The RNA-binding protein RIG-I is a key initiator of the antiviral innate immune response. The signaling that mediates the antiviral response downstream of RIG-I is transduced through the adaptor ...protein MAVS and results in the induction of type I and III interferons (IFNs). This signal transduction occurs at endoplasmic reticulum (ER)–mitochondrial contact sites, to which RIG-I and other signaling proteins are recruited following their activation. RIG-I signaling is highly regulated to prevent aberrant activation of this pathway and dysregulated induction of IFN. Previously, we identified UFL1, the E3 ligase of the ubiquitin-like modifier conjugation system called ufmylation, as one of the proteins recruited to membranes at ER–mitochondrial contact sites in response to RIG-I activation. Here, we show that UFL1, as well as the process of ufmylation, promote IFN induction in response to RIG-I activation. We found that following RNA virus infection, UFL1 is recruited to the membrane-targeting protein 14–3-3ε and that this complex is then recruited to activated RIG-I to promote downstream innate immune signaling. Importantly, we found that 14–3-3ε has an increase in UFM1 conjugation following RIG-I activation. Additionally, loss of cellular ufmylation prevents the interaction of 14–3-3ε with RIG-I, which abrogates the interaction of RIG-I with MAVS and thus the downstream signal transduction that induces IFN. Our results define ufmylation as an integral regulatory component of the RIG-I signaling pathway and as a posttranslational control for IFN induction.
Yoga is increasingly used in clinical settings for a variety of mental and physical health issues, particularly stress-related illnesses and concerns, and has demonstrated promising efficacy. Yet the ...ways in which yoga reduces stress remain poorly understood. To examine the empirical evidence regarding the mechanisms through which yoga reduces stress, we conducted a systematic review of the literature, including any yoga intervention that measured stress as a primary dependent variable and tested a mechanism of the relationship with mediation. Our electronic database search yielded 926 abstracts, of which 71 were chosen for further inspection and 5 were selected for the final systematic review. These five studies examined three psychological mechanisms (positive affect, mindfulness and self-compassion) and four biological mechanisms (posterior hypothalamus, interleukin-6, C-reactive protein and cortisol). Positive affect, self-compassion, inhibition of the posterior hypothalamus and salivary cortisol were all shown to mediate the relationship between yoga and stress. It is striking that the literature describing potential mechanisms is growing rapidly, yet only seven mechanisms have been empirically examined; more research is necessary. Also, future research ought to include more rigorous methodology, including sufficient power, study randomisation and appropriate control groups.
Background and Objectives: Managing stress is very important for first-year college students adjusting to undergraduate life. Aspects of emotion regulation, including mindfulness and the ability to ...regulate distressing emotion adaptively, often correlate positively with well-being. However, little research has examined overlapping and/or distinct effects of these constructs in predicting changes in adjustment over a stressful transition. Thus, the present study examined the contributions of mindfulness and adaptive emotion regulation abilities in maintaining well-being during the transition to college. We further examined experience with mind-body practices, which may promote mindfulness and positive adjustment.
Design: Online surveys were administered to 158 undergraduates near the beginning and end of their first semester.
Methods: Near semester start and end, students reported levels of mindfulness, adaptive emotion regulation abilities, emotional and spiritual well-being, and experience with mind-body practices.
Results: Compared to mindfulness, adaptive emotion regulation abilities largely demonstrated stronger cross-sectional and longitudinal associations with well-being. However, mindfulness uniquely protected against changes in depression for students with greater emotion regulation difficulties. Over half of participants reported having tried mind-body practices, but just 1% reported current use.
Conclusions: Promoting mindfulness practices and adaptive emotion regulation abilities at the start of college may build resilience in undergraduate students.
Summary
Objective
To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain‐of‐function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome.
...Methods
Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board (IRB)–approved KCNQ2 patient registry and database. We reviewed medical records and, where possible, interviewed parents and treating physicians using a structured, detailed phenotype inventory focusing on the neonatal presentation and subsequent course.
Results
Nine patients had encephalopathy from birth and presented with prominent startle‐like myoclonus, which could be triggered by sound or touch. In seven patients, electroencephalography (EEG) was performed in the neonatal period and showed a burst‐suppression pattern. However, myoclonus did not have an EEG correlate. In many patients the paroxysmal movements were misdiagnosed as seizures. Seven patients developed epileptic spasms in infancy. In all patients, EEG showed a slow background and multifocal epileptiform discharges later in life. Other prominent features included respiratory dysfunction (perinatal respiratory failure and/or chronic hypoventilation), hypomyelination, reduced brain volume, and profound developmental delay. One patient had a later onset, and sequencing indicated that a low abundance (~20%) R201C variant had arisen by postzygotic mosaicism.
Significance
Heterozygous KCNQ2 R201C and R201H gain‐of‐function variants present with profound neonatal encephalopathy in the absence of neonatal seizures. Neonates present with nonepileptic myoclonus that is often misdiagnosed and treated as seizures. Prognosis is poor. This clinical presentation is distinct from the phenotype associated with loss‐of‐function variants, supporting the value of in vitro functional screening. These findings suggest that gain‐of‐function and loss‐of‐function variants need different targeted therapeutic approaches.
The intestinal microbiota influences the development and function of the mucosal immune system. However, the exact mechanisms by which commensal microbes modulate immunity is not clear. We previously ...demonstrated that commensal Bacteroides ovatus ATCC 8384 reduces mucosal inflammation. Herein, we aimed to identify immunomodulatory pathways employed by B. ovatus. In germ-free mice, mono-association with B. ovatus shifted the CD11b+/CD11c+ and CD103+/CD11c+ dendritic cell populations. Because indole compounds are known to modulate dendritic cells, B. ovatus cell-free supernatant was screened for tryptophan metabolites by liquid chromatography–tandem mass spectrometry and larger quantities of indole-3-acetic acid were detected. Analysis of cecal and fecal samples from germ-free and B. ovatus mono-associated mice confirmed that B. ovatus could elevate indole-3-acetic acid concentrations in vivo. Indole metabolites have previously been shown to stimulate immune cells to secrete the reparative cytokine IL-22. Addition of B. ovatus cell-free supernatant to immature bone marrow–derived dendritic cells stimulated IL-22 secretion. The ability of IL-22 to drive repair in the intestinal epithelium was confirmed using a physiologically relevant human intestinal enteroid model. Finally, B. ovatus shifted the immune cell populations in trinitrobenzene sulfonic acid–treated mice and up-regulated colonic IL-22 expression, effects that correlated with decreased inflammation. Our data suggest that B. ovatus–produced indole-3-acetic acid promotes IL-22 production by immune cells, yielding beneficial effects on colitis.
The immune phenotype of perinatal anxiety Sherer, Morgan L.; Voegtline, Kristin M.; Park, Han-Sol ...
Brain, behavior, and immunity,
November 2022, 2022-11-00, 20221101, Letnik:
106
Journal Article
Recenzirano
•The antenatal immune response differs for women with anxiety symptoms compared to those without, suggestive of a unique immune phenotype of perinatal anxiety.•Compared to women in the Non-Anxiety ...group, women in the Anxiety group had lower levels of cytokine expression during pregnancy and increased levels postpartum.•Immune cell populations differ between our two groups with the Anxiety group showing a decrease in the ratio of B cells to T cells from pregnancy to postpartum, an increased ratio of cytotoxic to helper T cells throughout pregnancy, a modest increase in the TH1:TH2 ratio across pregnancy, and a lower ratio of TH17:TREG cells in the postpartum as compared with Non-Anxiety women.
Immune dysregulation has been linked to both psychiatric illness and pregnancy morbidity, including perinatal depression, but little is known about the immune phenotype of perinatal anxiety. Here, we sought to identify the unique immune profile of antenatal anxiety.
Pregnant women (n = 107) were followed prospectively at 2nd and 3rd trimesters (T2, T3) and 6 weeks postpartum (PP6). Each visit included a blood draw and psychological evaluation, with clinical anxiety assessed using the Spielberg State-Trait Anxiety Scale. We enrolled both healthy controls and participants with anxiety alone; those with comorbid depression were excluded. Multiplex cytokine assays and flow cytometry were used to examine the association of anxiety symptoms with secreted immune markers and PBMC-derived immune cells.
K cluster means revealed three clusters of anxiety symptomatology; due to low numbers in the highest severity anxiety group, these were collapsed into two groups: Non-Anxiety and Anxiety. Principal components analysis revealed two distinct clusters of cytokine secretion including one cluster that consisted of many innate immune cytokines and differed between groups. Compared to women in the Non-Anxiety group, women in the Anxiety group had lower levels of cytokine expression during pregnancy and an increase in levels into the postpartum, whereas Non-Anxiety women experienced a time-dependent decline. Immune cell populations also differed between our two groups, with the Anxiety group showing a decrease in the ratio of B cells to T cells from pregnancy to postpartum, whereas the Non-Anxiety women showed an increase in this ratio over time. Women in the Anxiety group also demonstrated an increased ratio of cytotoxic to helper T cells throughout pregnancy, a modest increase in the Th1:Th2 ratio across pregnancy, and a lower ratio of Th17:TREG cells in the postpartum as compared with Non-Anxiety women.
These data suggest that the immune response throughout the antenatal period differs for women with anxiety symptoms compared to those without, suggestive of a unique immune phenotype of perinatal anxiety.
Air pollution exposure is associated with negative health consequences among children and adolescents. Physical activity is recommended for all children/adolescents due to benefits to health and ...development. However, it is unclear if physically active children have additional protective benefits when exposed to higher levels of air pollution, compared to less active children. This systematic review evaluates all available literature since 2000 and examines if effect measure modification (EMM) exists between air pollution exposure and health outcomes among children/adolescents partaking in regular physical activity. PubMed, Science Direct, Scopus, Web of Science, and ProQuest Agricultural & Environmental Science databases were queried, identifying 2686 articles. Title/abstract screening and full-text review eliminated 2620 articles, and 56 articles were removed for evaluating individuals >21, leaving 10 articles for review. Of the included articles, half were conducted in China, three in the United States, and one each in Indonesia and Germany. Seven articles identified EMM between active children and air-pollution related health outcomes. Five of these indicated that children/adolescents do not experience any additional benefits from being physically active in higher levels of air pollution, with some studies implying active children may experience additional detriments, compared to less active children. However, the remaining two EMM studies highlighted modest benefits of having a higher activity level, even in polluted air. Overall, active children/adolescents may be at greater risk from air pollution exposure, but results were not consistent across all studies. Future studies assessing the intersection between air pollution and regular physical activity among children would be useful.
•Exercise can provide health benefits in clean areas, less likely in polluted areas.•In polluted areas, active children may have worse health outcomes versus less active.•Active children may be at greater risk from air pollution exposure, more studies needed.
As part of an initiative led by the Brain Injury Special Interest Group Mild Traumatic Brain Injury (TBI) Task Force of the American Congress of Rehabilitation Medicine (ACRM) to update the 1993 ACRM ...definition of mild TBI, the present study aimed to characterize current expert opinion on diagnostic considerations.
Cross-sectional web-based survey.
Not applicable.
An international, interdisciplinary group of clinician-scientists (N=31) with expertise in mild TBI completed the survey by invitation between May and July 2019 (100% completion rate).
Not applicable.
Ratings of agreement with statements related to the diagnosis of mild TBI and ratings of the importance of various clinical signs, symptoms, test findings, and contextual factors for increasing the likelihood that the individual sustained a mild TBI, on a scale ranging from 1 (“not at all important”) to 10 (“extremely important”).
Men (n=25; 81%) and Americans (n=21; 68%) were over-represented in the sample. The survey revealed areas of expert agreement (eg, acute symptoms are diagnostically useful) and disagreement (eg, whether mild TBI with abnormal structural neuroimaging should be considered the same diagnostic entity as “concussion”). Observable signs were generally rated as more diagnostically important than subjective symptoms (Wilcoxon signed ranks test, Z=3.77; P<.001; r=0.68). Diagnostic importance ratings for individual symptoms varied widely, with some common postconcussion symptoms (eg, fatigue) rated as unhelpful (<75% of respondents indicated at least 5 out of 10 importance). Certain acute test findings (eg, cognitive and balance impairments) and contextual factors (eg, absence of confounds) were consistently rated as highly important for increasing the likelihood of a mild TBI diagnosis (≥75% of respondents indicated at least 7 out of 10).
The expert survey findings identified several potential revisions to consider when updating the ACRM mild TBI definition, including preferentially weighing observable signs in a probabilistic framework, incorporating symptoms and test findings, and adding differential diagnosis considerations.
Deep learning has the potential to augment clinician performance in medical imaging interpretation and reduce time to diagnosis through automated segmentation. Few studies to date have explored this ...topic.
To develop and apply a neural network segmentation model (the HeadXNet model) capable of generating precise voxel-by-voxel predictions of intracranial aneurysms on head computed tomographic angiography (CTA) imaging to augment clinicians' intracranial aneurysm diagnostic performance.
In this diagnostic study, a 3-dimensional convolutional neural network architecture was developed using a training set of 611 head CTA examinations to generate aneurysm segmentations. Segmentation outputs from this support model on a test set of 115 examinations were provided to clinicians. Between August 13, 2018, and October 4, 2018, 8 clinicians diagnosed the presence of aneurysm on the test set, both with and without model augmentation, in a crossover design using randomized order and a 14-day washout period. Head and neck examinations performed between January 3, 2003, and May 31, 2017, at a single academic medical center were used to train, validate, and test the model. Examinations positive for aneurysm had at least 1 clinically significant, nonruptured intracranial aneurysm. Examinations with hemorrhage, ruptured aneurysm, posttraumatic or infectious pseudoaneurysm, arteriovenous malformation, surgical clips, coils, catheters, or other surgical hardware were excluded. All other CTA examinations were considered controls.
Sensitivity, specificity, accuracy, time, and interrater agreement were measured. Metrics for clinician performance with and without model augmentation were compared.
The data set contained 818 examinations from 662 unique patients with 328 CTA examinations (40.1%) containing at least 1 intracranial aneurysm and 490 examinations (59.9%) without intracranial aneurysms. The 8 clinicians reading the test set ranged in experience from 2 to 12 years. Augmenting clinicians with artificial intelligence-produced segmentation predictions resulted in clinicians achieving statistically significant improvements in sensitivity, accuracy, and interrater agreement when compared with no augmentation. The clinicians' mean sensitivity increased by 0.059 (95% CI, 0.028-0.091; adjusted P = .01), mean accuracy increased by 0.038 (95% CI, 0.014-0.062; adjusted P = .02), and mean interrater agreement (Fleiss κ) increased by 0.060, from 0.799 to 0.859 (adjusted P = .05). There was no statistically significant change in mean specificity (0.016; 95% CI, -0.010 to 0.041; adjusted P = .16) and time to diagnosis (5.71 seconds; 95% CI, 7.22-18.63 seconds; adjusted P = .19).
The deep learning model developed successfully detected clinically significant intracranial aneurysms on CTA. This suggests that integration of an artificial intelligence-assisted diagnostic model may augment clinician performance with dependable and accurate predictions and thereby optimize patient care.
Depression and fatigue are common among cancer patients and are associated with germline genetic variation. The goal of this pilot study was to examine genetic associations with depression and ...fatigue in the year after allogeneic hematopoietic cell transplant (HCT).
Blood was collected from patients and their donors before HCT. Patients completed self-report measures of depression and fatigue before HCT (T1), 90 days post-HCT (T2), and 1 year post-HCT (T3). Of the 384 genetic variants genotyped on a custom Illumina BeadChip microarray, 267 were retained for analysis based on quality control. Main effects of patient and donor variants as well as their interaction were examined using regression analyses. Significant variants were defined as those with a false discovery rate-adjusted p value of <.05.
The sample consisted of 59 patient-donor pairs. Mean levels of depression and fatigue did not change significantly over time ( p values of > .41). Increases in depression from T1 to T2 were associated with patient-donor interactions at rs1928040 ( p = 3.0 × 10 -4 ) and rs6311 ( p = 2.0 × 10 -4 ) in HTR2A . Increases in fatigue from T1 to T2 were associated with patient rs689021 in SORL1 ( p = 6.0 × 10 -5 ) and a patient-donor interaction at rs1885884 in HTR2A ( p < 1.0 × 10 -4 ).
Data suggest that variants in genes regulating the serotonergic system ( HTR2A ) and lipid metabolism ( SORL1 ) are associated with changes in depression and fatigue in allogeneic HCT patients, implicating patients' own genetic inheritance as well as that of donors. Additional studies are warranted to confirm these findings.
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