Search results

Osteopontin expression by CD103- dendritic cells drives intestinal inflammation.

28 June 2018

Intestinal CD103(-) dendritic cells (DCs) are pathogenic for colitis. Unveiling molecular mechanisms that render these cells proinflammatory is important for the design of specific immunotherapies. In this report, we demonstrated that mesenteric lymph node CD103(-) DCs express, among other proinflammatory cytokines, high levels of osteopontin (Opn) during experimental colitis. Opn expression by CD103(-) DCs was crucial for their immune profile and pathogenicity, including induction of T helper (Th) 1 and Th17 cell responses. Adoptive transfer of Opn-deficient CD103(-) DCs resulted in attenuated colitis in comparison to transfer of WT CD103(-) DCs, whereas transgenic CD103(-) DCs that overexpress Opn were highly pathogenic in vivo. Neutralization of secreted Opn expressed exclusively by CD103(-) DCs restrained disease severity. Also, Opn deficiency resulted in milder disease, whereas systemic neutralization of secreted Opn was therapeutic. We determined a specific domain of the Opn protein responsible for its CD103(-) DC-mediated proinflammatory effect. We demonstrated that disrupting the interaction of this Opn domain with integrin α9, overexpressed on colitic CD103(-) DCs, suppressed the inflammatory potential of these cells in vitro and in vivo. These results add unique insight into the biology of CD103(-) DCs and their function during inflammatory bowel disease.

Activin-A induces regulatory T cells that suppress T helper cell immune responses and protect from allergic airway disease.

2 July 2018

Activin-A is a pleiotropic cytokine that participates in developmental, inflammatory, and tissue repair processes. Still, its effects on T helper (Th) cell-mediated immunity, critical for allergic and autoimmune diseases, are elusive. We provide evidence that endogenously produced activin-A suppresses antigen-specific Th2 responses and protects against airway hyperresponsiveness and allergic airway disease in mice. Importantly, we reveal that activin-A exerts suppressive function through induction of antigen-specific regulatory T cells that suppress Th2 responses in vitro and upon transfer in vivo. In fact, activin-A also suppresses Th1-driven responses, pointing to a broader immunoregulatory function. Blockade of interleukin 10 and transforming growth factor beta1 reverses activin-A-induced suppression. Remarkably, transfer of activin-A-induced antigen-specific regulatory T cells confers protection against allergic airway disease. This beneficial effect is associated with dramatically decreased maturation of draining lymph node dendritic cells. Therapeutic administration of recombinant activin-A during pulmonary allergen challenge suppresses Th2 responses and protects from allergic disease. Finally, we demonstrate that immune cells infiltrating the lungs from individuals with active allergic asthma, and thus nonregulated inflammatory response, exhibit significantly decreased expression of activin-A's responsive elements. Our results uncover activin-A as a novel suppressive factor for Th immunity and a critical controller of allergic airway disease.

Initial Identification of a Blood-Based Chromosome Conformation Signature for Aiding in the Diagnosis of Amyotrophic Lateral Sclerosis.

16 August 2018

BACKGROUND: The identification of blood-based biomarkers specific to the diagnosis of amyotrophic lateral sclerosis (ALS) is an active field of academic and clinical research. While inheritance studies have advanced the field, a majority of patients do not have a known genetic link to the disease, making direct sequence-based genetic testing for ALS difficult. The ability to detect biofluid-based epigenetic changes in ALS would expand the relevance of using genomic information for disease diagnosis. METHODS: Assessing differences in chromosomal conformations (i.e. how they are positioned in 3-dimensions) represents one approach for assessing epigenetic changes. In this study, we used an industrial platform, EpiSwitch™, to compare the genomic architecture of healthy and diseased patient samples (blood and tissue) to discover a chromosomal conformation signature (CCS) with diagnostic potential in ALS. A three-step biomarker selection process yielded a distinct CCS for ALS, comprised of conformation changes in eight genomic loci and detectable in blood. FINDINGS: We applied the ALS CCS to determine a diagnosis for 74 unblinded patient samples and subsequently conducted a blinded diagnostic study of 16 samples. Sensitivity and specificity for ALS detection in the 74 unblinded patient samples were 83∙33% (CI 51∙59 to 97∙91%) and 76∙92% (46∙19 to 94∙96%), respectively. In the blinded cohort, sensitivity reached 87∙50% (CI 47∙35 to 99∙68%) and specificity was 75∙0% (34∙91 to 96∙81%). INTERPRETATIONS: The sensitivity and specificity values achieved using the ALS CCS identified and validated in this study provide an indication that the detection of chromosome conformation signatures is a promising approach to disease diagnosis and can potentially augment current strategies for diagnosing ALS. FUND: This research was funded by Oxford BioDynamics and Innovate UK. Work in the Oxford MND Care and Research Centre is supported by grants from the Motor Neurone Disease Association and the Medical Research Council. Additional support was provided by the Northeast ALS Consortium (NEALS).

Epigenetic signatures and early detection of neurodegenerative diseases: Development of stratifying biomarkers for amyotrophic. lateral sclerosis in Asian cohorts

12 July 2018

Progress and new frontiers in biomarkers for amyotrophic lateral sclerosis.

12 July 2018

How does sleep restriction therapy for insomnia work? A systematic review of mechanistic evidence and the introduction of the Triple-R model

23 July 2018

For over 30 years sleep restriction therapy (SRT) has been used to treat insomnia but we know very little about how this therapy exerts its effects. When SRT was first described, it was hypothesised to treat insomnia by addressing four key factors: strengthening homeostatic sleep pressure, inhibiting perpetuating practices (excessive time in bed), attenuating hyperarousal and tightening regulatory control of sleep by the endogenous circadian pacemaker. We conducted a systematic literature review in search of evidence for these putative mechanisms-of-action. A total of 15 randomised and non-randomised studies investigating SRT met inclusion criteria. For each study, we extracted all variables associated with the proposed mechanisms and assessed study quality using a structured appraisal tool. The extracted variables were: time in bed (TIB), napping, variability in sleep, markers of circadian rhythmicity, measurements of sleep pressure/sleepiness, and assessments of arousal. Overall study quality was poor as indicated by a mean quality score of 17 (out of a possible range of 0 to 31). No study indicated, or indeed was designed to test, whether changes in the proposed mechanisms act as mediators of treatment outcomes. Of all reviewed studies, most reported a reduction in TIB (10/10) and/or revealed a decrease in sleep onset latency (10/14), indexing increased sleep pressure. However, such changes were most often reported at the end of treatment, reflecting an outcome and not a mechanism of SRT per se. Evidence for reduction in arousal (4/4) and night-to-night sleep variability (2/2) was found in only a small number of uncontrolled studies while there was no evidence for change in circadian phase or periodicity (0/1). Our review suggests that SRT targets some of the hypothesised processes but specifically-designed mechanistic evaluations are needed. We introduce a new testable model of SRT mechanism-of-action (Triple-R) and set out a research agenda aimed at stimulating prospective investigations.

Health-related quality of life and psychological functioning in patients with primary malignant brain tumors: A systematic review of clinical, demographic and mental health factors

12 July 2018

© The Author(s) 2016. Background. The impact of primary malignant brain tumors on patient quality of life and psychological functioning is poorly understood, limiting the development of an evidence base for supportive interventions. We conducted a thorough systematic review and quality appraisal of the relevant literature to identify correlates of health-related quality of life (HRQoL) and psychological functioning (depression, anxiety and distress) in adults with primary malignant brain tumors. Method. Twenty-three articles met predefined inclusion criteria from a pool of peer-reviewed literature published between January 1984 and July 2015 (N 1/4 2407). Methodological quality of included studies was assessed using an adapted version of the Newcastle-Ottawa Scale. Results. The overall methodological quality of the literature was moderate. Factors relating consistently with HRQoL and/or psychological functioning were cognitive impairment, corticosteroid use, current or previous mental health difficulties, fatigue, functional impairment, performance status and motor impairment. Conclusions. Practitioners should remain alert to the presence of these factors as they may indicate patients at greater risk of poor HRQoL and psychological functioning. Attention should be directed towards improving patients' psychological functioning and maximizing functional independence to promote HRQoL. We outline several areas of future research with emphasis on improved methodological rigor.

Supraliminal But Not Subliminal Distracters Bias Working Memory Recall

12 July 2018

© 2015 APA, all rights reserved). Information of which observers are not consciously aware can nevertheless influence perceptual processes. Whether subliminal information might exert an influence on working memory (WM) representations is less clear, and relatively few studies have examined the interactions between subliminal and supraliminal information in WM. We present 3 experiments examining this issue. Experiments 1a and b replicated the finding that orientation stimuli can influence behavior subliminally in a visuomotor priming task. Experiments 2 and 3 used the same orientation stimuli, but participants had to remember a target orientation and report it back by adjusting a probe orientation after a memory delay. Before or after presentation of the target orientation, a subliminal or supraliminal distracter orientation was presented that was either irrelevant for task completion and never had to be reported (Experiment 2), or was relevant for task completion because it had to be reported on some trials (Experiment 3). In both experiments, presentation of a supraliminal distracter influenced WM recall of the target orientation. When the distracter was presented subliminally, however, there was no bias in orientation recall. These results suggest that information stored in WM is protected from influences of subliminal stimuli, while online information processing is modulated by subliminal information. (PsycINFO Database Record

Supraliminal But Not Subliminal Distracters Bias Working Memory Recall

12 July 2018

© 2015 APA, all rights reserved). Information of which observers are not consciously aware can nevertheless influence perceptual processes. Whether subliminal information might exert an influence on working memory (WM) representations is less clear, and relatively few studies have examined the interactions between subliminal and supraliminal information in WM. We present 3 experiments examining this issue. Experiments 1a and b replicated the finding that orientation stimuli can influence behavior subliminally in a visuomotor priming task. Experiments 2 and 3 used the same orientation stimuli, but participants had to remember a target orientation and report it back by adjusting a probe orientation after a memory delay. Before or after presentation of the target orientation, a subliminal or supraliminal distracter orientation was presented that was either irrelevant for task completion and never had to be reported (Experiment 2), or was relevant for task completion because it had to be reported on some trials (Experiment 3). In both experiments, presentation of a supraliminal distracter influenced WM recall of the target orientation. When the distracter was presented subliminally, however, there was no bias in orientation recall. These results suggest that information stored in WM is protected from influences of subliminal stimuli, while online information processing is modulated by subliminal information. (PsycINFO Database Record

Feature-based inhibition underlies the affective consequences of attention

12 July 2018

Rapid selection of a target in the presence of similar distractors can cause subsequent affective evaluation of a distractor to be more negative than that for the selected object. This distractor devaluation effect has previously been attributed to an association of attentional inhibition with the distractor's representation. Here, we investigated whether the associated inhibition leading to distractor devaluation is object based or feature based. Using colour-tinted face and building stimuli in a two-item simple visual search, followed by evaluation of face stimuli on a trustworthiness scale, we report that emotional evaluation was modified by prior attention whenever the search stimuli and the to-be-evaluated face shared the distractor feature, regardless of whether face identity seen in the two successive tasks matched or not. These data support the notion that inhibition can be feature-based and show that such inhibition can have emotional consequences.