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The ability to mount accelerated and efficient mucosal immune responses is critically important to prevent the establishment of many infections. Secretion of immunoglobulin A (IgA) is a key component in this first line of defense, but the underlying cellular mechanisms are still not completely understood. We have evaluated different routes of immunization and examined the requirements for IgA induction in the airway mucosa. We demonstrate that subcutaneous priming with a recombinant antigen in a T helper (Th)17-inducing adjuvant followed by airway boosting promotes high and sustained levels of IgA in the lungs. This response is associated with germinal center formation in the lung-draining lymph nodes. The lung IgA response is dependent on Th17 cells and absent if interleukin (IL)-17 is depleted or when priming with vaccines inducing only Th1 or Th2 responses. We used intravascular staining to demonstrate that IgA+ B cells and chemokine receptor 6 (CCR6)+Th17 cells are recruited to the lung parenchyma after the airway booster immunization. Once recruited to the lung parenchyma, the Th17 cells transform into resident lymphocytes that persist in the lung tissue for at least 10 weeks. Here, they facilitate the accelerated recruitment of T and B cells resulting in an accelerated IgA recall response to a second airway booster immunization.

C-terminal α-amidated peptides are attractive therapeutic targets, but preparative methods to access amidated pharmaceuticals are limited both on lab and manufacturing-scale. Here we report a straightforward and scalable approach to the C-terminal α-amidation of peptides and proteins from cysteine-extended polypeptide precursors. This amidation protocol consists of three highly efficient steps: 1) selective cysteine thiol substitution with a photolabel, 2) photoinduced decarboxylative elimination and 3) enamide cleavage by simple acidolysis or inverse electron demand Diels-Alder reaction. We provide a blueprint for applying this protocol to the semi-recombinant production of therapeutically relevant targets where gram scale C-terminal α-amidation is achieved in a photoflow reactor on a recombinantly prepared peptide YY analogue and a GLP-1/amylin co-agonist precursor peptide. Robust performance of this reaction cascade in flow highlights the potential of this chemistry to enable amidated drug leads to enter development that would not be viable on commercial scale using existing technology. C-terminal α-amidated peptides are attractive therapeutic targets, but preparative methods to access amidated pharmaceuticals are limited both on lab and manufacturing-scale. Here, the authors report a straightforward and scalable approach to the C-terminal α-amidation of peptides and proteins from cysteine-extended polypeptide precursors.

MicroRNAs can promote translation of specific mRNAs in quiescent (G0) mammalian cells and immature Xenopus laevis oocytes. We report that microRNA-mediated upregulation of target mRNAs in oocytes is dependent on nuclear entry of the microRNA; cytoplasmically-injected microRNA repress target mRNAs. Components of the activation microRNP, AGO, FXR1 (FXR1-iso-a) and miR16 are present in the nucleus and cytoplasm. Importantly, microRNA target mRNAs for upregulation, Myt1, TNFα and a reporter bearing the TNFα AU-rich, microRNA target sequence, are associated with AGO in immature oocyte nuclei and AGO2 in G0 human nuclei, respectively. mRNAs that are repressed or lack target sites are not associated with nuclear AGO. Crosslinking-coupled immunopurification revealed greater association of AGO2 with FXR1 in the nucleus compared to cytoplasm. Consistently, overexpression of FXR1-iso-a rescues activation of cytoplasmically-injected RNAs and in low density, proliferating cells. These data indicate the importance of a compartmentalized AGO2-FXR1-iso-a complex for selective recruitment for microRNA-mediated upregulation.

Many head and neck cancer (HNC) survivors experience reduced quality of life due to radiotherapy (RT)-related dysphagia. The aim of this prospective randomized trial was to evaluate the impact of prophylactic swallowing exercises on swallowing-related outcomes in HNC patients treated with curative RT. Patients treated with primary RT for HNC were candidates for this randomized protocol. Participants in the exercise group were instructed to perform swallowing exercises at home. Participants in the control group were given standard care. Patients were evaluated with modified barium swallow and several other secondary outcome measures at four and nine different time points, respectively. Data were analyzed according to intention-to-treat analyses. A total of 44 consecutive patients were included; 22 in each group. In general, there was no difference between the two groups regarding any of the dysphagia outcomes during and after treatment. Adherence to exercises was poor and dropouts due to especially fatigue were very frequent in both groups. Systematic swallowing exercises had no impact on swallowing outcomes within the first year after RT. Despite repeated supervised sessions, adherence to exercises was a major issue and dropouts were frequent in both the intervention and control group.

How do arousal-inducing contexts, such as frightening or romantic television programs, influence the effectiveness of basic persuasion heuristics? Three theoretical models make different predictions: (1) A general arousal model predicts that arousal should increase the effectiveness of heuristics, (2) an affective valence model predicts that effectiveness should depend on whether the context elicits positive or negative affect, and (3) an evolutionary model predicts that persuasiveness should depend on both the specific emotion elicited and the content of the particular heuristic. Three experiments examine how fear-inducing versus romantic contexts influence the effectiveness of two widely used heuristics—social proof (e.g., \"most popular\") and scarcity (e.g., \"limited edition\"). The results support the predictions from an evolutionary model, showing that fear can lead scarcity appeals to be counterpersuasive and that romantic desire can lead social proof appeals to be counterpersuasive. The findings highlight how an evolutionary theoretical approach can lead to novel theoretical and practical marketing insights.

The formation of carboxylic acids and dimer esters from α-pinene oxidation was investigated in a smog chamber and in ambient aerosol samples collected during the Biosphere Effects on Aerosols and Photochemistry Experiment (BEARPEX). Chamber experiments of α-pinene ozonolysis in dry air and at low NOx concentrations demonstrated formation of two dimer esters, pinyl-diaterpenyl (MW 358) and pinonyl-pinyl dimer ester (MW 368), under both low- and high-temperature conditions. Concentration levels of the pinyl-diaterpenyl dimer ester were lower than the assumed first-generation oxidation products cis-pinic and terpenylic acids, but similar to the second-generation oxidation products 3-methyl-1,2,3-butane tricarboxylic acid (MBTCA) and diaterpenylic acid acetate (DTAA). Dimer esters were observed within the first 30 min, indicating rapid production simultaneous to their structural precursors. However, the sampling time resolution precluded conclusive evidence regarding formation from gas- or particle-phase processes. CCN activities of the particles formed in the smog chamber displayed a modest variation during the course of experiments, with κ values in the range 0.06–0.09 (derived at a supersaturation of 0.19%). The pinyl-diaterpenyl dimer ester was also observed in ambient aerosol samples collected above a ponderosa pine forest in the Sierra Nevada Mountains of California during two seasonally distinct field campaigns in September 2007 and July 2009. The pinonyl-pinyl ester was observed for the first time in ambient air during the 2009 campaign, and although present at much lower concentrations, it was correlated with the abundance of the pinyl-diaterpenyl ester, suggesting similarities in their formation. The maximum concentration of the pinyl-diaterpenyl ester was almost 10 times higher during the warmer 2009 campaign relative to 2007, while the concentration of cis-pinic acid was approximately the same during both periods, and lack of correlation with levels of cis-pinic and terpenylic acids for both campaigns indicate that the formation of the pinyl-diaterpenyl ester was not controlled by their ambient abundance. In 2009 the concentration of the pinyl-diaterpenyl ester was well correlated with the concentration of DTAA, a supposed precursor of diaterpenylic acid, suggesting that the formation of pinyl-diaterpenyl dimer was closely related to DTAA. Generally, the pinyl-diaterpenyl ester was found at higher concentrations under higher temperature conditions, both in the smog-chamber study and in ambient air aerosol samples, and exhibited much higher concentrations at night relative to daytime in line with previous results. We conclude that analysis of pinyl dimer esters provides valuable information on pinene oxidation processes and should be included in studies of formation and photochemical aging of biogenic secondary organic aerosols, especially at high temperatures.

Accurate determination of biochemical methane potential (BMP) is important for both biogas research and practice. However, access to laboratory equipment limits the capacity of small laboratories or biogas plants to conduct reliable BMP assays, especially in low- and middle-income countries. This paper describes the development and validation of a new gas density-based method for measuring BMP (GD-BMP). In the GD-BMP method, biogas composition is determined from biogas density. Biogas density is based on bottle mass loss and biogas volume, and these can be accurately measured using only a standard laboratory scale, inexpensive syringes, and a simple manometer. Results from four experiments carried out in three different laboratories showed that the GD-BMP method is both accurate (no significant bias compared to gravimetric or volumetric methods with biogas analysis by gas chromatography) and precise (<3% relative standard deviation is possible). BMP values from the GD-BMP method were also comparable to those measured for the same substrates with an industry standard automated system (AMPTS II) in two independent laboratories (maximum difference 10%). Additionally, the GD-BMP method was shown to be accurate even in the presence of leakage by excluding leakage from mass loss measurements. The proposed GD-BMP method represents a significant breakthrough for both biogas research and the industry. With it, accurate BMP measurement is possible with only a minimal investment in supplies and equipment.

Recently developed instrumentation at the University of Washington has allowed for nonresonant x-ray emission spectra (XES) to be measured in a laboratory-setting with an inexpensive, easily operated system. We present a critical evaluation of this equipment by means of Kβ and valence-level XES measurements for several Co compounds. We find peak count rates of ∼5000 s for concentrated samples and a robust relative energy scale with reproducibility of 25 meV or better. We furthermore find excellent agreement with synchrotron measurements with only modest loss in energy resolution. Instruments such as ours, based on only conventional sources that are widely sold for elemental analysis by x-ray fluorescence, can fill an important role to diversify the research applications of XES both by their presence in non-synchrotron laboratories and by their use in conjunction with XAFS beamlines where the complementarity of XAFS and XES holds high scientific potential.

We have recently demonstrated a very favorable, inexpensive modernization of lab- based x-ray absorption fine structure (XAFS) and high-resolution x-ray emission spectroscopy (XES) using only commercially-available optics and x-ray tube sources. Here, we survey several proven instrument designs that can be readily implemented in any laboratory setting to achieve synchrotron-quality XAFS and XES for many systems in the 5 keV to 10 keV energy range. These approaches are based on our immediate experience with the development of: (1) an inexpensive, low-powered monochromator capable of performing either XAFS or XES, (2) a mid-scale XAFS user facility having 106 sec flux with sub-eV bandwidth on each of two independent beamlines, and (3) multiple XES spectrometers having outstanding performance that can complement synchrotron XAFS studies in battery and actinide research.

The circulating acute phase reactant C-reactive protein (CRP) has traditionally been characterized as an effector of nonclonal host resistance since it activates the classical complement cascade and mediates phagocytosis, but it is also capable of regulating inflammation. The three-dimensional structure of human CRP has revealed the molecular basis for complement activation and binding of phosphate monoesters. CRP gene expression by liver hepatocytes in response to cytokines (IL-1beta and IL-6) released in tissues requires several transcription factors which interact. Elevated levels of CRP are a prognostic marker for coronary artery disease; however, the role of CRP in atheriosclerosis remains unknown. CRP also mediates direct host protection to some microbial pathogens via its opsonic activity through certain Fcgamma-receptors. The CRP response may be one of the links between nonspecific innate immunity and specific clonal immunity.