predator Conflict Solution: Assessing the Impact of Bonelli's Eagle on Rabbits and Partridges

BACKGROUND: Predation may potentially lead to negative effects on both prey (directly via predators) and predators (indirectly via human persecution). Predation pressure studies are, therefore, of major interest in the fields of theoretical knowledge and conservation of prey or predator species, with wide ramifications and profound implications in human-wildlife conflicts. However, detailed works on this issue in highly valuable--in conservation terms--Mediterranean ecosystems are virtually absent. This paper explores the predator-hunting conflict by examining a paradigmatic, Mediterranean-wide (endangered) predator-two prey (small game) system. METHODOLOGY/PRINCIPAL FINDINGS: We estimated the predation impact ('kill rate' and 'predation rate', i.e., number of prey and proportion of the prey population eaten, respectively) of Bonelli's eagle Aquila fasciata on rabbit Oryctolagus cuniculus and red-legged partridge Alectoris rufa populations in two seasons (the eagle's breeding and non-breeding periods, 100 days each) in SE Spain. The mean estimated kill rate by the seven eagle reproductive units in the study area was c. 304 rabbits and c. 262 partridges in the breeding season, and c. 237 rabbits and c. 121 partridges in the non-breeding period. This resulted in very low predation rates (range: 0.3-2.5%) for both prey and seasons. CONCLUSIONS/SIGNIFICANCE: The potential role of Bonelli's eagles as a limiting factor for rabbits and partridges at the population scale was very poor. The conflict between game profitability and conservation interest of either prey or predators is apparently very localised, and eagles, quarry species and game interests seem compatible in most of the study area. Currently, both the persecution and negative perception of Bonelli's eagle (the 'partridge-eating eagle' in Spanish) have a null theoretical basis in most of this area

Sex Promotes Spatial and Dietary Segregation in a Migratory Shorebird during the Non-Breeding Season

Several expressions of sexual segregation have been described in animals, especially in those exhibiting conspicuous dimorphism. Outside the breeding season, segregation has been mostly attributed to size or age-mediated dominance or to trophic niche divergence. Regardless of the recognized implications for population dynamics, the ecological causes and consequences of sexual segregation are still poorly understood. We investigate the foraging habits of a shorebird showing reversed sexual dimorphism, the black-tailed godwit Limosa limosa, during the winter season, and found extensive segregation between sexes in spatial distribution, microhabitat use and dietary composition. Males and females exhibited high site-fidelity but differed in their distributions at estuary-scale. Male godwits (shorter-billed) foraged more frequently in exposed mudflats than in patches with higher water levels, and consumed more bivalves and gastropods and fewer polychaetes than females. Females tended to be more frequently involved and to win more aggressive interactions than males. However, the number of aggressions recorded was low, suggesting that sexual dominance plays a lesser role in segregation, although its importance cannot be ruled out. Dimorphism in the feeding apparatus has been used to explain sex differences in foraging ecology and behaviour of many avian species, but few studies confirmed that morphologic characteristics drive individual differences within each sex. We found a relationship between resource use and bill size when pooling data from males and females. However, this relationship did not hold for either sex separately, suggesting that differences in foraging habits of godwits are primarily a function of sex, rather than bill size. Hence, the exact mechanisms through which this segregation operates are still unknown. The recorded differences in spatial distribution and resource use might expose male and female to distinct threats, thus affecting population dynamics through differential mortality. Therefore, population models and effective conservation strategies should increasingly take sex-specific requirements into consideration

Operationalizing local ecological knowledge in climate change research : challenges and opportunities of citizen science

Current research on the local impacts of climate change is based on contrasting results from the simulation of historical trends in climatic variables produced with global models against climate data from independent observations. To date, these observations have mostly consisted of weather data from standardized meteorological stations. Given that the spatial distribution of weather stations is patchy, climate scientists have called for the exploration of new data sources. Knowledge developed by Indigenous Peoples and local communities with a long history of interaction with their environment has been proposed as a data source with untapped potential to contribute to our understanding of the local impacts of climate change. In this chapter, we discuss an approach that aims to bring insights from local knowledge systems to climate change research. First, we present a number of theoretical arguments that give support to the idea that local knowledge systems can contribute in original ways to the endeavors of climate change research. Then, we explore the potential of using information and communication technologies to gather and share local knowledge of climate change impacts. We do so through the examination of a citizen science initiative aiming to collect local indicators of climate change impacts: the LICCI project (www.licci.eu). Our findings illustrate that citizen science can inspire new approaches to articulate the inclusion of local knowledge systems in climate change research. However, this requires outlining careful approaches, with high ethical standards, toward knowledge validation and recognizing that there are aspects of local ecological knowledge that are incommensurable with scientific knowledge

The venom composition of the parasitic wasp Chelonus inanitus resolved by combined expressed sequence tags analysis and proteomic approach

<p>Abstract</p> <p>Background</p> <p>Parasitic wasps constitute one of the largest group of venomous animals. Although some physiological effects of their venoms are well documented, relatively little is known at the molecular level on the protein composition of these secretions. To identify the majority of the venom proteins of the endoparasitoid wasp <it>Chelonus inanitus </it>(Hymenoptera: Braconidae), we have randomly sequenced 2111 expressed sequence tags (ESTs) from a cDNA library of venom gland. In parallel, proteins from pure venom were separated by gel electrophoresis and individually submitted to a nano-LC-MS/MS analysis allowing comparison of peptides and ESTs sequences.</p> <p>Results</p> <p>About 60% of sequenced ESTs encoded proteins whose presence in venom was attested by mass spectrometry. Most of the remaining ESTs corresponded to gene products likely involved in the transcriptional and translational machinery of venom gland cells. In addition, a small number of transcripts were found to encode proteins that share sequence similarity with well-known venom constituents of social hymenopteran species, such as hyaluronidase-like proteins and an Allergen-5 protein.</p> <p>An overall number of 29 venom proteins could be identified through the combination of ESTs sequencing and proteomic analyses. The most highly redundant set of ESTs encoded a protein that shared sequence similarity with a venom protein of unknown function potentially specific of the <it>Chelonus </it>lineage. Venom components specific to <it>C. inanitus </it>included a C-type lectin domain containing protein, a chemosensory protein-like protein, a protein related to yellow-e3 and ten new proteins which shared no significant sequence similarity with known sequences. In addition, several venom proteins potentially able to interact with chitin were also identified including a chitinase, an imaginal disc growth factor-like protein and two putative mucin-like peritrophins.</p> <p>Conclusions</p> <p>The use of the combined approaches has allowed to discriminate between cellular and truly venom proteins. The venom of <it>C. inanitus </it>appears as a mixture of conserved venom components and of potentially lineage-specific proteins. These new molecular data enrich our knowledge on parasitoid venoms and more generally, might contribute to a better understanding of the evolution and functional diversity of venom proteins within Hymenoptera.</p