Endogenous FGF21 attenuates blood-brain barrier disruption in penumbra after delayed recanalization in MCAO rats through FGFR1/PI3K/Akt pathway. / å† æºæ€§FGF21通过FGFR1/PI3K/Akt通路减轻MCAOå¤§é¼ å»¶è¿Ÿè¡€ç®¡å†é€šåŽåŠæš—å¸¦çš„è¡€è„‘å±éšœæŸä¼¤ï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Restoration of blood circulation within "time window" is the principal treating goal for treating acute ischemic stroke. Previous studies revealed that delayed recanalization might cause serious ischemia/reperfusion injury. However, plenty of evidences showed delayed recanalization improved neurological outcomes in acute ischemic stroke. This study aims to explore the role of delayed recanalization on blood-brain barrier (BBB) in the penumbra (surrounding ischemic core) and neurological outcomes after middle cerebral artery occlusion (MCAO). METHODS: Recanalization was performed on the 3rd day after MCAO. BBB disruption was tested by Western blotting, Evans blue dye, and immunofluorescence staining. Infarct volume and neurological outcomes were evaluated on the 7th day after MCAO. The expression of fibroblast growth factor 21 (FGF21), fibroblast growth factor receptor 1 (FGFR1), phosphatidylinositol-3-kinase (PI3K), and serine/threonine kinase (Akt) in the penumbra were observed by immunofluorescence staining and/or Western blotting. RESULTS: The extraversion of Evans blue, IgG, and albumin increased surrounding ischemic core after MCAO, but significantly decreased after recanalization. The expression of Claudin-5, Occludin, and zona occludens 1 (ZO-1) decreased surrounding ischemic core after MCAO, but significantly increased after recanalization. Infarct volume reduced and neurological outcomes improved following recanalization (on the 7th day after MCAO). The expressions of Claudin-5, Occludin, and ZO-1 decreased surrounding ischemic core following MCAO, which were up-regulated corresponding to the increases of FGF21, p-FGFR1, PI3K, and p-Akt after recanalization. Intra-cerebroventricular injection of FGFR1 inhibitor SU5402 down-regulated the expression of PI3K, p-Akt, Occludin, Claudin-5, and ZO-1 in the penumbra, which weakened the beneficial effects of recanalization on neurological outcomes after MCAO. CONCLUSIONS: Delayed recanalization on the 3rd day after MCAO increases endogenous FGF21 in the penumbra and activates FGFR1/PI3K/Akt pathway, which attenuates BBB disruption in the penumbra and improves neurobehavior in MCAO rats.

Modeling supply chain viability and adaptation against underload cascading failure during the COVID-19 pandemic.

Supply chain viability concerns the entire supply system rather than one company or one single chain to survive COVID-19 disruptions. Mobility restriction and overall demand decline lead to systematically cascading disruptions that are more severe and longer lasting than those caused by natural disasters and political conflicts. In the present study, the authors find that large companies and manufacturers with traditional advantages suffer greater losses than small ones, which is conceptualized as the "Hub Paradox" by empirically investigating one Warp Knitting Industrial Zone of China. An underload cascading failure model is employed to simulate supply chain viability under disruptions. Numerical simulations demonstrate that when the load decreases beyond a threshold, the viability will drop down critically. Besides, supply chain viability depends on two aspects: the adaptive capability of the manufacturers themselves and the adaptive capability of the connections of the supply network. The comparison study demonstrates that enhancing cooperative relations between hub and non-hub manufacturers will facilitate the entire supply network viability. The present study sheds light on viable supply chain management. Compared with conventionally linear or resilient supply chains, intertwined supply networks can leverage viability with higher adaptation of redistributing production capacities among manufacturers to re-establish overall scale advantages. Finally, the present study also suggests solving the "Hub Paradox" from the perspective of complex adaptive system. Supplementary Information: The online version contains supplementary material available at 10.1007/s11071-022-07741-8.

Identification of a novel collagen type IV alpha-4 (COL4A4) mutation in a Chinese family with autosomal dominant Alport syndrome using exome sequencing.

BACKGROUND & OBJECTIVES: Alport syndrome (AS) is an inherited disorder characterized by glomerulonephritis and end-stage renal disease (ESRD). The aim of this study was to identify the gene responsible for the glomerulopathy in a Chinese family with autosomal dominant AS using exome sequencing. METHODS: A 4-generation, 30-member Chinese Han family was enrolled in this study. Exome sequencing was conducted in the proband of the family, and then direct sequencing was performed in family members of the pedigree and 100 normal controls. RESULTS: A novel frameshift mutation, c.3213delA (p.Gly1072GlufsFNx0169), in the collagen type IV alpha-4 gene (COL4A4) was found to be the genetic cause. Neither sensorineural hearing loss nor ocular abnormalities were present in the patients of this family. Other clinical features, such as age of onset, age of ESRD occurring and disease severity, varied among the patients of this family. INTERPRETATION & CONCLUSIONS: A novel frameshift mutation, c.3213delA (p.Gly1072GlufsFNx0169) in the COL4A4 gene, was identified in the Chinese pedigree with autosomal dominant AS. Our findings may provide new insights into the cause and diagnosis of AS and also have implications for genetic counselling.

Genetic analysis of the FBXO42 gene in Chinese Han patients with Parkinson's disease.

BACKGROUND: Parkinson's disease (PD), the second most common neurodegenerative disease, is characterized by loss of dopaminergic neurons in the substantia nigra. The clinical manifestations of PD encompass a variety of motor and non-motor symptoms. Mutations in the F-box protein 7 gene (FBXO7) have been identified to cause Parkinsonian-pyramidal syndrome, an autosomal recessive form of Parkinsonism. The F-box protein 42 gene (FBXO42), a paralog of the FBXO7 gene, is involved in the ubiquitin-proteasome system that may play a role in the pathogenesis of PD. METHODS: To determine whether the FBXO42 gene is associated with PD, we performed a systematic genetic analysis of the FBXO42 gene in 316 PD patients and 295 gender-, age-, and ethnicity-matched normal controls. RESULTS: We identified a novel variant c.1407T>C (p.S469S) and three known single nucleotide variants, including rs2273311, rs12069239 and rs35196193 in the FBXO42 gene in PD patient group. None of the three known variants displayed statistically significant difference in either genotypic or allelic distributions between patient and control groups (all P > 0.05). Haplotype analysis showed that a common haplotype (G-C-G) for the three single nucleotide variants conferred a 1.69-fold increased risk for PD (P = 0.008 after Bonferroni correction, OR = 1.69, 95% CI = 1.06-2.71). CONCLUSIONS: Our findings suggest that a haplotype of the FBXO42 gene might be associated with a higher susceptibility to PD.

Beyond beauty: A qualitative exploration of authenticity and its impacts on Chinese consumers' purchase intention in live commerce.

Live commerce is a phenomenally innovative form of social commerce in China. In this paper, the authors aim to explore the authenticity of live commerce. By employing a qualitative approach using in-depth interviews and grounded theory, 21 initial categories are classified into six core categories. Among them, authenticity-associated concepts are classified into explicit concepts and implicit concepts. Explicit concepts of authenticity are associated with objectively authentic cues, while implicit concepts of authenticity are associated with subjectively authentic experiences. Moreover, the study explores the relationship between explicit concepts of authenticity and product commitment, as well as the relationship between implicit concepts of authenticity and affective commitment. Both of these paths are found to influence consumers' shopping-related behaviors. Although consumers can more easily perceive explicitly authentic cues than implicitly authentic experiences, this study suggests that the latter may be more effective in inducing shopping behaviors. In addition, the effect of streamer attractiveness on opinion leader building is addressed, while authenticity is found to be an alternative approach to attract consumers both for attractive and nonattractive streamers. Finally, the study addresses theoretical implications and practical implications as well as suggestions for future research.

Measurement and Impactors of Tourism Carbon Dioxide Emission Efficiency in China.

With tourism carbon dioxide emission efficiency (TCDEE) as an undesired output, this study establishes an index system based on the inputs and outputs of TCDEE and measures the provincial TCDEE of China in 2010-2018, using the epsilon-based measure (EBM). In addition, the impactors of TCDEE were tested by the Tobit model. The main results are as follows: China's TCDEEs had obvious provincial differences. Only six provinces reached the efficient frontier of TCDEE, namely, Beijing, Tianjin, Inner Mongolia, Shanghai, Jiangsu, and Guangdong. The other provinces failed to reach this state, leaving a room for improvement. Most eastern provinces had relatively high TCDEEs, while the central and western provinces had relatively low TCDEEs. In the sample period, the TCDEEs in eastern, central, and western parts all changed in the shape of letter N. The TCDEEs of the eastern part were much higher than those of the central and western parts. According to the results of the Tobit model, TCDEE is clearly enhanced by the urbanization level, strongly inhibited by industrial structure, technical progress, opening-up, and environmental regulation, and not significantly affected by the tourism level.

Atractylenolide III alleviates isoflurane-induced injury in rat hippocampal neurons by activating the PI3K/Akt/mTOR pathway.

The use of anesthetics relieves discomfort in patients during operation, but extensive application of anesthetics can cause damage to the nervous system. Atractylenolide III (ATL-III) is an active ingredient derived from Baizhu, which is a kind of traditional Chinese medicines. Recent studies have shown that ATL-III alleviates inflammation and oxidative stress in various tissues by regulating the PI3K/Akt/mTOR signaling pathway. However, whether or not the application of ATL-III could relieve isoflurane-induced damage in rat hippocampal neurons remains unclear. In this study, rats were stimulated with isoflurane and treated with ATL-III (intragastric administration) simultaneously. After rats were sacrificed, apoptosis and autophagy in the hippocampal neurons were assessed using TUNEL assays and western blotting, respectively. Then, the expression of inflammatory factors was determined by q-PCR and ELISA. The levels of p-PI3K, p-Akt, and p-mTOR were quantified by western blotting. We found that ATL-III relieved isoflurane-induced apoptosis, autophagy and inflammation in hippocampal neurons in rats. ATL-III treatment also inhibited the expression of TNF-α, IL-1ß, and IL-6 in these cells. Furthermore, ATL-III promoted the expression of p-PI3K, p-Akt, and p-mTOR in the hippocampal neurons. All these results indicated that ATL-III alleviated isoflurane-induced injury in rat hippocampal neurons by activating the PI3K/Akt/mTOR signaling pathway. PRACTICAL APPLICATIONS: Whether or not Atractylenolide III (ATL-III) could alleviate neurotoxicity induced by anesthetics is unclear. In this study, we investigated the effect of ATL-III on anesthetic-induced nervous system damage. The findings from this study could also provide a novel therapy for the treatment of patients with anesthetic-induced nerve injury.

Exosomes of glioma cells deliver miR-148a to promote proliferation and metastasis of glioblastoma via targeting CADM1.

Exosomes are now considered to be involved in mediating cell-to-cell communication to promote or inhibit tumor progression. However, the role and molecular mechanism of exosomes in promoting glioblastoma (GBM) metastasis remains elusive. Here, we found that circulating exosomal miR-148a levels were significantly higher in serum from GBM patients compared with serum from healthy volunteers. In T98G cells, inhibition of miR-148a suppressed cell proliferation and metastasis. In addition, we identified Cell adhesion molecule 1 (CADM1) as a target gene of miR-148a using luciferase reporter assay. Both protein and mRNA levels of CADM1 were decreased in tissues from GBM patients. There was a strong negative correlation between exosomal miR-148a and CADM1 mRNA levels in samples of patients. Moreover, miR-148a antagonist increased p-STAT3 protein level to activate STAT3 pathway. In conclusion, our findings indicated that miR-148a delivered by exosomes may promote cancer cell proliferation and metastasis via targeting CADM1 to activate STAT3 pathway, suggesting a predictor and therapeutic target role of exosomal miR-148a in GBM patients.

Role of miR-181a in the process of apoptosis of multiple malignant tumors: A literature review.

It has been recognized that miR-181a expression is dysregulated and intimately associated with clinical prognosis in a variety of human cancers. However, the direct role of miR-181a in tumor progression has been elusive. Moreover, mounting evidence has demonstrated that cellular apoptosis, a physiological process of programmed cell death, is disrupted in various categories of human malignancies. Multiple apoptosisrelated genes have been proven to act as the target genes of miR-181a. In this study, we hypothesize that miR-181a probably plays a potential role in modulating the procession and apoptosis of cancer cells. We performed a literature review and elucidated how miR-181a modulated cellular apoptosis, especially the malignant neoplasm cells. We also unraveled the potential role of miR-181a in the diagnosis, treatment and clinical prognosis of multiple human malignancies - miR-181a plays a pivotal role in the development, treatment and prognosis of patients suffering from malignant tumors. It also participates in the development of cancer partially by modulating cellular apoptosis.

Identification of a missense HOXD13 mutation in a Chinese family with syndactyly type I-c using exome sequencing.

Syndactyly is one of the most common hereditary limb malformations, and is characterized by the fusion of specific fingers and/or toes. Syndactyly type I­c is associated with bilateral cutaneous or bony webbing of the third and fourth fingers and occasionally of the third to fifth fingers, with normal feet. The aim of the present study was to identify the genetic basis of syndactyly type I­c in four generations of a Chinese Han family by exome sequencing. Exome sequencing was conducted in the proband of the family, followed by direct sequencing of other family members of the same ancestry, as well as 100 ethnically­matched, unrelated normal controls. A missense mutation, c.917G>A (p.R306Q), was identified in the homeobox D13 gene (HOXD13). Sanger sequencing verified the presence of this mutation in all of the affected family members. By contrast, this mutation was absent in the unaffected family members and the 100 ethnically­matched normal controls. The results suggest that the c.917G>A (p.R306Q) mutation in the HOXD13 gene, may be responsible for syndactyly type I­c in this family. Exome sequencing may therefore be a powerful tool for identifying mutations associated with syndactyly, which is a disorder with high genetic and clinical heterogeneity. The results provide novel insights into the etiology and diagnosis of syndactyly, and may influence genetic counseling and the clinical management of the disease.

Modeling Periodic Impulsive Effects on Online TV Series Diffusion.

BACKGROUND: Online broadcasting substantially affects the production, distribution, and profit of TV series. In addition, online word-of-mouth significantly affects the diffusion of TV series. Because on-demand streaming rates are the most important factor that influences the earnings of online video suppliers, streaming statistics and forecasting trends are valuable. In this paper, we investigate the effects of periodic impulsive stimulation and pre-launch promotion on on-demand streaming dynamics. We consider imbalanced audience feverish distribution using an impulsive susceptible-infected-removed(SIR)-like model. In addition, we perform a correlation analysis of online buzz volume based on Baidu Index data. METHODS: We propose a PI-SIR model to evolve audience dynamics and translate them into on-demand streaming fluctuations, which can be observed and comprehended by online video suppliers. Six South Korean TV series datasets are used to test the model. We develop a coarse-to-fine two-step fitting scheme to estimate the model parameters, first by fitting inter-period accumulation and then by fitting inner-period feverish distribution. RESULTS: We find that audience members display similar viewing habits. That is, they seek new episodes every update day but fade away. This outcome means that impulsive intensity plays a crucial role in on-demand streaming diffusion. In addition, the initial audience size and online buzz are significant factors. On-demand streaming fluctuation is highly correlated with online buzz fluctuation. CONCLUSION: To stimulate audience attention and interpersonal diffusion, it is worthwhile to invest in promotion near update days. Strong pre-launch promotion is also a good marketing tool to improve overall performance. It is not advisable for online video providers to promote several popular TV series on the same update day. Inter-period accumulation is a feasible forecasting tool to predict the future trend of the on-demand streaming amount. The buzz in public social communities also represents a highly correlated analysis tool to evaluate the advertising value of TV series.

Genetic analysis of the FBXO48 gene in Chinese Han patients with Parkinson disease.

The F-box only protein 48 gene (FBXO48) is located in 2p13.3, the disease gene locus of Parkinson disease type 3 (PARK3), and it is one of the paralogs of the F-box only protein 7 gene (FBXO7), which is a causative gene of the Parkinson disease type 15 (PARK15; also known as Parkinsonian-pyramidal disease, PPD). To determine whether genetic mutation in the coding region of the FBXO48 gene plays a role in the etiology of PD, we screened DNA samples from 350 Chinese Han patients with PD. No mutation in the coding region of the FBXO48 gene was identified in our PD cohort, suggesting that mutations in the coding region of the FBXO48 gene play little or no role in the development of PD.

EIF4G1 Ala502Val and Arg1205His variants in Chinese patients with Parkinson disease.

Growing evidences show that genetic abnormalities play an important role in the etiopathogenesis of Parkinson disease (PD). At least 18 genetic loci and 13 disease-related genes for parkinsonism have been identified. Recently, the p.Ala502Val and p.Arg1205His variants in the eukaryotic translation initiation factor 4-gamma 1 gene (EIF4G1) were found to be associated with PD. To evaluate whether the EIF4G1 p.Ala502Val and p.Arg1205His variants are related to PD in Chinese Han population, we conducted genetic examination of these two variants in 425 PD patients from Mainland China and none was found in our patients. We did identify a known non-pathogenic polymorphism c.3660C>T (p.Ala1220Ala, rs143852330) in a 73-year-old male patient. Our results, consistent with other recent reports, suggest that the EIF4G1 p.Ala502Val and p.Arg1205His variants are a rare cause of PD, at least in Chinese population.

Genetic analysis of the leucine-rich repeat and lg domain containing Nogo receptor-interacting protein 1 gene in essential tremor.

Variants in the leucine-rich repeat and lg domain containing nogo receptor-interacting protein 1 gene (LINGO1) have been identified to be associated with the increased risk of essential tremor (ET), especially among Caucasians. To explore whether the LINGO1 gene plays a role in ET susceptibility, we performed a systematic genetic analysis of the coding region in the LINGO1 gene. Four nucleotide variants have been genotyped, including three known variants (rs2271398, rs2271397, and rs3743481), and a novel G → C transition (ss491228439). Extended analysis showed no significant difference in genotypic and allelic distributions between 151 patients and 301 control subjects for these four variants (all P > 0.05). However, further sex-stratified analysis revealed that the C allele of rs2271397 and ss491228439 contributed the risk of ET in female (P = 0.017, OR = 2.139, 95 % CI 1.135 ~ 4.030 for rs2271397 and P = 0.038, OR = 1.812, 95 % CI 1.027 ~ 3.194 for ss491228439). Haplotype analysis indicated that A465-C474-C714 haplotype was significantly associated with increased risk of ET in female (P = 0.041, OR = 1.800, 95 % CI 1.020 ~ 3.178). Our results indicate that the LINGO1 variants are associated with ET in Chinese Han female patients.