Efficacy of Citicoline Delivered via Brain Extracellular Space against Experimental Acute Ischemic Stroke in Rats.

Objective: Citicoline can be used to reduce acute ischemic stroke injury via venous infusion, however, its protective effects in the brain extracellular space remain largely unknown. Herein, we investigated the brain protective effects of citicoline administered via the brain extracellular space and sought precise effective dosage range that can protect against ischemic injury after experimental ischemic stroke in rats. Methods: Fifty-six Sprague-Dawley rats were randomly divided into control, intraperitoneal (IP), caudate-putamen (CPu)-25, CPu-40, CPu-50, CPu-60 and CPu-75 groups based on the infusion site and concentration of citicoline. Two hours after the administration of citicoline, the rats were subjected to a permanent middle cerebral artery occlusion to mimic acute ischemic stroke. Then, the brain infarct volume in rats after stroke was measured and their neurological deficiency was evaluated to explain the protective effects and effective dosage range of citicoline. Results: Compared to the control and IP groups, brain infarct volume of rats in CPu-40, CPu-50, and CPu-60 groups is significant smaller. Furthermore, the brain infarct volume of rats in CPu-50 is the least. Conclusions: Here, we showed that citicoline can decrease the brain infarct volume, thus protecting the brain from acute ischemic stroke injury. We also found that the appropriate effective citicoline dose delivered via the brain extracellular space is 50 mM. Our study provides novel insights into the precise treatment of acute ischemic stroke by citicoline via the brain extracellular space, further guiding the treatment of brain disease.

[Ursolic acid improved demyelination and interstitial fluid drainage disorders in schizophrenia mice].

OBJECTIVE: To unveil the pathological changes associated with demyelination in schizophrenia (SZ) and its consequential impact on interstitial fluid (ISF) drainage, and to investigate the therapeutic efficacy of ursolic acid (UA) in treating demyelination and the ensuing abnormalities in ISF drainage in SZ. METHODS: Female C57BL/6J mice, aged 6-8 weeks and weighing (20±2) g, were randomly divided into three groups: control, SZ model, and UA treatment. The control group received intraperitoneal injection (ip) of physiological saline and intragastric administration (ig) of 1% carboxymethylcellulose sodium (CMC-Na). The SZ model group was subjected to ip injection of 2 mg/kg dizocilpine maleate (MK-801) and ig administration of 1% CMC-Na. The UA treatment group underwent ig administration of 25 mg/kg UA and ip injection of 2 mg/kg MK-801. The treatment group received UA pretreatment via ig administration for one week, followed by a two-week drug intervention for all the three groups. Behavioral assessments, including the open field test and prepulse inhibition experiment, were conducted post-modeling. Subsequently, changes in the ISF partition drainage were investigated through fluorescent tracer injection into specific brain regions. Immunofluorescence analysis was employed to examine alterations in aquaporin 4 (AQP4) polarity distribution in the brain and changes in protein expression. Myelin reflex imaging using Laser Scanning Confocal Microscopy (LSCM) was utilized to study modifications in myelin within the mouse brain. Quantitative data underwent one-way ANOVA, followed by TukeyHSD for post hoc pairwise comparisons between the groups. RESULTS: The open field test revealed a significantly longer total distance [(7 949.39±1 140.55) cm vs. (2 831.01±1 212.72) cm, P < 0.001] and increased central area duration [(88.43±22.06) s vs. (56.85±18.58) s, P=0.011] for the SZ model group compared with the controls. The UA treatment group exhibited signifi-cantly reduced total distance [(2 415.80±646.95) cm vs. (7 949.39±1 140.55) cm, P < 0.001] and increased central area duration [(54.78±11.66) s vs. (88.43±22.06) s, P=0.007] compared with the model group. Prepulse inhibition test results demonstrated a markedly lower inhibition rate of the startle reflex in the model group relative to the controls (P < 0.001 for both), with the treatment group displaying significant improvement (P < 0.001 for both). Myelin sheath analysis indicated significant demyelination in the model group, while UA treatment reversed this effect. Fluorescence tracing exhibited a significantly larger tracer diffusion area towards the rostral cortex and reflux area towards the caudal thalamus in the model group relative to the controls [(13.93±3.35) mm2 vs. (2.79±0.94) mm2, P < 0.001 for diffusion area; (2.48±0.38) mm2 vs. (0.05±0.12) mm2, P < 0.001 for reflux area], with significant impairment of drainage in brain regions. The treatment group demonstrated significantly reduced tracer diffusion and reflux areas [(7.93±2.48) mm2 vs. (13.93±3.35) mm2, P < 0.001 for diffusion area; (0.50±0.30) mm2 vs. (2.48±0.38) mm2, P < 0.001 for reflux area]. Immunofluorescence staining revealed disrupted AQP4 polarity distribution and reduced AQP4 protein expression in the model group compared with the controls [(3 663.88±733.77) µm2 vs. (13 354.92±4 054.05) µm2, P < 0.001]. The treatment group exhibited restored AQP4 polarity distribution and elevated AQP4 protein expression [(11 104.68±3 200.04) µm2 vs. (3 663.88±733.77) µm2, P < 0.001]. CONCLUSION: UA intervention ameliorates behavioral performance in SZ mice, Thus alleviating hyperactivity and anxiety symptoms and restoring sensorimotor gating function. The underlying mechanism may involve the improvement of demyelination and ISF drainage dysregulation in SZ mice.

Mining the Influencing Factors and Their Asymmetrical Effects of mHealth Sleep App User Satisfaction From Real-world User-Generated Reviews: Content Analysis and Topic Modeling.

BACKGROUND: Sleep disorders are a global challenge, affecting a quarter of the global population. Mobile health (mHealth) sleep apps are a potential solution, but 25% of users stop using them after a single use. User satisfaction had a significant impact on continued use intention. OBJECTIVE: This China-US comparison study aimed to mine the topics discussed in user-generated reviews of mHealth sleep apps, assess the effects of the topics on user satisfaction and dissatisfaction with these apps, and provide suggestions for improving users' intentions to continue using mHealth sleep apps. METHODS: An unsupervised clustering technique was used to identify the topics discussed in user reviews of mHealth sleep apps. On the basis of the two-factor theory, the Tobit model was used to explore the effect of each topic on user satisfaction and dissatisfaction, and differences in the effects were analyzed using the Wald test. RESULTS: A total of 488,071 user reviews of 10 mainstream sleep apps were collected, including 267,589 (54.8%) American user reviews and 220,482 (45.2%) Chinese user reviews. The user satisfaction rates of sleep apps were poor (China: 56.58% vs the United States: 45.87%). We identified 14 topics in the user-generated reviews for each country. In the Chinese data, 13 topics had a significant effect on the positive deviation (PD) and negative deviation (ND) of user satisfaction. The 2 variables (PD and ND) were defined by the difference between the user rating and the overall rating of the app in the app store. Among these topics, the app's sound recording function (ß=1.026; P=.004) had the largest positive effect on the PD of user satisfaction, and the topic with the largest positive effect on the ND of user satisfaction was the sleep improvement effect of the app (ß=1.185; P<.001). In the American data, all 14 topics had a significant effect on the PD and ND of user satisfaction. Among these, the topic with the largest positive effect on the ND of user satisfaction was the app's sleep promotion effect (ß=1.389; P<.001), whereas the app's sleep improvement effect (ß=1.168; P<.001) had the largest positive effect on the PD of user satisfaction. The Wald test showed that there were significant differences in the PD and ND models of user satisfaction in both countries (all P<.05), indicating that the influencing factors of user satisfaction with mHealth sleep apps were asymmetrical. Using the China-US comparison, hygiene factors (ie, stability, compatibility, cost, and sleep monitoring function) and 2 motivation factors (ie, sleep suggestion function and sleep promotion effects) of sleep apps were identified. CONCLUSIONS: By distinguishing between the hygiene and motivation factors, the use of sleep apps in the real world can be effectively promoted.

Effectiveness of telehealth-based exercise interventions on pain, physical function and quality of life in patients with knee osteoarthritis: A meta-analysis.

OBJECTIVE: The objective of the study was to evaluate the effectiveness of telehealth-based exercise intervention on pain, physical function and quality of life in patients with knee osteoarthritis. DESIGN: A systematic review and meta-analysis of randomised controlled trials (RCTs). METHODS: Six databases (PubMed, Embase, Cochrane Library, CINAHL, PEDro and Web of Science Core Collection) were searched for relevant randomised controlled trials published from database inception to 3 June 2021. Reviewers independently screened the literature, extracted data and used the Cochrane Collaboration Risk of Bias Tool for quality assessment. A meta-analysis and subgroup analyses, stratified by control condition, intervention duration and delivery type, were conducted by Revman 5.4. The study was reported in compliance with PRISMA statement. RESULTS: A total of 9 independent RCTs with 861 participants were included. The meta-analysis showed that the telehealth-based exercise interventions significantly reduced pain in KOA patients (SMD = -0.28, 95% CI [-0.49, -0.08], p < .01) and produced similar effects to controls in terms of physical function and quality of life. Subgroup analysis revealed that telehealth-based exercise interventions were superior to the use of exercise booklet and usual care in terms of pain and physical function and were similar to face-to-face exercise treatment; a long-term (>3 months) intervention and the use of web and smartphone APPs to deliver exercise interventions were associated with better pain relief and physical function. CONCLUSIONS: Telehealth-based exercise intervention is an effective strategy for KOA management during the COVID-19 epidemic, and it is significantly better than usual care in reducing knee pain and improving physical function and was able to achieve the effects of traditional face-to-face exercise treatment. Although the duration and type of delivery associated with the effect of the intervention have been identified, patient preference and acceptability need to be considered in practice.

DLGAP1-AS2 promotes human colorectal cancer progression through trans-activation of Myc.

Substantial evidence suggests that non-coding RNA plays a vital role in human cancer, especially long non-coding RNA (lncRNA) with a length greater than 200nt. Herein, we found a lncRNA facilitating human colorectal cancer (CRC) progression. DLGAP1-AS2 was significantly increased in CRC tissues and cell lines. Knockdown of DLGAP1-AS2 inhibited CRC cell proliferation, migration, invasion in vitro, and tumor growth in vivo. The subcellular localization of DLGAP1-AS2 was translocated from the cytoplasm of normal cells to the nucleus of CRC cells due to reduced levels of N6-methyladenosine (m6A) modification. Further, through the screening of a series of signal pathways, we found that Myc pathway was involved in the effect of DLGAP1-AS2. Silencing of DLGAP1-AS2 markedly reduced Myc mRNA and protein levels. Blockade of Myc effectively abolished the enhanced aggressive behaviors of CRC cells caused by DLGAP1-AS2 overexpression. Mechanistically, DLGAP1-AS2 directly bound CTCF, a well-known transcriptional repressor of Myc, resulting in reduced binding of CTCF on Myc promoter and activating Myc transcription. The second hairpin structure of DLGAP1-AS2 was critical for the interaction between DLGAP1-AS2 and CTCF in the nucleus. Taken together, our study reveals the oncogenic regulatory axis of DLGAP1-AS2/CTCF/Myc in CRC, implying a promising targeted therapy for clinical application.

Correction of uneven illumination in color microscopic image based on fully convolutional network.

The correction of uneven illumination in microscopic image is a basic task in medical imaging. Most of the existing methods are designed for monochrome images. An effective fully convolutional network (FCN) is proposed to directly process color microscopic image in this paper. The proposed method estimates the distribution of illumination information in input image, and then carry out the correction of the corresponding uneven illumination through a feature encoder module, a feature decoder module, and a detail supplement module. In this process, overlapping residual blocks are designed to better transfer the illumination information, and in particular a well-designed weighted loss function ensures that the network can not only correct the illumination but also preserve image details. The proposed method is compared with some related methods on real pathological cell images qualitatively and quantitatively. Experimental results show that our method achieves the excellent performance. The proposed method is also applied to the preprocessing of whole slide imaging (WSI) tiles, which greatly improves the effect of image mosaicking.

Propofol rather than Isoflurane Accelerates the Interstitial Fluid Drainage in the Deep Rat Brain.

Objective: Different anesthetics have distinct effects on the interstitial fluid (ISF) drainage in the extracellular space (ECS) of the superficial rat brain, while their effects on ISF drainage in the ECS of the deep rat brain still remain unknown. Herein, we attempt to investigate and compare the effects of propofol and isoflurane on ECS structure and ISF drainage in the caudate-putamen (CPu) and thalamus (Tha) of the deep rat brain. Methods: Adult Sprague-Dawley rats were anesthetized with propofol or isoflurane, respectively. Twenty-four anesthetized rats were randomly divided into the propofol-CPu, isoflurane-CPu, propofol-Tha, and isoflurane-Tha groups. Tracer-based magnetic resonance imaging (MRI) and fluorescent-labeled tracer assay were utilized to quantify ISF drainage in the deep brain. Results: The half-life of ISF in the propofol-CPu and propofol-Tha groups was shorter than that in the isoflurane-CPu and isoflurane-Tha groups, respectively. The ECS volume fraction in the propofol-CPu and propofol-Tha groups was much higher than that in the isoflurane-CPu and isoflurane-Tha groups, respectively. However, the ECS tortuosity in the propofol-CPu and propofol-Tha groups was much smaller than that in isoflurane-CPu and isoflurane-Tha groups, respectively. Conclusions: Our results demonstrate that propofol rather than isoflurane accelerates the ISF drainage in the deep rat brain, which provides novel insights into the selective control of ISF drainage and guides selection of anesthetic agents in different clinical settings, and unravels the mechanism of how general anesthetics function.

The Effect of Thymoquinone on the Characteristics of the Brain Extracellular Space in Transient Middle Cerebral Artery Occlusion Rats.

The extracellular space (ECS) is the space between the neurons and the capillaries in the brain. The volume fraction (α) and the tortuosity (λ) are the main parameters used to describe its characteristics. Thymoquinone has been proved to possess anti-oxidant and anti-inflammatory activity. In this study, we used a gadolinium-diethylenetriaminepentacetate (Gd-DTPA)-enhanced magnetic resonance imaging (MRI) system to determine the effects of thymoquinone on ECS parameters in transient middle cerebral artery occlusion rats (tMCAO) to prove the neuroprotective effect of thymoquinone on brain tissue damage caused by ischemic stroke. Neurological examinations, 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (H&E) staining and assaying of ECS parameters using MRI were performed 24 h after surgery. We found that thymoquinone could improve the behavioural performance by neurological examinations. TTC staining indicated that thymoquinone significantly decreased the percentage of hemi-cerebral infarction. Also, H&E staining showed that thymoquinone could inhibit the neuron necrosis in the hippocampal CA1 region. We found that thymoquinone treatment could inhibit the changes in ECS diffusion parameters, which might prove that thymoquinone might protect brain tissue damage caused by ischemic stroke. Thymoquinone can protect the brain against cerebral ischemia-reperfusion injury, effectively ameliorate abnormalities in characteristics of ECS and decrease cerebral infarction in tMCAO rats.

Homogeneous orthogonal diffusion of drugs in the rat brain.

The study introduced a homogeneous orthogonal diffusion model to describe the diffusion pattern of agents in the rat brain. Magnetic resonance imaging was performed post-injection of paramagnetic drugs into the caudatum of the rat brain at predetermined time intervals. The signal intensity on magnetic resonance images was converted to agents' concentration, and the standard least square method was employed to estimate the diffusion coefficients. The diffusion coefficients calculated along the three orthogonal axes were D1  = (0.0097 ± 0.0036) mm2 /h, D2  = (0.0153 ± 0.0033) mm2 /h, and D3  = (0.0293 ± 0.0155) mm2 /h; the clearance rate constant was k = (0.2177 ± 0.0112)/h. The theoretical homogeneous orthogonal model can enhance our knowledge on both the biophysical characteristics of brain extracellular space and the interstitial drug delivery in the brain.

The roles of astrocyte in the brain pathologies following ischemic stroke.

Aim: In this work, we systematically explored the physiological functions of astrocytes and their roles following ischemic stroke, additionally, the potential therapy strategy targeting the astrocytes was also discussed. Methods: This work searched the PubMed database (including MEDLINE) until 14 Feb 2018, and furthermore, the studies were identified through cross-referencing and by consulting the experts in this field. Results: This study indicated that the astrocytes can not only play harmful roles following ischemic stroke through release of inflammatory factors and formation of glial scar but also have protective effects through quenching glutamate excitotoxicity and maintaining the clearance function of glymphatic system in brain. Conclusion: Owing to their important roles in physiological functions of brain and in the pathological conditions following ischemic stroke, the astrocytes might be a potential but promising therapeutic target for treating the ischemic stroke in the future.

Phospholipid transfer protein (PLTP) deficiency accelerates memory dysfunction through altering amyloid precursor protein (APP) processing in a mouse model of Alzheimer's disease.

Phospholipid transfer protein (PLTP) is a widely expressed lipid transfer protein participating in the transport of cholesterol and other lipids in the plasma and peripheral tissues. Recently, elevated amyloid ß (Aß) in young and aged PLTP-deficient brains had been reported. However, the role of PLTP in amyloid precursor protein (APP) processing and Alzheimer's disease (AD) pathology remains elusive. Here we first found that deficiency of PLTP accelerated memory dysfunction in APP/PS1ΔE9 AD model mice at the age of 3 months. Further characterization showed that PLTP deficiency increased soluble Aß peptides, and intracellular accumulation of Aß was illustrated, which might be due to disrupted APP turnover and the enhanced amyloidogenic pathway. Besides, reduced brain-derived neurotrophic factor (BDNF) was found in PLTP-deficient APP/PS1ΔE9 mice, and the BDNF level was negatively correlated with Aß42 content, instead of Aß40 content. In addition, autophagic dysfunction was found in the PLTP-deficient APP/PS1ΔE9 mice. Our data presented a novel model to link phospholipid metabolism to APP processing and also suggested that PLTP played an important role in Aß metabolism and would be useful to further elucidate functions of PLTP in AD susceptibility.

Quantitative Visualization of Dynamic Tracer Transportation in the Extracellular Space of Deep Brain Regions Using Tracer-Based Magnetic Resonance Imaging.

BACKGROUND This study assessed an innovative tracer-based magnetic resonance imaging (MRI) system to visualize the dynamic transportation of tracers in regions of deep brain extracellular space (ECS) and to measure transportation ability and ECS structure. MATERIAL AND METHODS Gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) was the chosen tracer and was injected into the caudate nucleus and thalamus. Real-time dynamic transportation of Gd-DTPA in ECS was observed and the results were verified by laser scanning confocal microscopy. Using Transwell assay across the blood-brain barrier, a modified diffusion equation was further simplified. Effective diffusion coefficient D* and tortuosity λ were calculated. Immunohistochemical staining and Western blot analysis were used to investigate the extracellular matrix contributing to ECS structure. RESULTS Tracers injected into the caudate nucleus were transported to the ipsilateral frontal and temporal cortices away from the injection points, while both of them injected into the thalamus were only distributed on site. Although the caudate nucleus was closely adjacent to the thalamus, tracer transportation between partitions was not observed. In addition, D* and the λ showed statistically significant differences between partitions. ECS was shown to be a physiologically partitioned system, and its division is characterized by the unique distribution territory and transportation ability of substances located in it. Versican and Tenascin R are possible contributors to the tortuosity of ECS. CONCLUSIONS Tracer-based MRI will improve our understanding of the brain microenvironment, improve the techniques for local delivery of drugs, and highlight brain tissue engineering fields in the future.

Disrupted white matter structural connectivity in heroin abusers.

Neurocognitive impairment is one of the factors that put heroin abusers at greater risk for relapse, and deficits in related functional brain connections have been found. However, the alterations in structural brain connections that may underlie these functional and neurocognitive impairments remain largely unknown. In the present study, we investigated topological organization alterations in the structural network of white matter in heroin abusers and examined the relationships between the network changes and clinical measures. We acquired diffusion tensor imaging datasets from 76 heroin abusers and 78 healthy controls. Network-based statistic was applied to identify alterations in interregional white matter connectivity, and graph theory methods were used to analyze the properties of global networks. The participants also completed a battery of neurocognitive measures. One increased subnetwork characterizing widespread abnormalities in structural connectivity was present in heroin users, which mainly composed of default-mode, attentional and visual systems. The connection strength was positively correlated with increases in fractional anisotropy in heroin abusers. Intriguingly, the changes in within-frontal and within-temporal connections in heroin abusers were significantly correlated with daily heroin dosage and impulsivity scores, respectively. These findings suggest that heroin abusers have extensive abnormal white matter connectivity, which may mediate the relationship between heroin dependence and clinical measures. The increase in white matter connectivity may be attributable to the inefficient microstructure integrity of white matter. The present findings extend our understanding of cerebral structural disruptions that underlie neurocognitive and functional deficits in heroin addiction and provide circuit-level markers for this chronic disorder.

ZNF804A variants confer risk for heroin addiction and affect decision making and gray matter volume in heroin abusers.

Drug addiction shares common neurobiological pathways and risk genes with other psychiatric diseases, including psychosis. One of the commonly identified risk genes associated with broad psychosis has been ZNF804A. We sought to test whether psychosis risk variants in ZNF804A increase the risk of heroin addiction by modulating neurocognitive performance and gray matter volume (GMV) in heroin addiction. Using case-control genetic analysis, we compared the distribution of ZNF804A variants (genotype and haplotype) in 1035 heroin abusers and 2887 healthy subjects. We also compared neurocognitive performance (impulsivity, global cognitive ability and decision-making ability) in 224 subjects and GMV in 154 subjects based on the ZNF804A variants. We found significant differences in the distribution of ZNF804A intronic variants (rs1344706 and rs7597593) allele and haplotype frequencies between the heroin and control groups. Decision-making impairment was worse in heroin abusers who carried the ZNF804A risk allele and haplotype. Subjects who carried more risk alleles and haplotypes of ZNF804A had greater GMV in the bilateral insular cortex, right temporal cortex and superior parietal cortex. The interaction between heroin addiction and ZNF804A variants affected GMV in the left sensorimotor cortex. Our findings revealed several ZNF804A variants that were significantly associated with the risk of heroin addiction, and these variants affected decision making and GMV in heroin abusers compared with controls. The precise neural mechanisms that underlie these associations are unknown, which requires future investigations of the effects of ZNF804A on both dopamine neurotransmission and the relative increases in the volume of various brain areas.

Neuroprotective Effects of a Standardized Flavonoid Extract from Safflower against a Rotenone-Induced Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is a major age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra par compacta (SNpc). Rotenone is a neurotoxin that is routinely used to model PD to aid in understanding the mechanisms of neuronal death. Safflower (Carthamus tinctorius. L.) has long been used to treat cerebrovascular diseases in China. This plant contains flavonoids, which have been reported to be effective in models of neurodegenerative disease. We previously reported that kaempferol derivatives from safflower could bind DJ-1, a protein associated with PD, and that a flavonoid extract from safflower exhibited neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD. In this study, a standardized safflower flavonoid extract (SAFE) was isolated from safflower and found to primarily contain flavonoids. The aim of the current study was to confirm the neuroprotective effects of SAFE in rotenone-induced Parkinson rats. The results showed that SAFE treatment increased body weight and improved rearing behavior and grip strength. SAFE (35 or 70 mg/kg/day) treatment reversed the decreased protein expression of tyrosine hydroxylase, dopamine transporter and DJ-1 and increased the levels of dopamine and its metabolite. In contrast, acetylcholine levels were decreased. SAFE treatment also led to partial inhibition of PD-associated changes in extracellular space diffusion parameters. These changes were detected using a magnetic resonance imaging (MRI) tracer-based method, which provides novel information regarding neuronal loss and astrocyte activation. Thus, our results indicate that SAFE represents a potential therapeutic herbal treatment for PD.

Effects of seasonal changes on the ovulation rate and embryo quality in superovulated Black Suffolk ewes.

OBJECTIVE: The objective of this study was to investigate the effects of seasonal changes on the superovulation in Black Suffolk ewes, particularly the ovulation rate and embryo quality. DESIGN: Black Suffolk ewes were superovulated either in May (n=22) or in September (n=21), 2013. After estrus synchronization with CIDR, the donor ewes were superovulated with PMSG and seven decreasing doses of FSH (twice daily at 07:00 and 19:00 for four consecutive days. Then, they were subjected to laparoscopic intrauterine artificial insemination. The viable morula and blastocysts were recovered and immediately transferred to recipients. RESULTS: Ewes that were superovulated in May had a much higher ovulation rate than those were superovulated in September (16.8 ± 3.23vs. 10.2 ± 2.94, p<0.01); however, the viability rate of the embryo was lower than that of September (56.0 ± 1.92% vs. 92.5 ± 3.26%, p<0.01). There was no significant difference in the survival rate of the transferred viable embryos (33.9 ± 1.00% vs. 36.7 ± 1.64%, p>0.05) and the number of offspring per donor ewe (3.1 ± 0.54 vs. 2.9 ± 0.72, p>0.05) between May and September. In contrast, the offspring/ova ratio of the donor ewes superovulated in May was lower than that of September (18.5 ± 1.64% vs. 32.8 ± 2.14%, p<0.01). CONCLUSIONS: The superovulation of Black Suffolk ewes may be affected by the seasonal changes. Generallly, The ewe's ovulation rate was higher in May, whereas the viability rate of embryo was higher in September.

[Diffusion of fluorescent and magnetic molecular probes in brain interstitial space].

OBJECTIVE: To compare the diffusion properties of fluorescent probes dextran-tetramethylrhodamine (DT) and lucifer yellow CH (LY) and magnetic probe gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) in porous media and to screen out a suitable fluorescent probe for optical imaging of brain interstitial space (ISS). METHODS: Agarose gels sample were divided into DT group, LY group and Gd-DTPA group, and the corresponding molecular probes were imported in each group. The dynamic diffusions of DT and LY in agarose gels at different time points (15, 30, 45, 60, 90, and 120 min) were scanned with laser scanning confocal microscope, the dynamic diffusion of Gd-DTPA was imaged with magnetic resonance imaging. The average diffusion speed of LY were demonstrated to be consistent with those of Gd-DTPA. The LY was introduced into caudate putamen of 18 rats, respectively, the diffusion of LY in the sequential slices of rat brain at different time points (0.5, 1, 2, 3, 7, 11 h) were scanned, and the results were compared with those of rats' brain with Gd-DTPA imported and imaged in vivo with magnetic resonance imaging. RESULTS: The diffusions of the three probes were isotropic in the agarose gels, and the average diffusion speeds of DT, LY and Gd-DTPA were: (0.07±0.02)×10(-2) mm2/s, (1.54±0.47)×10(-2) mm2/s, (1.45±0.50)×10(-2) mm2/s, respectively. The speed of DT was more slower than both LY and Gd-DTPA (ANOVA, F=367.15, P<0.001; Post-Hoc LSD, P<0.001), and there was no significant difference between the speeds of LY and Gd-DTPA (Post-Hoc LSD, P=0.091). The variation tendency of diffusion area of DT was different with both that of LY and that of Gd-DTPA (Bonferroni correction, α=0.0125, P<0.001), and there was no significant difference between LY and Gd-DTPA (Bonferroni correction, α=0.0125, P=0.203), in analysis by repeated measures data of ANOVA. The diffusions of LY and Gd-DTPA were anisotropy in rat caudate putamen,and the average diffusion speeds of LY and Gd-DTPA were: (1.03±0.29)×10(-3) mm2/s, (0.81±0.27)×10(-3) mm2/s, respectively, no significant difference was demonstrated (t=0.759, P=0.490); half-time of single intensity of LY and Gd-DTPA was (2.58±0.04) h, (2.46±0.10) h, respectively, no significant difference was found (t=2.025, P=0.113). The diffusion area ratios between LY and Gd-DTPA in rat caudate putamen was not statistically different at hours 0.5, 1, 2, 3 and 7 (t=2.249, P=0.088; t=2.582, P=0.061; t=1.966, P=0.121; t=0.132, P=0.674; t=0.032, P=0.976), while, a slightly difference was found at 11 h (t=2.917, P=0.043,in analysis by t test). CONCLUSION: LY present the same diffusion property with Gd-DTPA in porous media witch including agarose gels and live rat brain tissue, indicates that LY is a suitable fluorescent probe for optical imaging of brain ISS, and it can be used for microscopic, macro and in vitro measure of brain ISS.

Phospholipid transfer protein (PLTP) deficiency impaired blood-brain barrier integrity by increasing cerebrovascular oxidative stress.

Phospholipid transfer protein (PLTP) regulates lipid metabolism and plays an important role in oxidative stress. PLTP is highly expressed in blood-brain barrier (BBB), but the role of PLTP in BBB integrity is not clear. In this study, BBB permeability was detected with in vivo multiphoton imaging and Evans blue assay. We found that PLTP deficient mice exhibited increased BBB permeability, as well as decreased expression of tight junction proteins occludin, zona occludens-1 (ZO-1) and claudin-5 in brain vessels. Cerebrovascular oxidative stress increased in PLTP deficient mice, including increased levels of reactive oxygen species (ROS) and lipid peroxidation marker 4-hydroxy-2-nonenal (HNE) and reduced superoxide dismutase (SOD) activity. Dietary supplementation of antioxidant vitamin E increased BBB integrity and tight junction proteins expression via reducing cerebrovascular oxidative stress. These findings indicated an essential role of PLTP in maintaining BBB integrity, possibly through its ability to transfer vitamin E, and modulate cerebrovascular oxidative stress.

Blood-brain barrier dysfunction in mice induced by lipopolysaccharide is attenuated by dapsone.

Blood-brain barrier (BBB) dysfunction is a key event in the development of many central nervous system (CNS) diseases, such as septic encephalopathy and stroke. 4,4'-Diaminodiphenylsulfone (DDS, Dapsone) has displayed neuroprotective effect, but whether DDS has protective role on BBB integrity is not clear. This study was designed to examine the effect of DDS on lipopolysaccharide (LPS)-induced BBB disruption and oxidative stress in brain vessels. Using in vivo multiphoton imaging, we found that DDS administration significantly restored BBB integrity compromised by LPS. DDS also increased the expression of tight junction proteins occludin, zona occludens-1 (ZO-1) and claudin-5 in brain vessels. Level of reactive oxygen species (ROS) was reduced by DDS treatment, which may due to decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and NOX2 expression. Our results showed that LPS-induced BBB dysfunction could be attenuated by DDS, indicated that DDS has a therapeutic potential for treating CNS infection and other BBB related diseases.

PCNet: Prior Category Network for CT Universal Segmentation Model.

Accurate segmentation of anatomical structures in Computed Tomography (CT) images is crucial for clinical diagnosis, treatment planning, and disease monitoring. The present deep learning segmentation methods are hindered by factors such as data scale and model size. Inspired by how doctors identify tissues, we propose a novel approach, the Prior Category Network (PCNet), that boosts segmentation performance by leveraging prior knowledge between different categories of anatomical structures. Our PCNet comprises three key components: prior category prompt (PCP), hierarchy category system (HCS), and hierarchy category loss (HCL). PCP utilizes Contrastive Language-Image Pretraining (CLIP), along with attention modules, to systematically define the relationships between anatomical categories as identified by clinicians. HCS guides the segmentation model in distinguishing between specific organs, anatomical structures, and functional systems through hierarchical relationships. HCL serves as a consistency constraint, fortifying the directional guidance provided by HCS to enhance the segmentation model's accuracy and robustness. We conducted extensive experiments to validate the effectiveness of our approach, and the results indicate that PCNet can generate a high-performance, universal model for CT segmentation. The PCNet framework also demonstrates a significant transferability on multiple downstream tasks. The ablation experiments show that the methodology employed in constructing the HCS is of critical importance. The prompt and HCS can be accessed at https://github.com/PKU-MIPET/PCNet.