Proton Driven Plasma Wakefield Acceleration

Plasma wakefield acceleration, either laser driven or electron-bunch driven, has been demonstrated to hold great potential. However, it is not obvious how to scale these approaches to bring particles up to the TeV regime. In this paper, we discuss the possibility of proton-bunch driven plasma wakefield acceleration, and show that high energy electron beams could potentially be produced in a single accelerating stage.Comment: 13 pages, 4 figure

Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16.

Keratin 16 (K16) is a cytoskeletal scaffolding protein highly expressed at pressure-bearing sites of the mammalian footpad. It can be induced in hyperproliferative states such as wound healing, inflammation and cancer. Here we show that the inactive rhomboid protease RHBDF2 (iRHOM2) regulates thickening of the footpad epidermis through its interaction with K16. K16 expression is absent in the thinned footpads of irhom2-/- mice compared with irhom2+/+mice, due to reduced keratinocyte proliferation. Gain-of-function mutations in iRHOM2 underlie Tylosis with oesophageal cancer (TOC), characterized by palmoplantar thickening, upregulate K16 with robust downregulation of its type II keratin binding partner, K6. By orchestrating the remodelling and turnover of K16, and uncoupling it from K6, iRHOM2 regulates the epithelial response to physical stress. These findings contribute to our understanding of the molecular mechanisms underlying hyperproliferation of the palmoplantar epidermis in both physiological and disease states, and how this 'stress' keratin is regulated

Association between genetic variants in the Coenzyme Q10 metabolism and Coenzyme Q10 status in humans

<p>Abstract</p> <p>Background</p> <p>Coenzyme Q₁₀(CoQ₁₀) is essential for mitochondrial energy production and serves as an antioxidants in extra mitochondrial membranes. The genetics of primary CoQ₁₀deficiency has been described in several studies, whereas the influence of common genetic variants on CoQ₁₀status is largely unknown. Here we tested for non-synonymous single-nucleotidepolymorphisms (SNP) in genes involved in the biosynthesis (CoQ3^G272S, CoQ6^M406V, CoQ7^M103T), reduction (NQO1^P187S, NQO2^L47F) and metabolism (apoE3/4) of CoQ₁₀and their association with CoQ₁₀status. For this purpose, CoQ₁₀serum levels of 54 healthy male volunteers were determined before (T₀) and after a 14 days supplementation (T₁₄) with 150 mg/d of the reduced form of CoQ₁₀.</p> <p>Findings</p> <p>At T₀, the CoQ₁₀level of heterozygous NQO1^P187Scarriers were significantly lower than homozygous S/S carriers (0.93 ± 0.25 μM versus 1.34 ± 0.42 μM, p = 0.044). For this polymorphism a structure homology-based method (PolyPhen) revealed a possibly damaging effect on NQO1 protein activity. Furthermore, CoQ₁₀plasma levels were significantly increased in apoE4/E4 genotype after supplementation in comparison to apoE2/E3 genotype (5.93 ± 0.151 μM versus 4.38 ± 0.792 μM, p = 0.034). Likewise heterozygous CoQ3^G272Scarriers had higher CoQ₁₀plasma levels at T₁₄compared to G/G carriers but this difference did not reach significance (5.30 ± 0.96 μM versus 4.42 ± 1.67 μM, p = 0.082).</p> <p>Conclusions</p> <p>In conclusion, our pilot study provides evidence that NQO1^P187Sand apoE polymorphisms influence CoQ₁₀status in humans.</p

Genomic Convergence among ERRα, PROX1, and BMAL1 in the Control of Metabolic Clock Outputs

Metabolic homeostasis and circadian rhythms are closely intertwined biological processes. Nuclear receptors, as sensors of hormonal and nutrient status, are actively implicated in maintaining this physiological relationship. Although the orphan nuclear receptor estrogen-related receptor α (ERRα, NR3B1) plays a central role in the control of energy metabolism and its expression is known to be cyclic in the liver, its role in temporal control of metabolic networks is unknown. Here we report that ERRα directly regulates all major components of the molecular clock. ERRα-null mice also display deregulated locomotor activity rhythms and circadian period lengths under free-running conditions, as well as altered circulating diurnal bile acid and lipid profiles. In addition, the ERRα-null mice exhibit time-dependent hypoglycemia and hypoinsulinemia, suggesting a role for ERRα in modulating insulin sensitivity and glucose handling during the 24-hour light/dark cycle. We also provide evidence that the newly identified ERRα corepressor PROX1 is implicated in rhythmic control of metabolic outputs. To help uncover the molecular basis of these phenotypes, we performed genome-wide location analyses of binding events by ERRα, PROX1, and BMAL1, an integral component of the molecular clock. These studies revealed the existence of transcriptional regulatory loops among ERRα, PROX1, and BMAL1, as well as extensive overlaps in their target genes, implicating these three factors in the control of clock and metabolic gene networks in the liver. Genomic convergence of ERRα, PROX1, and BMAL1 transcriptional activity thus identified a novel node in the molecular circuitry controlling the daily timing of metabolic processes

Quick, accurate, smart: 3D computer vision technology helps assessing confined animals' behaviour

Mankind directly controls the environment and lifestyles of several domestic species for purposes ranging from production and research to conservation and companionship. These environments and lifestyles may not offer these animals the best quality of life. Behaviour is a direct reflection of how the animal is coping with its environment. Behavioural indicators are thus among the preferred parameters to assess welfare. However, behavioural recording (usually from video) can be very time consuming and the accuracy and reliability of the output rely on the experience and background of the observers. The outburst of new video technology and computer image processing gives the basis for promising solutions. In this pilot study, we present a new prototype software able to automatically infer the behaviour of dogs housed in kennels from 3D visual data and through structured machine learning frameworks. Depth information acquired through 3D features, body part detection and training are the key elements that allow the machine to recognise postures, trajectories inside the kennel and patterns of movement that can be later labelled at convenience. The main innovation of the software is its ability to automatically cluster frequently observed temporal patterns of movement without any pre-set ethogram. Conversely, when common patterns are defined through training, a deviation from normal behaviour in time or between individuals could be assessed. The software accuracy in correctly detecting the dogs' behaviour was checked through a validation process. An automatic behaviour recognition system, independent from human subjectivity, could add scientific knowledge on animals' quality of life in confinement as well as saving time and resources. This 3D framework was designed to be invariant to the dog's shape and size and could be extended to farm, laboratory and zoo quadrupeds in artificial housing. The computer vision technique applied to this software is innovative in non-human animal behaviour science. Further improvements and validation are needed, and future applications and limitations are discussed.</p

Antifungal Activity of Microbial Secondary Metabolites

Secondary metabolites are well known for their ability to impede other microorganisms. Reanalysis of a screen of natural products using the Caenorhabditis elegans-Candida albicans infection model identified twelve microbial secondary metabolites capable of conferring an increase in survival to infected nematodes. In this screen, the two compound treatments conferring the highest survival rates were members of the epipolythiodioxopiperazine (ETP) family of fungal secondary metabolites, acetylgliotoxin and a derivative of hyalodendrin. The abundance of fungal secondary metabolites indentified in this screen prompted further studies investigating the interaction between opportunistic pathogenic fungi and Aspergillus fumigatus, because of the ability of the fungus to produce a plethora of secondary metabolites, including the well studied ETP gliotoxin. We found that cell-free supernatant of A. fumigatus was able to inhibit the growth of Candida albicans through the production of a secreted product. Comparative studies between a wild-type and an A. fumigatus ΔgliP strain unable to synthesize gliotoxin demonstrate that this secondary metabolite is the major factor responsible for the inhibition. Although toxic to organisms, gliotoxin conferred an increase in survival to C. albicans-infected C. elegans in a dose dependent manner. As A. fumigatus produces gliotoxin in vivo, we propose that in addition to being a virulence factor, gliotoxin may also provide an advantage to A. fumigatus when infecting a host that harbors other opportunistic fungi

The plasticity of Plasmodium falciparum gametocytaemia in relation to age in Burkina Faso

BACKGROUND: Malaria transmission depends on the presence of gametocytes in the peripheral blood. In this study, the age-dependency of gametocytaemia was examined by microscopy and molecular tools. METHODS: A total of 5,383 blood samples from individuals of all ages were collected over six cross sectional surveys in Burkina Faso. One cross-sectional study used quantitative nucleic acid sequence based amplification (QT-NASBA) for parasite quantification (n = 412). The proportion of infections with concurrent gametocytaemia and median proportion of gametocytes among all parasites were calculated. RESULTS: Asexual parasite prevalence and gametocyte prevalence decreased with age. Gametocytes made up 1.8% of the total parasite population detected by microscopy in the youngest age group. This proportion gradually increased to 18.2% in adults (p < 0.001). Similarly, gametocytes made up 0.2% of the total parasite population detected by QT-NASBA in the youngest age group, increasing to 5.7% in adults (p < 0.001). This age pattern in gametocytaemia was also evident in the proportion of gametocyte positive slides without concomitant asexual parasites which increased from 13.4% (17/127) in children to 45.6% (52/114) in adults (OR 1.55, 95% CI 1.38-1.74, p < 0.001). CONCLUSIONS: The findings of this study suggest that although gametocytes are most commonly detected in children, the proportion of asexual parasites that is committed to develop into gametocytes may increase with age. These findings underscore the importance of adults for the human infectious reservoir for malaria

The two tryptophans of β2-microglobulin have distinct roles in function and folding and might represent two independent responses to evolutionary pressure

We have recently discovered that the two tryptophans of human β2-microglobulin have distinctive roles within the structure and function of the protein. Deeply buried in the core, Trp95 is essential for folding stability, whereas Trp60, which is solvent-exposed, plays a crucial role in promoting the binding of β2-microglobulin to the heavy chain of the class I major histocompatibility complex (MHCI). We have previously shown that the thermodynamic disadvantage of having Trp60 exposed on the surface is counter-balanced by the perfect fit between it and a cavity within the MHCI heavy chain that contributes significantly to the functional stabilization of the MHCI. Therefore, based on the peculiar differences of the two tryptophans, we have analysed the evolution of β2-microglobulin with respect to these residues

Novel measures of cardiovascular health and its association with prevalence and progression of age-related macular degeneration: the CHARM study

<p>Abstract</p> <p>Background</p> <p>To determine if novel measures of cardiovascular health are associated with prevalence or progression of age-related macular degeneration (AMD).</p> <p>Methods</p> <p>Measures of the cardiovascular system: included intima media thickness (IMT), pulse wave velocity (PWV), systemic arterial compliance (SAC), carotid augmentation index (AI). For the prevalence study, hospital-based AMD cases and population-based age- and gender-matched controls with no signs of AMD in either eye were enrolled. For the progression component, participants with early AMD were recruited from two previous studies; cases were defined as progression in one or both eyes and controls were defined as no progression in either eye.</p> <p>Results</p> <p>160 cases and 160 controls were included in the prevalence component. The upper two quartiles of SAC, implying good cardiovascular health, were significantly associated with increased risk of AMD (OR = 2.54, 95% CL = 1.29, 4.99). High PWV was associated with increased prevalent AMD. Progression was observed in 82 (32.3%) of the 254 subjects recruited for the progression component. Higher AI (worse cardiovascular function) was protective for AMD progression (OR = 0.30, 95%CL = 0.13, 0.69). Higher aortic PWV was associated with increased risk of AMD progression; the highest risk was seen with the second lowest velocity (OR = 6.22, 95% CL = 2.35, 16.46).</p> <p>Conclusion</p> <p>The results were unexpected in that better cardiovascular health was associated with increased risk of prevalent AMD and progression. Inconsistent findings between the prevalence and progression components could be due to truly different disease etiologies or to spurious findings, as can occur with inherent biases in case control studies of prevalence. Further investigation of these non-invasive methods of characterizing the cardiovascular system should be undertaken as they may help to further elucidate the role of the cardiovascular system in the etiology of prevalent AMD and progression.</p