Vaccine-induced inflammation and inflammatory monocytes promote CD4+ T cell-dependent immunity against murine salmonellosis.

Prior infection can generate protective immunity against subsequent infection, although the efficacy of such immunity can vary considerably. Live-attenuated vaccines (LAVs) are one of the most effective methods for mimicking this natural process, and analysis of their efficacy has proven instrumental in the identification of protective immune mechanisms. Here, we address the question of what makes a LAV efficacious by characterising immune responses to a LAV, termed TAS2010, which is highly protective (80-90%) against lethal murine salmonellosis, in comparison with a moderately protective (40-50%) LAV, BRD509. Mice vaccinated with TAS2010 developed immunity systemically and were protected against gut-associated virulent infection in a CD4+ T cell-dependent manner. TAS2010-vaccinated mice showed increased activation of Th1 responses compared with their BRD509-vaccinated counterparts, leading to increased Th1 memory populations in both lymphoid and non-lymphoid organs. The optimal development of Th1-driven immunity was closely correlated with the activation of CD11b+Ly6GnegLy6Chi inflammatory monocytes (IMs), the activation of which can be modulated proportionally by bacterial load in vivo. Upon vaccination with the LAV, IMs expressed T cell chemoattractant CXCL9 that attracted CD4+ T cells to the foci of infection, where IMs also served as a potent source of antigen presentation and Th1-promoting cytokine IL-12. The expression of MHC-II in IMs was rapidly upregulated following vaccination and then maintained at an elevated level in immune mice, suggesting IMs may have a role in sustained antigen stimulation. Our findings present a longitudinal analysis of CD4+ T cell development post-vaccination with an intracellular bacterial LAV, and highlight the benefit of inflammation in the development of Th1 immunity. Future studies focusing on the induction of IMs may reveal key strategies for improving vaccine-induced T cell immunity.

An evaluation of empirical and statistically based smoke plume injection height parametrisations used within air quality models.

Air quality models are used to assess the impact of smoke from wildland fires, both prescribed and natural, on ambient air quality and human health. However, the accuracy of these models is limited by uncertainties in the parametrisation of smoke plume injection height (PIH) and its vertical distribution. We compared PIH estimates from the plume rise method (Briggs) in the Community Multiscale Air Quality (CMAQ) modelling system with observations from the 2013 California Rim Fire and 2017 prescribed burns in Kansas. We also examined PIHs estimated using alternative plume rise algorithms, model grid resolutions and temporal burn profiles. For the Rim Fire, the Briggs method performed as well or better than the alternatives evaluated (mean bias of less than ±5-20% and root mean square error lower than 1000 m compared with the alternatives). PIH estimates for the Kansas prescribed burns improved when the burn window was reduced from the standard default of 12 h to 3 h. This analysis suggests that meteorological inputs, temporal allocation and heat release are the primary drivers for accurately modelling PIH.

Onco-miR-21 Promotes Stat3-Dependent Gastric Cancer Progression.

MicroRNA-21 (miR-21) is a small, non-coding RNA overexpressed in gastric cancer and many other solid malignancies, where it exhibits both pro-and anti-tumourigenic properties. However, the pathways regulating miR-21 and the consequences of its inhibition in gastric cancer remain incompletely understood. By exploiting the spontaneous Stat3-dependent formation of inflammation-associated gastric tumors in Gp130F/F mice, we functionally established miR-21 as a Stat3-controlled driver of tumor growth and progression. We reconciled our discoveries by identifying several conserved Stat3 binding motifs upstream of the miR-21 gene promoter, and showed that the systemic administration of a miR-21-specific antisense oligonucleotide antagomir reduced the established gastric tumor burden in Gp130F/F mice. We molecularly delineated the therapeutic benefits of miR-21 inhibition with the functional restoration of PTEN in vitro and in vivo, alongside an attenuated epithelial-to-mesenchymal transition and the extracellular matrix remodeling phenotype of tumors. We corroborated our preclinical findings by correlating high STAT3 and miR-21 expression with the reduced survival probability of gastric cancer patients. Collectively, our results provide a molecular framework by which miR-21 mediates inflammation-associated gastric cancer progression, and establish miR-21 as a robust therapeutic target for solid malignancies characterized by excessive Stat3 activity.

Bright Light Therapy to Treat Depression in Individuals with Mild/Moderate or Severe Dementia.

This secondary analysis examined whether the benefits of bright light therapy on depression are greater in persons with mild/moderate or severe dementia. Exploratory analyses were also conducted to determine if bright light treatment targets different depressive symptom clusters based on dementia severity. Analyses using total scores from the instruments, Depressive Symptom Assessment for Older Adults and the Cornell Scale for Depression in Dementia, showed that bright light exposure is an equally effective intervention for depression in persons with both mild/moderate and severe dementia. Analyses of individual depressive subscales revealed that for disagreeable behavior and sleep impairment, bright light therapy appears to have greater benefits in persons with severe dementia than for those with mild/moderate dementia. Overall, this investigation supports the use of bright light therapy to treat depression regardless of dementia severity.

The impact of US wildland fires on ozone and particulate matter: a comparison of measurements and CMAQ model predictions from 2008 to 2012.

Wildland fire emissions are routinely estimated in the US Environmental Protection Agency's National Emissions Inventory, specifically for fine particulate matter (PM2.5) and precursors to ozone (O3); however, there is a large amount of uncertainty in this sector. We employ a brute-force zero-out sensitivity method to estimate the impact of wildland fire emissions on air quality across the contiguous US using the Community Multiscale Air Quality (CMAQ) modelling system. These simulations are designed to assess the importance of wildland fire emissions on CMAQ model performance and are not intended for regulatory assessments. CMAQ ver. 5.0.1 estimated that fires contributed 11% to the mean PM2.5 and less than 1% to the mean O3 concentrations during 2008-2012. Adding fires to CMAQ increases the number of 'grid-cell days' with PM2.5 above 35 µg m-3 by a factor of 4 and the number of grid-cell days with maximum daily 8-h average O3 above 70 ppb by 14%. Although CMAQ simulations of specific fires have improved with the latest model version (e.g. for the 2008 California wildfire episode, the correlation r = 0.82 with CMAQ ver. 5.0.1 v. r = 0.68 for CMAQ ver. 4.7.1), the model still exhibits a low bias at higher observed concentrations and a high bias at lower observed concentrations. Given the large impact of wildland fire emissions on simulated concentrations of elevated PM2.5 and O3, improvements are recommended on how these emissions are characterised and distributed vertically in the model.

Generation of an inducible mouse model to reversibly silence Stat3.

Signal transducer and activator of transcription 3 (Stat3) is a transcription factor that has many essential roles during inflammation, development and cancer. Stat3 is therefore an attractive therapeutic target in many diseases. While current Stat3 knockout mouse models led to a better understanding of the role of Stat3, the irreversible nature of Stat3 ablation does not model the effects of transient Stat3 therapeutic inhibition, and does not inform on potential dosage effects of Stat3. Using RNAi technology, we have generated a new mouse model allowing the inducible and reversible silencing of Stat3 in vivo, which mirrors the effects of specific Stat3 therapeutic interference. We showed that upon Doxycycline-mediated activation of the Stat3 short-hairpin RNA, Stat3 expression was efficiently reduced by about 80% in multiple organs and cell types. Moreover, Stat3 reduction was sufficient to reduce tumor burden in a clinically-validated mouse model of gastric cancer. Finally, we demonstrated that Stat3 silencing during embryonic development led to reduced birth rate without leading to complete embryonic lethality, in contrast to full Stat3 ablation. In conclusion, this new mouse model will be invaluable to understand the effects of Stat3 therapeutic interference and Stat3 dosage effects.

Effect of Bright Light Exposure on Depression and Agitation in Older Adults with Dementia.

This study examined the effects of bright light exposure on three measures of depression and four measures of agitation in persons with dementia residing in long-term care. Using a randomized controlled design, participants were randomly assigned to receive either bright light (n = 30) or low intensity light (n = 30) for eight weeks. Bright light exposure was associated with significant improvement in depression and agitation, while participants receiving low intensity light displayed higher levels of depression and agitation or no significant change. Findings support the use of bright light exposure to reduce depression and agitation in this population.

mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice.

Gastrointestinal cancers are frequently associated with chronic inflammation and excessive secretion of IL-6 family cytokines, which promote tumorigenesis through persistent activation of the GP130/JAK/STAT3 pathway. Although tumor progression can be prevented by genetic ablation of Stat3 in mice, this transcription factor remains a challenging therapeutic target with a paucity of clinically approved inhibitors. Here, we uncovered parallel and excessive activation of mTOR complex 1 (mTORC1) alongside STAT3 in human intestinal-type gastric cancers (IGCs). Furthermore, in a preclinical mouse model of IGC, GP130 ligand administration simultaneously activated mTORC1/S6 kinase and STAT3 signaling. We therefore investigated whether mTORC1 activation was required for inflammation-associated gastrointestinal tumorigenesis. Strikingly, the mTORC1-specific inhibitor RAD001 potently suppressed initiation and progression of both murine IGC and colitis-associated colon cancer. The therapeutic effect of RAD001 was associated with reduced tumor vascularization and cell proliferation but occurred independently of STAT3 activity. We analyzed the mechanism of GP130-mediated mTORC1 activation in cells and mice and revealed a requirement for JAK and PI3K activity but not for GP130 tyrosine phosphorylation or STAT3. Our results suggest that GP130-dependent activation of the druggable PI3K/mTORC1 pathway is required for inflammation-associated gastrointestinal tumorigenesis. These findings advocate clinical application of PI3K/mTORC1 inhibitors for the treatment of corresponding human malignancies.

Childhood victimization, poly-victimization, and adjustment to college in women.

This study examines the relationships among poly-victimization (i.e., high cumulative levels of victimization), six aggregate categories of childhood victimization (property crime, physical assault, peer and sibling, witnessed and indirect, sexual, child maltreatment), and college adjustment in females. This study first examines the relative contributions of poly-victimization and individual categories of childhood victimization in predicting college adjustment. The study then examines whether poly-victimization contributes any unique variance, beyond that accounted for by the combination of all six aggregate categories. Regression analyses reveal that a) poly-victimization accounts for a significant proportion of variability in scores for college adjustment, beyond that accounted for by any of the six categories of childhood victimization alone, and b) the categories of childhood victimization contribute little to no variability beyond that accounted for by poly-victimization. Furthermore, poly-victimization accounts for a significant proportion of variability in college adjustment, beyond that already accounted for by the simultaneous entry of all six categories as predictor variables. Finally, although victimization does not predict GPA, it predicts other domains of college adjustment. Results suggest that counselors working with college students should a) assess multiple categories of victimization and poly-victimization, and b) evaluate clients' adjustment to college across multiple domains (e.g., academic, social, interpersonal).

Polyvictimization, childhood victimization, and psychological distress in college women.

Two studies examined the relationships among polyvictimization (i.e., high cumulative levels of victimization), six categories of childhood victimization (i.e., property crime, physical assault, peer/sibling, witnessed/indirect, sexual, and child maltreatment), and current psychological symptomatology in college females. Results indicated that exposure to multiple types of childhood victimization is common. Regression analyses revealed that polyvictimization accounted for a significant proportion of variability in scores for psychological distress beyond that accounted for by any victimization category alone. Moreover, the six categories separately accounted for little to no variability beyond that accounted for by polyvictimization. Finally, polyvictimization accounted for a significant proportion of variability in scores for psychological distress, beyond that already accounted for through the simultaneous entry of all six categories of victimization. Findings reiterate the importance for clinicians and researchers to comprehensively assess multiple categories of childhood victimization and polyvictimization and provide preliminary evidence that the total number of lifetime victimizations is at least as important, if not more important, than individual categories of victimization in predicting psychological distress.

Searching from the top down: ageing and attentional guidance during singleton detection.

Previous investigations of adult age differences in visual search suggest that an age-related decline may exist in attentional processes dependent on the observer's knowledge of task-relevant features (top-down processing). The present experiments were conducted to examine age-related changes in top-down attentional guidance during a highly efficient form of search, singleton detection. In Experiment 1 reaction times to detect targets were lower when target features were constant (feature condition) than when target features were allowed to vary between trials (mixed condition), and this reaction time benefit was similar for younger and older adults. Experiments 2 and 3 investigated possible interactions between top-down and bottom-up (stimulus-driven) processes. Experiment 2 demonstrated that search times for both age groups could be improved when targets varied on an additional feature from distractors (double-feature condition) but only when top-down control was available (feature search). In Experiment 3, the availability of top-down guidance enabled both younger and older adults to override the distracting effects of a noninformative spatial location cue. 'l'hese findings indicate that top-down attentional control mechanisms interact with bottom-up processes to guide search for targets, and that in the context of singleton detection these mechanisms of top-down control are preserved for older adults.

Cardiovascular reactivity and family history of hypertension: a meta-analysis.

A regression-based meta-analysis examined the degree to which the effects of a family history of hypertension on cardiovascular reactivity are moderated by the magnitude of cardiovascular responses elicited in challenge/task conditions. Mean change scores for negative family history groups were regressed on mean change scores for positive family history groups. The slopes of separate regression lines obtained for systolic and diastolic blood pressure and heart rate were significantly less than 1.0 and the y-intercepts for these regression lines were significantly greater than zero. This pattern indicates that family history differences in cardiovascular reactivity to stress are greatest in situations that elicit the smallest baseline-stressor change scores in non-family-history groups.

Age differences in factor analysis of EEG.

This study examined age differences in the factor structure of EEG using a 128-electrode system. Running EEG records were obtained from healthy younger and healthy older adults before, during, and after they performed a 13-minute Continuous Performance Task. Factor analyses were conducted on each five-second segment of EEG data by treating the voltages obtained at each electrode site as variables and each measurement epoch as a case. Results showed that the EEG records of older adults yielded significantly more factors than those of younger adults in every task condition. In addition, eigenvalues for the first common factor derived from EEG data sets were significantly larger in the EEG recordings of younger adults than older adults. The results are interpreted to indicate a greater degree of complexity in the spatial distribution of EEG activity in older adults, possibly reflecting an age-related decrease in the degree of coordination among cortical areas.

Application of a risk assessment based approach to designing ambient air quality monitoring networks for evaluating non-cancer health impacts.

An ambient air quality monitoring network has been established using risk assessment techniques to evaluate adverse health effects from exposures to airborne contaminants. The risk assessment method was compared to traditional methods of establishing air quality monitoring networks: identifying m aximum concentration impacts or maximum total population. Results suggest that the health risk method best predicted the location of adverse, non-carcinogenic respiratory illnesses during the evaluation period. Spearman Rank Correlation Coefficient, r(s), values obtained using the risk assessment method were statistically greater than the values obtained using the concentration and population methods. The concentration method was the least accurate predictor of adverse effects.

Biogenic Fraction of Ambient VOC: Comparison of Radiocarbon, Chromatographic, and Emissions Inventory Estimates for Atlanta, Georgia.

Previously reported volatile organic compounds (VOC) radiocarbon (14C) measurements for 1992 summertime Atlanta, GA, have been compared with chromatographic data and emissions inventory predictions. The chromatographic approach that was used provided a more comprehensive VOC characterization than typically achieved, and the emissions inventory was research-grade level (date-, site-, and time-specific). The comparisons are in general agreement that biogenic emissions contribute only modestly (<10%) to the VOC content of the particular ambient samples that were collected and measured. The choices of sampling site (near city-center) and times (early morning and late evening) are major influences on the results, which consequently should not be regarded as representing the average VOC biogenic impact for the Atlanta area.