Helicobacter pylori chronic infection and mucosal inflammation switches the human gastric glycosylation pathways

Helicobacter pylori exploits host glycoconjugates to colonize the gastric niche. Infection can persist for decades promoting chronic inflammation, and in a subset of individuals lesions can silently progress to cancer. This study shows that H. pylori chronic infection and gastric tissue inflammation result in a remodeling of the gastric glycophenotype with increased expression of sialyl-Lewis a/x antigens due to transcriptional up-regulation of the B3GNT5, B3GALT5, and FUT3 genes. We observed that H. pylori infected individuals present a marked gastric local pro-inflammatory signature with significantly higher TNF-a levels and demonstrated that TNF-induced activation of the NF-kappaB pathway results in B3GNT5 transcriptional up-regulation. Furthermore, we show that this gastric glycosylation shift, characterized by increased sialylation patterns, favors SabA-mediated H. pylori attachment to human inflamed gastric mucosa. This study provides novel clinically relevant insights into the regulatory mechanisms underlying H. pylori modulation of host glycosylation machinery, and phenotypic alterations crucial for life-long infection. Moreover, the biosynthetic pathways here identified as responsible for gastric mucosa increased sialylation, in response to H. pylori infection, can be exploited as drug targets for hindering bacteria adhesion and counteract the infection chronicity.IPATIMUP integrates the i3S Research Unit, which is partially supported by FCT, the Portuguese Foundation for Science and Technology (PEst C/SAU/LA0003/2013). This work is funded by FEDER funds through the Operational Programme for Competitiveness Factors-COMPETE (NORTE 07 0124 FEDER 000024; FCOMP-01-0124-FEDER028188; FCOMP-01-0124-FEDER 041276) and National Funds through the FCT-Foundation for Science and Technology (EXPL/CTM-BIO/0762/2013, PTDC/BBB-EBI/0786/2012) and acknowledges support by the EuropeanUnion (Seventh Framework Programme GastricGlycoExplorer project, grant number 316929). Grants were received from FCT, POPH (Programa Operacional Potencial Humano) and FSE (Fundo Social Europeu) (SFRH/BPD/75871/2011 to AM;SFRH/SINTD/60034/2009 to RMP; SFRH/BPD/84084/2012 to RMF; SFRH/BPD/89764/2012 to PO). AM acknowledges EMBO for a Short-Term Fellowship (EMBO ASTF 330-212). Transcript analysis was funded by NIH (grant P41GM103490) to KWM

Distinct Binding and Immunogenic Properties of the Gonococcal Homologue of Meningococcal Factor H Binding Protein

Neisseria meningitidis is a leading cause of sepsis and meningitis. The bacterium recruits factor H (fH), a negative regulator of the complement system, to its surface via fH binding protein (fHbp), providing a mechanism to avoid complement-mediated killing. fHbp is an important antigen that elicits protective immunity against the meningococcus and has been divided into three different variant groups, V1, V2 and V3, or families A and B. However, immunisation with fHbp V1 does not result in cross-protection against V2 and V3 and vice versa. Furthermore, high affinity binding of fH could impair immune responses against fHbp. Here, we investigate a homologue of fHbp in Neisseria gonorrhoeae, designated as Gonococcal homologue of fHbp (Ghfp) which we show is a promising vaccine candidate for N. meningitidis. We demonstrate that Gfhp is not expressed on the surface of the gonococcus and, despite its high level of identity with fHbp, does not bind fH. Substitution of only two amino acids in Ghfp is sufficient to confer fH binding, while the corresponding residues in V3 fHbp are essential for high affinity fH binding. Furthermore, immune responses against Ghfp recognise V1, V2 and V3 fHbps expressed by a range of clinical isolates, and have serum bactericidal activity against N. meningitidis expressing fHbps from all variant groups

Post-Training Dephosphorylation of eEF-2 Promotes Protein Synthesis for Memory Consolidation

Memory consolidation, which converts acquired information into long-term storage, is new protein synthesis-dependent. As protein synthesis is a dynamic process that is under the control of multiple translational mechanisms, however, it is still elusive how these mechanisms are recruited in response to learning for memory consolidation. Here we found that eukaryotic elongation factor-2 (eEF-2) was dramatically dephosphorylated within 0.5–2 hr in the hippocampus and amygdala of mice following training in a fear-conditioning test, whereas genome-wide microarrays did not reveal any significant change in the expression level of the mRNAs for translational machineries or their related molecules. Moreover, blockade of NMDA receptors with MK-801 immediately following the training significantly impeded both the post-training eEF-2 dephosphorylation and memory retention. Notably, with an elegant sophisticated transgenic strategy, we demonstrated that hippocampus-specific overexpression of eEF-2 kinase, a kinase that specifically phosphorylates and hence inactivates eEF-2, significantly inhibited protein synthesis in the hippocampus, and this effects was more robust during an “ongoing” protein synthesis process. As a result, late phase long-term potentiation (L-LTP) in the hippocampus and long-term hippocampus-dependent memory in the mice were significantly impaired, whereas short-term memory and long-term hippocampus-independent memory remained intact. These results reveal a novel translational underpinning for protein synthesis pertinent to memory consolidation in the mammalian brain

The emerging dental workforce: why dentistry? A quantitative study of final year dental students' views on their professional career

<p>Abstract</p> <p>Background</p> <p>Dental graduates are joining a profession experiencing changes in systems of care, funding and skill mix. Research into the motivation and expectations of the emerging workforce is vital to inform professional and policy decisions. The objective of this research was to investigate final year dental students' perceived motivation for their choice of career in relation to sex, ethnicity and mode of entry.</p> <p>Methods</p> <p>Self-administered questionnaire survey of all final year dental students at King's College London. Data were entered into SPSS; statistical analysis included Chi Squared tests for linear association, multiple regression, factor analysis and logistic regression.</p> <p>Results</p> <p>A response of 90% (n = 126) was achieved. The majority were aged 23 years (59%), female (58%) and Asian (70%). One in 10 were mature students. Eighty per cent identified 11 or more 'important' or 'very important' influences, the most common of which were related to features of the job: 'regular working hours' (91%), 'degree leading to recognised job' (90%) and 'job security' (90%). There were significant differences in important influences by sex (males > females: 'able to run own business'; females > males: 'a desire to work with people'), ethnic group (Asians > white: 'wish to provide public service', 'influence of friends', 'desire to work in healthcare', having 'tried an alternative career/course' and 'work experience') and mode of entry (mature > early entry: 'a desire to work with people'). Multivariate analysis suggested 61% of the variation in influences is explained by five factors: the 'professional job' (31%), 'healthcare-people' (11%), 'academic-scientific' (8%), 'careers-advising' (6%), and 'family/friends' (6%). The single major influence on choice of career was a 'desire to work with people'; Indian students were twice as likely to report this as white or other ethnic groups.</p> <p>Conclusion</p> <p>Final year dental students report a wide range of important influences on their choice of dentistry, with variation by sex, ethnicity and mode of entry in relation to individual influences. Features of the 'professional job', followed by 'healthcare and people' were the most important underlying factors influencing choice of career.</p

The alpha-kinase family: an exceptional branch on the protein kinase tree

The alpha-kinase family represents a class of atypical protein kinases that display little sequence similarity to conventional protein kinases. Early studies on myosin heavy chain kinases in Dictyostelium discoideum revealed their unusual propensity to phosphorylate serine and threonine residues in the context of an alpha-helix. Although recent studies show that some members of this family can also phosphorylate residues in non-helical regions, the name alpha-kinase has remained. During evolution, the alpha-kinase domains combined with many different functional subdomains such as von Willebrand factor-like motifs (vWKa) and even cation channels (TRPM6 and TRPM7). As a result, these kinases are implicated in a large variety of cellular processes such as protein translation, Mg2+ homeostasis, intracellular transport, cell migration, adhesion, and proliferation. Here, we review the current state of knowledge on different members of this kinase family and discuss the potential use of alpha-kinases as drug targets in diseases such as cancer

Approaches in biotechnological applications of natural polymers

Natural polymers, such as gums and mucilage, are biocompatible, cheap, easily available and non-toxic materials of native origin. These polymers are increasingly preferred over synthetic materials for industrial applications due to their intrinsic properties, as well as they are considered alternative sources of raw materials since they present characteristics of sustainability, biodegradability and biosafety. As definition, gums and mucilages are polysaccharides or complex carbohydrates consisting of one or more monosaccharides or their derivatives linked in bewildering variety of linkages and structures. Natural gums are considered polysaccharides naturally occurring in varieties of plant seeds and exudates, tree or shrub exudates, seaweed extracts, fungi, bacteria, and animal sources. Water-soluble gums, also known as hydrocolloids, are considered exudates and are pathological products; therefore, they do not form a part of cell wall. On the other hand, mucilages are part of cell and physiological products. It is important to highlight that gums represent the largest amounts of polymer materials derived from plants. Gums have enormously large and broad applications in both food and non-food industries, being commonly used as thickening, binding, emulsifying, suspending, stabilizing agents and matrices for drug release in pharmaceutical and cosmetic industries. In the food industry, their gelling properties and the ability to mold edible films and coatings are extensively studied. The use of gums depends on the intrinsic properties that they provide, often at costs below those of synthetic polymers. For upgrading the value of gums, they are being processed into various forms, including the most recent nanomaterials, for various biotechnological applications. Thus, the main natural polymers including galactomannans, cellulose, chitin, agar, carrageenan, alginate, cashew gum, pectin and starch, in addition to the current researches about them are reviewed in this article.. }To the Conselho Nacional de Desenvolvimento Cientfíico e Tecnológico (CNPq) for fellowships (LCBBC and MGCC) and the Coordenação de Aperfeiçoamento de Pessoal de Nvíel Superior (CAPES) (PBSA). This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit, the Project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462) and COMPETE 2020 (POCI-01-0145-FEDER-006684) (JAT)

Nature and significance of small volume fall deposits at composite volcanoes: Insights from the October 14, 1974 Fuego eruption, Guatemala

The first of four successive pulses of the 1974 explosive eruption of Fuego volcano, Guatemala, produced a small volume (∼0.02 km3 DRE) basaltic sub-plinian tephra fall and flow deposit. Samples collected within 48 h after deposition over much of the dispersal area (7–80 km from the volcano) have been size analyzed down to 8 φ (4 µm). Tephra along the dispersal axis were all well-sorted (σ φ = 0.25–1.00), and sorting increased whereas thickness and median grain size decreased systematically downwind. Skewness varied from slightly positive near the vent to slightly negative in distal regions and is consistent with decoupling between coarse ejecta falling off the rising eruption column and fine ash falling off the windblown volcanic cloud advecting at the final level of rise. Less dense, vesicular coarse particles form a log normal sub-population when separated from the smaller (Mdφ < 3φ or < 0.125 mm), denser shard and crystal sub-population. A unimodal, relatively coarse (Mdφ = 0.58φ or 0.7 mm σ φ = 1.2) initial grain size population is estimated for the whole (fall and flow) deposit. Only a small part of the fine-grained, thin 1974 Fuego tephra deposit has survived erosion to the present day. The initial October 14 pulse, with an estimated column height of 15 km above sea level, was a primary cause of a detectable perturbation in the northern hemisphere stratospheric aerosol layer in late 1974 to early 1975. Such small, sulfur-rich, explosive eruptions may substantially contribute to the overall stratospheric sulfur budget, yet leave only transient deposits, which have little chance of survival even in the recent geologic record. The fraction of finest particles (Mdφ = 4–8φ or 4–63 µm) in the Fuego tephra makes up a separate but minor size mode in the size distribution of samples around the margin of the deposit. A previously undocumented bimodal–unimodal–bimodal change in grain size distribution across the dispersal axis at 20 km downwind from the vent is best accounted for as the result of fallout dispersal of ash from a higher subplinian column and a lower “co-pf” cloud resulting from pyroclastic flows. In addition, there is a degree of asymmetry in the documented grain-size fallout pattern which is attributed to vertically veering wind direction and changing windspeeds, especially across the tropopause. The distribution of fine particles (<8 µm diameter) in the tephra deposit is asymmetrical, mainly along the N edge, with a small enrichment along the S edge. This pattern has hazard significance

Phosphorylation of DARPP-32 at Threonine-34 is required for cocaine action.

International audienceMice lacking DARPP-32, a striatal-enriched phosphoprotein, show abnormal behavioral and biochemical responses to cocaine, but the role of individual phosphorylation sites in DARPP-32 in these responses is unknown. We show here that mutation of Thr-34 in DARPP-32 mimicked the behavioral phenotype of the constitutive DARPP-32 knockout in cocaine-induced place conditioning, locomotor activity, and sensitization paradigms. In contrast, mutations of Thr75 did not affect conditioned place preference or the acute locomotor response to cocaine, but DARPP-32 Thr-75 mutants showed no locomotor sensitization in response to repeated cocaine administration. Consistent with these behavioral findings, we found that cocaine regulation of gene expression in striatum, including the acute induction of the immediate early genes c-fos and arc (activity-regulated cytoskeletal-associated gene), was abolished in DARPP-32 Thr-34 mutants, but not in Thr-75 mutants. Similarly, induction of the transcription factor DeltaFosB in the ventral striatum (nucleus accumbens) by chronic cocaine was diminished by the Thr-34, but not the Thr-75, mutation. These findings highlight distinct roles of the Thr-34 and Thr-75 phosphorylation sites of DARPP-32 in mediating short- and long-term behavioral and biochemical actions of cocaine