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Background: Rhabdomyolysis (RM) associated acute kidney injury (AKI) is the most common systemic complication of RM. The present study aimed to assess the clinical characteristics and risk factors for intensive care unit (ICU) transfer for patients with RM-associated AKI.Methods: We included all patients who were age ≥ 18 years old with a diagnosis of RM from September 2012 to October 2018 and divided them into RM-associated AKI group and RM without AKI group. The primary outcome was transferring to ICU treatment. Regression analysis was performed to identify factors associated with ICU treatment and recovery of renal function.Results: Among the 149 patients with RM, 68 (45.6%) developed AKI. The percentage of patients with AKI who transferred to ICU was higher than patients without AKI (33.8% versus 12.3%, P < 0.002). Additionally, patients with AKI had higher percentage of undergoing dialysis (19.1% versus 2.5%, P < 0.01), all-cause mortality (13.2% versus 1.2%, P < 0.01), cost of hospitalization [10.8 1,000 yuan, IQR (5.5, 3.5) versus 5.9 1,000 yuan, IQR 5.9 (3.6, 9.9), P = 0.03], as well as longer length of hospital stay [8.0 (5.0, 14.0)] versus [6.0 (4.0, 11.0)], P = 0.02). Moreover, most patients with AKI achieved complete recovery (77.9%) at discharge. After adjusting for potential risk factors, RM-associated AKI remained an independent risk factor for ICU transfer (OR = 3.0, 95% CI, 1.11–8.3, P = 0.03). However, ICU transfer was not associated with recovery of renal function (OR = 0.88, 95% CI, 0.22–3.57, P = 0.856).Conclusion: RM leaded to AKI in most patients. RM-associated AKI could cause worse clinical outcome and predict ICU transfer for patients with RM.

Protein ubiquitination shows remarkable topological and functional diversity through the polymerization of ubiquitin via different linkages. Deciphering the cellular ubiquitin code is of central importance to understand the physiology of the cell. Among the eight possible linkages, K29-linked polyubiquitin is a relatively abundant type of polyubiquitin in both human and yeast cells. However, our understanding of its function is rather limited due to the lack of specific binders as tools to detect K29-linked polyubiquitin. In this study, we screened and characterized a synthetic antigen-binding fragment, termed sAB-K29, that can specifically recognize K29-linked polyubiquitin using chemically synthesized K29-linked diubiquitin. We further determined the crystal structure of this fragment bound to the K29-linked diubiquitin, which revealed the molecular basis of specificity. Using sAB-K29 as a tool, we uncovered that K29-linked ubiquitination is involved in different kinds of cellular proteotoxic stress response as well as cell cycle regulation. In particular, we showed that K29-linked ubiquitination is enriched in the midbody and downregulation of the K29-linked ubiquitination signal arrests cells in G1/S phase.

We explored the protective effect of spironolactone on cardiac function in the patients undergoing coronary artery bypass grafting (CABG) by determining serum hypoxia-inducible factor-1α (HIF-1α) before and after CABG. We used the propensity score matching method retrospectively to select 174 patients undergoing CABG in our hospital from March 2018 to December 2019. Of the 174 patients, 87 patients taking spironolactone for more than 3 months before CABG were used as a test group and other 87 patients who were not taking spironolactone as a control group. In all patients, serum HIF-1α and troponin I levels were determined before as well as 24 hours and 7 days after CABG, serum N-terminal probrain natriuretic peptide (NT-proBNP) level was determined before as well as 12, 24, and 36 hours after CABG, and electrocardiographic monitoring was performed within 36 hours after CABG. The results indicated that there were no significant differences in the HIF-1α level between the test group and the control group before and 7 days after CABG, but the HIF-1α level was significantly lower in the test group than that in the control group 24 hours after CABG (P < 0.01). The 2 groups were not significantly different in the troponin I level at any time point. There was no significant difference in the serum NT-proBNP level between the test group and the control group before CABG, but NT-proBNP (BNP) levels were all significantly lower in the test group than those in the control group at postoperative 12, 24, and 36 hour time points (all P

Appetitive locomotion is essential for animals to approach rewards, such as food and prey. The neuronal circuitry controlling appetitive locomotion is unclear. In a goal-directed behavior—predatory hunting, we show an excitatory brain circuit from the superior colliculus (SC) to the substantia nigra pars compacta (SNc) to enhance appetitive locomotion in mice. This tectonigral pathway transmits locomotion-speed signals to dopamine neurons and triggers dopamine release in the dorsal striatum. Synaptic inactivation of this pathway impairs appetitive locomotion but not defensive locomotion. Conversely, activation of this pathway increases the speed and frequency of approach during predatory hunting, an effect that depends on the activities of SNc dopamine neurons. Together, these data reveal that the SC regulates locomotion-speed signals to SNc dopamine neurons to enhance appetitive locomotion in mice., Goal-oriented movement is a fundamental animal behaviour. Here, the authors show that neurons in the superior colliculus project to the substantia nigra pars compacta, regulating dopaminergic signaling and specifically appetitive locomotion in mice.

Silybin is widely used as a hepatoprotective agent in various liver disease therapies and has been previously identified as a CYP3A inhibitor. However, little is known about the effect of silybin on CYP3A and the regulatory mechanism during high-fat-diet (HFD)-induced liver inflammation. In our study, we found that silybin restored CYP3A expression and activity that were decreased by HFD and conditioned medium (CM) from palmitate (PA)-treated Kupffer cells. Moreover, silybin suppressed liver inflammation in HFD-fed mice and inhibited NF-κB translocation into the nucleus through elevation of SIRT2 expression and promotion of p65 deacetylation. This effect was confirmed by overexpression of SIRT2, which suppressed p65 nuclear translocation and restored CYP3A transcription affected by CM. The hepatic NAD+ concentration markedly decreased in HFD-fed mice and CM-treated hepatocytes/HepG2 cells but increased after silybin treatment. Supplementing NMN as an NAD+ donor inhibited p65 acetylation, decreased p65 nuclear translocation, and restored cyp3a transcription in both HepG2 cells and mouse hepatocytes. These results suggest that silybin regulates metabolic enzymes during liver inflammation by a mechanism related to the increase in NAD+ and SIRT2 levels. In addition, silybin enhanced the intracellular NAD+ concentration by decreasing PARP1 expression. In summary, silybin increased NAD+ concentration, promoted SIRT2 expression and lowered p65 acetylation both in vivo and in vitro, which supported the recovery of CYP3A expression. These findings indicate that the NAD+/SIRT2 pathway plays an important role in CYP3A regulation during NAFLD. Significance Statement This research revealed the differential regulation of CYP3A by silybin under physiological and fatty liver pathological conditions. In the treatment of NAFLD, silybin restored, not inhibited, CYP3A expression and activity through the NAD+/SIRT2 pathway in accordance with its anti-inflammatory effect.

Superhydrophobic surfaces have attracted attention due to their hydrophobic, self-cleaning, anti-icing, and oil/water separation properties. The present study used a nonwoven fabric as a flexible substrate and constructed a high-adhesive superhydrophobic surface by coating the fabric with polydimethylsiloxane (PDMS)-co -polymethyl hydrogen siloxane (PMHS) polymers and embedding mesoporous SiO2 nanoparticles. The water contact angle (WCA) of the superhydrophobic surface was up to 165.2° at a PDMS to PMHS ratio of 4:1. The adhesion to deionized water was 99.7 μN. High hydrophobicity was maintained, even after sandpaper abrasions and flowing water impact. The surface was resistant to acid, alkali, brine, strong oxidation, and heavy metal solutions. The coating exhibited anti-icing and oil/water separation properties. This study provides a facile and effective method for constructing multifunctional superhydrophobic coatings on flexible substrates.

BACKGROUND AND PURPOSE: In acute stroke patients with large vessel occlusions, it would be helpful to be able to predict the difference in the size and location of the final infarct based on the outcome of reperfusion therapy. Our aim was to demonstrate the value of deep learning–based tissue at risk and ischemic core estimation. We trained deep learning models using a baseline MR image in 3 multicenter trials. MATERIALS AND METHODS: Patients with acute ischemic stroke from 3 multicenter trials were identified and grouped into minimal (≤20%), partial (20%-80%), and major (≥80%) reperfusion status based on 4- to 24-hour follow-up MR imaging if available or into unknown status if not. Attention-gated convolutional neural networks were trained with admission imaging as input and the final infarct as ground truth. We explored 3 approaches: 1) separate: train 2 independent models with patients with minimal and major reperfusion; 2) pretraining: develop a single model using patients with partial and unknown reperfusion, then fine-tune it to create 2 separate models for minimal and major reperfusion; and 3) thresholding: use the current clinical method relying on apparent diffusion coefficient and time-to-maximum of the residue function maps. Models were evaluated using area under the curve, the Dice score coefficient, and lesion volume difference. RESULTS: Two hundred thirty-seven patients were included (minimal, major, partial, and unknown reperfusion: n = 52, 80, 57, and 48, respectively). The pretraining approach achieved the highest median Dice score coefficient (tissue at risk = 0.60, interquartile range, 0.43–0.70; core = 0.57, interquartile range, 0.30–0.69). This was higher than the separate approach (tissue at risk = 0.55; interquartile range, 0.41–0.69; P = .01; core = 0.49; interquartile range, 0.35–0.66; P = .04) or thresholding (tissue at risk = 0.56; interquartile range, 0.42–0.65; P = .008; core = 0.46; interquartile range, 0.16–0.54; P < .001). CONCLUSIONS: Deep learning models with fine-tuning lead to better performance for predicting tissue at risk and ischemic core, outperforming conventional thresholding methods.

Gastric cancer (GC) is one of the most common cancers, with most patients often succumbing to death as a result of tumor metastasis. Recent work has demonstrated that gastrin is closely associated with GC metastasis. However, the specific molecular mechanisms underlying this relationship remain to be unveiled. In this study, we assessed the impact of gastrin and the Wnt/β-catenin inhibitor XAV939 on the epithelial-mesenchymal transition (EMT) of the SGC-7901 and MKN45 GC cell lines, and we determined that gastrin-17 significantly decreased E-cadherin expression and upregulated the expression of Snail1 and N-cadherin in GC cells. In addition, gastrin 17 also significantly increased the expression of Wnt3α in a dose-dependent manner. Consistent with these results, gastrin-17 promoted GC cell invasion, proliferation, and migration in a dose-dependent fashion, and these effects were inhibited by XAV939. Together, these results indicated that gastrin-17 induced GC cell EMT, migration, and invasion via the Wnt/β-catenin signaling pathway, which suggests that this gastrin/Wnt/β-catenin signaling axis may represent a therapeutic target for the prevention of GC metastasis.

The screening and treatment of laryngeal squamous cell carcinoma (LSCC) still perplexes clinicians, making it necessary to explore new markers. To this end, this research examined the underlying molecular mechanism of LSCC based on high-throughput datasets (n = 249) from multiple databases. It also identified transcription factors (TFs) independently associated with LSCC prognosis. Through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, differential expression genes of LSCC were deemed relevant to the extracellular matrix and its related structures or pathways, suggesting that the extracellular matrix plays an important role in LSCC. At the same time, several hub genes that may also have important roles in LSCC were identified via protein–protein interaction analysis, including CDC45, TPX2, AURKA, KIF2C, NUF, MUC1, MUC7, MUC4, MUC15, and MUC21. Eight unreported LSCC prognostic TFs – BCAT1, CHD4, FOXA2, GATA6, HNF1A, HOXB13, MAFF, and TCF4 – were screened via Kaplan–Meier curves. Cox analysis determined for the first time that HOXB13 expression and gender were independently associated with LSCC prognosis. Compared to control tissues, elevated expression of HOXB13 was found in LSCC tissues (standardized mean difference = 0.44, 95% confidence interval [0.13–0.76]). HOXB13 expression also makes it feasible to screen LSCC from non-LSCC (area under the curve = 0.77), and HOXB13 may play an essential role in LSCC by regulating HOXB7. In conclusion, HOXB13 may be a novel marker for LSCC clinical screening and treatment.

Purpose: To evaluate the relationship between corneal biomechanical parameters and lamina cribrosa (LC) curvature in normal tension glaucoma (NTG). Methods: 95 eyes of 56 NTG patients were enrolled in this prospective, observational study. Corneal biomechanical parameters, including stiffness parameters at applanation 1 (SP-A1), deformation amplitude ratio (DA ratio), inverse concave radius and biomechanically corrected intraocular pressure estimate (bIOP), were captured using the Corneal Visualization Scheimpflug Technology instrument (Corvis-ST). LC curvature was evaluated by mean adjusted LC curvature index (maLCCI) averaged by the measurements on 12 radial B-scan images obtained using swept-source optical coherence tomography (SS-OCT). Linear mixed models were constructed to assess the relationship between corneal biomechanical parameters and LC curvature. Results: The mean age of participants was 51.04 ± 13.74 years (range, 24–82 years). The SP-A1 and maLCCI were 93.50 ± 13.82 mm Hg/mm and 7.57 ± 1.58, respectively. In univariate and multivariate analysis, SP-A1 ( p Conclusions: The greater posterior LC curvature was associated with lower corneal stiffness parameters and younger eyes in NTG patients. Clinical Trial Registration: Chinese Clinical Trial Registry, ChiCTR1900021465.

Introduction: To evaluate the association of focal lamina cribrosa (LC) defect with asymmetric visual field (VF) loss in normal-tension glaucoma (NTG) through intereye comparisons. Methods: Paired eyes were divided into better and worse eyes according to the mean deviation (MD), and ocular parameters were compared between them. Furthermore, patients in the asymmetric group were classified as subgroup A (one eye with LC defect and the fellow one without), subgroup B (both eyes without LC defect), and subgroup C (both eyes with LC defect). Generalized estimation equation approach was used to evaluate the association between ocular parameters and asymmetric VF. Results: A total of 140 eyes of 70 NTG patients were included in the asymmetric group. LC defects were more common in better eyes than that in worse eyes (27/70 [38.57%] vs. 10/70 [14.29%], p = 0.001), and all eyes with LC defect had myopia. Multivariate analysis revealed that the presence of LC defect was significantly associated with better eyes in the asymmetric group (odds ratio, 0.27; p = 0.001). For subgroup A, eyes with LC defects exhibited lower peak IOP (p = 0.011) and lower mean IOP (p = 0.018) than the fellow eyes without. In addition, longer AL (p = 0.025) and larger tilt ratio (p = 0.032) were found in eyes with LC defects. For subgroup B without LC defects, larger tilt ratio was shown to be a risk factor for VF loss (odds ratio, 6.13; p = 0.001). There was no significant difference of binocular parameters except for MD (p < 0.001) in subgroup C. Conclusions: LC defects in myopia were suggested to be associated with better eyes in NTG with asymmetric VF loss. However, in patients without LC defect, larger tilt ratio was a risk factor for VF defect. There might be different pathological mechanisms in asymmetric VF loss for different NTG subtypes.

Background Incomplete aneurysmal occlusion is a common feature of immediate posttreatment angiography. The safety and outcomes of acutely ruptured intracranial aneurysms (RIAs) with incomplete occlusion after stent-assisted coiling (SAC) and no-stent coiling (NSC) have not been well clarified. Progressive occlusion of stents can promote the complete occlusion of intracranial aneurysms (IAs), but it remains to be determined if progressive occlusion in acutely RIAs with incomplete occlusion after coiling may be enhanced by protective stenting. This study aimed to evaluate the safety and outcomes of those aneurysms after SAC and NSC; And to discover whether the stents can promote progressive aneurysm occlusion in such lesions or not. Methods We reviewed 199 patients with acutely RIAs underwent endovascular coiling and developed incomplete occlusion in the past seven years. The patients’ clinical and imaging information were recorded and analyzed. Univariate and multivariate analyses were performed to determine the association of recurrence rate with potential risk factors. Results SAC group had wider aneurysms neck (3.471 mm vs 2.830 mm, P = 0.009) and smaller dome-to-neck ratio (1.536 vs 2.111, P = 0.001) than in NSC group. There was no significant difference between the two groups in total procedure-related complications rate (31.7% vs 23.5%, P = 0.195), procedure-related mortality (6.9% vs 2.0%, P = 0.170) and modified Rankin Scale (mRS) score at 6-month follow-up (P > 0.05). However, SAC group had significantly higher ischemic complications rate (21.8% vs 8.2%, P = 0.007) and complete occlusion rate (65.6% vs 48.3%, P = 0.020), and lower recurrence rate (15.6% vs 28.1%, P = 0.042) than NSC group based on 6-month follow-up angiograms. Additionally, Multivariable analysis showed NSC was an independent risk factor for aneurysm recurrence (Odds Ratio [OR]: 4.061; P = 0.018). Conclusions Acutely RIAs with incomplete occlusion after SAC is associated with higher complications rate and mortality, but has an acceptable safety profile and similar clinical outcome compared to NSC, as well as gives patients superior angiography outcome by progressive occlusion of stents.

Artificial intelligence (AI) advancements have significant implications for medical imaging. Stroke is the leading cause of disability and the fifth leading cause of death in the United States. AI applications for stroke imaging are a topic of intense research. AI techniques are well-suited for dealing with vast amounts of stroke imaging data and a large number of multidisciplinary approaches used in classification, risk assessment, segmentation tasks, diagnosis, prognosis, and even prediction of therapy responses. This article addresses this topic and seeks to present an overview of machine learning and/or deep learning applied to stroke imaging.

BACKGROUND: Male Kunming mice were divided into the normal diet group (control group) and the high-fat diet group (HF group, 185 g·kg-1 protein, 600 g·kg-1 fat and 205 g·kg-1 carbohydrate). After eight weeks' feeding, the behavioral and biochemical indicators in serum were determined. The double bottle preference experiment was used to study the preference of mice for five sweeteners. The contents of monoamine neurotransmitters and genes expression related to dopamine (DA) and opioid receptor were also determined. RESULTS: The body weight of the mice in HF group increased significantly (p < 0.05) after 36 days compared with the control group. While the feed intake of HF group increased sharply in the first 12 days, and then it became basically unchanged. The preference of the HF group for all the five sweeteners was very significantly lower (p < 0.01) than that of the control group. The depression-related behavior was observed in the HF group mice. The contents of TG, TC and LDLC in the HF group were extremely higher (p < 0.01) than that of the control group. The genes expression related to DA and opioid receptor in the HF group was significantly lower than that of the control group, except for the preproenkephalin (PENK). CONCLUSIONS: In summary, this study suggested that a long-term high-fat diet could result in the decrease of the preference for sweeteners on mice due to the long-term consumption of high-fat diet could result in a state of reward hypofunction on mice. This article is protected by copyright. All rights reserved.

Tumor-associated macrophages (TAM)s are critical regulators of glioma progression. As yet, however, TAMs in isocitrate dehydrogenase (IDH) mutated lower-grade gliomas (LGGs) have not been thoroughly investigated. The aim of this study was to determine whether 1p/19q co-deletion status affects the TAM phenotype or its prevalence in IDH mutated LGGs. TAMs in IDH mutated LGGs were analyzed using transcriptome data from 230 samples in the TCGA database in combination with transcriptome data from single-cell RNA sequencing of IDH-mutated LGGs. Proteins potentially involved in TAM regulation were examined by immuno-staining in primary LGG samples harboring IDH mutations. Essential signaling pathways regulating TAM phenotypes were investigated in a glioma mouse model using small molecule inhibitors. Most of the TAMs in IDH-mutated LGGs expressed the M1 activation markers CD86 and TNF, whereas a subset of individual TAMs co-expressed both M1 and M2-related markers. Bioinformatics analysis in combination with immuno-staining of IDH-mutated patient samples revealed higher amounts of TAMs expressing M2-related markers in 1p/19q non-codeletion IDH-mutated LGGs compared to 1p/19q codeletion LGGs. The levels of transforming growth factor beta 1 (TGFβ1) and macrophage colony-stimulating factor (M-CSF) were significantly higher in 1p/19q non-codeletion LGGs than in 1p/19q codeletion LGGs. M-CSF and TGFβ1 signal inhibition decreased tumor growth and modulated the TAM phenotype in a glioma mouse model. Our data indicate that 1p/19q co-deletion status relates to distinct TAM infiltration in gliomas, which is likely mediated by M-CSF and TGFβ1 signaling. M-CSF and TGFβ1 signaling may play a pivotal role in regulating the TAM phenotype in glioma.

This study focused on the effect of short-term intake of sweeteners on feed intake, solution consumption and neurotransmitters release on mice. The results showed that the free drinking of 10 mM sucralose solution, 100 mM maltose solution, 3 mM saccharin solution and 3 g/L stevioside solution for 32 days will not affect the normal development of the body weight and feed intake of the mice. The consumption of maltose solution was significantly higher than that of the other sweeteners. The leptin and insulin levels increased significantly after the short-term intake of these four sweeteners. The dopamine (DA) content in the whole brain of the mice increased significantly only in the maltose group. These results indicate that the short-term intake of the preferred concentrations of maltose, stevioside, sucralose and saccharin will not affect the body weight and feed intake of the mice. Mice prefer maltose solution to other sweeteners solutions. The 100 mM maltose solution and 3 mM saccharin solution could result in the oxidative stress on mice after 32 days’ short-term intake. Compared with other sweeteners, only sugars that could be broken down into small molecules of glucose might have a positive effect on dopamine levels.

Long non-coding RNA (lncRNA) Ewing sarcoma associated transcript 1 (EWSAT1) is an oncogene in a variety of tumors. Here, we planned to demonstrate EWSAT1 function in cervical cancer and further illustrate its underlying mechanism. EWSAT1 expression in cervical cancer was evaluated through qRT-PCR. Colony forming capacity was measured by colony formation assay and cell proliferation ability was measured by CCK-8 kit. Wound healing experiment was applied to test the cell migration and transwell assay was applied to test the invasion ability. Luciferase assay was employed to demonstrate EWSAT1 and miR-330-5p interaction. In cervical cancer, the expression of EWSAT1 was enhanced and contributed to the poor prognosis. Downregulated EWSAT1 expression inhibited Hela cell migration, proliferation, and invasion. EWSAT1 targeted to miR-330-5p and upregulated cytoplasmic polyadenylation element-binding protein 4 (CPEB4) expression by sponging miR-330-5p. Our study revealed that EWSAT1 enhances CPEB4 expression through sponging miR-330-5p, thereby promoting cervical cancer development, which might provide potential therapeutic targets for clinically cervical cancer patients.

XB130 is a novel adapter protein that behaves as a tumor promoter or suppressor mediating cell proliferation and metastasis in the development of different human tumors. Altered expression of XB130 has been verified in human non-small cell-lung cancer (NSCLC). However, the exact effect of XB130 on NSCLC is not well-understood. In this study, we investigated the biological function and posttranscriptional regulation of XB130 in NSCLC. First, the effects of XB130 silence on NSCLC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) were examined. Then the targeting relationship between XB130 and miR-203, miR-219, or miR-4782-3p was demonstrated by dual-luciferase reporter assay. Finally, the effects of miR-203, miR-219, and miR-4782-3p on NSCLC cell function were studied, respectively. We found that XB130 silence significantly inhibited cell growth, migration and invasion, and reversed EMT. Furthermore, XB130 was posttranscriptionally regulated by miR-203, miR-219, and miR-4782-3p. Overexpression of miR-203, miR-219, or miR-4782-3p inhibited cell growth, migration and invasion, and reversed EMT, just like the role of XB130 in NSCLC cells, whereas the suppressive effects of microRNA (miRNA) overexpression were weakened by miRNA inhibitors or ectopic expression of XB130 in NSCLC cells. These data demonstrate that XB130 is posttranscriptionally regulated by miR-203, miR-219, and miR-4782-3p and mediates the proliferation and metastasis of NSCLC cells.

Background Studies have suggested that chronic social stress specifically downregulates endothelial tight junction protein expression in the nucleus accumbens (NAc), thus increasing blood-brain barrier (BBB) permeability and promoting depression-like behaviors. However, the molecular mechanism underlying the reduction in tight junction protein, particularly in the NAc, is largely uncharacterized. Methods We performed comparative metabolomic profiling of the nucleus accumbens, prefrontal cortex, and hippocampus of social defeat–stressed mice to identify the molecular events that mediate BBB breakdown. Results We identified the levels of cyclic adenosine monophosphate (cAMP) that were specifically reduced in the NAc and positively correlated with the degree of social avoidance. Replenishing cAMP in the NAc was sufficient to improve BBB integrity and depression-like behaviors. We further found that cAMP levels were markedly decreased in neurons of the NAc, rather than in endothelial cells, astrocytes, or microglia. RNA-sequencing data showed that adenylate cyclase 5 (Adcy5), an enzyme responsible for the synthesis of cAMP from adenosine triphosphate (ATP), was predominantly expressed in the NAc; it also resided exclusively in neurons. Endogenous modulation of cAMP synthesis in neurons through the knockdown of Adcy5 in the NAc regulated the sensitivity to social stress. Moreover, deficient neuronal cAMP production in the NAc decreased the expression of reelin, while supplementary injection of exogenous reelin into the NAc promoted BBB integrity and ameliorated depression-like behaviors. Conclusions Chronic social stress diminished cAMP synthesis in neurons, thus damaging BBB integrity in the NAc and promoting stress vulnerability. These results characterize neuron-produced cAMP in the NAc as a biological mechanism of neurovascular pathology in social stress.

Mounting evidence indicates the impact of gender difference on the assessment, treatment, and outcome of patients with acute myocardial infarction (AMI). However, gender-specific prognostic markers of AMI are still lacking. The present study aimed to investigate gender-specific markers of poor prognosis (all-cause mortality or readmission) in a cohort of AMI patients followed up for 6 months. Compared with males (n = 157), females (n = 40) were older and more frequent with previous medical history of hypertension and diabetes mellitus. During the 6-month follow-up, BUN ≥ 7.73 mM, myoglobin ≥ 705.8 ng/mL, and Killip classification 2-4 were identified as the independent predictors of poor prognosis for male AMI patients, while D-dimer ≥ 0.43 mg/L as an independent predictor of poor prognosis in female AMI patients. In conclusion, our data suggest that prognostic markers for AMI patients may differ according to genders. Gender-specific prognostic markers may be useful to guide the risk stratification, clinical therapy, and medications for AMI patients.

The effect of short-term intake of high- and low-concentrations of sucrose solution on the neurochemistry of male and female mice was studied. The body weight, feed intake, sucrose solution consumption and brain monoamine neurotransmitters were determined after 34 days' intake of 1% and 8% sucrose solutions. The gene expression and protein levels related to dopamine and opioids were also determined. The results showed that the intake of 1% and 8% sucrose solution for 34 days did not cause significant changes in the weight development of both male and female mice. The preference for sucrose varies with sex. Both males and females had greater preference for the high concentration sucrose solution than the low concentration sucrose solution. The continuous intake of sucrose stimulated the release of monoamine neurotransmitters (DA, 5-HT, NE) in the brains of mice, and the reward effect of 8% sucrose solution is significantly higher than that of 1% sucrose solution. The sex of mice did not affect the release of neurotransmitters. The gene expressions of D1 and D2 were up-regulated in the 1% sucrose group of male mice, while the OPRM1 gene expression was down-regulated. The expression of these three genes in the 8% sucrose group of male mice was all down-regulated, while the gene expressions of D1 and D2 in the 1% and 8% sucrose group (p < 0.05) of female mice were both up-regulated.

To compare the clinical results and functional outcomes between two-dimensional conventional radiation therapy (2DRT) and intensity-modulated radiation therapy (IMRT) in nasopharyngeal carcinoma (NPC) with skull-base invasion. A total of 1258 patients were subclassified into two groups: mild skull-base invasion group (792; 63%) and severe skull-base invasion group (466; 37%). Patients were pair matched (1:1 ratio) using six clinical factors into 2DRT or IMRT groups. The Kaplan–Meier method and Cox regression model were performed to assess overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS). Toxicities were evaluated. IMRT significantly improved four-year OS compared with 2DRT (65.6% vs. 81.8%, P = 0.000), DFS (57.3% vs. 73.3%, P = 0.000) and LRRFS (76.5% vs. 87.5%, P = 0.003) in NPC with severe skull-base invasion, but similar results were observed in patients with mild skull-base invasion (P > 0.05). In patients with severe invasion, radiation therapy techniques were found to be an independent prognostic factor for OS (HR = 0.457, P = 0.000), DFS (HR = 0.547, P = 0.000) and LRRFS (HR = 0.503, P = 0.004). IMRT was associated with better OS. In subgroups analysis, IMRT group also had a better survival in OS, DFS (P

Liver has an ability to regenerate itself in mammals, whereas the mechanism has not been fully explained. Here we used a GC/MS-based metabolomic method to profile the dynamic endogenous metabolic change in the serum of C57BL/6J mice at different times after 2/3 partial hepatectomy (PHx), and nine machine learning methods including Least Absolute Shrinkage and Selection Operator Regression (LASSO), Partial Least Squares Regression (PLS), Principal Components Regression (PCR), k-Nearest Neighbors (KNN), Support Vector Machines (SVM), Random Forest (RF), eXtreme Gradient Boosting (xgbDART), Neural Network (NNET) and Bayesian Regularized Neural Network (BRNN) were used for regression between the liver index and metabolomic data at different stages of liver regeneration. We found a tree-based random forest method that had the minimum average Mean Absolute Error (MAE), Root Mean Squared Error (RMSE) and the maximum R square (R2) and is time-saving. Furthermore, variable of importance in the project (VIP) analysis of RF method was performed and metabolites with VIP ranked top 20 were selected as the most critical metabolites contributing to the model. Ornithine, phenylalanine, 2-hydroxybutyric acid, lysine, etc. were chosen as the most important metabolites which had strong correlations with the liver index. Further pathway analysis found Arginine biosynthesis, Pantothenate and CoA biosynthesis, Galactose metabolism, Valine, leucine and isoleucine degradation were the most influenced pathways. In summary, several amino acid metabolic pathways and glucose metabolism pathway were dynamically changed during liver regeneration. The RF method showed advantages for predicting the liver index after PHx over other machine learning methods used and a metabolic clock containing four metabolites is established to predict the liver index during liver regeneration.

Disrupted myelin and impaired myelin repair have been observed in the brains of patients and various mouse models of Alzheimer’s disease (AD). Clemastine, an H1-antihistamine, shows the capability to induce oligodendrocyte precursor cell (OPC) differentiation and myelin formation under different neuropathological conditions featuring demyelination via the antagonism of M1 muscarinic receptor. In this study, we investigated if aged APPSwe/PS1dE9 mice, a model of AD, can benefit from chronic clemastine treatment. We found the treatment reduced brain amyloid-beta deposition and rescued the short-term memory deficit of the mice. The densities of OPCs, oligodendrocytes, and myelin were enhanced upon the treatment, whereas the levels of degraded MBP were reduced, a marker for degenerated myelin. In addition, we also suggest the role of clemastine in preventing OPCs from entering the state of cellular senescence, which was shown recently as an essential causal factor in AD pathogenesis. Thus, clemastine exhibits therapeutic potential in AD via preventing senescence of OPCs.

Background and AimsThe heat shock protein (Hsp) 90α is induced by stress and regulates inflammation through multiple pathways. Elevated serum Hsp90α had been found in nonalcoholic steatohepatitis (NASH). Geranylgeranylacetone (GGA, also called teprenone) is a terpenoid derivative. It was reported to induce Hsp and alleviate insulin resistance. We aimed to evaluate the Hsp90α as a biomarker in predicting metabolic-associated fatty liver disease (MAFLD) and define the therapeutic effects of geranylgeranylacetone for the disease.MethodsA clinical study was conducted to analyze the elements associated with Hsp90α, and a predictive model of MAFLD was developed based on Hsp90α. The histopathological correlation between Hsp90α and MAFLD was investigated through a diet-induced mouse model. Furthermore, GGA was applied to the mouse model.ResultsSerum Hsp90α was increased in patients with MAFLD. A positive linear relationship was found between age, glycosylated hemoglobin (HbA1c), MAFLD, and serum Hsp90α. Meanwhile, a negative linear relationship with body mass index (BMI) was found. A model using Hsp90α, BMI, HbA1c, and ALT was established for predicting MAFLD. The area under the receiver operating characteristic (ROC) curves was 0.94 (95% CI 0.909–0.971, p = 0.000). The sensitivity was 84.1%, and the specificity was 93.1%. In vitro experiments, GGA induced Hsp90α in steatosis cells. In the mice model, Hsp90α decreased in the GGA treatment group. Hepatic steatosis, inflammation, insulin resistance, and glucose intolerance were improved in the GGA-treated group. Serum Hsp90α was positively correlated with steatohepatitis activity according to hepatic histopathology.ConclusionsSerum Hsp90α was elevated in MAFLD, and a positive correlation between serum Hsp90α and the grade of activity of steatohepatitis was observed. The model using BMI, HbA1c, and alanine aminotransferase (ALT) had a good value to predict MAFLD. The findings also revealed the effectiveness of GGA in the treatment of MAFLD.

Background: Recent studies have demonstrated that airway basal stem cells (BCs) transplantation can ameliorate bleomycin-induced idiopathic pulmonary fibrosis (IPF) through lung regeneration promotion. However, BCs under oxidative stress in the alveolar microenvironment are poor in survival, causing unsatisfied efficacy of BCs transplantation. In this study, we investigated whether Coenzyme Q10(CoQ10) counteracts oxidative stress in the alveolar microenvironment, thus improved the efficacy of BCs transplantation for IPF treatment.Methods: The protective effects of CoQ10 on H2O2-induced BCs apoptosis and cytoplasmic reactive oxygen species (ROS) level were tested by flow cytometry in vitro. The therapeutic effects of BCs combined with CoQ10 were compared to a single BCs transplantation protocol in IPF treatment after two weeks and were evaluated by parameters including changes of body weight and survival rate, as well as various levels of pulmonary inflammation, α-SMA expression and hydroxyproline (HYP) in IPF mice lung tissues.Results: CoQ 10 preincubation with BCs (10 mM, 24 h) significantly reduced the late apoptosis of BCs and the number of oxidative stressful BCs as a result of H2O2 stimulation (1mM, 6h) in vitro. IPF mice models were constructed through bleomycin (5 mg/Kg) intratracheal instillation. Bleomycin-induced IPF mice showed weight loss continuously and mortality increased progressively during modeling. Serious pulmonary inflammatory cell infiltration, collagen fiber proliferation, and collagen protein deposition were observed in lung tissues of IPF mice. Though BCs transplantation alone improved indicators above in bleomycin-induced IPF mice to some extent, the combination with CoQ10 improved the transplantation efficacy and obtained better therapeutic effects.Conclusion：CoQ10 blocked H2O2-induced apoptosis of BCs and ROS production in vitro, and enhanced the efficacy of BCs transplantation on bleomycin-induced IPF in mice.

Background The mortality of humans due to rabies in China has been declining in recent years, but it is still a significant public health problem. According to the global framework, China strives to achieve the goal of eliminating human rabies before 2030. Methods We reviewed the epidemiology of human deaths from rabies in mainland China from 2004 to 2018. We identified high risk regions, age and occupational groups, and used a continuous deterministic susceptibility-exposure-infection-recovery (SEIR) model with periodic transmission rate to explore seasonal rabies prevalence in different human populations. The SEIR model was used to simulate the data of human deaths from rabies reported by the Chinese Center for Disease Control and Prevention (China CDC). We calculated the relative transmission intensity of rabies from canines to different human groups, and they provided a reliable epidemiological basis for further control and prevention of human rabies. Results Results showed that human deaths from rabies exhibited regional differences and seasonal characteristics in mainland China. The annual human death from rabies in different regions, age groups and occupational groups decreased steadily across time. Nevertheless, the decreasing rates and the calculated R0s of canines of various human groups were different. The transmission intensity of rabies from canines to human populations was the highest in the central regions of China, in people over 45 years old, and in farmers. Conclusions Although the annual cases of human deaths from rabies have decreased steadily since 2007, the proportion of human deaths from rabies varies with region, age, gender, and occupation. Further enhancement of public awareness and immunization status in high-risk population groups and blocking the transmission routes of rabies from canines to humans are necessary. The concept of One Health should be abided and human, animal, and environmental health should be considered simultaneously to achieve the goal of eradicating human rabies before 2030., Author summary Animal and human rabies were still significant public health problems in China. In the past 15 years, although the annual human deaths from rabies have decreased steadily, the proportion change in human deaths from rabies varied with diverse population groups. This condition reflected the different recognition and attention to rabies of various populations. We applied a continuous deterministic SEIR model to study the spread of rabies among canines and from canines to different human groups. Numerical simulation results showed that the proportion of human deaths from rabies in central regions, the populations over 45 years old and the farmers in China increase year by year, and transmission intensity of rabies from canines to the above groups are higher than the nationwide level. Finally, our research indicated that to achieve the ultimate goal of eliminating human rabies by 2030, the immunization status of high-risk human groups and mammals in corresponding areas should be enhanced, and the cooperation with various departments related to human, animal and the environment should be enhanced in line with the concept of One Health.

OBJECTIVE The CagA (cytotoxin-related gene A, CagA) protein is an important factor for the pathogenicity of Helicobacter pylori (H. pylori). Although H. pylori has previously been shown to activate the NLRP3 inflammasome, it remains unclear what role CagA plays in this process. In the current study, we aimed to investigate the effect of CagA on NLRP3 activation and how it is linked to gastric cancer cell migration and invasion. METHODS CagA positive H. pylori strain (Hp/CagA+) and CagA gene knockout mutant (Hp/ΔCagA) infected and the pcDNA3.1/CagA plasmid transfected gastric epithelial cell lines, respectively. The morphological alterations of cells under a microscope; the NLRP3 inflammasome-related markers: NLRP3, caspase-1, and ASC protein levels were detected by Western blot, IL-1β and IL-18 levels were determined by ELISA; cell migration and invasion were determined by transwell assay; and the pyroptosis levels and intracellular ROS were determined by flow cytometry analysis. Then, pretreated with 5 mM NAC for 2 h and subsequently transfected with the pcDNA3.1/CagA plasmid for 48 h, the effects of NAC pretreatment on CagA-induced NLRP3 inflammasome-related markers expression and cell pyroptosis were examined, finally assessed the effect of CagA on migration and invasion in NLRP3-silenced cells. RESULTS We found that Hp/CagA+ strain infection and pcDNA3.1/CagA vector transfection result in NLRP3 inflammasome activation, generation of intracellular ROS, and increased invasion and migration of gastric cancer cells. Moreover, we found that ROS inhibition via NAC effectively blocks NLRP3 activation and pyroptosis. Silencing of NLRP3 reduces the effects of CagA on gastric cancer cell migration and invasion. CONCLUSION Our study shows that CagA can promote the invasion and migration of gastric cancer cells by activating NLRP3 inflammasome pathway. These findings provide novel insights into the mechanism of gastric cancer induction by H. pylori.