Proteomic profiling of prostate cancer reveals molecular signatures under antiandrogen treatment.

BACKGROUND: Tumorigenesis and progression of prostate cancer (PCa) are indispensably dependent on androgen receptor (AR). Antiandrogen treatment is the principal preference for patients with advanced PCa. However, the molecular characteristics of PCa with antiandrogen intervention have not yet been fully uncovered. METHODS: We first performed proteome analysis with 32 PCa tumor samples and 10 adjacent tissues using data-independent acquisition (DIA)- parallel accumulation serial fragmentation (PASEF) proteomics. Then label-free quantification (LFQ) mass spectrometry was employed to analyze protein profiles in LNCaP and PC3 cells. RESULTS: M-type creatine kinase CKM and cartilage oligomeric matrix protein COMP were demonstrated to have the potential to be diagnostic biomarkers for PCa at both mRNA and protein levels. Several E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) were significantly altered in PCa and PCa cells under enzalutamide treatment, and these proteins might reprogram proteostasis at protein levels in PCa. Finally, we discovered 127 significantly varied proteins in PCa samples with antiandrogen therapy and further uncovered 4 proteins in LNCaP cells upon enzalutamide treatment. CONCLUSIONS: Our research reveals new potential diagnostic biomarkers for prostate cancer and might help resensitize resistance to antiandrogen therapy.

"Listen to your heart": A novel interoceptive strategy for real-time fMRI neurofeedback training of anterior insula activity.

Real-time fMRI (rt-fMRI) neurofeedback (NF) training is a novel non-invasive technique for volitional brain modulation. Given the important role of the anterior insula (AI) in human cognitive and affective processes, it has become one of the most investigated regions in rt-fMRI studies. Most rt-fMRI insula studies employed emotional recall/imagery as the regulation strategy, which may be less effective for psychiatric disorders characterized by altered emotional processing. The present study thus aimed to examine the feasibility of a novel interoceptive strategy based on heartbeat detection in rt-fMRI guided AI regulation and its associated behavioral changes using a randomized double-blind, sham feedback-controlled between-subject design. 66 participants were recruited and randomly assigned to receive either NF from the left AI (LAI) or sham feedback from a control region while using the interoceptive strategy. N = 57 participants were included in the final data analyses. Empathic and interoceptive pre-post training changes were collected as behavioral measures of NF training effects. Results showed that participants in the NF group exhibited stronger LAI activity than the control group with LAI activity being positively correlated with interoceptive accuracy following NF training, although there were no significant increases of LAI activity over training sessions. Importantly, ability of LAI regulation could be maintained in a transfer session without feedback. Successful LAI regulation was associated with strengthened functional connectivity of the LAI with cognitive control, memory and learning, and salience/interoceptive networks. The present study demonstrated for the first time the efficacy of a novel regulation strategy based on interoceptive processing in up-regulating LAI activity. Our findings also provide proof of concept for the translational potential of this strategy in rt-fMRI AI regulation of psychiatric disorders characterized by altered emotional processing.

SIRT2 promotes cell proliferation and migration through mediating ERK1/2 activation and lactosylceramide accumulation in prostate cancer.

BACKGROUND: Prostate cancer (PCa) is an age-related malignancy with a high incidence and mortality rate due to lack of efficacy drugs for its therapy in late castration-resistant stage. Sirtuin 2 (SIRT2), a NAD+ -dependent protein deacetylase, is associated with age-related diseases. However, SIRT2 roles in PCa are unclear yet. METHODS: Data of SIRT2 expression were extracted from TCGA cohort and GSE54460 cohort. Realtime quantitative PCR and immunohistochemistry were employed to analyze the expression of SIRT2 in PCa tissues. Cell counting Kit-8 assay, lentiviral transduction, flow cytometry, transwell experiments, western blot and metabolomic analysis were performed to explore the functions of SIRT2. RESULTS: SIRT2 exhibited increased expression in castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). Overexpression of SIRT2 promoted cell proliferation, the proportion of S phase, migration and invasion, and reduced apoptosis rate. The increased phosphorylated ERK1/2 indicated the regulation of SIRT2 to cell proliferation, migration and invasion through activation of ERK1/2 pathway. Furthermore, SIRT2 affected cell metabolic profile and induces lactosylceramide production through upregulation of B4GALT5, which further contributes cell migration and invasion. CONCLUSIONS: Our data suggested that SIRT2 is overexpressed in CRPC and NEPC and could promote cell growth and migration through activating ERK1/2 pathway and inducing lactosylceramide production, indicating that SIRT2 has the potential to be a new target for the treatment of PCa.

H3K27me3 Inactivates SFRP1 to Promote Cell Proliferation via Wnt/ß-Catenin Signaling Pathway in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Histone methylations are generally considered to play an important role in multiple cancers by regulating cancer-related genes. AIMS: This study aims to investigate the effects of H3K27me3-mediated inactivation of tumor suppressor gene SFRP1 and its function in esophageal squamous cell carcinoma (ESCC). METHODS: We performed ChIP-seq on H3K27me3-enriched genomic DNA fragments in ESCC cells to screen out tumor suppressor genes that may be regulated by H3K27me3. ChIP-qPCR and Western blot were employed to explore the regulating mechanisms between H3K27me3 and SFRP1. Expression level of SFRP1 was assessed by quantitative real-time polymerase chain reaction (q-PCR) in 29 pairs of ESCC surgical samples. SFRP1 function in ESCC cells were detected by cell proliferation assay, colony formation assay and wound-healing assay. RESULTS: Our results indicated that H3K27me3 was widely distributed in the genome of ESCC cells. Specifically, we found that H3K27me3 deposited on the upstream region of SFRP1 promoter and inactivated SFRP1 expression. Furthermore, we found SFRP1 was significantly down-regulated in ESCC tissues compared with the adjacent non-tumor tissues, and SFRP1 expression was significantly associated with TNM stage and lymph node metastasis. In vitro cell-based assay indicated that over-expression of SFRP1 significantly suppressed cell proliferation and negatively correlated with the expression of ß-catenin in the nucleus. CONCLUSIONS: Our study revealed a previously unrecognized finding that H3K27me3-mediated SFRP1 inhibit the cell proliferation of ESCC through inactivation of Wnt/ß-catenin signaling pathway.

Transcriptomic profiling of lipopolysaccharide-challenged bovine mammary epithelial cells treated with forsythoside A.

Mastitis is usually caused by a variety of pathogenic bacteria that seriously impact the health and milk-production ability of dairy cows, with consequent, economically detrimental effects on the dairy industry. Forsythoside A (FTA), isolated from the fruit and leaves of Forsythia suspensa (Thunb.) Vahl (Oleaceae), has been reported to have significant antioxidant, anti-inflammatory, and antibacterial effects. However, it is not clear whether FTA exerts a protective effect against lipopolysaccharide (LPS)-induced bovine mastitis and its potential gene signature. In this study, high-throughput sequencing technology was performed to analyze the differences between the mRNA and enrichment pathway of bovine mammary epithelial cells of the control, LPS, and LPS + FTA groups. The results showed that there were 139 differentially expressed genes (DEGs) (p-value < 0.05, |log2FoldChange| > 1, FPKM > 1) in the LPS group compared with the control group, including 121 up-regulated genes and 18 down-regulated genes, which were mainly enriched in the cellular response to lipopolysaccharide, cytokine activity, protein binding, and IL-17 signaling pathway based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, respectively. Compared with the control group and LPS + FTA group, there were 349 DEGs, including 322 up-regulated genes and 27 down-regulated genes. They were mainly enriched in protein localization to organelles, centrosomes, binding, and the IL-17 signaling pathway, based on GO and KEGG analysis. Compared to the LPS group, the LPS + FTA group had 272 DEGs, including 259 up-regulated genes and 13 down-regulated genes, which were mainly enriched in RNA processing, IL-6 receptor binding, and the lysosome pathway, based on GO and KEGG analyses. It can be seen that LPS stimulation induced the expression of inflammation-related genes, IL-17 and IL-6, whereas FTA treatment promoted the expression of the spliceosome-, lysosome-, and oxidative stress-related genes HSP70, HSPA8, and PARP2. The study utilized RNA-sequencing analysis of FTA against LPS-challenged bovine mammary epithelial cells to explore key mRNA findings that may be strongly associated with inflammation and oxidative stress, and provides a theoretical reference for further elucidation of molecular mechanisms of bovine mastitis and therapeutic effects of FTA against bovine mastitis.

H3K9me3, H3K36me3, and H4K20me3 Expression Correlates with Patient Outcome in Esophageal Squamous Cell Carcinoma as Epigenetic Markers.

BACKGROUND: Histone methylation, as an essential pattern of posttranslational modifications, contributes to multiple cancer-related biological processes. Dysregulation of histone methylation is now considered a biomarker for cancer prognosis. AIMS: This study investigated and evaluated the potential role of four histone lysine trimethylation markers as biomarkers for esophageal squamous cell carcinoma (ESCC) prognosis. METHODS: Tissue arrays were made from 135 paraffin-embedded ESCC samples and examined for histone markers by immunohistochemistry, and 10 pairs of cancer and noncancerous mucosa tissues from ESCC patients were investigated with Western blot. Chi-squared test, Kaplan-Meier analysis with log-rank test, and Cox proportional hazard trend analyses were performed to assess the prognostic values of the markers. RESULTS: Histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 9 trimethylation (H3K9me3), and histone 4 lysine 20 trimethylation (H4K20me3), but not histone 3 lysine 36 trimethylation (H3K36me3), showed stronger immunostaining signals in tumor tissues than in the corresponding adjacent non-neoplastic mucosa tissues. The expression patterns of H3K36me3, H3K9me3, and H4K20me3 correlated with tumor infiltrating depth, lymph node involvement, and pTNM stage. Low-scoring H3K9me3 and H4K20me3 predicted better prognosis, while H3K36me3 manifested the opposite trend. Poor prognosis occurred in ESCC patients with expression patterns of high levels of H3K9me3, high levels of H4K20me3, and low levels of H3K36me3 expression. CONCLUSIONS: H3K9me3, H4K20me3, and H3K36me3 showed a close relationship with clinical features and were considered independent risk factors for survival of ESCC patients. The combination of H3K9me3, H4K20me3, and H3K36me3 expression, rather than the expression of a single histone marker, is believed to further enhance evaluations of ESCC prognosis and management.

Impact of long-term care insurance on health inequality in older adults in China based on the concentration index approach.

BACKGROUND: Several studies have shown that social security would reduce health inequalities. However, little was known about the relationship between long-term care insurance and health inequality. We aimed to evaluate the impact of long-term care insurance on health status and health inequality in older adults using a nationally representative cohort. METHODS: Based on four waves of data from the China Health and Retirement Longitudinal Study (CHARLS 2011, 2013, 2015 and 2018), we used the staggered difference in difference (DID) design with the order probit regression models and the concentration index approach as well as decomposition analysis to assess the contribution of long-term care insurance towards residents' health status and health inequality in older adults aged ≥65 y. We further used the semi-parametric DID model for robustness testing. RESULTS: Long-term care insurance demonstrated its role, improving self-assessed health in the study population (ßcoefficient: 0.090, 95% CI 0.087 to 0.092, p<0.001). The estimation results of the semi-parametric DID were consistent with those of the staggered DID. The income-related health concentration index was 0.0005, having a contribution rate of 1.639% to health inequality in older adults. Decomposition analysis revealed that different policies and residential areas were more influential on the observed health inequalities. CONCLUSIONS: The findings implied that long-term care insurance has widened the health inequality while improving health status in older adults. Additional investment in more comprehensive insurance coverage and increased accessibility to enhance implementation of long-term care insurance is warranted to close the gap.

Intranasal oxytocin improves interoceptive accuracy and heart-beat evoked potentials in a cardiac interoceptive task.

BACKGROUND: Interoception represents perception of the internal bodily state which is closely associated with social/emotional processing and physical health in humans. Understanding the mechanism underlying interoceptive processing, particularly its modulation, is thus of great importance. Given overlap between oxytocinergic pathways and interoceptive signaling substrates in both peripheral visceral organs and the brain, intranasal oxytocin administration is a promising approach for modulating interoceptive processing. METHODS: In a double-blind, placebo-controlled, between-subject design, 72 healthy male participants performed a cardiac interoceptive task during electroencephalograph (EEG) and electrocardiograph (ECG) recording to examine whether intranasal administration of the neuropeptide oxytocin can modulate interoceptive processing. We also collected data in a resting state to examine whether we could replicate previous findings. RESULTS: Results showed that in the interoceptive task oxytocin increased interoceptive accuracy at the behavioral level which was paralleled by larger heartbeat-evoked potential amplitudes at frontocentral and central regions on the neural level. However, there were no significant effects of oxytocin on EEG or ECG during resting-state. CONCLUSIONS: These findings suggest that oxytocin may only have a facilitatory effect on interoceptive processing during task-based conditions. Our findings not only provide new insights into the modulation of interoceptive processing via targeting the oxytocinergic system but also provide proof of concept evidence for the therapeutic potential of intranasal oxytocin in mental disorders with dysfunctional interoception.

Effect of esketamine-based opioid-sparing anesthesia strategy on postoperative pain and recovery quality in patients undergoing total laparoscopic hysterectomy: A randomized controlled trail.

Objective: Opioid-sparing anesthesia reduces intraoperative use of opioids and postoperative adverse reactions. The current study investigated the effect of esketamine-based opioid-sparing anesthesia on total laparoscopic hysterectomy patients' recovery. Methods: Ninety patients undergoing total laparoscopic hysterectomy were randomly assigned to esketamine-based group (group K) or opioid-based group (group C). The allocation to groups was unknown to patients, surgeons, and postoperative medical staff. The inability to implement blinding for anesthesiologists was due to the distinct procedures followed by the various groups while administering drugs. The QoR-40 and VAS were used to measure recovery quality. Postoperative adverse events, perioperative opioid consumption, and intraoperative hemodynamics were secondary endpoints. Results: There was an absence of notable discrepancy in the baseline data observed between the two groups. The QoR-40 scores exhibited greater values in group K when compared to group C on the first day following the surgical procedure (160.91 ± 9.11 vs 151.47 ± 8.35, respectively; mean difference 9.44 [95 %CI: 5.78-13.11]; P < 0.01). Within 24 h of surgery, the VAS score of group K was lower at rest and during movement. (P < 0.05 for each). Group K had much lower rates of nausea and vomiting within 24 h of surgery. (P < 0.05 for each). Group K received significantly lower total doses of sufentanil and remifentanil than group C. (17.28 ± 2.59 vs 43.43 ± 3.52; 0.51 ± 0.15 vs 1.24 ± 0.24). The proportion of patients who used ephedrine in surgery was higher in group C than in group K (P < 0.05). Conclusions: Esketamine-based opioid-sparing anesthesia strategy is feasible and enhanced recuperation following surgery by decreasing adverse effects associated with opioids and pain scores compared to an opioid-based anesthetic regimen.

LCP1-mediated cytoskeleton alterations involve in arsenite-triggered malignant phenotype of human immortalized prostate stromal cells.

The connection between continuous arsenic exposure and prostate cancer is already established. However, the exact mechanisms of arsenic tumorigenesis are far from clear. Here, we employed human prostate stromal immortalized cells (WPMY-1) continuous exposure to 1 and 2 µM arsenite for 29 weeks to identify the malignant phenotype and explore the underlying molecular mechanism. As expected, continuous low-dose arsenite exposure led to the malignant phenotype of WPMY-1 cells. Quantitative proteomics identified 517 differentially expressed proteins (DEPs), of which the most remarkably changed proteins (such as LCP1 and DDX58, etc.) and the bioinformatic analysis were focused on the regulation of cytoskeleton, cell adhesion, and migration. Further, cell experiments showed that continuous arsenite exposure altered cytoskeleton structure, enhanced cell adhesive capability, and raised the levels of reactive oxygen species (ROS), ATM, p-ATM, p-ERK1/2, and LCP1 proteins. N-acetylcysteine (NAC) treatment antagonized the increase of LCP1 proteins, and LCP1 knockdown partially restored F-actin organization caused by arsenic. Overall, the results demonstrated that ROS-ATM-ERK1/2 signaling pathway was involved in the activation of LCP1, leading to cytoskeleton alterations. These alterations are believed to play a significant role in arsenite-triggered tumor microenvironment cell-acquired malignant phenotype, which could provide potential biomarkers with therapeutic implications for prostate cancer.

Neural and behavioral evidence for oxytocin's facilitatory effects on learning in volatile and stable environments.

Outcomes of past decisions profoundly shape our behavior. However, choice-outcome associations can become volatile and adaption to such changes is of importance. The present study combines pharmaco-electroencephalography with computational modeling to examine whether intranasal oxytocin can modulate reinforcement learning under a volatile vs. a stable association. Results show that oxytocin increases choice accuracy independent of learning context, which is paralleled by a larger N2pc and a smaller P300. Model-based analyses reveal that while oxytocin promotes learning by accelerating value update of outcomes in the volatile context, in the stable context it does so by improving choice consistency. These findings suggest that oxytocin's facilitatory effects on learning may be exerted via improving early attentional selection and late neural processing efficiency, although at the computational level oxytocin's actions are highly adaptive between learning contexts. Our findings provide proof of concept for oxytocin's therapeutic potential in mental disorders with adaptive learning dysfunction.

Transcutaneous auricular vagus nerve stimulation enhanced emotional inhibitory control via increasing intrinsic prefrontal couplings.

Background: Inhibitory control represents a core executive function that critically facilitates adaptive behavior and survival in an ever-changing environment. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has been hypothesized to improve behavioral inhibition performance, however the neurocomputational mechanism of taVNS-induced neuroenhancement remains elusive. Method: In the current study, we investigated the efficacy of taVNS in a sham-controlled between-subject functional near infrared spectroscopy (fNIRS) experiment with an emotional face Go/No-Go paradigm in ninety healthy young adults. Results: After a data quality check, eighty-two subjects were included in the final data analysis. Behaviorally, the taVNS improved No-Go response accuracy, together with computational modeling using Hierarchical Bayesian estimation of the Drift Diffusion Model (HDDM) indicating that it specifically reduced the information accumulation rate for Go responses, and this was negatively associated with increased accuracy of No-Go responses. On the neural level, taVNS enhanced engagement of the bilateral inferior frontal gyrus (IFG) during inhibition of angry expression faces and modulated functional couplings (FCs) within the prefrontal inhibitory control network. Mediation models revealed that taVNS-induced facilitation of inhibitory control was critically mediated by a decreased information accumulation for Go responses and concomitantly enhanced neurofunctional coupling between the inferior and orbital frontal cortex. Discussion: Our findings demonstrate a potential for taVNS to improve emotional inhibitory control via reducing pre-potent responses and enhancing FCs within prefrontal inhibitory control networks, suggesting a promising therapeutic role in treating specific disorders characterized by inhibitory control deficits.

Differential features of early childhood motor skill development and working memory processing: evidence from fNIRS.

Objective: The study investigated the differential characteristics associated with motor skill development and working memory processing during early childhood, thereby providing insights for understanding motor learning and cognitive development in young children. Methods: In total, 101 preschool children (age: 4-6 years) were recruited for this study. The motor skill development level and the working memory capacity of the children were assessed using the MOBAK Motor Development Assessment Scale and a block task paradigm, respectively. Functional near-infrared spectroscopy brain imaging technology was used to monitor hemodynamic signals in the prefrontal cortex (PFC) of the children while they completed different memory tasks. MATLAB software and the Homer2 plugin were used to calculate the oxygenated hemoglobin (Oxy-Hb) concentration in relevant brain regions during the tasks. Results: (1) The low motor skill group exhibited significantly lower accuracy during the three-memory load condition than during the two-memory load condition. Under both two-memory and three-memory load conditions, the high motor skill group exhibited significantly higher accuracy than the low motor skill group. (2) Significant differences in the Oxy-Hb concentration were observed in the left dorsolateral PFC (L-DLPFC), and right and left triangular part of the Broca's area (R-PTBA and L-PTBA, respectively) between the two memory difficulty levels for the high motor skill group. The Oxy-Hb concentration was significantly higher during the three-memory load condition than during the two-memory load condition. Under the two-memory load condition, the high motor skill group exhibited significantly higher Oxy-Hb concentration in the L-DLPFC and L-PTBA regions than in the low motor skill group. Under the three-memory load condition, the high motor skill group exhibited significantly higher Oxy-Hb concentration in the L-DLPFC, R-PTBA, and L-PTBA regions than the low motor skill group. Conclusion: A close association was observed between the motor skill levels and working memory in young children, with higher motor skill levels being associated with more pronounced brain activation patterns during working memory tasks.

Correction: From 2 dimensions to 3rd dimension: Quantitative prediction of anterior chamber depth from anterior segment photographs via deep-learning.

[This corrects the article DOI: 10.1371/journal.pdig.0000193.].

From 2 dimensions to 3rd dimension: Quantitative prediction of anterior chamber depth from anterior segment photographs via deep-learning.

Anterior chamber depth (ACD) is a major risk factor of angle closure disease, and has been used in angle closure screening in various populations. However, ACD is measured from ocular biometer or anterior segment optical coherence tomography (AS-OCT), which are costly and may not be readily available in primary care and community settings. Thus, this proof-of-concept study aims to predict ACD from low-cost anterior segment photographs (ASPs) using deep-learning (DL). We included 2,311 pairs of ASPs and ACD measurements for algorithm development and validation, and 380 pairs for algorithm testing. We captured ASPs with a digital camera mounted on a slit-lamp biomicroscope. Anterior chamber depth was measured with ocular biometer (IOLMaster700 or Lenstar LS9000) in data used for algorithm development and validation, and with AS-OCT (Visante) in data used for testing. The DL algorithm was modified from the ResNet-50 architecture, and assessed using mean absolute error (MAE), coefficient-of-determination (R2), Bland-Altman plot and intraclass correlation coefficients (ICC). In validation, our algorithm predicted ACD with a MAE (standard deviation) of 0.18 (0.14) mm; R2 = 0.63. The MAE of predicted ACD was 0.18 (0.14) mm in eyes with open angles and 0.19 (0.14) mm in eyes with angle closure. The ICC between actual and predicted ACD measurements was 0.81 (95% CI 0.77, 0.84). In testing, our algorithm predicted ACD with a MAE of 0.23 (0.18) mm; R2 = 0.37. Saliency maps highlighted the pupil and its margin as the main structures used in ACD prediction. This study demonstrates the possibility of predicting ACD from ASPs via DL. This algorithm mimics an ocular biometer in making its prediction, and provides a foundation to predict other quantitative measurements that are relevant to angle closure screening.

Increasing the activities of protective enzymes is an important strategy to improve resistance in cucumber to powdery mildew disease and melon aphid under different infection/infestation patterns.

Powdery mildew, caused by Sphaerotheca fuliginea (Schlecht.) Poll., and melon aphids (Aphis gossypii Glover) are a typical disease and insect pest, respectively, that affect cucumber production. Powdery mildew and melon aphid often occur together in greenhouse production, resulting in a reduction in cucumber yield. At present there are no reports on the physiological and biochemical effects of the combined disease and pest infection/infestation on cucumber. This study explored how cucumbers can regulate photosynthesis, protective enzyme activity, and basic metabolism to resist the fungal disease and aphids. After powdery mildew infection, the chlorophyll and free proline contents in cucumber leaves decreased, while the activities of POD (peroxidase) and SOD (superoxide dismutase) and the soluble protein and MDA (malondialdehyde) contents increased. Cucumber plants resist aphid attack by increasing the rates of photosynthesis and basal metabolism, and also by increasing the activities of protective enzymes. The combination of powdery mildew infection and aphid infestation reduced photosynthesis and basal metabolism in cucumber plants, although the activities of several protective enzymes increased. Aphid attack after powdery mildew infection or powdery mildew infection after aphid attack had the opposite effect on photosynthesis, protective enzyme activity, and basal metabolism regulation. Azoxystrobin and imidacloprid increased the contents of chlorophyll, free proline, and soluble protein, increased SOD activity, and decreased the MDA content in cucumber leaves. However, these compounds had the opposite effect on the soluble sugar content and POD and CAT (catalase) activities. The mixed ratio of the two single agents could improve the resistance of cucumber to the combined infection of powdery mildew and aphids. These results show that cucumber can enhance its pest/pathogen resistance by changing physiological metabolism when exposed to a complex infection system of pathogenic microorganisms and insect pests.

Therapeutic applications of transcutaneous auricular vagus nerve stimulation with potential for application in neurodevelopmental or other pediatric disorders.

Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) as a newly developed technique involves stimulating the cutaneous receptive field formed by the auricular branch of the vagus nerve in the outer ear, with resulting activation of vagal connections to central and peripheral nervous systems. Increasing evidence indicates that maladaptive neural plasticity may underlie the pathology of several pediatric neurodevelopmental and psychiatric disorders, such as autism spectrum disorder, attention deficit hyperactivity disorder, disruptive behavioral disorder and stress-related disorder. Vagal stimulation may therefore provide a useful intervention for treating maladaptive neural plasticity. In the current review we summarize the current literature primarily on therapeutic use in adults and discuss the prospects of applying taVNS as a therapeutic intervention in specific pediatric neurodevelopmental and other psychiatric disorders. Furthermore, we also briefly discuss factors that would help optimize taVNS protocols in future clinical applications. We conclude from these initial findings that taVNS may be a promising alternative treatment for pediatric disorders which do not respond to other interventions.

Early signs of geographic spread of COVID-19: lessons learnt from outbreaks in Wuhan 2020 and Nanjing 2021.

BACKGROUND: Knowing the spatiotemporal pattern of the early geographic spread of coronavirus disease 2019 (COVID-19) would inform the preparedness for a possible recurrence of COVID-19. METHODS: We ascertained the number of confirmed cases during the early spread of COVID-19 during the Wuhan outbreak in 2020 and the Nanjing outbreak in 2021. RESULTS: We observed a speeding-up pattern of geographic spread, in particular to cities of no particular orientation then outflowing to commercial cities during the first month of both the Wuhan and Nanjing outbreaks. CONCLUSION: Re-emergence of COVID-19 indicates it is becoming endemic, with new outbreaks and a risk of increased transmission remaining a challenge to local public health institutions. Social distancing and lockdowns should continue in response to any potential widespread and focal outbreaks.

Hypoxia-inducible factor-1α cooperates with histone Lys methylation to predict prognosis in esophageal squamous cell carcinoma.

Aim: To investigate hypoxia-inducible factor-1α (HIF-1α) and histone methylation markers as potential indicators of prognosis in esophageal squamous cell carcinoma (ESCC). Patients & methods: The prognostic value of HIF-1α and histone methylation markers levels was analyzed using Kaplan-Meier survival analysis. Results: HIF-1α protein expression was higher in ESCC tumors than in paracancerous tissues. Histone H3 Lys9 trimethylation (H3K9me3), histone H3 Lys27 trimethylation (H3K27me3), histone H3 Lys4 trimethylation (H3K4me3) and histone H4 Lys20 trimethylation (H4K20me3) were significantly upregulated in ESCC tissues. HIF-1α was only positively correlated with H3K9me3 and H3K4me3 expression. Kaplan-Meier analysis indicated that H3K9me3, H3K27me3, H4K20me3 and histone H3 Lys36 trimethylation (H3K36me3) were independent indicators of prognosis for ESCC. Conclusion: This study identified a pattern of epigenetic methylation markers and HIF-1α expression in ESCC, and their combined evaluation might improve survival prediction for ESCC patients.

Decreased homotopic interhemispheric functional connectivity in children with autism spectrum disorder.

While several functional and structural changes occur in large-scale brain networks in autism spectrum disorder (ASD), reduced interhemispheric resting-state functional connectivity (rsFC) between homotopic regions may be of particular importance as a biomarker. ASD is an early-onset developmental disorder and neural alterations are often age-dependent. Although there is some evidence for homotopic interhemispheric rsFC alterations in language processing regions in ASD children, wider analyses using large data sets have not been performed. The present study, therefore, conducted a voxel-based homotopic interhemispheric rsFC analysis in 146 ASD and 175 typically developing children under-age 10 and examined associations with symptom severity in the autism brain imaging data exchange data sets. Given the role of corpus callosum (CC) in interhemispheric connectivity and reported CC volume changes in ASD we additionally examined whether there were parallel volumetric changes. Results demonstrated decreased homotopic rsFC in ASD children in the posterior cingulate cortex (PCC) and precuneus of the default mode network, the precentral gyrus of the mirror neuron system, and the caudate of the reward system. Homotopic rsFC of the PCC was associated with symptom severity. Furthermore, although no significant CC volume changes were found in ASD children, there was a significant negative correlation between the anterior CC volumes and homotopic rsFC strengths in the caudate. The present study shows that a reduced pattern of homotopic interhemispheric rsFC in ASD adults/adolescents is already present in children of 5-10 years old and further supports their potential use as a general ASD biomarker. LAY SUMMARY: Homotopic interhemispheric functional connectivity plays an important role in synchronizing activity between the two hemispheres and is altered in adults and adolescents with autism spectrum disorder (ASD). In the present study focused on children with ASD, we have observed a similar pattern of decreased homotopic connectivity, suggesting that alterations in homotopic interhemispheric connectivity may occur early in ASD and be a useful general biomarker across ages.