Abnormal functional connectivity of the reward network is associated with social communication impairments in autism spectrum disorder: A large-scale multi-site resting-state fMRI study.

BACKGROUND: The social motivation hypothesis proposes that the social deficits of autism spectrum disorder (ASD) are related to reward system dysfunction. However, functional connectivity (FC) patterns of the reward network in ASD have not been systematically explored yet. METHODS: The reward network was defined as eight regions of interest (ROIs) per hemisphere, including the nucleus accumbens (NAc), caudate, putamen, anterior cingulate cortex (ACC), ventromedial prefrontal cortex (vmPFC), orbitofrontal cortex (OFC), amygdala, and insula. We computed both the ROI-wise resting-state FC and seed-based whole-brain FC in 298 ASD participants and 348 typically developing (TD) controls from the Autism Brain Imaging Data Exchange I dataset. Two-sample t-tests were applied to obtain the aberrant FCs. Then, the association between aberrant FCs and clinical symptoms was assessed with Pearson's correlation or Spearman's correlation. In addition, Neurosynth Image Decoder was used to generate word clouds verifying the cognitive functions of the aberrant pathways. Furthermore, a three-way multivariate analysis of variance (MANOVA) was conducted to examine the effects of gender, subtype and age on the atypical FCs. RESULTS: For the within network analysis, the left ACC showed weaker FCs with both the right amygdala and left NAc in ASD compared with TD, which were negatively correlated with the Autism Diagnostic Observation Schedule (ADOS) total scores and Social Responsiveness Scale (SRS) total scores respectively. For the whole-brain analysis, weaker FC (i.e., FC between the left vmPFC and left calcarine gyrus, and between the right vmPFC and left precuneus) accompanied by stronger FC (i.e., FC between the left caudate and right insula) were exhibited in ASD relative to TD, which were positively associated with the SRS motivation scores. Additionally, we detected the main effect of age on FC between the left vmPFC and left calcarine gyrus, of subtype on FC between the right vmPFC and left precuneus, of age and age-by-gender interaction on FC between the left caudate and right insula. CONCLUSIONS: Our findings highlight the crucial role of abnormal FC patterns of the reward network in the core social deficits of ASD, which have the potential to reveal new biomarkers for ASD.

Impaired segregation of the attention deficit hyperactivity disorder related pattern in children.

BACKGROUND: Inattention is a key characteristic of attention deficit hyperactivity disorder (ADHD). Specific brain abnormalities associated with this symptom form a discernible pattern related with ADHD in children (i.e., ADHD related pattern) in our earlier research. The developmental processes of segregation and integration may be crucial to ADHD. However, how brains reconfigure these processes of the ADHD related pattern in different subtypes of ADHD and across sexes remain unclear. METHODS: Nested-spectral partition method was applied to identify effects of subtype and sex on segregation and integration of the ADHD related pattern, using 145 ADHD patients and 135 typically developing controls (TDC) aged 7-14. Relationships between the measures and inattention symptoms were also investigated. RESULTS: Children with ADHD exhibited lower segregation of the ADHD related pattern (p = 1.17 × 10-8) than TDCs. Only the main effect of subtype was significant (p = 1.14 × 10-5). Both ADHD-C (p = 2.16 × 10-6) and ADHD-I (p = 2.87 × 10-6) patients had lower segregation components relative to the TDC. Moreover, segregation components were negatively correlated with inattention scores. CONCLUSIONS: This study identified impaired segregation in the ADHD related pattern of children with ADHD and found shared neural bases among different subtypes and sexes.

Abnormal individualized peak functional connectivity toward potential repetitive transcranial magnetic stimulation treatment of autism spectrum disorder.

Functional connectivity (FC) derived from resting-state functional magnetic resonance imaging has been widely applied to guide precise repetitive transcranial magnetic stimulation (rTMS). The left, right, and bilateral dorsolateral prefrontal cortices (DLPFC) have been used as rTMS treatment target regions for autism spectrum disorder (ASD), albeit with moderate efficacy. Thus, we aimed to develop an individualized localization method for rTMS treatment of ASD. We included 266 male ASDs and 297 male typically-developed controls (TDCs) from the Autism Brain Imaging Data Exchange Dataset. The nucleus accumbens (NAc) was regarded as a promising effective region, which was used as a seed and individualized peak FC strength in the DLPFC was compared between ASD and TDC. Correlation analysis was conducted between individualized peak FC strength and symptoms in ASD. We also investigated the spatial distribution of individualized peak FC locations in the DLPFC and conducted voxel-wise analysis to compare NAc-based FC between the two groups. ASD showed stronger peak FC in the right DLPFC related to TDC (Cohen's d = -.19, 95% CI: -0.36 to -0.03, t = -2.30, p = .02). Moreover, negative correlation was found between the peak FC strength in the right DLPFC and Autism Diagnostic Observation Schedule (ADOS) scores, which assessed both the social communication and interaction (r = -.147, p = .04, uncorrected significant), and stereotyped behaviors and restricted interests (r = -.198, p = .02, corrected significant). Peak FC locations varied substantially across participants. No significant differences in NAc-based FC in the DLPFC were found in the voxel-wise comparison. Our study supports the use of individualized peak FC-guided precise rTMS treatment of male ASD. Moreover, stimulating the right DLPFC might alleviate core symptoms of ASD.

Edge-centric functional network analyses reveal disrupted network configuration in autism spectrum disorder.

BACKGROUND: Neuroscientific evidence suggests that the pathological symptoms associated with autism spectrum disorders (ASD) are not confined to a single brain region but involve networks of the brain on a larger spatial scale. Analyzing diagrams of edge-edge interactions could provide important perspectives on the organization and function of complex systems. METHODS: Resting-state fMRI data from 238 ASD patients and 311 healthy controls (HCs) were included in the current study. We used the thalamus as the mediating node to calculate the edge functional connectivity (eFC) of the brain network and compared the ASD subjects and HCs. RESULTS: Compared with the HCs, the ASD subjects exhibited abnormalities in the central node thalamus and four brain regions (amygdala, nucleus accumbens, pallidum and hippocampus), as well as in the eFC formed by the inferior frontal gyrus (IFG) (or middle temporal gyrus (MTG)). In addition, ASD subjects showed variable characteristics of the eFC between nodes in different networks. CONCLUSIONS: The changes in these brain regions may be due to the disturbance in the reward system, which leads to coherence in the instantaneous comovement of the functional connections formed by these brain regions in ASD. This notion also reveals a functional network feature between the cortical and subcortical regions in ASD.

The origin and evolution of emerged swine acute diarrhea syndrome coronavirus with zoonotic potential.

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a newly discovered alphacoronavirus with zoonotic potential that causes diarrhea and vomiting mainly in piglets. Having emerged suddenly in 2017, the prevailing opinion is that the virus originated from HKU2, an alphacoronavirus whose primary host is bats, and at some unknown point achieved interspecies transmission via some intermediate. Here, we further explore the evolutionary history and possible cross-species transmission event for SADS-CoV. Coevolutionary analysis demonstrated that HKU2 may have achieved host switch via SADS-related (SADSr)-CoV, which was isolated from the genus Rhinolophus in 2017. SADS-CoV, HKU2, and SADSr-CoV share similar codon usage patterns and showed a lower tendency to use CpG, which may reflect a method of immune escape. The analyses of virus-host coevolution and recombination support SADSr-CoV is the direct source of SADS-CoV that may have undergone recombination events during its formation. Structure-based spike glycoprotein variance analysis revealed a more nuanced evolutionary pathway to receptor recognition for host switch. We did not find a possible positive selection site, and the dN/dS of the S gene was only 0.29, which indicates that the current SADS-CoV is slowly evolving. These results provide new insights that may help predict future cross-species transmission, and possibly surveil future zoonotic outbreaks and associated public health emergencies.

Disrupted network integration and segregation involving the default mode network in autism spectrum disorder.

Changes in the brain's default mode network (DMN) in the resting state are closely related to autism spectrum disorder (ASD). Module segmentation can effectively elucidate the neural mechanism of ASD and explore intra- and inter-network connections by means of the participation coefficient (PC). We used that resting-state fMRI data from 269 ASD patients and 340 healthy controls (HCs) in the current study. From the results, ASD subjects showed a significantly higher PC of the DMN than HC subjects. This difference was related to lower intra-module connections within the DMN and higher inter-network connections between the DMN and other networks. When the subjects were split into age groups, the results were verified in the 7-12- and 12-18-year-old age groups but not in the young adult group (18-25 years). When the subjects were divided according to different subtypes of ASD, the results were also observed in the classic autism and pervasive developmental disorder groups, but not in the Asperger disorder group. In conclusions, less developed network segregation in the DMN could be a valid biomarker for ASD. This provides network scientists with new insights into the intermodular connectivity configurations of complex networks from different dimensions in a systematic and comprehensive manner.

Transcriptomic analysis reveals crucial regulatory roles of immediate-early response genes and related signaling pathways in coronavirus infectious bronchitis virus infection.

Coronavirus infection of cells differentially regulates the expression of host genes and their related pathways. In this study, we present the transcriptomic profile of cells infected with gammacoronavirus infectious bronchitis virus (IBV). In IBV-infected human non-small cell lung carcinoma cells (H1299 cells), a total of 1162 differentially expressed genes (DEGs), including 984 upregulated and 178 downregulated genes, was identified. These DEGs were mainly enriched in MAPK and Wnt signaling pathways, and 5 out of the 10 top upregulated genes in all transcripts were immediate-early response genes (IEGs). In addition, the induction of 11 transcripts was validated in IBV-infected H1299 and Vero cells by RT-qPCR. The accuracy, reliability and genericity of the transcriptomic data were demonstrated by functional characterization of these IEGs in cells infected with different coronaviruses in our previous publications. This study provides a reliable transcriptomic profile of host genes and pathways regulated by coronavirus infection.

Danggui Niantong granules ameliorate rheumatoid arthritis by regulating intestinal flora and promoting mitochondrial apoptosis.

CONTEXT: Danggui Niantong Granules (DGNTG) are a valid and reliable traditional herbal formula, commonly used in clinical practice to treat rheumatoid arthritis (RA). However, the mechanism of its effect on RA remains unclear. OBJECTIVE: An investigation of the therapeutic effects of DGNTG on RA. MATERIALS AND METHODS: Twenty-four male Sprague-Dawley (SD) rats were divided into four groups: control, model, DGNTG (2.16 g/kg, gavage), methotrexate (MTX) (1.35 mg/kg, gavage) for 28 days. The morphology of synovial and ankle tissues was observed by haematoxylin-eosin staining. The responses of mitochondrial apoptosis were assessed by qPCR, Western blotting and immunohistochemical staining. Rat faeces were analysed by 16S rRNA sequencing. RESULTS: Our results showed that DGNTG treatment reduced AI scores (7.83 ± 0.37 vs. 4.67 ± 0.47, p < 0.01) and paw volumes (7.63 ± 0.17 vs. 6.13 ± 0.11, p < 0.01) compared with the model group. DGNTG also increased the expression of Bax (0.34 ± 0.03 vs. 0.73 ± 0.03, p < 0.01), cytochrome c (CYTC) (0.24 ± 0.02 vs. 0.64 ± 0.01, p < 0.01) and cleaved caspase-9 (0.24 ± 0.04 vs. 0.83 ± 0.08, p < 0.01), and decreased bcl-2 (1.70 ± 0.11 vs. 0.60 ± 0.09, p < 0.01) expression. DGNTG treatment regulated the structure of gut microbiota. DISCUSSION AND CONCLUSIONS: DGNTG ameliorated RA by promoting mitochondrial apoptosis, which may be associated with regulating gut microbiota structure. DGNTG can be used as a supplement and alternative drug for the treatment of RA; its ability to prevent RA deserves further study.

NIR-PTT/ROS-Scavenging/Oxygen-Enriched Synergetic Therapy for Rheumatoid Arthritis by a pH-Responsive Hybrid CeO2-ZIF-8 Coated with Polydopamine.

Rheumatoid arthritis (RA) is an inflammatory type of arthritis that causes joint pain and damage. The inflammatory cell infiltration (e.g., M1 macrophages), the poor O2 supply at the joint, and the excess reactive oxygen species (ROS)-induced oxidative injury are the main causes of RA. We herein report a polydopamine (PDA)-coated CeO2-dopped zeolitic imidazolate framework-8 (ZIF-8) nanocomposite CeO2-ZIF-8@PDA (denoted as CZP) that can synergistically treat RA. Under near-infrared (NIR) light irradiation, PDA efficiently scavenges ROS and results in an increased temperature in the inflamed area because of its good light-to-heat conversion efficiency. The rise of temperature serves to obliterate hyper-proliferative inflammatory cells accumulated in the diseased area while vastly promoting the collapse of the acidic-responsive skeleton of ZIF-8 to release the encapsulated CeO2. The released CeO2 exerts its catalase-like activity to relieve hypoxia by generating oxygen via the decomposition of H2O2 highly expressed in the inflammatory sites. Thus, the constructed CZP composite can treat RA through NIR-photothermal/ROS-scavenging/oxygen-enriched combinative therapy and show good regression of pro-inflammatory cytokines and hypoxia-inducible factor-1α (HIF-1α) in vitro and promising therapeutic effect on RA in rat models. The multimodal nano-platform reported herein is expected to shed light on the design of synergistic therapeutic nanomedicine for effective RA therapy.

Gray Matter Network Associated With Attention in Children With Attention Deficit Hyperactivity Disorder.

Background: Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent childhood-onset neurodevelopmental disorders; however, the underlying neural mechanisms for the inattention symptom remain elusive for children with ADHD. At present, the majority of studies have analyzed the structural MRI (sMRI) with the univariate method, which fails to demonstrate the interregional covarying relationship of gray matter (GM) volumes among brain regions. The scaled subprofile model of principal component analysis (SSM-PCA) is a multivariate method, which can detect more robust brain-behavioral phenotype association compared to the univariate analysis method. This study aims to identify the GM network associated with attention in children with ADHD by applying SSM-PCA to the sMRI. Methods: The sMRI of 209 children with ADHD and 209 typically developing controls (TDCs) aged 7-14 years from the ADHD-200 dataset was used for anatomical computation, and the GM volume in each brain region was acquired. Then, SSM-PCA was applied to the GM volumes of all the subjects to capture the GM network of children with ADHD (i.e., ADHD-related pattern). The relationship between the expression of ADHD-related pattern and inattention symptom was further investigated. Finally, the influence of sample size on the analysis of this study was explored. Results: The ADHD-related pattern mainly included putamen, pallium, caudate, thalamus, right accumbens, superior/middle/inferior frontal cortex, superior occipital cortex, superior parietal cortex, and left middle occipital cortex. In addition, the expression of the ADHD-related pattern was related to inattention scores measured by the Conners' Parent Rating Scale long version (CPRS-LV; r = 0.25, p = 0.0004) and the DuPaul ADHD Rating Scale IV (ADHD-RS; r = 0.18, p = 0.03). Finally, we found that when the sample size was 252, the results of ADHD-related pattern were relatively reliable. Similarly, the sample size needed to be 162 when exploring the relationship between ADHD-related pattern and behavioral indicator measured by CPRS-LV. Conclusion: We captured a GM network associated with attention in children with ADHD, which is different from that in adolescents and adults with ADHD. Our findings may shed light on the diverse neural mechanisms of inattention and provide treatment targets for children with ADHD.

Triphenyl phosphate (TPP) promotes hepatocyte toxicity via induction of endoplasmic reticulum stress and inhibition of autophagy flux.

Triphenyl phosphate (TPP), a commonly used organophosphate flame retardant, is frequently found in environmental and biota samples, indicating widespread human exposure. Recent studies have shown that TPP causes hepatotoxicity, but the underlying cellular mechanisms are not fully elucidated. Here, by using normal hepatocyte AML12 cells as a model, we showed that TPP induced apoptotic cell death. RNA sequencing analyses revealed that differentially expressed genes induced by TPP were related to endoplasmic reticulum (ER) stress and autophagy. Immunostaining and western blot results further confirmed that TPP activated ER stress. Interestingly, though TPP increased LC3-II, a canonical marker for autophagy, TPP inhibited autophagy flux rather than induced autophagy. Interestingly, TPP-induced ER stress facilitated autophagy flux inhibition and apoptosis. Furthermore, inhibition of autophagy aggravated, and activation of autophagy attenuated apoptosis induced by TPP. Collectively, these results uncovered that ER stress and autophagy flux inhibition were responsible for TPP-induced apoptosis in mouse hepatocytes. Thus, our foundlings provided novel insight into the potential mechanisms of TPP-induced hepatocyte toxicity.

The Location Reliability of the Resting-State fMRI FC of Emotional Regions Towards rTMS Therapy.

Resting-state magnetic resonance imaging (RS-fMRI) studies indicated that the repetitive transcranial magnetic stimulation (rTMS) exerts antidepression effect through the functional connectivity (FC) of the DLPFC with the subgenual anterior cingulate cortex (sgACC), pregneual ACC (pgACC), or nucleus accumbens (NAc). It is proposed that the FC-guided individualized precise stimulation on the DLPFC would be more effective. The current study systematically investigated the reliability of the RS-fMRI FC location as well as the FC strength with multiple potential factors. We aimed to provide a stable stimulation target for future FC-guided TMS therapy for affective related disorders. Twenty-one subjects under RS-fMRI conditions with the first two times (V1, V2) scanned on a GE 3 T scanner and the third visit (V3) on a Siemens 3 T scanner. Then the FC strength and location reliability were assessed by using intra-class correlation (ICC) and intra-individual distance, respectively. The factors included deep seed ROIs (midline (mid-) sgACC, left pgACC, mid-pgACC, and left NAc), eyes closed (EC) vs eyes open (EO), frequency bands, FC algorithm (Pearson vs Spearman), scanning length (half a session vs whole session), and location method (FC peak vs center of gravity (COG)). The reliability of the voxel-wise FC strength was low to moderate. The intra-individual distances of the COG were 3.8-7.3 mm across all factors, much smaller than that of FC peak (approximately 30 mm). The COG of seed-based FC might be a potential rTMS stimulation target. Anyway, all potential stimulation targets should be tested in future rTMS treatment studies.

A review of objective assessments for hyperactivity in attention deficit hyperactivity disorder.

Hyperactivity is one of the three core symptoms of attention deficit hyperactivity disorder (ADHD) that is a common childhood mental disorder. Objective assessments of hyperactivity are seldom utilized compared with measures of inattention and impulsivity during clinical diagnosis and evaluation. Acceleration-sensitive devices (e.g., Actigraph) and motion tracking systems (e.g., QbTest) are two main groups of devices that can be used to objectively measure hyperactivity. The Actigraph and QbTest have good discriminant validity, convergent validity, and sensitivity to the effects of stimulants. Furthermore, the assessment setting (i.e., research laboratory, school, or home) can greatly influence the presence and severity of hyperactivity. Nevertheless, objective assessments for hyperactivity have poor ability to distinguish ADHD from other disorders, or among the three types of ADHD. Thus, further studies are needed to assess objective measurements of hyperactivity in terms of discriminant and convergent validity, test-retest reliability in different settings, and correlations with brain activity.

Coix seed polysaccharides alleviate type 2 diabetes mellitus via gut microbiota-derived short-chain fatty acids activation of IGF1/PI3K/AKT signaling.

Type 2 diabetes mellitus (T2DM) has become a worldwide concern in recent years. Coix seed (CS) as a homologous substance of traditional Chinese medicine and food, its polysaccharides can improve the symptoms of patients with metabolic disorders. Since most plant polysaccharides are difficult to digest and absorb, we hypothesized that Coix seed polysaccharides (CSP) exert hypoglycemic effects through the gut. In this study, the underlying mechanisms regulating hypoglycemic effects of CSP on a T2DM mouse model were investigated. After treatment with CSP, serum insulin and high-density lipoprotein cholesterol levels were increased, while total cholesterol, triglycerides and low-density lipoprotein cholesterol levels were decreased in T2DM mice. In addition, CSP treatment helped repair the intestinal barrier and modulated the gut microbial composition in T2DM mice, mainly facilitating the growth of short-chain fatty acid (SCFA)-producing bacteria, Spearman's analysis revealed these bacteria were positively related with the hypoglycemic efficacy of CSP. Colonic transcriptome analysis indicated the hypoglycemic effect of CSP was associated with the activation of the IGF1/PI3K/AKT signaling pathway. Correlative analysis revealed that this activation may result from the increase of SCFAs-producing bacteria by CSP. GC-MS detection verified that CSP treatment increased fecal SCFAs levels. Molecular docking revealed that SCFAs could bind with IGF1, PI3K, and AKT. Our findings demonstrated that CSP treatment modulates gut microbial composition, especially of the SCFAs-producing bacteria, activates the IGF1/PI3K/AKT signaling pathways, and exhibits hypoglycemic efficacy.

Extract From Tetrastigma hemsleyanum Leaf Alleviates Pseudomonas aeruginosa Lung Infection: Network Pharmacology Analysis and Experimental Evidence.

Tetrastigma hemsleyanum Diels & Gilg (T. hemsleyanum) has attracted much attention due to its ability on pneumonia, bronchitis, and immune-related diseases, while its functional components and underlying mechanism of action on pneumonia have not been fully elucidated. Herein, we used a systematic network pharmacology approach to explore the action mechanism of T. hemsleyanum leaf in the treatment of pneumonia. In this study, the results of network pharmacology demonstrated that there were 34 active components and 80 drug-disease targets in T. hemsleyanum leaf, which were strongly in connection with signal transduction, inflammatory response, and the oxidation-reduction process. Subsequently, a mouse model of pneumonia induced by Pseudomonas aeruginosa (P. aeruginosa) was established to validate the predicted results of network pharmacology. In the animal experiments, aqueous extract of T. hemsleyanum leaf (EFT) significantly attenuated the histopathological changes of lung tissue in P. aeruginosa-induced mice and reduced the number of bacterial colonies in BALFs by 96.84% (p < 0.01). Moreover, EFT treatment suppressed the increase of pro-inflammatory cytokines IL-17, IL-6, and TNF-α in lung tissues triggered by P. aeruginosa, which led to the increase of Th17 cells (p < 0.05). High concentration of EFT treatment (2.0 g/kg) obviously increased the anti-inflammatory cytokine levels, accompanied by the enhancement of Treg proportion in a dose-dependent manner and a notable reversal of transcription factor RORγt expression. These findings demonstrated that network pharmacology was a useful tool for TCM research, and the anti-inflammatory effect of EFT was achieved by maintaining Th17/Treg immune homeostasis and thereby suppressing the inflammatory immune response.

Induction of the Proinflammatory Chemokine Interleukin-8 Is Regulated by Integrated Stress Response and AP-1 Family Proteins Activated during Coronavirus Infection.

Infection induces the production of proinflammatory cytokines and chemokines such as interleukin-8 (IL-8) and IL-6. Although they facilitate local antiviral immunity, their excessive release leads to life-threatening cytokine release syndrome, exemplified by the severe cases of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this study, we investigated the roles of the integrated stress response (ISR) and activator protein-1 (AP-1) family proteins in regulating coronavirus-induced IL-8 and IL-6 upregulation. The mRNA expression of IL-8 and IL-6 was significantly induced in cells infected with infectious bronchitis virus (IBV), a gammacoronavirus, and porcine epidemic diarrhea virus, an alphacoronavirus. Overexpression of a constitutively active phosphomimetic mutant of eukaryotic translation initiation factor 2α (eIF2α), chemical inhibition of its dephosphorylation, or overexpression of its upstream double-stranded RNA-dependent protein kinase (PKR) significantly enhanced IL-8 mRNA expression in IBV-infected cells. Overexpression of the AP-1 protein cJUN or its upstream kinase also increased the IBV-induced IL-8 mRNA expression, which was synergistically enhanced by overexpression of cFOS. Taken together, this study demonstrated the important regulatory roles of ISR and AP-1 proteins in IL-8 production during coronavirus infection, highlighting the complex interactions between cellular stress pathways and the innate immune response.

Low-intensity pulsed ultrasound promotes osteoarthritic cartilage regeneration by BMSC-derived exosomes via modulating the NF-κB signaling pathway.

Osteoarthritis is the most common disabling joint disease throughout the world, and the effect of therapy on its course is still unsatisfactory in clinical practice. Recent studies have shown that mesenchymal stem cell (MSC)-derived exosomes can promote cartilage repair and regeneration in osteoarthritis, indicating that these exosomes could be a novel and promising strategy for treating osteoarthritis. This study investigated whether low-intensity pulsed ultrasound (LIPUS) enhances the effects of bone marrow MSC (BMSC)-derived exosomes on cartilage regeneration in osteoarthritis and examined the underlying mechanism. Our results revealed that BMSC-derived exosomes display the typical morphological features of exosomes. LIPUS-mediated BMSC-derived exosomes promoted cartilage regeneration, increased chondrocyte proliferation and extracellular matrix synthesis, suppressed inflammation, and inhibited the interleukin (IL)-1ß-induced activation of the nuclear factor kappa B (NF-κB) pathway. In brief, LIPUS enhances the promoting effects of BMSC-derived exosomes on osteoarthritic cartilage regeneration, mainly by strengthening the inhibition of inflammation and further enhancing chondrocyte proliferation and cartilage matrix synthesis. The underlying mechanism could be related to the inhibition of the IL-1ß-induced activation of the NF-κB pathway.

Echo Time Dependency of Local Activity Metrics of Resting-State Functional MRI.

Local activity metrics of resting-state functional MRI (RS-fMRI), such as the amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo), and degree centrality (DC), are widely used to detect brain abnormalities based on signal fluctuations. Although signal changes with echo time (TE) have been widely studied, the effect of TE on local activity metrics has not been investigated. RS-fMRI datasets from 12 healthy subjects with eyes open (EO) and eyes closed (EC) were obtained with a four-echo gradient-echo-planar imaging pulse sequence with the following parameters: repetition time/TE1/TE2/TE3/TE4 = 2,000/13/30.93/48.86/66.79 ms. Six representative regions were selected for simulating the spatial feature of TE dependency of local activity metrics. Moreover, whole-brain local activity metrics were calculated from each echo dataset and compared between EO and EC conditions. Dice overlap coefficient (DOC) was then employed to calculate the overlap between the T maps. We found that all the local activity metrics displayed different TE dependency characteristics, while their overall change patterns were similar: an initial large change followed by a slow variation. The T maps for local activity metrics also varied greatly with TE. For ALFF, fALFF, ReHo, and DC, the DOCs for voxels in four TE datasets were 6.87, 0.73, 5.08, and 0.93%, respectively. Collectively, these findings demonstrate that local metrics are greatly dependent on TE. Therefore, TE should be carefully considered for the optimization of data acquisition and multi-center data analysis in RS-fMRI.

Gammacoronavirus Avian Infectious Bronchitis Virus and Alphacoronavirus Porcine Epidemic Diarrhea Virus Exploit a Cell-Survival Strategy via Upregulation of cFOS to Promote Viral Replication.

Coronaviruses have evolved a variety of strategies to optimize cellular microenvironment for efficient replication. In this study, we report the induction of AP-1 transcription factors by coronavirus infection based on genome-wide analyses of differentially expressed genes in cells infected with avian coronavirus infectious bronchitis virus (IBV). Most members of the AP-1 transcription factors were subsequently found to be upregulated during the course of IBV and porcine epidemic diarrhea virus (PEDV) infection of cultured cells as well as in IBV-infected chicken embryos. Further characterization of the induction kinetics and functional roles of cFOS in IBV replication demonstrated that upregulation of cFOS at early to intermediate phases of IBV replication cycles suppresses IBV-induced apoptosis and promotes viral replication. Blockage of nuclear translocation of cFOS by peptide inhibitor NLSP suppressed IBV replication and apoptosis, ruling out the involvement of the cytoplasmic functions of cFOS in the replication of IBV. Furthermore, knockdown of ERK1/2 and inhibition of JNK and p38 kinase activities reduced cFOS upregulation and IBV replication. This study reveals an important function of cFOS in the regulation of coronavirus-induced apoptosis, facilitating viral replication.IMPORTANCE The ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by a newly emerged zoonotic coronavirus (SARS-CoV-2), highlights the importance of coronaviruses as human and animal pathogens and our knowledge gaps in understanding the cellular mechanisms, especially mechanisms shared among human and animal coronaviruses, exploited by coronaviruses for optimal replication and enhanced pathogenicity. This study reveals that upregulation of cFOS, along with other AP-1 transcription factors, as a cell-survival strategy is such a mechanism utilized by coronaviruses during their replication cycles. Through induction and regulation of apoptosis of the infected cells at early to intermediate phases of the replication cycles, subtle but appreciable differences in coronavirus replication efficiency were observed when the expression levels of cFOS were manipulated in the infected cells. As the AP-1 transcription factors are multi-functional, further studies of their regulatory roles in proinflammatory responses may provide new insights into the pathogenesis and virus-host interactions during coronavirus infection.

Higher Sensitivity and Reproducibility of Wavelet-Based Amplitude of Resting-State fMRI.

The fast Fourier transform (FFT) is a widely used algorithm used to depict the amplitude of low-frequency fluctuation (ALFF) of resting-state functional magnetic resonance imaging (RS-fMRI). Wavelet transform (WT) is more effective in representing the complex waveform due to its adaptivity to non-stationary or local features of data and many varieties of wavelet functions with different shapes being available. However, there is a paucity of RS-fMRI studies that systematically compare between the results of FFT versus WT. The present study employed five cohorts of datasets and compared the sensitivity and reproducibility of FFT-ALFF with those of Wavelet-ALFF based on five mother wavelets (namely, db2, bior4.4, morl, meyr, and sym3). In addition to the conventional frequency band of 0.0117-0.0781 Hz, a comparison was performed in sub-bands, namely, Slow-6 (0-0.0117 Hz), Slow-5 (0.0117-0.0273 Hz), Slow-4 (0.0273-0.0742 Hz), Slow-3 (0.0742-0.1992 Hz), and Slow-2 (0.1992-0.25 Hz). The results indicated that the Wavelet-ALFF of all five mother wavelets was generally more sensitive and reproducible than FFT-ALFF in all frequency bands. Specifically, in the higher frequency band Slow-2 (0.1992-0.25 Hz), the mean sensitivity of db2-ALFF results was 1.54 times that of FFT-ALFF, and the reproducibility of db2-ALFF results was 2.95 times that of FFT-ALFF. The findings suggest that wavelet-ALFF can replace FFT-ALFF, especially in the higher frequency band. Future studies should test more mother wavelets on other RS-fMRI metrics and multiple datasets.