Stage-specificity of STING activation in intrahepatic cholangiocarcinoma determines the efficacy of its agonism.

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive cancer with an extremely poor prognosis, and new treatment options are needed. Recently, immunotherapy has emerged as an efficient treatment against malignant tumors, but less effective in iCCA. Activation of stimulator of interferon genes (STING) signaling could reignite immunologically inert tumors, but the expression and role of STING in iCCA remains to be determined. Here, we show STING is expressed in iCCA, and patients with high expression of STING in early-stage iCCA have a longer overall survival than those have low expression. Increased immune cell infiltration in early-stage iCCA corresponds to elevated STING expression. In mice iCCA models, treatment with the STING agonist MSA-2 show stage-specific inhibitory effects on tumors, with beneficial effects in early-stage tumors but not with advanced-stage cancer. This discrepancy was associated with greater programmed cell death ligand 1 (PD-L1) expression in advanced-stage tumors. Combination therapy targeting PD-L1 and MSA-2 strikingly reduced tumor burden in such tumors compared to either monotherapy. Cumulatively, these data demonstrate that STING agonism monotherapy improves the immune landscape of the tumor microenvironment in early-stage iCCA, while combination therapy ameliorates advanced-stage iCCA.

Effects of a color gradient and emoji in AR-HUD warning interfaces in autonomous vehicles on takeover performance and driver emotions.

OBJECTIVE: This study examined the effects of color gradients and emojis in an augmented reality-head-up display (AR-HUD) warning interface on driver emotions and takeover performance. METHODS: A total of 48 participants were grouped into four different warning interfaces for a simulated self-driving takeover experiment. Two-way analysis of variance and the Kruskal-Wallis test was used to analyze takeover time, mood, task load, and system availability. RESULTS: Takeover efficiency and task load did not significantly differ among the interfaces, but the interfaces with a color gradient and emoji positively affected drivers' emotions. Emojis also positively affected emotional valence, and the color gradient had a high emotional arousal effect. Both the color gradient and the emoji interfaces had an inhibitory effect on negative emotions. The emoji interface was easier to learn, reducing driver learning costs. CONCLUSIONS: These findings offer valuable insights for designing safer and more user-friendly AR-HUD interfaces for self-driving cars.

Integrative Analysis of Morphine-Induced Differential Circular RNAs and ceRNA Networks in the Medial Prefrontal Cortex.

Circular RNAs (circRNAs) are a novel type of non-coding RNAs. Despite the fact that the functional mechanisms of most circRNAs remain unknown, emerging evidence indicates that circRNAs could sponge microRNAs (miRNAs), bind to RNA binding proteins (RBP), and even be translated into protein. Recent research has demonstrated the crucial roles played by circRNAs in neuropsychiatric disorders. The medial prefrontal cortex (mPFC) is a crucial component of drug reward circuitry and exerts top-down control over cognitive functions. However, there is currently limited knowledge about the correlation between circRNAs and morphine-associated contextual memory in the mPFC. Here, we performed morphine-induced conditioned place preference (CPP) in mice and extracted mPFC tissue for RNA-sequencing. Our study represented the first attempt to identify differentially expressed circRNAs (DEcircRNAs) and mRNAs (DEmRNAs) in the mPFC after morphine-induced CPP. We identified 47 significantly up-regulated DEcircRNAs and 429 significantly up-regulated DEmRNAs, along with 74 significantly down-regulated DEcircRNAs and 391 significantly down-regulated DEmRNAs. Functional analysis revealed that both DEcircRNAs and DEmRNAs were closely associated with neuroplasticity. To further validate the DEcircRNAs, we conducted qRT-PCR, Sanger sequencing, and RNase R digestion assays. Additionally, using an integrated bioinformatics approach, we constructed ceRNA networks and identified critical circRNA/miRNA/mRNA axes that contributed to the development of morphine-associated contextual memory. In summary, our study provided novel insights into the role of circRNAs in drug-related memory, specifically from the perspective of ceRNAs.

Neuroprotective Effect of Hydrogen Sulfide Subchronic Treatment Against TBI-Induced Ferroptosis and Cognitive Deficits Mediated Through Wnt Signaling Pathway.

Emerging evidence shows that targeting ferroptosis may be a potential therapeutic strategy for treating traumatic brain injury (TBI). Hydrogen sulfide (H2S) has been proven to play a neuroprotective role in TBI, but little is known about the effects of H2S on TBI-induced ferroptosis. In addition, it is reported that the Wnt signaling pathway can also actively regulate ferroptosis. However, whether H2S inhibits ferroptosis via the Wnt signaling pathway after TBI remains unclear. In this study, we first found that in addition to alleviating neuronal damage and cognitive impairments, H2S remarkably attenuated abnormal iron accumulation, decreased lipid peroxidation, and improved the expression of glutathione peroxidase 4, demonstrating the potent anti-ferroptosis action of H2S after TBI. Moreover, Wnt3a or liproxstatin-1 treatment obtained similar results, suggesting that activation of the Wnt signaling pathway can render the cells less susceptible to ferroptosis post-TBI. More importantly, XAV939, an inhibitor of the Wnt signaling pathway, almost inversed ferroptosis inactivation and reduction of neuronal loss caused by H2S treatment, substantiating the involvement of the Wnt signaling pathway in anti-ferroptosis effects of H2S. In conclusion, the Wnt signaling pathway might be the critical mechanism in realizing the anti-ferroptosis effects of H2S against TBI. TBI induces ferroptosis-related changes characterized by iron overload, impaired antioxidant system, and lipid peroxidation at the chronic phase after TBI. However, NaHS subchronic treatment reduces the susceptibility to TBI-induced ferroptosis, at least partly by activating the Wnt signaling pathway.

Phosphorylation of Neurofilament Light Chain in the VLO Is Correlated with Morphine-Induced Behavioral Sensitization in Rats.

Neurofilament light chain (NF-L) plays critical roles in synapses that are relevant to neuropsychiatric diseases. Despite postmortem evidence that NF-L is decreased in opiate abusers, its role and underlying mechanisms remain largely unknown. We found that the microinjection of the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) into the ventrolateral orbital cortex (VLO) attenuated chronic morphine-induced behavioral sensitization. The microinjection of TSA blocked the chronic morphine-induced decrease of NF-L. However, our chromatin immunoprecipitation (ChIP)-qPCR results indicated that this effect was not due to the acetylation of histone H3-Lysine 9 and 14 binding to the NF-L promotor. In line with the behavioral phenotype, the microinjection of TSA also blocked the chronic morphine-induced increase of p-ERK/p-CREB/p-NF-L. Finally, we compared chronic and acute morphine-induced behavioral sensitization. We found that although both chronic and acute morphine-induced behavioral sensitization were accompanied by an increase of p-CREB/p-NF-L, TSA exhibited opposing effects on behavioral phenotype and molecular changes at different addiction contexts. Thus, our findings revealed a novel role of NF-L in morphine-induced behavioral sensitization, and therefore provided some correlational evidence of the involvement of NF-L in opiate addiction.

Moderate Intensity of Treadmill Exercise Rescues TBI-Induced Ferroptosis, Neurodegeneration, and Cognitive Impairments via Suppressing STING Pathway.

Traumatic brain injury (TBI) is a universal leading cause of long-term neurological disability and causes a huge burden to an ever-growing population. Moderate intensity of treadmill exercise has been recognized as an efficient intervention to combat TBI-induced motor and cognitive disorders, yet the underlying mechanism is still unclear. Ferroptosis is known to be highly implicated in TBI pathophysiology, and the anti-ferroptosis effects of treadmill exercise have been reported in other neurological diseases except for TBI. In addition to cytokine induction, recent evidence has demonstrated the involvement of the stimulator of interferon genes (STING) pathway in ferroptosis. Therefore, we examined the possibility that treadmill exercise might inhibit TBI-induced ferroptosis via STING pathway. In this study, we first found that a series of ferroptosis-related characteristics, including abnormal iron homeostasis, decreased glutathione peroxidase 4 (Gpx4), and increased lipid peroxidation, were detected at 44 days post TBI, substantiating the involvement of ferroptosis at the chronic stage following TBI. Furthermore, treadmill exercise potently decreased the aforementioned ferroptosis-related changes, suggesting the anti-ferroptosis role of treadmill exercise following TBI. In addition to alleviating neurodegeneration, treadmill exercise effectively reduced anxiety, enhanced spatial memory recovery, and improved social novelty post TBI. Interestingly, STING knockdown also obtained the similar anti-ferroptosis effects after TBI. More importantly, overexpression of STING largely reversed the ferroptosis inactivation caused by treadmill exercise following TBI. To conclude, moderate-intensity treadmill exercise rescues TBI-induced ferroptosis and cognitive deficits at least in part via STING pathway, broadening our understanding of neuroprotective effects induced by treadmill exercise against TBI.

Influence of optical zone on myopic correction in small incision lenticule extraction: a short-term study.

BACKGROUND: To evaluate the influence of preoperative optical zone on myopic correction in small incision lenticule extraction. METHODS: In this retrospective clinical study, 581 eyes from 316 patients underwent SMILE were selected, including 117 eyes in the small optical zone group (range from 6.0 to 6.4 mm) and 464 eyes in the large optical zone group (range from 6.5 to 6.8 mm). The measurements included uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), spherical, and cylinder were measured preoperatively and 3 months postoperatively. Propensity score match (PSM) analysis was performed with age, gender, eye (right/left), keratometry and preoperative spherical equivalent between two different groups. The influence of optical zones on postoperative refractive outcomes were evaluated using univariate regression analysis. RESULTS: In total, 78 pairs of eyes were selected by PSM (match ratio 1:1). There were no differences in the age, gender, eye (right/left), keratometry or preoperative spherical equivalent between the small and large optical zone groups. However, the difference of postoperative spherical equivalent was significantly between groups. Patients with larger optical zones had a trend towards less undercorrection (P = 0.018). Univariate linear regression model analysis found that each millimeter larger optical zone resulted in 8.13% or 0.39D less undercorrection (P < 0.001). The dependency between the optical zones and postoperative spherical equivalent was significant in the higher preoperative myopia group (r = 0.281, P < 0.001), but not significant in the lower myopia group (r = 0.028, P = 0.702). CONCLUSION: The diameter of optical zones would affect postoperative refractive outcomes in small incision lenticule extraction. This study indicated that larger optical zones induced less undercorrection, especially in patients with high myopia.

The impact of different AR-HUD virtual warning interfaces on the takeover performance and visual characteristics of autonomous vehicles.

OBJECTIVE: The objective of this study was to determine the different effects of the arrow-pointing augmented reality head-up display (AR-HUD) interface, virtual shadow AR-HUD interface, and non-AR-HUD interface on autonomous vehicle takeover efficiency and driver eye movement characteristics in different driving scenarios. METHODS: Thirty-six participants were selected to carry out a simulated driving experiment, and the eye movement index and takeover time were analyzed. RESULTS: The arrow pointing AR-HUD interface and the virtual shadow AR-HUD interface could effectively reduce the driver's visual distraction, improve the efficiency of obtaining visual information, reduce the number of times the driver's eyes leave the road, and improve the efficiency of the takeover compared with the non-AR-HUD interface, but there was no significant difference in eye movement indexes between the arrow pointing AR-HUD interface and the more eye-catching virtual shadow AR-HUD interface. When specific scenarios were considered, it was found that in the scenario of emergency braking of the vehicle in front, the arrow pointing AR-HUD interface and the virtual shadow AR-HUD interface had more advantages in takeover efficiency than the non-AR-HUD interface. However, in the scenarios of a rear vehicle overtaking the vehicle ahead and non-motor vehicles running red lights, there was no significant difference in takeover efficiency. For the non-motor vehicle invading the line, emergency U-turn of the vehicle in front, and pedestrian crossing scenarios, the virtual shadow AR-HUD interface had the highest takeover efficiency. CONCLUSIONS: These research results can help improve the active safety of autonomous vehicle AR-HUD interfaces.

Influence of Multi-Modal Warning Interface on Takeover Efficiency of Autonomous High-Speed Train.

As a large-scale public transport mode, the driving safety of high-speed rail has a profound impact on public health. In this study, we determined the most efficient multi-modal warning interface for automatic driving of a high-speed train and put forward suggestions for optimization and improvement. Forty-eight participants were selected, and a simulated 350 km/h high-speed train driving experiment equipped with a multi-modal warning interface was carried out. Then, the parameters of eye movement and behavior were analyzed by independent sample Kruskal-Wallis test and one-way analysis of variance. The results showed that the current level 3 warning visual interface of a high-speed train had the most abundant warning graphic information, but it failed to increase the takeover efficiency of the driver. The visual interface of the level 2 warning was more likely to attract the attention of drivers than the visual interface of the level 1 warning, but it still needs to be optimized in terms of the relevance of and guidance between graphic-text elements. The multi-modal warning interface had a faster response efficiency than the single-modal warning interface. The auditory-visual multi-modal interface had the highest takeover efficiency and was suitable for the most urgent (level 3) high-speed train warning. The introduction of an auditory interface could increase the efficiency of a purely visual interface, but the introduction of a tactile interface did not improve the efficiency. These findings can be used as a basis for the interface design of automatic driving high-speed trains and help improve the active safety of automatic driving high-speed trains, which is of great significance to protect the health and safety of the public.

Estimation of thyroid volume from scintigraphy through 2D/3D registration of a statistical shape model.

Accurate measurement of thyroid volume is important for thyroid disease diagnosis and therapy. In nuclear medicine, the thyroid volume is usually estimated from scintigraphy images using empirical equations. However, due to the lack of volumetric information from the scintigraphy image, the accuracy of equation-based estimation is imperfect. To solve this problem, this paper proposes a method which registers a 3D thyroid statistical shape model (SSM) to a single-view scintigraphy image to achieve more accurate volume estimation. The SSM was constructed based on a training set of segmented 3D CT images, and the thyroid shape variations between the training subjects were modelled using the point distribution model. For thyroid volume estimation, the SSM was projected into the scintigraphy image of the target patient, and then the projected model shape was nonrigidly registered with the patient's scintigraphy image. The resultant 2D deformation file was back-projected to 3D space to guide the deformation of the 3D SSM. This process was repeated iteratively until convergence, and the volume of the finally deformed SSM was considered as the estimation of the patient's thyroid volume. For validation, this method was evaluated based on a test set of 20 scintigraphy images, achieving an estimation error of -2.10% ± 5.20% which was much less than the error of the conventional equation-based method (35.76% ± 15.20%) based on the same test set. The robustness of this method was further tested using a challenging case, i.e. a scintigraphy image with a large thyroid tumor. For this case, the volume estimation error was only 6.08%. Our method has significantly improved the accuracy of thyroid volume estimation from scintigraphy images, and it will enhance the value of scintigraphy imaging for thyroid disease diagnosis and radioiodine therapy.