ABSTRACT
Alternative splicing (AS) generates multiple RNA isoforms and increases the complexities of transcriptomes and proteomes. However, it remains unclear how RNA structures contribute to AS regulation. Here, we systematically search transcriptomes for secondary structures with concealed branch sites (BSs) in the alternatively spliced introns and predict thousands of them from six organisms, of which many are evolutionarily conserved. Intriguingly, a highly conserved stem-loop structure with concealed BSs is found in animal SF3B3 genes and colocalizes with a downstream poison exon (PE). Destabilization of this structure allows increased usage of the BSs and results in enhanced PE inclusion in human and Drosophila cells, leading to decreased expression of SF3B3. This structure is experimentally validated using an in-cell SHAPE-MaP assay. Through RNA interference screens of 28 RNA-binding proteins, we find that this stem-loop structure is sensitive to U2 factors. Furthermore, we find that SF3B3 also facilitates DNA repair and protects genome stability by enhancing interaction between ERCC6/CSB and arrested RNA polymerase II. Importantly, both Drosophila and human cells with the secondary structure mutated by genome editing exhibit altered DNA repair in vivo. This study provides a novel and common mechanism for AS regulation of PEs and reveals a physiological function of SF3B3 in DNA repair.
Subject(s)
Alternative Splicing , Exons , Introns , Animals , Humans , Conserved Sequence , Drosophila/genetics , Drosophila melanogaster/genetics , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Exons/genetics , Introns/genetics , Nucleic Acid Conformation , RNA Splicing Factors/genetics , RNA Splicing Factors/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Codon, NonsenseABSTRACT
Sleep loss robustly disrupts mood and emotion regulation in healthy individuals but can have a transient antidepressant effect in a subset of patients with depression. The neural mechanisms underlying this paradoxical effect remain unclear. Previous studies suggest that the amygdala and dorsal nexus (DN) play key roles in depressive mood regulation. Here, we used functional MRI to examine associations between amygdala- and DN-related resting-state connectivity alterations and mood changes after one night of total sleep deprivation (TSD) in both healthy adults and patients with major depressive disorder using strictly controlled in-laboratory studies. Behavioral data showed that TSD increased negative mood in healthy participants but reduced depressive symptoms in 43% of patients. Imaging data showed that TSD enhanced both amygdala- and DN-related connectivity in healthy participants. Moreover, enhanced amygdala connectivity to the anterior cingulate cortex (ACC) after TSD associated with better mood in healthy participants and antidepressant effects in depressed patients. These findings support the key role of the amygdala-cingulate circuit in mood regulation in both healthy and depressed populations and suggest that rapid antidepressant treatment may target the enhancement of amygdala-ACC connectivity.
Subject(s)
Depressive Disorder, Major , Adult , Humans , Depressive Disorder, Major/diagnostic imaging , Depressive Disorder, Major/drug therapy , Sleep Deprivation/diagnostic imaging , Amygdala/diagnostic imaging , Gyrus Cinguli/diagnostic imaging , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Magnetic Resonance Imaging/methodsABSTRACT
Sleep loss impacts a broad range of brain and cognitive functions. However, how sleep deprivation affects risky decision-making remains inconclusive. This study used functional MRI to examine the impact of one night of total sleep deprivation (TSD) on risky decision-making behavior and the underlying brain responses in healthy adults. In this study, we analyzed data from N = 56 participants in a strictly controlled 5-day and 4-night in-laboratory study using a modified Balloon Analogue Risk Task. Participants completed two scan sessions in counter-balanced order, including one scan during rested wakefulness (RW) and another scan after one night of TSD. Results showed no differences in participants' risk-taking propensity and risk-induced activation between RW and TSD. However, participants showed significantly reduced neural activity in the anterior cingulate cortex and bilateral insula for loss outcomes, and in bilateral putamen for win outcomes during TSD compared with RW. Moreover, risk-induced activation in the insula negatively correlated with participants' risk-taking propensity during RW, while no such correlations were observed after TSD. These findings suggest that sleep loss may impact risky decision-making by attenuating neural responses to decision outcomes and impairing brain-behavior associations.
Subject(s)
Decision Making , Sleep Deprivation , Adult , Humans , Decision Making/physiology , Brain , Cognition , Gyrus Cinguli , Magnetic Resonance Imaging , Risk-TakingABSTRACT
Sleep spindles (SP) are one of the few known electrophysiological neuronal biomarkers of interindividual differences in cognitive abilities and aptitudes. Recent simultaneous electroencephalography with functional magnetic resonance imaging (EEG-fMRI) studies suggest that the magnitude of the activation of brain regions recruited during spontaneous spindle events is specifically related to Reasoning abilities. However, it is not known if the relationship with cognitive abilities differs between uncoupled spindles, uncoupled slow waves (SW), and coupled SW-SP complexes, nor have the functional-neuroanatomical substrates that support this relationship been identified. Here, we investigated the functional significance of activation of brain areas recruited during SW-coupled spindles, uncoupled spindles, and uncoupled slow waves. We hypothesize that brain activations time locked to SW-coupled spindle complexes will be primarily associated to Reasoning abilities, especially in subcortical areas. Our results provide direct evidence that the relationship between Reasoning abilities and sleep spindles depends on spindle coupling status. Specifically, we found that the putamen and thalamus, recruited during coupled SW-SP events were positively correlated with Reasoning abilities. In addition, we found a negative association between Reasoning abilities and hippocampal activation time-locked to uncoupled SWs that might reflect a refractory mechanism in the absence of new, intensive hippocampal-dependent memory processing.
Subject(s)
Sleep, Slow-Wave , Sleep/physiology , Electroencephalography/methods , Cognition , Brain/physiologyABSTRACT
Sleep consolidates procedural memory for motor skills, and this process is associated with strengthened functional connectivity in hippocampal-striatal-cortical areas. It is unknown whether similar processes occur for procedural memory that requires cognitive strategies needed for problem-solving. It is also unclear whether a full night of sleep is indeed necessary for consolidation to occur, compared with a daytime nap. We examined how resting-state functional connectivity within the hippocampal-striatal-cortical network differs after offline consolidation intervals of sleep, nap, or wake. Resting-state fMRI data were acquired immediately before and after training on a procedural problem-solving task that requires the acquisition of a novel cognitive strategy and immediately prior to the retest period (i.e., following the consolidation interval). ROI to ROI and seed to whole-brain functional connectivity analyses both specifically and consistently demonstrated strengthened hippocampal-prefrontal functional connectivity following a period of sleep versus wake. These results were associated with task-related gains in behavioral performance. Changes in functional communication were also observed between groups using the striatum as a seed. Here, we demonstrate that at the behavioral level, procedural strategies benefit from both a nap and a night of sleep. However, a full night of sleep is associated with enhanced functional communication between regions that support problem-solving skills.
Subject(s)
Memory Consolidation , Sleep , Brain/diagnostic imaging , Magnetic Resonance Imaging , Motor Skills , HumansABSTRACT
The study investigated the protective effect and mechanism of 2-phenylethyl-beta-glucopyranoside(Phe) from Huaizhong No.1 Rehmannia glutinosa on hypoxic pulmonary hypertension(PH), aiming to provide a theoretical basis for clinical treatment of PAH. Male C57BL/6N mice were randomly divided into normal group, model group, positive drug(bosentan, 100 mg·kg~(-1)) group, and low-and high-dose Phe groups(20 and 40 mg·kg~(-1)). Except for the normal group, all other groups were continuously subjected to model induction in a 10% hypoxic environment for 5 weeks, with oral administration for 14 days starting from the 3rd week. The cardiopulmonary function, right ventricular pressure, cough and asthma index, lung injury, cell apoptosis, oxidative stress-related indicators, immune cells, and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/hypoxic inducible factor 1α(HIF-1α) pathway-related proteins or mRNA levels were examined. Furthermore, hypoxia-induced pulmonary arterial smooth muscle cell(PASMC) were used to further explore the mechanism of Phe intervention in PH combined with PI3K ago-nist(740Y-P). The results showed that Phe significantly improved the cardiopulmonary function of mice with PH, decreased right ventricular pressure, cough and asthma index, and lung injury, reduced cell apoptosis, oxidative stress-related indicators, and nuclear levels of phosphorylated Akt(p-Akt) and phosphorylated mTOR(p-mTOR), inhibited the expression levels of HIF-1α and PI3K mRNA and proteins, and maintained the immune cell homeostasis in mice. Further mechanistic studies revealed that Phe significantly reduced the viability and migration ability of hypoxia-induced PASMC, decreased the expression of HIF-1α and PI3K proteins and nuc-lear levels of p-Akt and p-mTOR, and this effect was blocked by 740Y-P. Therefore, it is inferred that Phe may exert anti-PH effects by alleviating the imbalance of oxidative stress and apoptosis in lung tissues and regulating immune levels, and its mechanism may be related to the regulation of the PI3K/Akt/mTOR/HIF-1α pathway. This study is expected to provide drug references and research ideas for the treatment of PH.
Subject(s)
Glucosides , Hypertension, Pulmonary , Hypoxia-Inducible Factor 1, alpha Subunit , Hypoxia , Mice, Inbred C57BL , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Rehmannia , TOR Serine-Threonine Kinases , Animals , Male , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/genetics , Mice , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/physiopathology , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Rehmannia/chemistry , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinases/genetics , Glucosides/pharmacology , Hypoxia/drug therapy , Hypoxia/physiopathology , Hypoxia/metabolism , Signal Transduction/drug effects , Humans , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/chemistry , Apoptosis/drug effectsABSTRACT
This study investigated associations between psychological resilience and characteristics of white matter microstructure in pediatric concussion. This is a case control study and a planned substudy of a larger randomized controlled trial. Children with an acute concussion or orthopedic injury were recruited from the emergency department. Participants completed both the Connor-Davidson Resilience Scale 10 and an MRI at 72 h and 4-weeks post-injury. The association between resiliency and fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) at both timepoints were examined. We examined whether these associations were moderated by group. The association between resiliency captured at 72 h and diffusion tensor imaging metrics at 4 weeks was also investigated. Clusters were extracted using a significance threshold of threshold-free cluster enhancement corrected p < .05. A total of 66 children with concussion (median (IQR) age = 12.88 (IQR: 11.80-14.36); 47% female) and 29 children with orthopedic-injury (median (IQR) age = 12.49 (IQR: 11.18-14.01); 41% female) were included. A negative correlation was identified in the concussion group between 72 h resilience and 72 h FA. Meanwhile, positive correlations were identified in the concussion group with concussion between 72 h resilience and both 72 h MD and 72 h RD. These findings suggest that 72 h resilience is associated with white matter microstructure of the forceps minor, superior longitudinal fasciculus, and anterior thalamic radiation at 72 h post-concussion. Resilience seems to be associated with neural integrity only in the acute phase of concussion and thus may be considered when researching concussion recovery.
Subject(s)
Brain Concussion , Resilience, Psychological , White Matter , Humans , Child , Female , Male , White Matter/diagnostic imaging , Diffusion Tensor Imaging/methods , Brain , Benchmarking , Case-Control Studies , Brain Concussion/diagnostic imaging , AnisotropyABSTRACT
Human risk tolerance is highly idiosyncratic and individuals often show distinctive preferences when faced with similar risky situations. However, the neural underpinnings of individual differences in risk-taking remain unclear. Here we combined structural and perfusion MRI and examined the associations between brain anatomy and individual risk-taking behavior/risk tolerance in a sample of 115 healthy participants during the Balloon Analogue Risk Task, a well-established sequential risky decision paradigm. Both whole brain and region-of-interest analyses showed that the left cerebellum gray matter volume (GMV) has a strong association with individual risk-taking behavior and risk tolerance, outperforming the previously reported associations with the amygdala and right posterior parietal cortex (PPC) GMV. Left cerebellum GMV also accounted for risk tolerance and risk-taking behavior changes with aging. However, regional cerebral blood flow (CBF) provided no additional predictive power. These findings suggest a novel cerebellar anatomical contribution to individual differences in risk tolerance. Further studies are necessary to elucidate the underestimated important role of cerebellum in risk-taking.
Subject(s)
Gray Matter , Magnetic Resonance Imaging , Brain/diagnostic imaging , Cerebellum/diagnostic imaging , Gray Matter/physiology , Humans , Risk-TakingABSTRACT
After being activated by antigen, helper T lymphocytes switch from a resting state to clonal expansion. This switch requires inactivation of the transcription factor Foxo1, a suppressor of proliferation expressed in resting helper T lymphocytes. In the early antigen-dependent phase of expansion, Foxo1 is inactivated by antigen receptor-mediated post-translational modifications. Here we show that in the late phase of expansion, Foxo1 was no longer post-translationally regulated but was inhibited post-transcriptionally by the interleukin 2 (IL-2)-induced microRNA miR-182. Specific inhibition of miR-182 in helper T lymphocytes limited their population expansion in vitro and in vivo. Our results demonstrate a central role for miR-182 in the physiological regulation of IL-2-driven helper T cell-mediated immune responses and open new therapeutic possibilities.
Subject(s)
Interleukin-2/immunology , MicroRNAs/immunology , T-Lymphocytes, Helper-Inducer/cytology , T-Lymphocytes, Helper-Inducer/immunology , Animals , Arthritis/immunology , Cell Proliferation , Cells, Cultured , Disease Models, Animal , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BLABSTRACT
During sleep we lack conscious awareness of the external environment. Yet, our internal mental state suggests that high-level cognitive processes persist. The nature and extent to which the external environment is processed during sleep remain largely unexplored. Here, we used an fMRI synchronization-based approach to examine responses to a narrative during wakefulness and sleep. The stimulus elicited the auditory network and a frontoparietal pattern of activity, consistent with high-level narrative plot-following. During REM sleep, the same frontoparietal pattern was observed in one of three participants, and partially in one other, confirming that it is possible to track and follow the moment-to-moment complexities of a narrative during REM sleep. Auditory network recruitment was observed in both non-REM and REM sleep, demonstrating preservation of low-level auditory processing, even in deep sleep. This novel approach investigating cognitive processing at different levels of awareness demonstrates that the brain can meaningfully process the external environment during REM sleep.
Subject(s)
Electroencephalography , Sleep , Acoustic Stimulation , Humans , Sleep/physiology , Sleep, REM/physiology , Wakefulness/physiologyABSTRACT
Emotion processing is known to interact with memory. Ovarian steroid hormones, such as progesterone and estradiol, modulate emotion processing and memory. However, it is unclear how these hormones influence brain activity when emotion processing is integrated with working memory (WM). Therefore, the objective of this study was to examine the relationship between endogenous hormonal concentration and brain activity during emotion processing in the context of a WM n-back task in 74 young women using functional magnetic resonance imaging (fMRI). Results show that positive emotion processing activates reward-related areas, such as the caudate and putamen, whereas negative emotion processing activates a corticolimbic network, including the amygdala and hippocampus. Furthermore, our findings provide evidence that progesterone modulates more bottom-up brain activation during both positive and negative emotion processing, whereas estradiol activates lateralized, top-down regulation. These findings provide insight on the neural correlates of emotion processing during an n-back task in young women and highlight how important it is to consider women's endogenous hormonal concentration in neurobiological and cognition research.
Subject(s)
Estradiol , Progesterone , Brain/diagnostic imaging , Brain Mapping , Emotions , Female , Humans , Magnetic Resonance Imaging , Memory, Short-TermABSTRACT
Myeloid-derived suppressor cells (MDSC) are induced during active TB disease to restore immune homeostasis but instead exacerbate disease outcome due to chronic inflammation. Autophagy, in conventional phagocytes, ensures successful clearance of M.tb. However, autophagy has been demonstrated to induce prolonged MDSC survival. Here we investigate the relationship between autophagy mediators and MDSC in the context of active TB disease and during anti-TB therapy. We demonstrate a significant increase in MDSC frequencies in untreated active TB cases with these MDSC expressing TLR4 and significantly more mTOR and IL-6 than healthy controls, with mTOR levels decreasing during anti-TB therapy. Finally, we show that HMGB1 serum concentrations decrease in parallel with mTOR. These findings suggest a complex interplay between MDSC and autophagic mediators, potentially dependent on cellular localisation and M.tb infection state.
Subject(s)
Autophagy/immunology , Myeloid-Derived Suppressor Cells/immunology , Tuberculosis/immunology , Antitubercular Agents/therapeutic use , Autophagy/drug effects , HMGB1 Protein/immunology , HMGB1 Protein/metabolism , Humans , Interleukin-6/immunology , Interleukin-6/metabolism , Myeloid-Derived Suppressor Cells/drug effects , Myeloid-Derived Suppressor Cells/metabolism , TOR Serine-Threonine Kinases/immunology , TOR Serine-Threonine Kinases/metabolism , Tuberculosis/drug therapy , Tuberculosis/metabolismABSTRACT
EEG studies have shown that interindividual differences in the electrophysiological properties of sleep spindles (e.g., density, amplitude, duration) are highly correlated with trait-like "reasoning" abilities (i.e., "fluid intelligence"; problem-solving skills; the ability to employ logic or identify complex patterns), but not interindividual differences in STM or "verbal" intellectual abilities. Previous simultaneous EEG-fMRI studies revealed brain activations time-locked to spindles. Our group has recently demonstrated that the extent of activation in a subset of these regions was related to interindividual differences in reasoning intellectual abilities, specifically. However, spindles reflect communication between spatially distant and functionally distinct brain areas. The functional communication among brain regions related to spindles and their relationship to reasoning abilities have yet to be investigated. Using simultaneous EEG-fMRI sleep recordings and psychophysiological interaction analysis, we identified spindle-related functional communication among brain regions in the thalamo-cortical-BG system, the salience network, and the default mode network. Furthermore, the extent of the functional connectivity of the cortical-striatal circuitry and the thalamo-cortical circuitry was specifically related to reasoning abilities but was unrelated to STM or verbal abilities, thus suggesting that individuals with higher fluid intelligence have stronger functional coupling among these brain areas during spontaneous spindle events. This may serve as a first step in further understanding the function of sleep spindles and the brain network functional communication, which support the capacity for fluid intelligence.
Subject(s)
Brain Waves , Brain/physiology , Cognition/physiology , Sleep/physiology , Adult , Brain Mapping , Electroencephalography , Humans , Intelligence/physiology , Magnetic Resonance Imaging , Neural Pathways/physiology , Polysomnography , Problem Solving/physiology , Young AdultABSTRACT
The Balloon Analogue Risk Task (BART) provides a reliable and ecologically valid model for the assessment of individual risk-taking propensity and is frequently used in neuroimaging and developmental research. Although the test-retest reliability of risk-taking behavior during the BART is well established, the reliability of brain activation patterns in response to risk-taking during the BART remains elusive. In this study, we used functional magnetic resonance imaging (fMRI) and evaluated the test-retest reliability of brain responses in 34 healthy adults during a modified BART by calculating the intraclass correlation coefficients (ICC) and Dice's similarity coefficients (DSC). Analyses revealed that risk-induced brain activation patterns showed good test-retest reliability (median ICC â= â0.62) and moderate to high spatial consistency, while brain activation patterns associated with win or loss outcomes only had poor to fair reliability (median ICC â= â0.33 for win and 0.42 for loss). These findings have important implications for future utility of the BART in fMRI to examine brain responses to risk-taking and decision-making.
Subject(s)
Brain Mapping/standards , Brain/physiology , Decision Making/physiology , Magnetic Resonance Imaging/standards , Neuropsychological Tests/standards , Risk-Taking , Adult , Brain/diagnostic imaging , Female , Humans , Male , Reproducibility of Results , Young AdultABSTRACT
Millions of women worldwide use oral contraceptives (OCs), often starting during puberty/adolescence. It is, however, unknown how OC use during this critical period of development affects the brain. The objective of the current study was to examine resting state functional connectivity (FC) in the default mode network (DMN), central executive network (CEN), salience network (SN), reward network (RN), and subcortical limbic network of the brain using independent component analysis (ICA) between pubertal- and adult-onset OC users (n = 27) and naturally cycling women (n = 48). It was hypothesized that OC use would result in network-specific increases and decreases in FC and that pubertal-onset OC use would result in differences to the aforementioned networks compared to adult-onset OC use. Pubertal-onset OC use is related to heightened FC in the SN compared to adult-onset OC users. In general, OC use also increases connectivity in the SN, CEN, RN, and subcortical limbic network compared to NC women. No significant differences in connectivity were observed in the DMN between OC users and NC women. These findings provide a mechanistic insight for the altered executive functioning and emotion/reward processing previously seen in OC users, which may then increase their vulnerability to mental health conditions.
Subject(s)
Brain/drug effects , Contraceptives, Oral/therapeutic use , Puberty/drug effects , Adolescent , Adult , Brain/diagnostic imaging , Brain/physiology , Brain Mapping/methods , Case-Control Studies , Contraceptives, Oral/adverse effects , Executive Function/drug effects , Female , Humans , Magnetic Resonance Imaging/methods , Male , Nerve Net/drug effects , Nerve Net/physiology , Puberty/physiology , Puberty/psychology , Rest/psychology , Young AdultABSTRACT
Millions of women worldwide use oral contraceptives (i.e., birth control pill; OCs), often starting during puberty/adolescence; however, it is unknown how OC use during this critical period of development affects the brain, especially with regard to emotional working memory. Here, we examined stress reactivity, and brain structure and function in OC users using the Trier Social Stress Test and structural and functional magnetic resonance imaging (MRI). Our results show that OC use during puberty/adolescence gives rise to a blunted stress response and alters brain activation during working memory processing. OC use, in general, is also linked to increased prefrontal brain activation during working memory processing for negatively arousing stimuli. OC use is also related to significant structural changes in brain regions implicated in memory and emotional processing. Together, these findings highlight that OC use induces changes to brain structure and function and alters stress reactivity. These findings may provide a mechanistic insight for the increased vulnerability to mood-related mental illness in women after OC use.
Subject(s)
Brain/drug effects , Contraceptives, Oral, Combined/pharmacology , Stress, Physiological/drug effects , Stress, Psychological/metabolism , Adolescent , Adult , Affect/drug effects , Age Factors , Brain/anatomy & histology , Brain/diagnostic imaging , Brain/physiology , Case-Control Studies , Contraception/methods , Emotions/drug effects , Executive Function/drug effects , Female , Humans , Hydrocortisone/analysis , Hydrocortisone/metabolism , Memory/drug effects , Memory/physiology , Saliva/chemistry , Saliva/metabolism , Stress, Psychological/diagnostic imaging , Stress, Psychological/pathology , Stress, Psychological/physiopathology , Young AdultABSTRACT
Arterial spin labeled (ASL) perfusion magnetic resonance imaging (MRI) is increasingly used to assess regional brain activity and cerebrovascular function in both healthy and clinical populations. ASL perfusion imaging provides a quantitative measure of regional brain activity by determining absolute cerebral blood flow (CBF) values at a resting state or during task performance. However, the comparative reliability of these ASL measures is not well characterized. It is also unclear whether the test-retest reliability of absolute CBF or task-induced CBF change measures would be comparable to the reliability of task performance. In this study, fifteen healthy participants were scanned three times in a strictly controlled in-laboratory study while at rest and during performing a simple and reliable psychomotor vigilance test (PVT). The reliability of absolute CBF and task-induced CBF changes was evaluated using the intraclass correlation coefficient (ICC) and compared to that of task performance. Absolute CBF showed excellent test-retest reliability across the three scans for both resting and PVT scans. The reliability of regional absolute CBF was comparable to that of behavioral measures of PVT performance, and was slightly higher during PVT scans as compared with resting scans. Task-induced regional CBF changes demonstrated only poor to moderate reliability across three scans. These findings suggest that absolute CBF measures are more reliable than task-induced CBF changes for characterizing regional brain function, especially for longitudinal and clinical studies.
Subject(s)
Arousal/physiology , Brain/physiology , Cerebrovascular Circulation/physiology , Neuroimaging/methods , Perfusion Imaging/methods , Adult , Brain/blood supply , Female , Humans , Image Processing, Computer-Assisted/methods , Magnetic Resonance Imaging/methods , Male , Reproducibility of Results , Rest/physiology , Spin LabelsABSTRACT
BACKGROUND: Noninvasive biomarkers are urgently needed for patients with nonalcoholic steatohepatitis (NASH) to assist in diagnosis, monitoring disease progression and assessing treatment response. Recently several exploratory studies showed that circulating level of microRNA is associated with NASH and correlated with disease severity. Although these data were encouraging, the application of circulating microRNA as biomarkers for patient screening and stratification need to be further assessed under well-controlled conditions. RESULTS: The expression of circulating microRNAs were profiled in diet-induced NASH progression and regression models to assess the diagnostic and prognostic values and the translatability between preclinical mouse model and men. Since these mice had same genetic background and were housed in the same conditions, there were minimal confounding factors. Histopathological lesions were analyzed at distinct disease progression stages along with microRNA measurement which allows longitudinal assessment of microRNA as NASH biomarkers. Next, differentially expressed microRNAs were identified and validated in an independent cohorts of animals. Thirdly, these microRNAs were examined in a NASH regression model to assess whether they would respond to NASH treatment. MicroRNA profiling in two independent cohorts of animals validated the up-regulation of 6 microRNAs (miR-122, miR-192, miR-21, miR-29a, miR-34a and miR-505) in NASH mice, which was designated as the circulating microRNA signature for NASH. The microRNA signature could accurately distinguish NASH mice from lean mice, and it responded to chow diet treatment in a NASH regression model. To further improve the performance of microRNA-based biomarker, a new composite biomarker was proposed, which consists of miR-192, miR-21, miR-505 and ALT. The new composite biomarker outperformed the microRNA signature in predicting NASH mice which had NAS > 3, and deserves further validations in large scale studies. CONCLUSION: The present study supported the translation of circulating microRNAs between preclinical models and humans in NASH pathogenesis and progression. The microRNA-based composite biomarker may be used for non-invasive diagnosis, clinical monitoring and assessing treatment response for NASH.
Subject(s)
Biomarkers/blood , Circulating MicroRNA/genetics , Gene Expression Profiling , Liver/metabolism , Non-alcoholic Fatty Liver Disease/diagnosis , Animals , Circulating MicroRNA/blood , Disease Progression , Humans , Male , Mice , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/blood , Non-alcoholic Fatty Liver Disease/genetics , PrognosisABSTRACT
Increased disease susceptibility during early life has been linked to immune immaturity, regulatory T-cell/TH2 immune biasing and hyporesponsiveness. The contribution of myeloid derived suppressor cells (MDSCs) remains uninvestigated. Here, we assessed peripheral MDSC in HIV-infected and -uninfected children with tuberculosis (TB) disease before, during and after TB treatment, along with matched household contacts (HHCs), HIV-exposed, -infected and -uninfected children without recent TB exposure. Serum analytes and enzymes associated with MDSC accumulation/activation/function were measured by colorimetric- and fluorescence arrays. Peripheral frequencies of cells phenotypically resembling MDSCs were significantly increased in HIV-exposed uninfected (HEU) and M.tb-infected children, but peaked in children with TB disease and remained high following treatment. MDSC in HIV-infected (HI) children were similar to unexposed uninfected controls; however, HAART-mediated MDSC restoration to control levels could not be disregarded. Increased MDSC frequencies in HHC coincided with enhanced indoleamine-pyrrole-2,3-dioxygenase (IDO), whereas increased MDSC in TB cases were linked to heightened IDO and arginase-1. Increased MDSC were paralleled by reduced plasma IP-10 and thrombospondin-2 levels in HEU and significantly increased plasma IL-6 in HI HHC. Current investigations into MDSC-targeted treatment strategies, together with functional analyses of MDSCs, could endorse these cells as novel innate immune regulatory mechanism of infant HIV/TB susceptibility.
Subject(s)
Coinfection , HIV Infections/immunology , Mycobacterium tuberculosis/immunology , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism , Tuberculosis/immunology , Antiretroviral Therapy, Highly Active , Arginase/blood , Biomarkers , Cell Count , Child, Preschool , Cytokines/blood , Cytokines/metabolism , Female , HIV Infections/diagnosis , HIV Infections/drug therapy , Humans , Immunophenotyping , Indoleamine-Pyrrole 2,3,-Dioxygenase/blood , Infant , Male , Phenotype , Tuberculosis/diagnosis , Tuberculosis/drug therapy , Tuberculosis/prevention & controlABSTRACT
Microsporidia Nosema bombycis CQ1 can be vertically transmitted in silkworm Bombyx mori but Vairimorpha necatrix BM cannot. Therefore, the pathological differences in silkworm infected with these two microsporidia required clarification. Here, we compared the virulence of N. bombycis CQ1 and V. necatrix BM against silkworm. The pathological characteristics in intestine, testis and ovary were surveyed using paraffin sections, scanning electron microscopy and transmission electron microscopy. Our data firstly showed that the virulence of V. necatrix BM was weaker than that of N. bombycis CQ1. Secondly, the typical symptom of V. necatrix BM infection is making xenomas, which are full of pathogens in different stages, at the posterior of intestine. However, no xenomas were formed surrounding intestines infected with N. bombycis CQ1. Thirdly, N. bombycis CQ1 can cluster spores near the trachea while infecting ovaries. It is worth noting that N. bombycis CQ1 infected epithelial cells and connective tissues of ovaries, while V. necatrix BM did not. Although silkworm ovaries can not be infected by V. necatrix BM in vivo, it can infect embryonic and ovarian cell lines in vitro. This study is the first report about comparing infection features of N. bombycis CQ1 and V. necatrix BM in silkworm tissues and it provided elaborate and visual information of pathological characteristics which can help to explain the different transmission strategies of these two microsporidia.