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Due to advances in sequencing technology, somatically mutated cancer antigens, or neoantigens, are now readily identifiable and have become compelling targets for immunotherapy. In particular, neoantigen-targeted vaccines have shown promise in several pre-clinical and clinical studies. However, to date, neoantigen-targeted vaccine studies have involved tumors with exceptionally high mutation burdens. It remains unclear whether neoantigen-targeted vaccines will be broadly applicable to cancers with intermediate to low mutation burdens, such as ovarian cancer. To address this, we assessed whether a derivative of the murine ovarian tumor model ID8 could be targeted with neoantigen vaccines. We performed whole exome and transcriptome sequencing on ID8-G7 cells. We identified 92 somatic mutations, 39 of which were transcribed, missense mutations. For the 17 top predicted MHC class I binding mutations, we immunized mice subcutaneously with synthetic long peptide vaccines encoding the relevant mutation. Seven of 17 vaccines induced robust mutation-specific CD4 and/or CD8 T cell responses. However, none of the vaccines prolonged survival of tumor-bearing mice in either the prophylactic or therapeutic setting. Moreover, none of the neoantigen-specific T cell lines recognized ID8-G7 tumor cells in vitro, indicating that the corresponding mutations did not give rise to bonafide MHC-presented epitopes. Additionally, bioinformatic analysis of The Cancer Genome Atlas data revealed that only 12% (26/220) of HGSC cases had a ≥90% likelihood of harboring at least one authentic, naturally processed and presented neoantigen versus 51% (80/158) of lung cancers. Our findings highlight the limitations of applying neoantigen-targeted vaccines to tumor types with intermediate/low mutation burdens.

We show that the in vivo generation of cytokine-producing CD4 T cells specific for a given major histocompatibility class-II (MHCII)-binding peptide of hen egg lysozyme (HEL) is facilitated when mice are immunized with splenic antigen presenting cells (APC) pulsed with this HEL peptide and another peptide that binds a different MHCII molecule. This enhanced generation of peptide-specific effector CD4 T cells requires that the same splenic APC be pulsed with both peptides. Pulsed B cells, but not pulsed dendritic cells (DCs), can mediate CD4 T cell cooperation, which can be blocked by disrupting OX40-OX40L (CD134-CD252) interactions. In addition, the generation of HEL peptide-specific CD4 T cell memory is greater when mice are primed with B cells pulsed with the two peptides than with B cells pulsed with the HEL- peptide alone. Based on our findings, we suggest CD4 T cell cooperation is important for vaccine design, underlies the phenomenon of \"epitope-spreading\" seen in autoimmunity, and that the efficacy of B cell-depletion in the treatment of human cell-mediated autoimmune disease is due to the abrogation of the interactions between autoimmune CD4 T cells that facilitates their activation.

Rice (Oryza sativa L.) is one of the most important food crops worldwide. However, it is also a valuable tool in assessing toxicity of organic and inorganic compounds. For more than 20 years, it has been an approved species for standardized phytotoxicity experiments. The objective of this study is to determine germination and radicle (root) and coleoptile (shoot) growth of rice seeds exposed to three insecticides and two herbicides, commonly used in the agricultural production landscape. Although no germination effects of pesticide exposure were observed, significant growth effects were noted between pesticide treatments. Coleoptile growth was significantly (p ≤ 0.05) lowered in metolachlor/atrazine mixture, diazinon, and lambda-cyhalothrin exposures when compared with controls. Radicles of fipronil-exposed seeds were significantly larger (p ≤ 0.05) when compared with controls. This research contributes to the phytotoxicity assessment database, in addition to laying the foundation for the use of rice as a phytoremediation tool for agricultural pesticide runoff.

Increased focus is being placed on the ability of native vegetation to mitigate potential harmful effects of agricultural runoff, especially pyrethroid insecticides. Replicate 379 L Rubbermaid tubs (1.25 m [l] x 0.6 m [w] x 0.8 m [h]) were planted with individual species of cutgrass (Leersia oryzoides), cattails (Typha latifolia), bur-reed (Sparganium americanum), and powdery alligator-flag (Thalia dealbata), all common wetland macrophytes found in the Mississippi Delta, USA, agricultural region. Permethrin-enriched water (target concentration, 5 μg L⁻¹) was pumped in at a 4-h hydraulic retention time at one end of the tub and discharged at the far end. Water samples were collected from discharge at 1-h intervals for 12 h and analyzed for permethrin concentrations. Permethrin removal rates were compared for the four different plant treatments and nonvegetated sediment-water controls. Results indicated that no particular single plant species was more effective at removing permethrin in water relative to unplanted controls. Overall mass reductions (from inflow to outflow) for cis-permethrin ranged from 67% ± 6% in T. latifolia to 71% ± 2% in L. oryzoides. The trans-permethrin overall mass reductions ranged from 76% ± 4% in S. americanum to 82% ± 2% in the unplanted control. Sediment and plant samples collected at the study conclusion indicated that 77%-95% of measured permethrin mass was associated with sediment for mesocosms planted with L. oryzoides, T. latifolia, and T. dealbata. Conversely, mesocosms planted with S. americanum had 83% of measured mass associated with the plant material. Specific plant-pesticide retention studies can lead to improved planning for best management practices and remediation techniques such as constructed wetlands and vegetated agricultural drainage ditches.

Worldwide, commercially available waterpipes vary widely in design and durability, including differences in fabrication materials, degree of leak-tight fit, and flow path diameter. Little is known about how the components of the waterpipe may influence puffing behavior and user's exposure to toxins. To systematically evaluate exposure, it is necessary to use a standardized research-grade waterpipe (RWP) when conducting clinical and laboratory-based trials. We developed a RWP that is configured with an in-line topography system which allows real-time measurement and recording of the smoke volume drawn through the RWP. The RWP was calibrated across the flow rate range expected for waterpipe tobacco smoking and the calibration was verified for known puff volumes using a smoking machine. Operation of the RWP was qualified in a cohort of experienced waterpipe smokers, each smoker using the RWP ad libitum in a laboratory setting while smoker topography and subjective effects data were collected. RWP machine smoking was highly reproducible and yielded puff volumes that agreed well with true values. User acceptance was comparable, and puffing behavior was similar in pattern, with more frequent puffing in the beginning of the session, but significantly different in intensity from that used to estimate the majority of toxicant exposure reported in the literature. The RWP operates with known precision and accuracy and is well accepted by experienced smokers. This tool can be used to determine the extent to which puffing behaviors are affected by the waterpipe design, components, and/or accessories, tobacco nicotine content, sweet flavorings and/or additives known to increase addictiveness. This study describes a standardized RWP, equipped with a puffing topography analyzer, which can operate with known precision and accuracy, and is well-accepted by experienced smokers in terms of satisfaction and reward. The RWP is an important tool for determining if puffing behaviors, and thus estimated toxin exposures, are affected by the waterpipe design, components, and/or accessories, tobacco nicotine content, sweet flavorings, and/or additives that are known to increase addictiveness.

Extended abstract of a paper presented at Microscopy and Microanalysis 2012 in Phoenix, Arizona, USA, July 29 – August 2, 2012.

Flooded post-harvest rice paddies were examined as systems for reducing diazinon (organophosphate insecticide) concentrations in stormwater runoff. Two paddies were cultivated in Oryza sativa L. and amended with a 3-h simulated stormwater diazinon runoff event. Initial diazinon adsorption peaked at 347 and 571 μg kg⁻¹ (3% mass load reduction) for mean above-ground plant tissue concentrations in each pond, respectively. Subsequent senescence of above-ground tissue showed significant decreases in tissue mass (r ² = 0.985) and adsorbed diazinon mass (90 ± 4% and 82 ± 1%) within 1 month of amendment. There were no corollary increases in water column diazinon concentrations. Furthermore, control O. sativa tissue placed within the treatment ponds had below-detectable levels of diazinon throughout the decomposition phase, suggesting a lack of within pond transference of dissipated diazinon. This study shows the relative effectiveness of diazinon adsorption by post-harvest rice plants and a potential mitigation strategy of senescence and pesticide degradation for contaminated tailwater.

The hit, break, and cut classes of verbs are grammatically relevant in Kimaragang, as in English. The relevance of such classes for determining how arguments are expressed suggests that the meaning of a verb is composed of (a) systematic components of meaning (the event template); and (b) idiosyncratic properties of the individual root. Assuming this approach to be essentially correct, I compare grammatical phenomena in Kimaragang that are sensitive to verb class membership with phenomena that are not classsensitive. The tendency that emerges is that class-sensitive alternations do not seem to be affix-dependent, and are quite restricted in their ability to introduce new arguments into the argument structure.

Charged lepton flavor violation is forbidden in the Standard Model but possible in several new physics scenarios. In many of these models, the radiative decays τ± → ℓ±γ (ℓ = e, μ) are predicted to have a sizeable probability, making them particularly interesting channels to search at various experiments. An updated search via τ± → ℓ±γ using full data of the Belle experiment, corresponding to an integrated luminosity of 988 fb–1, is reported for charged lepton flavor violation. No significant excess over background predictions from the Standard Model is observed, and the upper limits on the branching fractions, B(τ± → μ±γ) ≤ 4.2 × 10–8 and B(τ± → e±γ) ≤ 5.6 × 10–8, are set at 90% confidence level.