Separation, enrichment and cytoprotection of antioxidant peptides from Xuanwei ham using aqueous two-phase extraction.

An ethanol/(NH4)2SO4 biphasic (aqueous two-phase) system was designed to effectively separate antioxidant peptides from Xuanwei ham, and its potential to prevent ultraviolet A-induced damage to skin cells was explored. Optimization via single factor experiments and response surface methodology revealed that under 20 % ethanol aqueous solution (w/w), 25.5 % (NH4)2SO4 aqueous solution (w/w), and pH 8.80 conditions, the optimal extraction ratio was 59.0 ± 1.73 %. In vitro antioxidant activity and cellular assays showed that the peptide purified in the upper phase exhibited strong antioxidant activity, increasing the viability of HaCat cells damaged by UVA irradiation from 56.14 ± 1.05 % to 66.3 ± 1.76 %. We used an in silico peptide screening strategy and identified 10 with potential antioxidant activity, emphasizing the important role of amino acids Pro, Gly, and Ala in antioxidant activity.

Secular trends in sleep and circadian problems among adolescents in Hong Kong: From 2011-2012 to 2017-2019.

OBJECTIVE: The study aimed to investigate secular trends in sleep and circadian problems in Hong Kong Chinese adolescents. METHODS: This study analyzed cross-sectional data from two large-scale school-based sleep surveys conducted in 2011-2012 and 2017-2019. Sleep and circadian problems, including sleep-wake pattern, insomnia, chronotype, social jetlag, daytime sleepiness, and other sleep-related factors, were compared between two survey years. RESULTS: A total of 8082 adolescents (5639 students in 2011-2012 [Mean age: 14.4 years, 50.9% boys] and 2443 students in 2017-2019 [Mean age: 14.7 years, 54.0% boys]) were included in this 7-year study. The average time in bed of Hong Kong adolescents decreased from 8.38 hours to 8.08 hours from 2011-2012 to 2017-2019. There was a 0.28-hour delay in weekday bedtime, 0.54-hour advance in weekend wake-up time, and a 0.36-hour decline in average time in bed, resulting in increased trends of sleep loss (Time in bed <8h: OR = 2.06, 95%CI: 1.44-2.93, p < 0.01; Time in bed <7h: OR = 2.73, 95%CI: 1.92-3.89, p < 0.01), daytime sleepiness (OR = 1.70, 95%CI: 1.34-2.16, p < 0.01), and evening chronotype (OR = 1.26, 95%CI: 1.08-1.48, p < 0.01). The increased trend in insomnia disorder, however, was insignificant when covariates were adjusted. CONCLUSION: A secular trend of reduced time in bed, delay in weekday bedtime, advance in weekend wake-up time, increase in evening chronotype and daytime sleepiness from 2011-2012 to 2017-2019 were observed. There is a timely need for systematic intervention to promote sleep health in adolescents.

Enhanced deep unrolling networks for snapshot compressive hyperspectral imaging.

Snapshot compressive hyperspectral imaging necessitates the reconstruction of a complete hyperspectral image from its compressive snapshot measurement, presenting a challenging inverse problem. This paper proposes an enhanced deep unrolling neural network, called EDUNet, to tackle this problem. The EDUNet is constructed via the deep unrolling of a proximal gradient descent algorithm and introduces two innovative modules for gradient-driven update and proximal mapping reflectivity. The gradient-driven update module leverages a memory-assistant descent approach inspired by momentum-based acceleration techniques, for enhancing the unrolled reconstruction process and improving convergence. The proximal mapping is modeled by a sub-network with a cross-stage spectral self-attention, which effectively exploits the inherent self-similarities present in hyperspectral images along the spectral axis. It also enhances feature flow throughout the network, contributing to reconstruction performance gain. Furthermore, we introduce a spectral geometry consistency loss, encouraging EDUNet to prioritize the geometric layouts of spectral curves, leading to a more precise capture of spectral information in hyperspectral images. Experiments are conducted using three benchmark datasets including KAIST, ICVL, and Harvard, along with some real data, comprising a total of 73 samples. The experimental results demonstrate that EDUNet outperforms 15 competing models across four metrics including PSNR, SSIM, SAM, and ERGAS.

Mild hypothermia reduces lipopolysaccharide-induced microglial activation via down-regulation of Tent5c.

Microglial activation is a critical factor in the pathogenesis and progression of neuroinflammatory diseases. Mild hypothermia, known for its neuroprotective properties, has been shown to alleviate microglial activation. In this study, we explore the differentially expressed (DE) mRNAs and long non-coding RNAs (lncRNAs) in BV-2 microglial cells under different conditions: normal temperature (CN), mild hypothermia (YT), normal temperature with lipopolysaccharide (LPS), and mild hypothermia with LPS (LPS + YT). Venn analysis revealed 119 DE mRNAs that were down-regulated in the LPS + YT vs LPS comparison but up-regulated in the CN vs LPS comparison, primarily enriched in Gene Ontology terms related to immune and inflammatory responses. Furthermore, through Venn analysis of YT vs CN and LPS + YT vs LPS comparisons, we identified 178 DE mRNAs and 432 DE lncRNAs. Among these transcripts, we validated the expression of Tent5c at the protein and mRNA levels. Additionally, siRNA-knockdown of Tent5c attenuated the expression of pro-inflammatory genes (TNF-α, IL-1ß, Agrn, and Fpr2), cellular morphological changes, NLRP3 and p-P65 protein levels, immunofluorescence staining of p-P65 and number of cells with ASC-speck induced by LPS. Furthermore, Tent5c overexpression further potentiated the aforementioned indicators in the context of mild hypothermia with LPS treatment. Collectively, our findings highlight the significant role of Tent5c down-regulation in mediating the anti-inflammatory effects of mild hypothermia.

Transcranial Ultrasound Stimulation Improves Memory Performance of Parkinsonian Mice.

Cognitive impairment is one of the most common non-motor symptoms of Parkinson's disease (PD). Previous studies have demonstrated that low-intensity transcranial ultrasound stimulation can significantly suppress the motor symptoms of PD. However, whether ultrasound stimulation can improve cognitive ability in PD and the related neural oscillation mechanism remain unclear to date. To evaluate the effect of ultrasound stimulation on memory ability in PD and explore its neural oscillation mechanism. Ultrasonography was used for 7-day stimulation of the CA1 in transgenic mice with PD. The working memory ability of the PD mice was then tested using novel object discrimination, and the local field potential and spikes in the mice CA1 were recorded at the same time as in the behavioral test. We found that ultrasound stimulation of the PD mice CA1 for 4 days: 1) significantly increased their learning and memory ability, although the learning and memory ability on the 7th day after the stimulation stopped was not significantly different from that before stimulation (P>0.05); 2) significantly increased the relative power of theta, low gamma, and high gamma frequency bands of the local field potential, and the phase amplitude coupling strength between theta and low gamma and between theta and high gamma; and 3) modulated the phase-locking angle between the spike of interneuron and theta wave to a 180°-360° rise cycle. Transcranial ultrasound stimulation can improve the learning and memory abilities of PD mice, and evoking neural oscillations in the CA1 is the potential mechanism.

Comparing the Long-Term Cardiovascular Outcomes of Lumbo-Peritoneal, Ventriculo-Peritoneal, or Non-Shunting Treatment after Idiopathic Normal Pressure Hydrocephalus: A Nationwide Retrospective Cohort Study.

Purpose: With advances in medical technology, the average lifespan has increased, leading to a growing significance of idiopathic normal pressure hydrocephalus (iNPH), particularly in the elderly population. Most patients with iNPH have been treated either with ventriculo-peritoneal shunts (VPS) or conservative measures. However, lumbo-peritoneal shunts (LPS) have emerged as an alternative treatment option for iNPH in recent decades, extensive research still lacks comparing outcomes with LPS to those with VPS or non-surgical treatment. The aim of the resent study is to disclose the long-term therapeutic outcomes of LPS, VPS, and non-shunting in patients with iNPH. Methods: We used the National Health Insurance Research Database in Taiwan to assess the long-term outcomes of these treatment options. We enrolled 5,537 iNPH patients who received shunting surgery, of which 5,254 were VPS and 283 were LPS. To compare the difference between each group, matching was conducted by propensity score matching using a 1:1 ratio based on LPS patients. Primary outcomes included death and major adverse cardiovascular events (MACEs) Results: Our findings show that VPS resulted in significantly more MACEs than non-surgical treatment (Odds ratio: 1.83, 95% confidence interval: 1.16-2.90). In addition, both VPS and LPS groups had significantly lower overall mortality rates than non-shunting group. Moreover, LPS had lower overall mortality but similar MACEs rates to VPS. Conclusions: Based on these findings, we propose that the LPS is preferable to the VPS, and surgical treatment should be considered the primary choice over conservative treatment unless contraindications are present.

Comprehensive exercise reduces traumatic brain injury deficits via improving the neural network function of hippocampal CA1 and medial entorhinal cortex.

The present study aimed to investigate the alterations in functional interaction between hippocampal CA1 and medial entorhinal cortex (MEC) after moderate traumatic brain injury (TBI) in C57BL/6J mice, and the possible beneficial effects of comprehensive exercise (CE). Following TBI, two microelectrodes were implanted into CA1 and MEC for extracellular recording. We found a clear synchronization of neuronal firing in CA1 and MEC, particularly within 100 Hz and peaked at 20-30 Hz range. TBI induced a significant reduction (P < 0.001) of the coherences of firing between 20-40 Hz frequency band. The mean power spectral densities (PSD) of all group mice in MEC were steadily larger than the values in CA1 in both 20-40 Hz and 56-100 Hz ranges. TBI induced significant and consistent increases of averaged 20-40 Hz or 56-100 Hz PSD (P < 0.001 or P < 0.01) in both CA1 and MEC. Injured mice displayed more varied firing patterns, and showed increased burst frequency (BF), burst duration (BD), inter-spike intervals (ISI) and inter-burst interval (IBI). Injured mice also showed worsened neurological function, sleep, gait performance, and working memory. CE facilitated the restoration of aforementioned electrophysiological characteristics and functional deficits in TBI mice. These results suggest that the beneficial effects of CE on TBI functional deficits may be partly attributed to improved neuronal network interaction between CA1 and MEC.

Dynamics of nutrients, sensory quality and microbial communities and their interactions during co-fermentation of pineapple by-products and whey protein.

In this study, a new fermented food was developed using pineapple by-products and whey protein (2.6%) as raw materials through the co-fermentation of autochthonous lactic acid bacteria and yeast. To better understand the fermentation mechanism and the impact of microorganisms on the entire fermentation system, we tracked the changes in carbohydrate and amino acid profiles, organoleptic quality and microbial community during the fermentation process. Compared with unfermented samples, dietary fiber and free amino acids increased significantly as fermentation proceeded. The fermented samples were significantly lower in astringency and bitterness and significantly higher in sourness, umami and richness. The fermented products were richer in volatile compounds with floral, cheesy, fruity and other flavors. Relevant analyses showed that the core microbial community was highly correlated with the quality attributes of the fermented products. Microorganisms such as Lactococcus, Weissella, Hanseniaspora, Saccharomyces and Lachancea contributed significantly to the fermented products.

[Effects of Land Use Types on Water Quality at Different Buffer Scales: Tianjin Section of the Haihe River Basin as an Example].

It is important to explore the relationship between land use types and water quality to improve the surface water environment. Based on monthly water quality monitoring data from 16 nationally controlled surface water quality monitoring stations in Tianjin and land use data in 2021, GIS spatial analysis and mathematical and statistical methods were used to study the influence of land use types on surface water quality in buffer zones at different scales. The results showed that:① the land use types in the study area were mainly construction land, farmland, and water areas, which had significant effects on river water quality. Except for water temperature (WT) and pH, the farmland, construction land, and water areas were negatively correlated with each water quality indicator; forest land and grassland were positively correlated with dissolved oxygen (DO) and total nitrogen (TN) and negatively correlated with other water quality indicators. ② The water quality indicators showed obvious spatial differences in different seasons. The pH, DO and TN concentrations were higher in the dry season, whereas the permanganate index, ammonia nitrogen (NH4+-N), and total phosphorus (TP) concentrations were higher in the rainy season. ③ The results of the RDA analysis showed that the 800 m buffer zone land use had the greatest explanatory power for water quality changes in the dry season (50.4%), whereas the 3 000 m buffer zone land use could explain the water quality changes in the rainy season to the greatest extent (49.6%); from the average explanation rate of the dry and rainy seasons, the 3 000 m buffer zone was the best impact scale (50.0%) on water quality indicators in Tianjin. ④ The partial least squares regression (PLSR) analysis showed that the most important variables affecting surface water quality changes were construction land, farmland, and water areas. The predictive ability of the PLSR model of most water quality indicators was stronger in the dry season than that in the rainy season. In the dry season, all water quality indicators, except WT and pH, were most influenced by farmland. In the rainy season, construction land had the greatest influence on WT and NH4+-N concentrations, and the most important influencing factor for the remaining water quality indicators was still farmland. This study showed that the rational planning of land use types within 3 000 m of rivers or lakes was beneficial to improving the water quality of surface water.

Modulatory Effect of Low-Intensity Transcranial Ultrasound Stimulation on Behaviour and Neural Oscillation in Mouse Models of Alzheimer's Disease.

Transcranial ultrasound stimulation (TUS) is a noninvasive brain neuromodulation technique. The application of TUS for Alzheimer's disease (AD) therapy has not been widely studied. In this study, a long-term course (28 days) of TUS was used to stimulate the hippocampus of APP/PS1 mice. We examined the modulatory effect of TUS on behavior and neural oscillation in AD mice. We found that TUS can 1) improve the learning and memory abilities of AD mice; 2) reduce the phase-amplitude coupling of delta-epsilon, delta-gamma and theta-gamma frequency bands of local field potential, and increase the relative power of epsilon frequency bands in AD mice; 3) reduce the spike firing rate of interneurons and inhibit the phase-locked angle deflection between the theta frequency bands and the spikes of the two types of neurons that develops with the progression of the disease in AD mice. In summary, we demonstrate that TUS could effectively improve cognitive behavior and modulate neural oscillation with AD.

Effect of Shenlingyigan decoction on inflammatory factors related to liver injury regulated by TLR3 signaling pathway.

Background: To investigate the therapeutic effect of Shenlingyigan decoction on acute liver injury. Further explored the mechanisms involved in the therapeutic properties of Shenlingyigan decoction by test several key proteins (TLR3, TRIF, TBK1, IRF3, IFNß, IL-1 and IL-6) within the TLR3 signaling pathway. Methods: The mouse acute liver injury model group was established by pretreatment with D-GalN and Poly (I:C) induction. The acute liver injury mouse treatment groups were gavage with different doses of Shenlingyigan decoction for 3 days. The therapeutic effects of Shenlingyigan decoction were preliminarily evaluated using organ indices, tissue images, and HE staining. Furthermore, potential associated signaling pathways and target effects were predicted through network pharmacology. Western blot experiments were conducted to examine the expression of relevant proteins (TLR3, TRIF, TBK1, IRF3, IL-1, and IL-6). In addition, immunofluorescence assays were performed to assess the localization of IRF3 and IFNß expression in the cytoplasm and nucleus. Finally, the effects of Shenlingyigan decoction on the expression of TLR3, TRIF, TBK1 and IRF3 genes were further studied by QT-PCR. Results: The liver organ index, the tissue photos and HE staining showed that Shenlingyigan decoction could reduce inflammation by decreasing the presence of inflammatory cells and downregulating the expression of IL-1 and IL-6. The result of network pharmacology showed 709 potential drug and disease overlapping targets. Toll-like receptor signaling pathway was related with these targets through KEGG analysis. Besides, TLR3, TBK1, IRF3, IL6, were important targets associated with viral hepatitis. Westernblot and Immunofluorescence analysis showed that Shenlingyigan decoction reduced the expression of TLR3 and TBK1 in mice with liver injury, while increasing the expression of IRF3. Shenlingyigan decoction does not significantly affect the expression of TRIF and IFNß; however, it enhances the expression of IRF3 in the nucleus, consequently leading to increased expression of IFNß in the nucleus. The results of QT-PCR showed that Shenlingyigan decoction could down-regulate the expression of TLR3, TRIF and TBK1 genes, and up-regulate the expression of IRF3 gene. Conclusions: Shenlingyigan decoction participated in immune responses by effecting the expression of TLR3 signaling pathway-related factors to treat the acute liver injury.

Waste to Wealth: Dynamics and metabolic profiles of the conversion of jackfruit flake into value-added products by different fermentation methods.

Thus far, little is known about whether jackfruit flake, a byproduct of jackfruit, can be used as a fermentation substrate to obtain value-added products through microbial fermentation. Here, jackfruit flake puree was fermented by three different ways: spontaneous fermentation (JF), inoculated with LAB (JFL), inoculated co-fermentation with LAB and yeast (JFC). In contrast to JF, the total polyphenol and flavonoid content and syndrome-associated enzyme inhibition are significantly increased in JFC at the end of fermentation. Electronic tongue analysis revealed that the JFC was significantly lower in astringency and higher in bitterness. 41 volatile compounds were identified during fermentation by HS-SPME-GC-MS, and JFC was richer in honey, rose, and fruity flavors. A total of 290 compounds were screened for discriminative pre- and post-fermentation differential metabolites by non-target metabolomics analysis. These results provide a potential reference for the conversion of jackfruit waste into functional products using fermentation.

Prioritized single vitrified blastocyst to be warmed between grades 3 or 4 blastocyst on day 5 transfer cycles.

PURPOSE: Selecting the optimal blastocyst to implant during cryopreservation and warming is critial for in vitro fertilization success. Therefore, the aim of this study was to explore which blastocyst should be prioritized to be thawed when facing a single vitrified blastocyst on day 5 transfer. METHODS: A retrospective study including 1,976 single vitrified-warmed blastocyst transfer cycles was conducted from January 2016 to December 2020. RESULTS: We found that grade 4 vitrified blastocyst had a higher clinical pregnancy (60.64% vs. 49.48%, P < 0.001) and live birth rates (50.12% vs 39.59%, P < 0.001) than the grade 3 vitrified blastocyst. However, no statistical difference was found between groups in miscarriage rate, birth weight, or gestational age. Besides, the grade 4 vitrified-thawed blastocyst had significant potential to develop into grade 6 blastocyst after further culturing for 16 h (73.68% vs. 48.60%, P < 0.001). The grade 6 transferred blastocyst was markedly higher in both clinical pregnancy rate (61.88% vs. 51.53%, P < 0.001) and live birth rate (50.91% vs. 40.46%, P < 0.001) compared to grade 5 transferred blastocyst. CONCLUSIONS: Grade 4 vitrified blastocyst is recommended when facing single vitrified blastocyst on day 5 transfer. More importantly, the "embryonic escape hypothesis" was firstly proposed to reveal the findings.

A comparative study of laparoscopic choledocholithotomy with primary suture and T-tube drainage.

To investigate the clinical efficacy of laparoscopic choledocholithotomy with one-stage suture. The clinical data of 68 patients who underwent laparoscopic choledocholithotomy in our hospital from January 2015 to December 2021 were retrospectively analyzed. Among them, 29 patients underwent laparoscopic primary closure (PC group) and 39 underwent T-tube drainage (T-tube group). All patients were diagnosed with choledocholithiasis by B-ultrasound, CT or MRCP. The operation time, intraoperative blood loss, pain index, incidence of shoulder and back pain, postoperative satisfaction, postoperative bowel function recovery time, hospitalization time and expenses, and operation-related complications in the 2 groups were compared. 29 cases in PC group were successfully operated, and 39 cases in the T-tube drainage group (T-tube group) were successfully operated. The average operation time, postoperative bowel function recovery time, postoperative pain index, hospitalization time and expenses in PC group were significantly shorter or lower than those in T-tube group (P < .05) and the patient satisfaction in PC group was significantly higher than that in T-tube group (P < .05). In addition, the intraoperative blood loss and the incidence of surgical complications were similar between the 2 groups (P > .05). After laparoscopic common bile duct exploration, primary suture of common bile duct is a safe and effective treatment method, but the incidence of bile leakage is high, and clinical indications for surgery should be strictly controlled.

[Feasibility of a novel type of complex anterior cervical fixation by using Mimics software].

OBJECTIVE: To investigate the feasibility of mimics software in analyzing a new type of complex anterior cervical fixation -- anterior transpedicular screw fixation+zero notch internal fixation. METHODS: From January 2021 to September 2022, 50 normal pedestrians who underwent cervical spine CT scanning were selected for C1-C7 segment scanning, including 27 males and 23 females, aged from 25 to 65 years old with an average of (46.0 ± 9.0) years old. The dicom format is exported and engraved into the CD, and use the mimics software to perform 3D reconstruction of each segment. A simulated screw is placed on the image according to the critical value of zero notch screw (head and tail angle 44°, internal angle 29°). The position of zero notch screw in each segment is observed to determine the feasibility of anterior transpedicular screw fixation plus zero notch internal fixation. RESULTS: For the upper zero notch screws the three-dimensional images of the cervical spine across all 50 subjects within the C3-C7 segments demonstrated safe position, with no instances of intersection with ATPS. For the lower zero notch screw, in C3-C4 and C4-C5, 4 out of 50 subjects are in the safe position in the three-dimensional images of cervical vertebrae, and 46 cases could achieve secure screw placement when the maximum caudal angle is(32.3±1.9) ° and (36.1±2.2) °, respectively. In C5-C6 and C6-C7 segments, no lower zero notch screws intersected with ATPS, and all screws are in safe positions. CONCLUSION: Lower cervical anterior pedicle screw fixation plus zero notch internal fixation can achieve successful nail placement through the selected entry point and position.

Single versus double blastocyst transfer in first and second frozen-thawed embryo transfer cycle in advance-aged women: a two-center retrospective cohort study.

BACKGROUND: The present evidence is deficient for the trade-offs between the pros and cons of single blastocyst transfer (SBT) versus double blastocyst transfer (DBT) in frozen-thawed embryo transfer cycles for women in advanced reproductive age, especially in the second cycle. The current study aimed to investigate the impact of transferred blastocyst numbers on pregnancy outcomes in the first and second embryo transfer for women ≥ 35 years. METHODS: This was a retrospective cohort study including 1284 frozen-thawed blastocyst transfer (FBT) cycles from two reproductive centers. We analyzed the pregnancy outcomes after SBT and DBT in the first and second FBT cycles. Moreover, stratified analysis was conducted by maternal age. RESULTS: In the first FBT cycle, the LBR was higher in the DBT group than that in the SBT group [52.3% vs. 33.9%; adjusted odds ratio (aOR), 1.65; 95% confidence interval (CI), 1.26-2.15, P < 0.001]. However, the LBR of the DBT group showed no remarkable difference compared with that of the SBT group in the second cycle of FBT (44.3% vs. 33.3%; aOR, 1.30; 95% CI, 0.81-2.08; P = 0.271). Furthermore, stratified analysis by age showed a higher LBR for the DBT group than the SBT group in patients aged 38-42 years (43.1% vs. 33.9%; aOR, 2.27; 95% CI, 1.05-4.90; P = 0.036). CONCLUSIONS: The present study demonstrated that the SBT regimen is a better choice for both, the first and second frozen-thawed embryo transfer cycles, for women aged 35-37 years. Additionally, the DBT regimen is still recommended to achieve a high LBR in women aged 38-42 years in the second FBT cycle. These findings may be beneficial for deciding the embryo transfer regimens in women of advanced reproductive age.

Siamese Cooperative Learning for Unsupervised Image Reconstruction from Incomplete Measurements.

Image reconstruction from incomplete measurements is one basic task in imaging. While supervised deep learning has emerged as a powerful tool for image reconstruction in recent years, its applicability is limited by its prerequisite on a large number of latent images for model training. To extend the application of deep learning to the imaging tasks where acquisition of latent images is challenging, this paper proposes an unsupervised deep learning method that trains a deep model for image reconstruction with the access limited to measurement data. We develop a Siamese network whose twin sub-networks perform reconstruction cooperatively on a pair of complementary spaces: the null space of the measurement matrix and the range space of its pseudo inverse. The Siamese network is trained by a self-supervised loss with three terms: a data consistency loss over available measurements in the range space, a data consistency loss between intermediate results in the null space, and a mutual consistency loss on the predictions of the twin sub-networks in the full space. The proposed method is applied to four imaging tasks from different applications, and extensive experiments have shown its advantages over existing unsupervised solutions.

Macrophage P2Y6 receptor deletion attenuates atherosclerosis by limiting foam cell formation through phospholipase Cß/store-operated calcium entry/calreticulin/scavenger receptor A pathways.

BACKGROUND AND AIMS: Macrophage-derived foam cells play a causal role during the pathogenesis of atherosclerosis. P2Y6 receptor (P2Y6R) highly expressed has been considered as a disease-causing factor in atherogenesis, but the detailed mechanism remains unknown. This study aims to explore P2Y6R in regulation of macrophage foaming, atherogenesis, and its downstream pathways. Furthermore, the present study sought to find a potent P2Y6R antagonist and investigate the feasibility of P2Y6R-targeting therapy for atherosclerosis. METHODS: The P2Y6R expression was examined in human atherosclerotic plaques and mouse artery. Atherosclerosis animal models were established in whole-body P2Y6R or macrophage-specific P2Y6R knockout mice to evaluate the role of P2Y6R. RNA sequencing, DNA pull-down experiments, and proteomic approaches were performed to investigate the downstream mechanisms. High-throughput Glide docking pipeline from repurposing drug library was performed to find potent P2Y6R antagonists. RESULTS: The P2Y6R deficiency alleviated atherogenesis characterized by decreasing plaque formation and lipid deposition of the aorta. Mechanically, deletion of macrophage P2Y6R significantly inhibited uptake of oxidized low-density lipoprotein through decreasing scavenger receptor A expression mediated by phospholipase Cß/store-operated calcium entry pathways. More importantly, P2Y6R deficiency reduced the binding of scavenger receptor A to CALR, accompanied by dissociation of calreticulin and STIM1. Interestingly, thiamine pyrophosphate was found as a potent P2Y6R antagonist with excellent P2Y6R antagonistic activity and binding affinity, of which the pharmacodynamic effect and mechanism on atherosclerosis were verified. CONCLUSIONS: Macrophage P2Y6R regulates phospholipase Cß/store-operated calcium entry/calreticulin signalling pathway to increase scavenger receptor A protein level, thereby improving foam cell formation and atherosclerosis, indicating that the P2Y6R may be a potential therapeutic target for intervention of atherosclerotic diseases using P2Y6R antagonists including thiamine pyrophosphate.

Thalamic connectivity topography in newborns with spina bifida: association with neurological functional level but not developmental outcome at 2 years.

Spina bifida affects spinal cord and cerebral development, leading to motor and cognitive delay. We investigated whether there are associations between thalamocortical connectivity topography, neurological function, and developmental outcomes in open spina bifida. Diffusion tensor MRI was used to assess thalamocortical connectivity in 44 newborns with open spina bifida who underwent prenatal surgical repair. We quantified the volume of clusters formed based on the strongest probabilistic connectivity to the frontal, parietal, and temporal cortex. Developmental outcomes were assessed using the Bayley III Scales, while the functional level of the lesion was assessed by neurological examination at 2 years of age. Higher functional level was associated with smaller thalamo-parietal, while lower functional level was associated with smaller thalamo-temporal connectivity clusters (Bonferroni-corrected P < 0.05). Lower functional levels were associated with weaker thalamic temporal connectivity, particularly in the ventrolateral and ventral anterior nuclei. No associations were found between thalamocortical connectivity and developmental outcomes. Our findings suggest that altered thalamocortical circuitry development in open spina bifida may contribute to impaired lower extremity function, impacting motor function and independent ambulation. We hypothesize that the neurologic function might not merely be caused by the spinal cord lesion, but further impacted by the disruption of cerebral neuronal circuitry.