DNA Vaccines Encoding Antigen Targeted to MHC Class II Induce Influenza-Specific CD8+ T Cell Responses, Enabling Faster Resolution of Influenza Disease

Current influenza vaccines are effective but imperfect, failing to cover against emerging strains of virus and requiring seasonal administration to protect against new strains. A key step to improving influenza vaccines is to improve our understanding of vaccine induced protection. Whilst it is clear that antibodies play a protective role, vaccine induced CD8+ T cells can improve protection. To further explore the role of CD8+ T cells we used a DNA vaccine that encodes antigen dimerised to an immune cell targeting module. Immunising CB6F1 mice with the DNA vaccine in a heterologous prime boost regime with the seasonal protein vaccine improved the resolution of influenza disease compared to protein alone. This improved disease resolution was dependent on CD8+ T cells. However, DNA vaccine regimes that induced CD8+ T cells alone were not protective and did not boost the protection provided by protein. The MHC targeting module used was an anti-I-Ed single chain antibody specific to the BALB/c strain of mice. To test the role of MHC targeting we compared the response between BALB/c, C57BL/6 mice and an F1 cross of the two strains (CB6F1). BALB/c mice were protected, C57BL/6 were not and the F1 had an intermediate phenotype; showing that the targeting of antigen is important in the response. Based on these findings, and in agreement with other studies using different vaccines, we conclude that in addition to antibody, inducing a protective CD8 response is important in future influenza vaccines

Comparative analysis of enzymatically produced novel linear DNA constructs with plasmids for use as DNA vaccines

The use of DNA to deliver vaccine antigens offers many advantages, including ease of manufacture and cost. However, most DNA vaccines are plasmids and must be grown in bacterial culture, necessitating elements which are either unnecessary for effective gene delivery (e.g. bacterial origins of replication) or undesirable (e.g. antibiotic resistance genes). Removing these elements may improve the safety profile of DNA for the delivery of vaccines. Here we describe a novel, double-stranded, linear DNA construct produced by an enzymatic process that solely encodes an antigen expression cassette, comprising antigen, promoter, polyA tail and telomeric ends. We compared these constructs (called ‘Doggybones’ because of their shape) with conventional plasmid DNA. Using luciferase-expressing constructs, we demonstrated that expression levels were equivalent between Doggybones and plasmids both in vitro and in vivo. When mice were immunized with DNA constructs expressing the HIV envelope protein gp140, equivalent humoral and cellular responses were induced. Immunizations with either construct type expressing haemagluttinin were protective against H1N1 influenza challenge. This is the first example of an effective DNA vaccine which can be produced on a large scale by enzymatic processes

Investigation of Natural Effective Gamma Dose Rates case study: Ardabil Province in Iran

Gamma rays pose enough energy to form charged particles and adversely affect human health. Since, the external exposure of human beings to natural environmental gamma radiation normally exceeds that from all man-made sources combined, natural background gamma dose rates and corresponding annual effective doses were determined for selected cities of Ardabil province from 2009 to 2010. Outdoor gamma dose rates were measured using an Ion Chamber Survey Meter in 105 locations in selected districts. Average absorbed dose for Ardabil, Sar-Ein, Germy, Neer, Shourabil Recreational Lake, and Kosar were determined as 265, 219, 344, 233, 352, and 358 nSvh-1, respectively. Although dose rates recorded for Germi and Kosar are comparable with some areas with high natural radiation background, however, the dose rates in other districts are well below the levels reported for such locations. Average annual effective dose due to indoor and outdoor gamma radiation for Ardabil province was estimated to be 1.73 (1.35-2.39) mSv, which is on average 2 times higher than the world population weighted average

A rapid, efficient, and facile solution for dental hypersensitivity: The tannin–iron complex

Dental hypersensitivity due to exposure of dentinal tubules under the enamel layer to saliva is a very popular and highly elusive technology priority in dentistry. Blocking water flow within exposed dentinal tubules is a key principle for curing dental hypersensitivity. Some salts used in "at home" solutions remineralize the tubules inside by concentrating saliva ingredients. An "in-office" option of applying dense resin sealants on the tubule entrance has only localized effects on well-defined sore spots. We report a self-assembled film that was formed by facile, rapid (4 min), and efficient (approximately 0.5 g/L concentration) dip-coating of teeth in an aqueous solution containing a tannic acid-iron(III) complex. It quickly and effectively occluded the dentinal tubules of human teeth. It withstood intense tooth brushing and induced hydroxyapatite remineralisation within the dentinal tubules. This strategy holds great promise for future applications as an effective and user-friendly desensitizer for managing dental hypersensitivity.111310Ysciescopu

B Cells Regulate Neutrophilia during Mycobacterium tuberculosis Infection and BCG Vaccination by Modulating the Interleukin-17 Response

We have previously demonstrated that B cells can shape the immune response to Mycobacterium tuberculosis, including the level of neutrophil infiltration and granulomatous inflammation at the site of infection. The present study examined the mechanisms by which B cells regulate the host neutrophilic response upon exposure to mycobacteria and how neutrophilia may influence vaccine efficacy. To address these questions, a murine aerosol infection tuberculosis (TB) model and an intradermal (ID) ear BCG immunization mouse model, involving both the μMT strain and B cell-depleted C57BL/6 mice, were used. IL (interleukin)-17 neutralization and neutrophil depletion experiments using these systems provide evidence that B cells can regulate neutrophilia by modulating the IL-17 response during M. tuberculosis infection and BCG immunization. Exuberant neutrophilia at the site of immunization in B cell-deficient mice adversely affects dendritic cell (DC) migration to the draining lymph nodes and attenuates the development of the vaccine-induced Th1 response. The results suggest that B cells are required for the development of optimal protective anti-TB immunity upon BCG vaccination by regulating the IL-17/neutrophilic response. Administration of sera derived from M. tuberculosis-infected C57BL/6 wild-type mice reverses the lung neutrophilia phenotype in tuberculous μMT mice. Together, these observations provide insight into the mechanisms by which B cells and humoral immunity modulate vaccine-induced Th1 response and regulate neutrophila during M. tuberculosis infection and BCG immunization. © 2013 Kozakiewicz et al

Inhibition of autophagy, lysosome and VCP function impairs stress granule assembly

Stress granules (SGs) are mRNA-protein aggregates induced during stress, which accumulate in many neurodegenerative diseases. Previously, the autophagy-lysosome pathway and valosin-containing protein (VCP), key players of the protein quality control (PQC), were shown to regulate SG degradation. This is consistent with the idea that PQC may survey and/or assist SG dynamics. However, despite these observations, it is currently unknown whether the PQC actively participates in SG assembly. Here, we describe that inhibition of autophagy, lysosomes and VCP causes defective SG formation after induction. Silencing the VCP co-factors UFD1L and PLAA, which degrade defective ribosomal products (DRIPs) and 60S ribosomes, also impaired SG assembly. Intriguingly, DRIPs and 60S, which are released from disassembling polysomes and are normally excluded from SGs, were significantly retained within SGs in cells with impaired autophagy, lysosome or VCP function. Our results suggest that deregulated autophagy, lysosomal or VCP activities, which occur in several neurodegenerative (VCP-associated) diseases, may alter SG morphology and composition

Effects of a penthiopyrad and picoxystrobin fungicide mixtureon phoma stem canker (Leptosphaeria spp.) on UK winteroilseed rape

© Koninklijke Nederlandse Planteziektenkundige Vereniging 2016. This is a pre-copyedited, author-produced PDF of an article accepted for publication in European Journal of Plant Pathology following peer review. The final publication [Sewell, T.R., Moloney, S., Ashworth, M. et al., European Journal of Plant Pathology (2016) 145: 675-685, first published online April 5, 2016] is available at Springer via doi: http://dx.doi.org/10.1007/s10658-016-0916-8In the UK, fungicides are often used to controlphoma stem canker on winter oilseed rape. Field trialswere established near Boxworth, Cambridgeshire for fourcropping seasons (2011/2012, 2012/2013, 2013/2014 and2014/15) to test the efficacy of a new fungicide mixtureRefinzar® (penthiopyrad + picoxystrobin) by comparisonto an existing fungicide Proline 275® (prothioconazole)against phoma stem canker (Leptosphaeria spp.) andthe effect on winter oilseed rape (cv. Catana) yield. Ineach season, weather data were collected from a weatherstation at Boxworth and the release of ascospores wasmonitored using a nearby Burkard spore sampler. Thepatterns of ascospore release differed between seasonsand related to weather conditions. Fungicidespenthiopyrad + picoxystrobin and prothioconazole wereapplied in October/November when 10 % of plants hadphoma leaf spotting (T1, early), 4/8 weeks after T1 (T2,late) or at both T1 and T2 (combined). When phoma leafspot symptoms were assessed in autumn/winter,penthiopyrad + picoxystrobin and prothioconazole bothdecreased numbers of phoma leaf spots caused byL. maculans; there were few leaf spots caused byL. biglobosa. Penthiopyrad + picoxystrobin andprothioconazole both reduced phoma stem canker severitybefore harvest compared to the untreated control butdid not increase yield in these seasons when epidemicswere not severe. In 2013/2014, the presence ofL. maculans and L. biglobosa in upper stem lesions orstem base cankers was determined by species-specificPCR. The proportions of stems with L. maculans DNAwere much greater than those with L. biglobosa DNA forboth upper stem lesions and basal stem cankers. Theseresults suggest that both penthiopyrad + picoxystrobinand prothioconazole can decrease phoma stem cankerseverity on winter oilseed rape in severe disease seasons.Peer reviewe

Elliptic logarithms, diophantine approximation and the Birch and Swinnerton-Dyer conjecture

Most, if not all, unconditional results towards the abc-conjecture rely ultimately on classical Baker's method. In this article, we turn our attention to its elliptic analogue. Using the elliptic Baker's method, we have recently obtained a new upper bound for the height of the S-integral points on an elliptic curve. This bound depends on some parameters related to the Mordell-Weil group of the curve. We deduce here a bound relying on the conjecture of Birch and Swinnerton-Dyer, involving classical, more manageable quantities. We then study which abc-type inequality over number fields could be derived from this elliptic approach.Comment: 20 pages. Some changes, the most important being on Conjecture 3.2, three references added ([Mas75], [MB90] and [Yu94]) and one reference updated [BS12]. Accepted in Bull. Brazil. Mat. So

Circumstellar disks and planets. Science cases for next-generation optical/infrared long-baseline interferometers

We present a review of the interplay between the evolution of circumstellar disks and the formation of planets, both from the perspective of theoretical models and dedicated observations. Based on this, we identify and discuss fundamental questions concerning the formation and evolution of circumstellar disks and planets which can be addressed in the near future with optical and infrared long-baseline interferometers. Furthermore, the importance of complementary observations with long-baseline (sub)millimeter interferometers and high-sensitivity infrared observatories is outlined.Comment: 83 pages; Accepted for publication in "Astronomy and Astrophysics Review"; The final publication is available at http://www.springerlink.co

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT