Carbonic anhydrase 2 mediates anti-obesity effects of black tea as thermogenic activator

Obesity is a metabolic disorder due to over-accumulation of adipose tissue and ultimately becomes a“disease”.Brown adipose tissue(BAT)thermogenesis and white adipose tissue(WAT)browning emerge as a potential strategy of anti-obesity by dissipating energy as heat.However,drugs based on adipose tissue thermogenesis have not been successfully approved yet.In current study,we found that black tea extract(BTE)obtained by patentauthorized manufacturing process prevented body weight gain as novel thermogenic activator with reduction of adiposity,improvement of adipose distribution,and glucose metabolism improvement in diet-induced obesity mice.Mechanismly,anti-obesity effect of BTE depends on promoting BAT thermogenesis and WAT browning with upregulation of uncoupling protein 1(UCP1),especially visceral adipose tissue(VAT)with browning resistance.Specifically,utilizing in silico approach of network pharmacology and molecular docking,we identified carbonic anhydrase 2(CA2)in nitrogen metabolism as anti-obesity target of BTE and further elucidated that protein kinase B(AKT)signaling pathway linked CA2 and UCP1.Meanwhile gut microbiota regulation may prompt the CA2-dependent thermogenesis activation.Our findings demonstrated anti-obesity effect of BTE as thermogenic activator through CA2-mediated BAT thermogenesis and WAT browning via CA2-AKT-UCP1 signaling pathway,which could be developed as promising anti-obesity agent with good safety and efficacy.

Gut microbiota-based pharmacokinetic-pharmacodynamic study and molecular mechanism of specnuezhenide in the treatment of colorectal cancer targeting carboxylesterase

Specnuezhenide(SNZ)is among the main components of Fructus Ligustri Lucidi,which has antiinflammation,anti-oxidation,and anti-tumor effect.The low bioavailability makes it difficult to explain the mechanism of pharmacological effect of SNZ.In this study,the role of the gut microbiota in the metabolism and pharmacokinetics characteristics of SNZ as well as the pharmacological meaning were explored.SNZ can be rapidly metabolized by the gut microbiome,and two intestinal bacterial metabolites of SNZ,salidroside and tyrosol,were discovered.In addition,carboxylesterase may be the main intestinal bacterial enzyme that mediates its metabolism.At the same time,no metabolism was found in the incubation system of SNZ with liver microsomes or liver homogenate,indicating that the gut microbiota is the main part involved in the metabolism of SNZ.In addition,pharmacokinetic studies showed that salidroside and tyrosol can be detected in plasma in the presence of gut microbiota.Interestingly,tumor development was inhibited in a colorectal tumor mice model administered orally with SNZ,which indicated that SNZ exhibited potential to inhibit tumor growth,and tissue distribution studies showed that salidroside and tyrosol could be distributed in tumor tissues.At the same time,SNZ modulated the structure of gut microbiota and fungal group,which may be the mechanism governing the antitumoral activity of SNZ.Furthermore,SNZ stimulates the secretion of short-chain fatty acids by intestinal flora in vitro and in vivo.In the future,targeting gut microbes and the interaction between natural products and gut microbes could lead to the discovery and development of new drugs.

TNFR2 is a potent prognostic biomarker for post-transplant lung metastasis in patients with hepatocellular carcinoma

Objective:Lung metastasis is a common and fatal complication of liver transplantation for hepatocellular carcinoma(HCC).The precise prediction of post-transplant lung metastasis in the early phase is of great value.Methods:The mRNA profiles of primary and paired lung metastatic lesions were analyzed to determine key signaling pathways.We enrolled 241 HCC patients who underwent liver transplantation from three centers.Tissue microarrays were used to evaluate the prognostic capacity of tumor necrosis factor(TNF),tumor necrosis factor receptor 1(TNFR1),and TNFR2,particularly for post-transplant lung metastasis.Results:Comparison of primary and lung metastatic lesions revealed that the TNF-dependent signaling pathway was related to lung metastasis of HCC.The expression of TNF was degraded in comparison to that in para-tumor tissues(P<0.001).The expression of key receptors in the TNF-dependent signaling pathway,TNFR1 and TNFR2,was higher in HCC tissues than in para-tumor tissues(P<0.001).TNF and TNFR1 showed no relationship with patients’outcomes,whereas elevated TNFR2 in tumor tissue was significantly associated with worse overall survival(OS)and increased recurrence risk(5-year OS rate:31.9%vs.62.5%,P<0.001).Notably,elevated TNFR2 levels were also associated with an increased risk of post-transplant lung metastasis(hazard ratio:1.146;P<0.001).Cox regression analysis revealed that TNFR2,Hangzhou criteria,age,and hepatitis B surface antigen were independent risk factors for post-transplant lung metastasis,and a novel nomogram was established accordingly.The nomogram achieved excellent prognostic efficiency(area under time-dependent receiver operating characteristic=0.755,concordance-index=0.779)and was superior to conventional models,such as the Milan criteria.Conclusions:TNFR2 is a potent prognostic biomarker for predicting post-transplant lung metastasis in patients with HCC.A nomogram incorporating TNFR2 deserves to be a helpful prognostic tool in liver transplantation for HCC.

Coking of Pt/γ-Al_(2)O_(3) catalyst in landfill gas deoxygen and its effects on catalytic performance

Catalytic oxidation of CH_(4) has been proved to be an attractive option for landfill gas(LFG) upgrading.However, coking of catalysts in catalytic LFG deoxygen has been clearly observed in industrial applications. In this regard, it is necessary to investigate whether coke deposition originates from CH_(4) or volatile organic compounds present in LFG, and the influence of coke deposition on catalytic performance. Herein,we evaluate the LFG deoxygen on Pt/γ-Al_(2)O_(3) catalyst in simulated LFG(CH_(4), CO_(2), O_(2), N_(2)) and its co-feed with representative volatile organic compounds, ethylbenzene, toluene, benzene and cyclohexane. The results show that the coking of the catalyst is originated from volatile organic compounds rather than CH_(4). The Pt/γ-Al_(2)O_(3) catalyst does not deactivate during LFG deoxygen process, even significant amount of coke deposited, up to 18.15%(mass). Characterization analyses reveal that although coke deposition overall covers the catalyst surface, resulting in mesopores blockage and a reduced number of accessible Pt sites, however, the coke formed, H-rich carbonaceous components, behaves as counterpart for O_(2) elimination. Besides, the coke deposited is mainly filamentous. Thus, coke formation has little negative effect on the overall catalytic performance of Pt/γ-Al_(2)O_(3) catalyst ultimately. The results obtained in this work are helpful for the rational design of robust Pt based catalysts for LFG deoxygen without undue attention to their coking properties, and also favor the innovation of more attractive purification scheme configurations.

A review on thermal conductivity of magnesium and its alloys

This review summarizes recent researching works the thermal conductivity of Mg–Zn,Mg–Al,Mg–Mn and Mg–RE alloys.Solute atoms,heat treatment,deformation and temperature,which have significant influence on the thermal conductivity of magnesium alloys,are highlighted.For an individual solute atom,its effects on thermal conductivity are highly dependent on its chemical valence,radius and extra-nuclear electrons.The thermal conductivity of Mg alloys is decreased by solution treatment,but improved by aging and/or annealing treatments.As for the deformed Mg alloys,the thermal conductivity along transverse or normal direction is superior to that of along extrusion or rolling direction.We expect this review is helpful for those who are working on developing Mg alloys with superior thermal conductivity.©2020 Published by Elsevier B.V.on behalf of Chongqing University.

颗粒细胞EGF类因子信号通路在调控卵母细胞成熟和发育中的作用

动物体内卵泡排卵前促黄体素(luteinizing hormone, LH)诱导了卵丘颗粒细胞扩散,并启动卵母细胞恢复减数分裂。普遍认为,卵泡壁层颗粒细胞表达LH受体,卵母细胞及其周围卵丘细胞不表达LH受体,LH通过作用于卵泡壁层颗粒细胞产生信号分子,这些信号分子作用于卵丘颗粒细胞介导了LH生物作用。然而,一直以来,关于排卵前介导LH作用而诱导卵母细胞成熟的机制一直存在争议。目前研究认为,LH作用于卵泡壁层颗粒细胞后产生了EGF类因子,并与颗粒细胞的受体结合,促进了卵母细胞的成熟和发育。由于体外成熟的卵丘卵母细胞复合体来源于生长卵泡,其卵丘颗粒细胞EGF类因子信号系统不完善,目前的体外成熟培养体系难以模拟卵泡内的生理环境,导致卵母细胞体外发育能力较差,限制了这些卵母细胞的利用效率。本文综述了颗粒细胞EGF类因子信号系统、EGF类因子在调控卵母细胞成熟中的作用及对卵母细胞发育能力的影响,为优化卵母细胞体外成熟培养体系,完善卵丘颗粒细胞的EGF类因子的信号系统,进而提高卵母细胞体外成熟效率提供理论依据。

胃血管解剖及其在食管癌管状胃重建中的应用

目的:本研究旨在了解胃血管,尤其是胃网膜右动脉的解剖情况,为食管癌术中管状胃的重建提供参考。方法:解剖由上海医学院提供的尸体28具,其中男性18具、女性10具。分别观察并测量各条胃供血动脉的直径及长度,胃网膜右动脉的长度及其与胃大弯长度的比值,观察胃网膜左、右动脉的吻合情况。结果:最终可测得胃左动脉为25条,直径为3.40(2.10～6.40)mm;胃右动脉21条,直径为1.97(0.68～3.56)mm;胃网膜左动脉26条,直径为1.87(0.80～2.96)mm;胃网膜右动脉28条,直径为2.82(1.58～4.80)mm,长度为216.71(120～318)mm;胃大弯长度为356.39(248～487)mm。胃网膜右动脉长度与胃大弯长度的平均比值为0.61(0.45～0.82)。28具尸体中,17具发现胃网膜左、右动脉的终支有吻合支,占60.7%。结论:通过尸体解剖,对胃的供应血管进行观察和统计,计算得到胃各供应血管长度和直径,推测胃网膜右动脉平均提供胃大弯侧61%的血供,在60.7%的标本中发现有胃网膜左、右动脉的吻合支。通过基础解剖数据,以期为食管癌术中管状胃血供的估算及管状胃的最佳重建提供参考。

Hierarchical interacting multiple model algorithm based on improved current model

Interacting multiple models is the hotspot in the research of maneuvering target models at present. A hierarchical idea is introduced into IMM algorithm. The method is that the whole models are organized as two levels to co-work, and each cell model is an improved ＂current＂ statistical model. In the improved model, a kind of nonlinear fuzzy membership function is presented to get over the limitation of original model, which can not track weak maneuvering target precisely. At last, simulation experiments prove the efficient of the novel algorithm compared to interacting multiple model and hierarchical interacting multiple model based original ＂current＂ statistical model in tracking precision.

Endogenous adult neurogenesis and cognitive function recovery following traumatic brain injury in the rat hippocampus

BACKGROUND：Endogenous neural progenitor cells play a beneficial role for cognitive recovery following traumatic brain injury.However,there are few classification-control studies aimed at varying graded brain trauma.OBJECTIVE：To observe the effects of adult endogenous neurogenesis on cognitive function repair and regeneration of neural progenitor cells following varying graded traumatic hippocampal injury to determine the significance of endogenous neurogenesis in the repair of brain injury.DESIGN,TIME AND SETTING：A randomized,controlled,animal experiment was performed at the Key Laboratory of Injuries,Variations and Regeneration of Nervous System,Tianjin Medical University General Hospital,from February to October 2009.MATERIALS：Mouse anti-rat 5-bromodeoxyuridine （BrdU） and neuronal nuclei （NeuN） monoclonal antibodies were purchased from Millipore Corporation,USA.METHODS：A total of 45 Wistar rats were randomly assigned to three groups.Mild and severe injury groups were respectively subjected to （182 ± 2） kPa and （284 ± 4） kPa lateral fluid percussion to establish models of brain injury,and the control group was subjected to surgery with no lateral fluid percussion.MAIN OUTCOME MEASURES：Cognitive function was estimated using the Morris water maze.Proliferation,survival,and differentiation of newly generated cells in the injured hippocampus were observed through the use of immunofluorescent staining.RESULTS：At 7 days post-injury,the number of BrdU＋ cells in the hippocampal dentate gyrus significantly increased in the mild and severe injury groups compared with the control group （P〈0.01）.At 61 days post-injury,the number of BrdU7NeuN＋ cells in the hippocampal dentate gyrus was significantly greater in the mild injury group compared with the severe injury and control groups （P〈 0.01）.In addition,the control group exhibited the greatest proportion of surviving cells that differentiated into mature neurons compared with the injury groups （P〈 0.01）.Moreover,at 61 days post-injury,cognitive function in rats with mild injury recovered to normal levels,whereas the severe injury group exhibited cognitive deficits （P〈 0.01）.CONCLUSION：Traumatic brain injury may be a stimulation factor for proliferation of neural progenitor cells in the adult hippocampus but severe brain trauma does not lead to an increased number of newly generated cells.Endogenous adult neurogenesis repairs neurological functions to an extent.However,recovery of neurological function remains limited following severe traumatic brain injury.

High-Performance Ionic Thermoelectric Supercapacitor for Integrated Energy Conversion-Storage

Converting low-grade waste heat into usable electricity and storing it simultaneously requires a new technology that realize the directional migration of electrons or ions under temperature difference and enrichment on the electrodes.Although the urgent demand of energy conversion-storage(ECS)has emerged in the field of wearable electronic,achieving the integrated bi-functional device remains challenge due to the different mechanisms of electrical transportation and storage.Here,we report an ionic thermoelectric supercapacitor that relies on the synergistic functions of thermoelectricity and supercapacitor in the thermoelectric ionogel electrolyte and high-performance hydrogel electrodes to enhance the ECS performance under a thermal gradient.The thermoelectric electrolyte is composed of polyacrylamide hydrogel and sodium carboxymethyl cellulose(PMSC),possessing cross-linked network with excellent cation selectivity,while the ionic thermoelectric properties are further improved in the presence of NaCl.The corresponding Seebeck coefficient and ionic conductivity of the NaCl–PMSC electrolyte reach 17.1 mV K^(-1)and 26.8 mS cm^(-1),respectively.Owing to good stretchability of both gel-based electrolyte and electrode,the fullstretchable integrated ECS device,termed ionic thermoelectric supercapacitor,presents promising thermal-charge storage capability(~1.3 mC,ΔT≈10 K),thus holds promise for wearable energy harvesting.

Joint Optimization of Admission Control and Rate Adaptation for Video Sharing over Multirate Wireless Community Cloud

Emerging wireless community cloud enables usergenerated video content to be shared and consumed in a social context. However, the nature of shared wireless medium and timevarying channels seriously limits the quality of service(QoS), partially owing to the lack of mechanisms for effectively utilizing multi-rate channel resources. In this paper, the joint optimization of admission control and rate adaptation is proposed, resulting in a bandwidth-aware rate-adaptive admission control(BRAC) scheme to provide bandwidth guarantee for sharing social multimedia contents. The analytical approach leads to the following major contributions:(1) a bandwidth-aware rate selection(BRS) algorithm to optimally meet the bandwidth requirement of the data session and channel conditions at the physical layer;(2) a routing-coupled rate adaption and admission control algorithm to admit data sessions with bandwidth guarantee. Moreover, extensive numerical simulations suggest that BRAC is efficient and effective in meeting the bandwidth requirements for sharing social multimedia contents. These insights will shed light on communication system implementation for multimedia content sharing over multirate wireless community cloud.

有机无机纳米杂化“多面手”——POSS的奥秘

多面体低聚倍半硅氧烷(POSS)是化学世界里纳米杂化改性材料的“多面手”。本文采用拟人化的手法,以故事情节的方式从POSS的类型及化学结构、组装方式、应用领域等方面揭开其神秘面纱,以期读者对其化学性质和应用前景获得较为深入的了解。

Current status and challenges in the application of microbial PHA particles

Polyhydroxyalkanoates(PHAs)are diversiform biopolyesters with a similar structure and different side chain groups,synthesized by a variety of microorganism.Due to their excellent biodegradability and biocompatibility,PHAs have been used for many applications,including medical implants,antibacterial agents and bioengineering.Nano-architecture is an emerging area for the use of PHAs.This review summarizes the current status and challenges of PHAs-based particles on the micro-and nano-scale,including their production,degradation,biological safety,and surface functionalization.We also focus on the applications of PHA particles in drug delivery systems,environment protection,tissue engi-neering,vaccine engineering,food science,biotechnology and cosmetics.Finally,the future development trends of PHAs-based particles are prospected.

基于复杂网络社团分析探讨《医宗金鉴》治疗便秘核心用药规律

目的利用数据挖掘技术探讨《医宗金鉴》治疗便秘的核心用药规律,为临床治疗便秘提供思路。方法整理《医宗金鉴》有关便秘的方剂,采用中医传承云计算平台V1.0对数据集进行频次统计、性味归经及功效统计、关联分析和复杂网络分析,并进行可视化展示。结果纳入治疗便秘方剂106首,涉及中药169味,总频次894次,高频中药有大黄、甘草、黄芩、当归等,以泻下药、补虚药、清热药为主,药味以辛、甘、苦为主,药性以寒、温为主,归经以肺、脾、胃、肝经为主。根据关联规则支持度,二阶关联分析得出大黄-黄芩、大黄-芒硝等10个药物组合,三阶关联分析得出大黄-当归-甘草,黄芩-黄连-大黄等9个药物组合,社团聚类分析得出12类聚类方。结论《医宗金鉴》治疗便秘用药遵循"温、清、补"思想,以通降法为主,以温中补虚、清热通便为基本治法,寒温并用,脏腑辨治。临证应以病为纲,辨证施治。

TBC1D1 is an energy-responsive polarization regulator of macrophages via governing ROS production in obesity

Energy status is linked to the production of reactive oxygen species(ROS)in macrophages,which is elevated in obesity.However,it is unclear how ROS production is upregulated in macrophages in response to energy overload for mediating the development of obesity.Here,we show that the Rab-GTPase activating protein(Rab GAP)TBC1D1,a substrate of the energy sensor AMP-activated protein kinase(AMPK),is a critical regulator of macrophage ROS production and consequent adipose inflammation for obesity development.TBC1D1 deletion decreases,whereas an energy overload-mimetic non-phosphorylatable TBC1D1^(S231A)Amutation increases,ROS production and M1-like polarization in macrophages.Mechanistically,TBC1D1 and its downstream target Rab8a form an energy-responsive complex with NOX2 for ROS generation.Transplantation of TBC1D1^(S231A)bone marrow aggravates diet-induced obesity whereas treatment with an ultra-stable Tt SOD for removal of ROS selectively in macrophages alleviates both TBC1D1~(S231A)mutation-and diet-induced obesity.Our findings therefore have implications for drug discovery to combat obesity.

Structural insight into the dual-antagonistic mechanism of AB928 on adenosine A_(2)receptors

The adenosine subfamily G protein-coupled receptors A_(2A)R and A_(2B)R have been identified as promising cancer immunotherapy candidates.One of the A_(2A)R/A_(2B)R dual antagonists,AB928,has progressed to a phaseⅡclinical trial to treat rectal cancer.However,the precise mechanism underlying its dual-antagonistic properties remains elusive.Herein,we report crystal structures of the A_(2A)R complexed with AB928 and a selective A_(2A)R antagonist 2-118.The structures revealed a common binding mode on A_(2A)R,wherein the ligands established extensive interactions with residues from the orthosteric and secondary pockets.In contrast,the cAMP assay and A_(2A)R and A_(2B)R molecular dynamics simulations indicated that the ligands adopted distinct binding modes on A_(2B)R.Detailed analysis of their chemical structures suggested that AB928 readily adapted to the A_(2B)R pocket,while 2-118 did not due to intrinsic differences.This disparity potentially accounted for the difference in inhibitory efficacy between A_(2B)R and A_(2A)R.This study serves as a valuable structural template for the future development of selective or dual inhibitors targeting A_(2A)R/A_(2B)R for cancer therapy.

Coordinate-wise monotonic transformations enable privacy-preserving age estimation with 3D face point cloud

The human face is a valuable biomarker of aging,but the collection and use of its image raise significant privacy concerns.Here we present an approach for facial data masking that preserves age-related features using coordinate-wise monotonic transformations.We first develop a deep learning model that estimates age directly from non-registered face point clouds with high accuracy and generalizability.We show that the model learns a highly indistinguishable mapping using faces treated with coordinate-wise monotonic transformations,indicating that the relative positioning of facial information is a low-level biomarker of facial aging.Through visual perception tests and computational3D face verification experiments,we demonstrate that transformed faces are significantly more difficult to perceive for human but not for machines,except when only the face shape information is accessible.Our study leads to a facial data protection guideline that has the potential to broaden public access to face datasets with minimized privacy risks.

Targeting cAMP in D1-MSNs in the nucleus accumbens, a new rapid antidepressant strategy

Studies have suggested that the nucleus accumbens(NAc)is implicated in the pathophysiology of major depression;however,the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated.Here,we identified a specific reduction of cyclic adenosine monophosphate(cAMP)in the subset of dopamine D1 receptor medium spiny neurons(D1-MSNs)in the NAc that promoted stress susceptibility,while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors.Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons(D2-MSNs)of depressed mice,however,the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs.We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration,but not a lower dose.The fast onset property of crocin was verified through multicenter studies.Moreover,crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN.These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc,and provide a potential rapid antidepressant drug candidate,crocin.

Gas-generating polymersomes-based amplified photoimmunotherapy for abscopal effect and tumor metastasis inhibition

Due to the heterogeneity of tumors,single phototherapy cannot completely ablate tumors and inhibit tumor metastasis.To overcome these,we formulated targeted and multifunctional polymersomes ABC@ICGIMQ-LHRH(AIRL)that encapsulated Toll-like receptor(TLR)7/8 agonist imiquimod(IMQ)and photosensitizer indocyanine green(ICG)in the hydrophobic layer as well as bubble-generator NH_(4)HCO_(3) in the hydrophilic cavity to inhibit the growth of primary and distant tumors,and prevent tumor metastasis through synergistic photoimmunotherapy.The AIRL polymersomes exhibited uniform and stable size,and high drug encapsulation efficiency,acid/reduction/laser responsiveness,excellent photothermal conversion efficiency,effective reactive oxygen species generation,high tumor accumulation.AIRL could be effectively internalized by dendritic cells(DCs),achieve lysosome escape and enhance DCs maturation.The synergistic photoimmunotherapy via AIRL polymersomes remarkably promoted the differentiation and activation of T cells,elevated strong systemic immune response to eradicate primary tumors and inhibit the growth of distant tumors.Simultaneously,the endurable immunological memory prevented tumor metastasis,which provided a promising nanoplatform for the combination therapy of cancer.