A novel technique of percutaneous transhepatic treatment of biliary-enteric anastomotic occlusive strictures with compliant balloon-occluded distal cholangiography and large-bore catheter: a retrospective case series.

Background: Endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic biliary balloon dilatation (PTBD) is a challenge in resolving biliary-enteric anastomotic occlusive strictures (BEAOS) and/or coexisting stones. The biliary-enteric anastomosis (BEA) often cannot be seen because of the surgically altered gastrointestinal anatomy. Here, a technique that combined percutaneous compliant-occluded distal cholangiography and the maintenance of a large-bore catheter is described to resolve this issue. Methods: A retrospective review of 10 patients who presented with BEAOS with/without coexisting stones who were treated with percutaneous compliant balloon-occluded distal cholangiography, bile duct stone removal, and the maintenance of a large-bore catheter between February 2017 and January 2021 was performed. Treatment response, laboratory examinations, including hepatic function tests, routine blood tests, and blood electrolytes, complications, and imaging data were evaluated. Paired t-tests were used to investigate the difference of laboratory examinations before and after the procedure. Results: All 10 cases were technically successful. A total of 9 stones in 6 patients were successfully removed by the compliant balloon. All catheters were removed after the patency of the stricture was confirmed by percutaneous transhepatic cholangiography (PTHC) 6 months later. No severe adverse events occurred during the perioperative period. There were 2 patients who experienced episodes of cholangitis during the follow-up period (mean, 17 months; range, 4-24 months), and neither BEAOS nor bile duct stones recurred within 2 years after the procedure. White blood cells (WBC), total bilirubin (TB), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were (6.0±1.4)×109/L and (6.0±1.6)×109/L (P=0.91), 31.4±15.7 and 29.6±10.3 µmol/L (P=0.74), 50.8±20.0 and 85.8±67.0 U/L (P=0.16), and 42.6±15.2 and 71.8±44.9 U/L (P=0.09) pre and postintervention, respectively. Conclusions: Percutaneous transhepatic compliant balloon-occluded distal cholangiography and the maintenance of a large-bore catheter probably provide an effective and safe alternative method for resolving BEAOS and/or coexisting stones.

Apolipoprotein E Polymorphism Impacts White Matter Injury Through Microglial Phagocytosis After Experimental Subarachnoid Hemorrhage.

Apolipoprotein E (apoE, protein; APOE, gene), divided into three alleles of E2, E3 and E4 in humans, is associated with the progression of white matter lesion load. However, mechanism evidence has not been reported regarding the APOE genotype in early white matter injury (WMI) under subarachnoid hemorrhage (SAH) conditions. In the present study, we investigated the effects of APOE gene polymorphisms, by constructing microglial APOE3 and APOE4-specific overexpression, on WMI and underlying mechanisms of microglia phagocytosis in a mice model of SAH. A total of 167 male C57BL/6J mice (weight 22-26 g) were used. SAH and bleeding environment were induced by endovascular perforation in vivo and oxyHb in vitro, respectively. Multi-technology approaches, including immunohistochemistry, high throughput sequencing, gene editing for adeno-associated viruses, and several molecular biotechnologies were used to validate the effects of APOE polymorphisms on microglial phagocytosis and WMI after SAH. Our results revealed that APOE4 significantly aggravated the WMI and decreased neurobehavioral function by impairing microglial phagocytosis after SAH. Indicators negatively associated with microglial phagocytosis increased like CD16, CD86 and the ratio of CD16/CD206, while the indicators positively associated with microglial phagocytosis decreased like Arg-1 and CD206. The increased ROS and aggravating mitochondrial damage demonstrated that the damaging effects of APOE4 in SAH may be associated with microglial oxidative stress-dependent mitochondrial damage. Inhibiting mitochondrial oxidative stress by Mitoquinone (mitoQ) can enhance the phagocytic function of microglia. In conclusion, anti-oxidative stress and phagocytosis protection may serve as promising treatments in the management of SAH.

Predicting Best-Selling New Products in a Major Promotion Campaign Through Graph Convolutional Networks.

Many e-commerce platforms, such as AliExpress, run major promotion campaigns regularly. Before such a promotion, it is important to predict potential best sellers and their respective sales volumes so that the platform can arrange their supply chains and logistics accordingly. For items with a sufficiently long sales history, accurate sales forecast can be achieved through the traditional statistical forecasting techniques. Accurately predicting the sales volume of a new item, however, is rather challenging with existing methods; time series models tend to overfit due to the very limited historical sales records of the new item, whereas models that do not utilize historical information often fail to make accurate predictions, due to the lack of strong indicators of sales volume among the item's basic attributes. This article presents the solution deployed at Alibaba in 2019, which had been used in production to prepare for its annual "Double 11" promotion event whose total sales amount exceeded U.S. $ 38 billion in a single day. The main idea of the proposed solution is to predict the sales volume of each new item through its connections with older products with sufficiently long sales history. In other words, our solution considers the cross-selling effects between different products, which has been largely neglected in previous methods. Specifically, the proposed solution first constructs an item graph, in which each new item is connected to relevant older items. Then, a novel multitask graph convolutional neural network (GCN) is trained by a multiobjective optimization-based gradient surgery technique to predict the expected sales volumes of new items. The designs of both the item graph and the GCN exploit the fact that we only need to perform accurate sales forecasts for potential best-selling items in a major promotion, which helps reduce computational overhead. Extensive experiments on both proprietary AliExpress data and a public dataset demonstrate that the proposed solution achieves consistent performance gains compared to existing methods for sales forecast.

Waterborne virus transport and the associated risks in a large lake.

Waterborne enteric viruses in lakes, especially at recreational water sites, may have a negative impact on human health. However, their fate and transport in lakes are poorly understood. In this study, we propose a coupled water quality and quantitative microbial risk assessment (QMRA) model to study the transport, fate and infection risk of four common waterborne viruses (adenovirus, enterovirus, norovirus and rotavirus), using Lake Geneva as a study site. The measured virus load in raw sewage entering the lake was used as the source term in the water quality simulations for a hypothetical scenario of discharging raw wastewater at the lake surface. After discharge into the lake, virus inactivation was modeled as a function of water temperature and solar irradiance that varied both spatially and temporally during transport throughout the lake. Finally, the probability of infection, while swimming at a popular beach, was quantified and compared among the four viruses. Norovirus was found to be the most abundant virus that causes an infection probability that is at least 10 times greater than the other viruses studied. Furthermore, environmental inactivation was found to be an essential determinant in the infection risks posed by viruses to recreational water users. We determined that infection risks by enterovirus and rotavirus could be up to 1000 times lower when virus inactivation by environmental stressors was accounted for compared with the scenarios considering hydrodynamic transport only. Finally, the model highlighted the role of the wind field in conveying the contamination plume and hence in determining infection probability. Our simulations revealed that for beaches located west of the sewage discharge, the infection probability under eastward wind was 43% lower than that under westward wind conditions. This study highlights the potential of combining water quality simulation and virus-specific risk assessment for a safe water resources usage and management.

Phosphoserine Aminotransferase 1: A Metabolic Enzyme Target of Cancers.

Phosphoserine aminotransferase 1 (PSAT1) catalyzes 3-phosphohydroxylpyruvate and glutamate into 3-phosphoserine and α-ketoglutamate. It integrates metabolic pathways critical for cell proliferation, survival, migration and epigenetics, such as glycolysis, de novo serine synthesis, citric acid cycle and one-carbon metabolism. The level of this enzyme has been disclosed to be closely related to the occurrence, progression and prognosis of cancers like non-small cell lung cancer, colorectal cancer, esophageal squamous cell carcinoma, breast cancer, etc. via metabolic catalyzation, PSAT1 offers anabolic and energic supports for these tumor cells, affecting their proliferation, survival, autophagy, migration and invasion. Such functions also influence the epigenetics of other noncancerous cells and drive them to serve tumor cells. Moreover, PSAT1 exerts a non-enzymatic regulation of the IGF1 pathway and nuclear PKM2 to promote EMT and cancer metastasis. Genetically manipulating PSAT1 alters tumor progression in vitro and in vivo. This paper reviews the role and action mechanism of PSAT1 in tumor biology and chemotherapy as well as the regulation of PSAT1 expression, exhibiting the perspective for PSAT1 as a new molecular marker and target for cancer diagnosis and treatment.

The O-GlcNAcylation and its promotion to hepatocellular carcinoma.

O-GlcNAcylation is a posttranslational modification that attaches O-linked ß-N-acetylglucosamine (O-GlcNAc) to the serine and threonine residues of proteins. Such a glycosylation would alter the activities, stabilities, and interactions of target proteins that are functional in a wide range of biological processes and diseases. Accumulating evidence indicates that O-GlcNAcylation is tightly associated with hepatocellular carcinoma (HCC) in its onset, growth, invasion and metastasis, drug resistance, and stemness. Here we summarize the discoveries of the role of O-GlcNAcylation in HCC and its function mechanism, aiming to deepen our understanding of HCC pathology, generate more biomarkers for its diagnosis and prognosis, and offer novel molecular targets for its treatment.

S100A8 regulates autophagy-dependent ferroptosis in microglia after experimental subarachnoid hemorrhage.

Targeting microglial activation has been shown to ameliorate early brain injury (EBI) after subarachnoid hemorrhage (SAH). Ferroptosis is a new form of programmed cell death after SAH, but these molecular features were not recognized as evidence of microglial function so far. In this study, we constructed microglial S100A8-specific knockdown and established the SAH model in vivo and in vitro. Multi-technology strategies, including high throughput sequencing, adeno-associated virus gene gene-editing and several molecular biotechnologies to validate the effects of S100A8 on microglial autophagy and ferroptosis after SAH. Our results revealed that the expression of S100A8 was significantly increased in brain tissue after SAH. Targeted microglial S100A8 inhibition improved neural function and neuronal apoptosis in mice after SAH. Further mechanism exploration found that favourable effects of S100A8 depletion in EBI may be through the inhibition of microglia autophagy-dependent ferroptosis. In conclusion, S100A8 may be a potential intervention target for microglial ferroptosis in EBI after SAH.

Cell cycle during neuronal migration and neocortical lamination.

OBJECTIVES: In order to understand the relationships between neocortical lamination and cell cycle, various cells, such as neural stem cell, migrating postmitotic neuron, Cajal-Retzius (CR) cell, and mature pyramidal cell in various cell phases were investigated in mouse cortices. METHODS: With mouse neocortex and hippocampus, the immunofluorescent labeling, BrdU assay, and DiI tracing technique were implemented in the study. RESULTS: (1) During mouse development, the neocortex expressed different proteins, such as FOXP2, CDP, and Nestin, which could be used as the markers for cortical lamination. (2) The neural stem cells were mainly located in the subventricular zone, with the expressions of Nestin, Cyclin A2, Cyclin E1, and CDT1, suggesting that they were in the repeated cell cycle. Furthermore, the migrating neurons in the neocortex were Cyclin D1- (G1 phase-specific marker) positive, suggesting that they were in the G1 phase. However, Pyramidal cells that developed from postmitotic migrating neurons and settled in the cortical plate were Cyclin D1- negative, suggesting that they were in the G0 phase. (3) Reelin positive CR cells appeared in the molecular layer of the neocortex in early embryonic day (E10), which could express Cyclin A2, Cyclin E1, and CDT1 as pyramidal cells, but not Cyclin D1, suggesting that they may have exited the cell cycle and entered the G0 phase. CONCLUSION: The neural migration, neural proliferation, and cell cycle alterations play an important role during cortical lamination. During the cortical development and lamination, the neural stem cells and migrating postmitotic neurons are in different cell cycle phases, but pyramidal cells and CR cells have exited the cell cycle.

Hypoxia-induced Tie1 drives stemness and cisplatin resistance in non-small cell lung carcinoma cells.

BACKGROUND: Drug resistance and metastasis involving hypoxic tumor environments and persistent stem cell populations are detrimental to the survival of patients with non-small cell lung carcinoma (NSCLC). Tie1 is upregulated in hypoxia and is believed to counteract the effectiveness of platinum agents by promoting the stemness properties in cells. We have investigated the association of Tie1 with HIF-1α and cisplatin resistance in NSCLC cell lines. METHODS: The expression of Tie1 in a pulmonary microvascular endothelial cell line (HPMEC) and NSCLC cell lines was detected using qRT-PCR and western blotting. The effect of Tie1 on cell stemness and migration was examined by sphere-forming and transwell assays in NSCLC cells with Tie1 silenced. The regulation of Tie1 by HIF-1α was evaluated by a dual-luciferase reporter assay and chromatin immunoprecipitation. RESULTS: We found that hypoxia could induce stemness and cisplatin resistance in vitro. Tie1 was expressed at low levels in NSCLC cells when compared with human pulmonary microvascular endothelial cells, however, its expression was increased by hypoxia. Additionally, Tie1 knockdown could reduce stemness properties and increase sensitivity to cisplatin in vitro and in a xenograft mouse model. The promoter of Tie1 contains two predicted hypoxia-response elements (HREs). We mutated both HRE sites and conducted chromatin immune-precipitation and promoter luciferase reporter assays and were able to conclude that the induction of Tie1 by hypoxia was HIF-1α-dependent. CONCLUSIONS: Our findings indicated that Tie1 is upregulated in a hypoxic environment by HIF-1α and contributes to tumorigenesis and cisplatin resistance through the promotion of stemness in NSCLC cells.

Various Bioactivity and Relationship of Structure-Activity of Matrine Analogues.

For the first time, the botanic source natural product matrine was reported to have more potent inhibitory activity against tobacco mosaic virus (TMV) than the commercial virucide ribavirin. On the basis of the structural diversity modification strategy, a series of matrine derivatives was synthesized and systematically evaluated for their antiviral activity against TMV, fungicidal activity, and insecticidal activity. As a result, compounds 3 (inhibitory rate 67.3%, 69.5%, 63.7%, 63.0% at 500 µg/mL for in vitro activity, inactivation, curative, and protection activities in vivo, respectively), 16 (66.7%, 60.7%, 63.8%, 68.9% at 500 µg/mL), and 32 (74.6%, 76.9%, 72.3%, 75.7% at 500 µg/mL) were found to have much higher anti-TMV activity than ribavirin (40.8%, 37.5%, 38.2%, 37.7% at 500 µg/mL), even exhibiting as well as NK-007 (70.3%, 66.1%, 68.4%, 67.5% at 500 µg/mL), which was an efficient compound created by our group previously. At the same time, it was found that matrine and its derivatives had a broad spectrum fungicidal activity (14 fungi), especially the inhibition of compound 32 against Phytophthora capsici Leonian reached 96.4% at a concentration of 50 µg/mL. What's more, all compounds exhibited very good insecticidal activity to five kinds of insects (including Mythimna Separate, Helicoverpa Armigera, Ostrinia Nubilalis, Plutella xylostella, and Culex Pipiens Pallens); especially, the inhibition rate of C. Pipiens Pallens of compound 22 could still reach 70% at 1 µg/mL.

The Drosophila F-box protein Slimb controls dSmurf protein turnover to regulate the Hippo pathway.

SMAD ubiquitination regulatory factors 1 and 2 (Smurf1/2) are members of the HECT domain E3 ligase family which play crucial roles in the regulation of cell cycle progression, planar cell polarity, cancer metastasis and cell apoptosis. We recently showed that the Drosophila homolog dSmurf controls the stability of Warts kinase to regulate the Hippo pathway. In the current study, we found that the F-box protein Slimb controls dSmurf protein level to regulate the Hippo pathway. Slimb physically associates with dSmurf as revealed by co-immunoprecipitation assay in S2 cells. The C-terminal WD40 repeats of Slimb (188-510 amino acid) and the C-terminal HECT domain of dSmurf (723-1061 amino acid) are necessary for their binding. Interaction with Slimb leads to the ubiquitination and degradation of dSmurf, resulting in negative regulation of dSmurf-mediated Yki phosphorylation and activity in the Hippo pathway. Thus our study revealed a new regulatory mechanism of the Hippo pathway which may provide implications for developing tumor treatment.

Pelle Modulates dFoxO-Mediated Cell Death in Drosophila.

Interleukin-1 receptor-associated kinases (IRAKs) are crucial mediators of the IL-1R/TLR signaling pathways that regulate the immune and inflammation response in mammals. Recent studies also suggest a critical role of IRAKs in tumor development, though the underlying mechanism remains elusive. Pelle is the sole Drosophila IRAK homolog implicated in the conserved Toll pathway that regulates Dorsal/Ventral patterning, innate immune response, muscle development and axon guidance. Here we report a novel function of pll in modulating apoptotic cell death, which is independent of the Toll pathway. We found that loss of pll results in reduced size in wing tissue, which is caused by a reduction in cell number but not cell size. Depletion of pll up-regulates the transcription of pro-apoptotic genes, and triggers caspase activation and cell death. The transcription factor dFoxO is required for loss-of-pll induced cell death. Furthermore, loss of pll activates dFoxO, promotes its translocation from cytoplasm to nucleus, and up-regulates the transcription of its target gene Thor/4E-BP. Finally, Pll physically interacts with dFoxO and phosphorylates dFoxO directly. This study not only identifies a previously unknown physiological function of pll in cell death, but also shed light on the mechanism of IRAKs in cell survival/death during tumorigenesis.

Design, Synthesis, Acaricidal Activity, and Mechanism of Oxazoline Derivatives Containing an Oxime Ether Moiety.

Two series of novel 2,4-diphenyl-1,3-oxazolines containing an oxime ether moiety were designed and synthesized via the key intermediate N-(2-chloro-1-(p-tolyl)ethyl)-2,6-difluorobenzamide. The bioassay results showed that the target compounds with an oxime ether substituent at the para position of 4-phenyl exhibited excellent acaricidal activity against Tetranychus cinnabarinus in the laboratory. Moreover, all of the target compounds had much higher activities than etoxazole, as the ovicidal and larvicidal activities of the target compounds I-a-I-l and II-a-II-n against T. cinnabarinus were all over 90% at 0.001 mg L-1, but etoxazole gave only 30% and 40% respectively at the same concentration. The activity order of compounds with regard to acaricidal activity in vivo was almost consistent with their affinity activity with sulfonylurea receptor (SUR) of Blattella germanica in vitro, hence, it was supposed that the acaricidal mechanism of action of the target compounds was that they can bind with the site of SUR and therefore inhibit chitin synthesis. Moreover, the eminent effect of the compound II-l, [2-(trifluoromethyl)benzaldehyde O-(4-(2-(2,6-difluorophenyl)-4,5-dihydrooxazol-4-yl)benzyl) oxime], against Panonychus citri and T. cinnabarinus in the field indicated that II-l exhibited a promising application prospect as a new candicate for controlling spider mites in the field.