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Background Airway fibrosis is one of the pathological characteristics of severe asthma. Transforming growth factor (TGF)-β has been known to promote epithelial-mesenchymal transition formation and to play a role in the progression of tissue fibrosis. Cellular communication network factor 2 (CCN2) and fibronectin (FN) are well-known markers of EMT and fibrosis. However, whether AREG is involved in TGF-β-induced CCN2 and FN expression in human lung epithelial cells is unknown. Methods AREG and FN were analyzed by immunofluorescence staining on ovalbumin-challenged mice. CCN2 and FN expression were evaluated in human lung epithelial (A459) cells following TGF or AREG treatment for the indicated times. Secreted AREG from A549 cells was detected by ELISA. Cell migration was observed by a wound healing assay. Chromatin immunoprecipitation was used to detect the c-Jun binding to the CCN2 promoter. Results AREG and FN expression colocalized in lung tissues from mice with ovalbumin-induced asthma by immunofluorescence staining. Moreover, TGF-β caused the release of AREG from A549 cells into the medium. Smad3 siRNA down-regulated AREG expression. AREG also stimulated CCN2 and FN expression, JNK and c-Jun phosphorylation, and cell migration in A549 cells. AREG small interfering (si) RNA inhibited TGF-β-induced expression of CCN2, FN, and cell migration. Furthermore, AREG-induced CCN2 and FN expression were inhibited by EGFR siRNA, a JNK inhibitor (SP600125), and an activator protein-1 (AP-1) inhibitor (curcumin). EGFR siRNA attenuated AREG-induced JNK and c-Jun phosphorylation. Moreover, SP600125 downregulated AREG-induced c-Jun phosphorylation. Conclusion These results suggested that AREG mediates the TGF-β-induced EMT in human lung epithelial cells through EGFR/JNK/AP-1 activation. Understanding the role of AREG in the EMT could foster the development of therapeutic strategies for airway remodeling in severe asthma.

Previous studies have reported increased cross-modal auditory and visual cortical activation in cochlear implant (CI) users, suggesting cross-modal reorganization of both visual and auditory cortices in CI users as a consequence of sensory deprivation and restoration. How these processes affect the functional connectivity of the auditory and visual system in CI users is however unknown. We here investigated task-induced intra-modal functional connectivity between hemispheres for both visual and auditory cortices and cross-modal functional connectivity between visual and auditory cortices using functional near infrared spectroscopy in post-lingually deaf CI users and age-matched normal hearing controls. Compared to controls, CI users exhibited decreased intra-modal functional connectivity between hemispheres and increased cross-modal functional connectivity between visual and left auditory cortices for both visual and auditory stimulus processing. Importantly, the difference between cross-modal functional connectivity for visual and for auditory stimuli correlated with speech recognition outcome in CI users. Higher cross-modal connectivity for auditory than for visual stimuli was associated with better speech recognition abilities, pointing to a new pattern of functional reorganization that is related to successful hearing restoration with a CI.

•The present study investigated the brain-to-brain connectivity during a peer collaboration task in young child dyads.•A reduction in connectivity was observed in the dyad group with ASD in the beta oscillation over the right parietal to left temporal coupling between subjects.•Increased full-band connectivity over the right-to-right temporal region following the task was observed in the TD-TD group, but not in the TD-ASD group.•Significant correlations were identified between ASD symptom rating scores and the selected significant interbrain connectivity index. Young children with autism spectrum disorder (ASD) traits frequently encounter difficulties in peer interaction. Assessing peer interaction performance is crucial but challenging within the clinical diagnostic paradigm of ASD. Hyperscanning, which simultaneously monitors brain activity in multiple individuals, has become a popular tool for assessing social interaction's neural features. The present study aims to investigate the brain-to-brain connectivity between child-dyads engaged in a game-like collaborative peer interaction task via the hyperscanning electroencephalogram (EEG) approach. The final sample comprised 66 young children: 18 child dyads with typical development (TD), TD-TD, and 15 with ASD traits matched to TD, TD-ASD. The study indicated a depressed level of connectivity in the dyad group with ASD as the responder, with a notable decrease observed in the beta oscillation over the right parietal to left temporal coupling between subjects. A pattern that differed from that observed in the TD-TD group was identified with regard to full-band connectivity over the right-to-right temporal region. It was observed that the TD-TD group exhibited enhanced connectivity following the completion of the task, which was not the case for the TD-ASD group. Significant correlations were observed between scores on the ASD symptom rating scale and the selected significant interbrain connectivity index. The application of a hyperscanning EEG paradigm demonstrated that the participating children with autistic traits exhibited an attenuated and apparently distinct alteration pattern of interbrain connectivity in comparison to a control group. These findings highlight the value of physiologically based measures in informing etiological and interventional studies in neuropsychiatry.

Cochlear implant (CI) users show higher auditory-evoked activations in visual cortex and higher visual-evoked activation in auditory cortex compared to normal hearing (NH) controls, reflecting functional reorganization of both visual and auditory modalities. Visual-evoked activation in auditory cortex is a maladaptive functional reorganization whereas auditory-evoked activation in visual cortex is beneficial for speech recognition in CI users. We investigated their joint influence on CI users’ speech recognition, by testing 20 postlingually deafened CI users and 20 NH controls with functional near-infrared spectroscopy (fNIRS). Optodes were placed over occipital and temporal areas to measure visual and auditory responses when presenting visual checkerboard and auditory word stimuli. Higher cross-modal activations were confirmed in both auditory and visual cortex for CI users compared to NH controls, demonstrating that functional reorganization of both auditory and visual cortex can be identified with fNIRS. Additionally, the combined reorganization of auditory and visual cortex was found to be associated with speech recognition performance. Speech performance was good as long as the beneficial auditory-evoked activation in visual cortex was higher than the visual-evoked activation in the auditory cortex. These results indicate the importance of considering cross-modal activations in both visual and auditory cortex for potential clinical outcome estimation.

Previous studies have observed lower visual cortex activation for visual processing in cochlear implant (CI) users compared to normal hearing controls, while others reported enhanced visual speechreading abilities in CI users. The present work investigated whether lower visual cortical activation for visual processing can be explained by a more efficient visual sensory encoding in CI users. Specifically, we investigated whether CI users show enhanced stimulus-specific adaptation for visual stimuli compared to controls. Auditory sensory adaptation was also investigated to explore the sensory specificity of the predicted effect. Twenty post-lingually deafened adult CI users and twenty age-matched controls were presented with repeated visual and auditory stimuli during simultaneous acquisition of electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS). By integrating EEG and fNIRS signals we found significantly enhanced visual adaptation and lower visual cortex activation in CI users compared to controls. That is, responses to repeated visual stimuli decreased more prominently in CI users than in controls. The results suggest that CI users process visual stimuli more efficiently than controls. •CI users showed enhanced visual adaptation compared to NH controls.•CI users showed decreased visual and auditory responses compared to NH controls.•EEG-informed simulation predicts group differences in fNIRS responses.•Latency difference in hemodynamic responses reflects difference in adaptation.

Background Intermittent theta burst stimulation (iTBS) is a form of repetitive transcranial stimulation that has been used to enhance upper limb (UL) motor recovery. However, only limited studies have examined its efficacy in patients with chronic stroke and therefore it remains controversial. Methods This was a randomized controlled trial that enrolled patients from a rehabilitation department. Twenty-two patients with first-ever chronic and unilateral cerebral stroke, aged 30–70 years, were randomly assigned to the iTBS or control group. All patients received 1 session per day for 10 days of either iTBS or sham stimulation over the ipsilesional primary motor cortex in addition to conventional neurorehabilitation. Outcome measures were assessed before and immediately after the intervention period: Modified Ashworth Scale (MAS), Fugl-Meyer Assessment Upper Extremity (FMA-UE), Action Research Arm Test (ARAT), Box and Block test (BBT), and Motor Activity Log (MAL). Analysis of covariance was adopted to compare the treatment effects between groups. Results The iTBS group had greater improvement in the MAS and FMA than the control group ( η 2  = 0.151–0.233; p  < 0.05), as well as in the ARAT and BBT ( η 2  = 0.161–0.460; p  < 0.05) with large effect size. Both groups showed an improvement in the BBT, and there were no significant between-group differences in MAL changes. Conclusions The iTBS induced greater gains in spasticity decrease and UL function improvement, especially in fine motor function, than sham TBS. This is a promising finding because patients with chronic stroke have a relatively low potential for fine motor function recovery. Overall, iTBS may be a beneficial adjunct therapy to neurorehabilitation for enhancing UL function. Further larger-scale study is warranted to confirm the findings and its long-term effect. Trial registration This trial was registered under ClinicalTrials.gov ID No. NCT01947413 on September 20, 2013.

Background Virtual reality and arm cycling have been reported as effective treatments for improving upper limb motor recovery in patients with stroke. Intermittent theta burst stimulation (iTBS) can increase ipsilesional cortical excitability, and has been increasingly used in patients with stroke. However, few studies examined the augmented effect of iTBS on neurorehabilitation program. In this study, we investigated the augmented effect of iTBS on virtual reality-based cycling training (VCT) for upper limb function in patients with stroke. Methods In this randomized controlled trial, 23 patients with stroke were recruited. Each patient received either 15 sessions of iTBS or sham stimulation in addition to VCT on the same day. Outcome measures were assessed before and after the intervention. Primary outcome measures for the improvement of upper limb motor function and spasticity were Fugl-Meyer Assessment-Upper Extremity (FMA-UE) and Modified Ashworth Scale Upper-Extremity (MAS-UE). Secondary outcome measures for activity and participation were Action Research Arm Test (ARAT), Nine Hole Peg Test (NHPT), Box and Block Test (BBT) and Motor Activity Log (MAL), and Stroke Impact Scale (SIS). Wilcoxon signed-rank tests were performed to evaluate the effectiveness after the intervention and Mann–Whitney U tests were conducted to compare the therapeutic effects between two groups. Results At post-treatment, both groups showed significant improvement in FMA-UE and ARAT, while only the iTBS + VCT group demonstrated significant improvement in MAS-UE, BBT, NHPT, MAL and SIS. The Mann–Whitney U tests revealed that the iTBS + VCT group has presented greater improvement than the sham group significantly in MAS-UE, MAL-AOU and SIS. However, there were no significant differences in the changes of the FMA-UE, ARAT, BBT, NHPT and MAL-QOM between groups. Conclusions Intermittent TBS showed augmented efficacy on VCT for reducing spasticity, increasing actual use of the affected upper limb, and improving participation in daily life in stroke patients. This study provided an integrated innovative intervention, which may be a promising therapy to improve upper limb function recovery in stroke rehabilitation. However, this study has a small sample size, and thus a further larger-scale study is warranted to confirm the treatment efficacy. Trial registration This trial was registered under ClinicalTrials.gov ID No. NCT03350087, retrospectively registered, on November 22, 2017

Background Trichoderma reesei (Ascomycota, Pezizomycotina) QM6a is a model fungus for a broad spectrum of physiological phenomena, including plant cell wall degradation, industrial production of enzymes, light responses, conidiation, sexual development, polyketide biosynthesis, and plant-fungal interactions. The genomes of QM6a and its high enzyme-producing mutants have been sequenced by second-generation-sequencing methods and are publicly available from the Joint Genome Institute. While these genome sequences have offered useful information for genomic and transcriptomic studies, their limitations and especially their short read lengths make them poorly suited for some particular biological problems, including assembly, genome-wide determination of chromosome architecture, and genetic modification or engineering. Results We integrated Pacific Biosciences and Illumina sequencing platforms for the highest-quality genome assembly yet achieved, revealing seven telomere-to-telomere chromosomes (34,922,528 bp; 10877 genes) with 1630 newly predicted genes and >1.5 Mb of new sequences. Most new sequences are located on AT-rich blocks, including 7 centromeres, 14 subtelomeres, and 2329 interspersed AT-rich blocks. The seven QM6a centromeres separately consist of 24 conserved repeats and 37 putative centromere-encoded genes. These findings open up a new perspective for future centromere and chromosome architecture studies. Next, we demonstrate that sexual crossing readily induced cytosine-to-thymine point mutations on both tandem and unlinked duplicated sequences. We also show by bioinformatic analysis that T. reesei has evolved a robust repeat-induced point mutation (RIP) system to accumulate AT-rich sequences, with longer AT-rich blocks having more RIP mutations. The widespread distribution of AT-rich blocks correlates genome-wide partitions with gene clusters, explaining why clustering of genes has been reported to not influence gene expression in T. reesei. Conclusion Compartmentation of ancestral gene clusters by AT-rich blocks might promote flexibilities that are evolutionarily advantageous in this fungus’ soil habitats and other natural environments. Our analyses, together with the complete genome sequence, provide a better blueprint for biotechnological and industrial applications.

Health related quality of life (HRQOL) reflects individuals perceived of wellness in health domains and is often deteriorated after stroke. Precise prediction of HRQOL changes after rehabilitation interventions is critical for optimizing stroke rehabilitation efficiency and efficacy. Machine learning (ML) has become a promising outcome prediction approach because of its high accuracy and easiness to use. Incorporating ML models into rehabilitation practice may facilitate efficient and accurate clinical decision making. Therefore, this study aimed to determine if ML algorithms could accurately predict clinically significant HRQOL improvements after stroke sensorimotor rehabilitation interventions and identify important predictors. Five ML algorithms including the random forest (RF), k-nearest neighbors (KNN), artificial neural network, support vector machine and logistic regression were used. Datasets from 132 people with chronic stroke were included. The Stroke Impact Scale was used for assessing multi-dimensional and global self-perceived HRQOL. Potential predictors included personal characteristics and baseline cognitive/motor/sensory/functional/HRQOL attributes. Data were divided into training and test sets. Tenfold cross-validation procedure with the training data set was used for developing models. The test set was used for determining model performance. Results revealed that RF was effective at predicting multidimensional HRQOL (accuracy: 85%; area under the receiver operating characteristic curve, AUC-ROC: 0.86) and global perceived recovery (accuracy: 80%; AUC-ROC: 0.75), and KNN was effective at predicting global perceived recovery (accuracy: 82.5%; AUC-ROC: 0.76). Age/gender, baseline HRQOL, wrist/hand muscle function, arm movement efficiency and sensory function were identified as crucial predictors. Our study indicated that RF and KNN outperformed the other three models on predicting HRQOL recovery after sensorimotor rehabilitation in stroke patients and could be considered for future clinical application.

Background Non-invasive techniques such as central intermittent theta burst stimulation (iTBS) and repetitive peripheral magnetic stimulation (rPMS) have shown promise in improving motor function for patients with stroke. However, the combined efficacy of rPMS and central iTBS has not been extensively studied. This randomized controlled trial aimed to investigate the synergistic effects of rPMS and central iTBS in patients with stroke. Method In this study, 28 stroke patients were randomly allocated to receive either 1200 pulses of real or sham rPMS on the radial nerve of the affected limb, followed by 1200 pulses of central iTBS on the ipsilesional hemisphere. The patients received the intervention for 10 sessions over two weeks. The primary outcome measures were the Fugl-Meyer Assessment-Upper Extremity (FMA-UE) and the Action Research Arm Test (ARAT). Secondary outcomes for activities and participation included the Functional Independence Measure-Selfcare (FIM-Selfcare) and the Stroke Impact Scale (SIS). The outcome measures were assessed before and after the intervention. Results Both groups showed significant improvement in FMA-UE and FIM-Selfcare after the intervention ( p  < 0.05). Only the rPMS + iTBS group had significant improvement in ARAT-Grasp and SIS-Strength and activity of daily living ( p  < 0.05). However, the change scores in all outcome measures did not differ between two groups. Conclusions Overall, the study’s findings suggest that rPMS may have a synergistic effect on central iTBS to improve grasp function and participation. In conclusion, these findings highlight the potential of rPMS as an adjuvant therapy for central iTBS in stroke rehabilitation. Further large-scale studies are needed to fully explore the synergistic effects of rPMS on central iTBS. Trial registration This trial was registered under ClinicalTrials.gov ID No.NCT04265365, retrospectively registered, on February 11, 2020.