Cholecystokinin octapeptide antagonizes apoptosis in human retinal pigment epithelial cells

Although cholecystokinin octapeptide-8 is important for neurological function, its neuroprotective properties remain unclear. We speculated that cholecystokinin octapeptide-8 can protect human retinal pigment epithelial cells against oxidative injury. In this study, retinal pigment epithelial cells were treated with peroxynitrite to induce oxidative stress. Peroxynitrite triggered apoptosis in these cells, and increased the expression of Fas-associated death domain, Bax, caspase-8 and Bcl-2. These changes were suppressed by treatment with cholecystokinin octapeptide-8. These results suggest that cholecystokinin octapeptide-8 can protect human retinal pigment epithelial cells against apoptosis induced by peroxynitrite.

Ultra-fast phosphating synthesis of metastable crystalline phase-controllable ultra-small MPX/CNT(M = Pd, Pt, Ru) for polyalcohol electrooxidation

A general approach is reported for ultra-fast phosphating synthesis of a series of ultra-small(<5 nm)noble metal phosphides(MPX/CNT,M=Pd,Pt,Ru)which are successfully produced in just 75 s for the first time.The catalytic performance of the catalysts can be optimized by controlling the nanomaterials as the metastable crystalline phases.By altering the phosphorus source under the same conditions,the hexagonal structured Pd_(7)P_(3)(NaH_(2)PO_(2).H_(2)O as P source)and monoclinic structured Pd_(6)P(Na_(4)P_(2)O_(7) as P source)can be prepared successfully.Both of them exhibit excellent polyol oxidation performance in alkaline media.Monoclinic Pd_(6)P/CNT and hexagonal Pd_(7)P_(3)/CNT have large ECSA which are confirmed as 82.1 m2 g^(-1)and 86.2 m2 g^(-1),respectively.Hexagonal Pd_(7)P_(3)/CNT has the highest mass activity of 6.14 A mgPd^(-1)(3.21 A mgPd^(-1)for Pd_(6)P/CNT)for GOR,which far exceeded Pt/C(2.81 A mgPt^(-1)).Meanwhile,the mass activity of monoclinic Pt_(5)P_(2)/CNT for EGOR achieved 12.4 A mg_(Pt)^(-1),which far exceeded Pt/C(6.8 A mg_(Pt)^(-1)).The stability test proved that the activity decay of these catalysts was negligible after the 12-hour durability test.Meanwhile,they have excellent CO anti-poisoning abilities.

基于鲁棒优化方法的供应链协同创新——非完全竞争市场下的问题

供应链协同问题是企业供应链管理领域的一个热门话题。本文通过对传统零售商-供应商柔性承诺(RSFC)问题进行改进和延伸,将条件置于非完全竞争市场,从零售商视角探讨了非完全竞争市场下"零售商-供应商"两级系统最优订购策略问题,在利润最大化原则下建立起了运筹学模型,采用鲁棒优化方法进行模型求解,比较了不同形式不确定性水平下的优化结果差异。

The norepinephrine transporter gene is associated with the retardation symptoms of major depressive disorder in the Han Chinese population

The norepinephrine transporter plays an important role in the pathophysiology and pharmacological treatment of major depressive disorder. Consequently, the norepinephrine transporter gene is an attractive candidate in major depressive disorder research. In the present study, we evaluated the depression symptoms of subjects with major depressive disorder, who were all from the North of China and of Hart Chinese origin, using the Hamilton Depression Scale. We examined the relationship between two single nucleotide polymorphisms in the norepinephrine transporter, rs2242446 and rs5569, and the retardation symptoms of major depressive disorder using quantitative trait testing with the UNPHASED program, rs5569 was associated with depressed mood, and the GG genotype may be a risk factor for this; rs2242446 was associated with work and interest, and the TT genotype may be a risk factor for loss of interest. Our findings suggest that rs2242446 and rs5569 in the norepinephrine transporter gene are associated with the retardation symptoms of depression in the Hart Chinese population.

NATURAL HISTORY OBSERVATION FOR ESOPHAGEAL AND CARDIA PRECURSORS BY REPETITIVE ENDOSCOPIC SCREENING OF 301 SUBJECTS IN SHEXIAN

OBJECTIVE To investigate the natural history of fast developing esophageal and cardia precursors.METHODS Repetitive endoscopic screenings were performed among 40-69-year-olds in the high-incidence areas for esophageal cancer in Shexian. RESULTS The initial diagnosis and the lag-time for 7 subsequently identified severe dysplasia （SD） subjects were as follows： in one subject 13 months after a baseline diagnosis of normal epithelium, in another subject 7 months after a baseline diagnosis of base cell hyperplasia （BCH）, in four subjects 3, 4, 4, and 10.5 months after baseline diagnosis of mild dysplasia （mD）, and in one subject 12.5 months after a baseline diagnosis of moderate dysplasia （MD）. The initial diagnosis and the lag-time for 6 subsequently identified carcinomas in situ or intramucosal carcinoma cases were： in one case 48 months after a baseline diagnosis of mD, in 2 cases 4 and 13 months after baseline diagnoses of MD, and in the other 3 cases 3.5, 9, and 17.5 months after baseline diagnoses of SD. The initial diagnosis and lag-time for 3 subsequently identified invasive cancer cases, were： in one case 50 months after a baseline diagnosis of MD, in 2 cases 14 and 19 months after baseline diagnoses of SD. In addition, during a 4-year-follow-up of 18 subjects after endoscopic mucosa resection, 9 of them were found to have developed precursors again at other sites, and also additional findings were obtained for 11 of the 16 dysplasia cases by repetitive biopsy in less than 2 months after the initial endoscopy. CONCLUSION A 5-year screening interval for BCH and mD, and a 3-year interval for MD may be too long for the fast developing precursors. Periodic screenings with shorter intervals should be considered to control the number of interval cases due to fast development, multifocal carcinogenesis, and false negative results inherent in one-time endoscopic biopsy sampling.

The progress in diagnosis and treatment of trigeminal neuralgia

Trigeminal neuralgia(TN)is characterized by recurrent facial acupuncture like,electric shock like,burning like pain and other common clinical cranial nerve diseases in the trigeminal nerve distribution area.Around the world,people who are 40 or more are at risk.The incidence rate of TN of female is slightly higher than that of male and most of the affecting areas are on the right side unilaterally,which affects maxillary nerve and mandibular nerve,yet seldom ophthalmic nerve.Although controversy exists in the pathogenesis of TN,the most accepted theory is microvascular compression,which forces on the demyelination of the sensory axon of the trigeminal nerve root.Additionally,slight touch,conversation and chewing may cause intolerable pain.The diagnosis of TN mainly depends on clinical manifestation.The treatment mainly includes medicine,operation,and some supplementary methods.Among them,antiepileptics and tricyclic antidepressants are the first-line treatment.Surgical treatment is mainly used for patients with TN who have failed in drug treatment or have intolerable side effects.The methods of operation include destructive or non-destructive operation.Deep brain stimulation(DBS)and motor cortex stimulation(MCS)are new therapeutic techniques emerged recently.This method is expected to alleviate the refractory TN with poor drug control or ineffective conventional surgical treatment.At present,this method has not been approved for clinical treatment.Of course,more clinical data collection processes are in progress.

Precise nanomedicine for intelligent therapy of cancer

Precise nanomedicine has been extensively explored for efficient cancer imaging and targeted cancer therapy, as evidenced by a few breakthroughs in their preclinical and clinical explorations. Here, we demonstrate the recent advances of intelligent cancer nanomedicine, and discuss the comprehensive understanding of their structure-function relationship for smart and efficient cancer nanomedicine including various imaging and therapeutic applications, as well as nanotoxicity. In particular, a few emerging strategies that have advanced cancer nanomedicine are also highlighted as the emerging focus such as tumor imprisonment, supramolecular chemotherapy, and DNA nanorobot. The challenge and outlook of some scientific and engineering issues are also discussed in future development. We wish to highlight these new progress of precise nanomedicine with the ultimate goal to inspire more successful explorations of intelligent nanoparticles for future clinical translations.

Chemiluminescence and electrochemiluminescence applications of metal nanoclusters

Due to strong photoluminescence,extraordinary photostability,excellent biocompatibility,and good water-solubility,metal nanoclusters have attracted enormous attention since discovered.They are found to be novel fluorescence labels for biological applications and environmental monitoring.Recently the chemiluminescence(CL) or electrochemiluminescence(ECL) of metal nanoclusters has received increasing attention.This review covers recent vibrant developments in this field of the past 5 years,and highlights different functions of metal nanoclusters in various CL and ECL systems,such as luminophores,catalysts,and quenchers.Latest synthetic methods of metal nanoclusters used in CL or ECL are also summarized.Furthermore,we discuss some perspectives and critical challenges of this field in the near future.

Molecularly engineered truncated tissue factor with therapeutic aptamers for tumor-targeted delivery and vascular infarction

Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy.Among vascular coagulation agents,the extracellular domain of coagulation-inducing protein tissue factor,truncated tissue factor(tTF),is the most widely used.Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation,free tTF cannot be used for cancer treatment on its own but must be combined with other moieties.We here developed a novel,tumor-specific tTF delivery system through coupling tTF with the DNA aptamer,AS1411,which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells.Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors,thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects.This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy.

DNA tetrahedron-based split aptamer probes for reliable imaging of ATP in living cells

Accurate detection and imaging of adenosine triphosphate(ATP)expression levels in living cells is of great value for understanding cell metabolism,physiological activities,and pathologic mechanisms.Here,we developed a DNA tetrahedron-based split aptamer probe(TD probe)for ratiometric fluorescence imaging of ATP in living cells.The TD probe is constructed by hybridizing two split ATP aptamer probes(Apt-a and Apt-b)to a DNA tetrahedron assembled by four DNA oligonucleotides(T1,T2,T3 and T4).In the presence of ATP,the TD probe will alter its structure from the open to closed state,thus bringing the separated donor and acceptor fluorophores into close proximity for high fluorescence resonance energy transfer(FRET)signals.The TD probe exhibits low cytotoxicity,efficient cell internalization and good biological stability.Moreover,based on the FRET“off”to“on”signal output mode,the TD probe can effectively avoid false-positive signals from complex biological matrices,which is significant for long-term reliable imaging in living cells.In addition,by changing the split aptamers attached to DNA tetrahedron,the proposed strategy may be extended for detecting various intracellular targets.Collectively,this strategy provides a valuable sensing platform for biomarkers analysis in living cells,thus having great potential for early clinical diagnosis and therapeutic evaluation.

RNAi screen to identify protein phosphatases that regulate the NF-kappaB signaling

NF-kappaB plays a critical role in cell survival,apoptosis,and inflammatory responses.Serine/threoninespecific phosphatases(PPs)represent the second major class of enzymes that catalyze the dephosphorylation of proteins.The roles of PPs regulating NF-kappaB activities are poorly understood.Here we describe an RNAi-based screen to identify the PPs that involve in regulating NFkappaB signaling.Thirty-four candidate PPs siRNAs were synthesized and primarily screened by NF-kappaB reporter gene assay in HeLa cells.PHLPP,one of the protein phosphatase type 2C family members(PP2C),was identified as a positive regulator of NF-kappaB signaling.Knock-down of PHLPP dramatically attenuated TNFα-stimulated NF-kappaB transcriptional activation.Knockdown of PHLPP led to enhancement of NF-kappaB/p65 nuclear import and retention,but decreased TNFα-induced phosphorylation at Ser276 on p65.This critical phosphorylation was also drastically reduced by knock-down of PKCalpha and Akt1,two important serine/threonine kinases dephosphorylated by PHLPP.The results together suggest that PHLPP-Akt-PKC may represent an important signaling loop that activates NF-kappaB/p65 signaling through critical serine phosphorylation.

A Dual Endogenous Stimuli-Responsive Framework Nucleic Acid Nanodevice for MicroRNA Imaging

Framework nucleic acids(FNAs)have emerged as intelligent sensing systems for the detection of tumor-related biomarkers in living cells.However,orthogonally controlled manipulation of FNAs-based nanodevices for on-site imaging of microRNAs(miRNAs)remains an intractable challenge.Herein,we report a dual endogenous stimuli-responsive FNA nanodevice that can perform miRNA sensing and imaging in a tumor-specificmanner.The sensing function of the nanodevice is silent(OFF)by rationally incorporating adenosine 5′-triphosphate(ATP)aptamer and an abasic site,which can also be activated(ON)with ATP and human apurinic/apyrimidinic endonuclease 1(APE1)in tumor cells,enabling on-site and efficient miRNA imaging with improved tumor specificity.Furthermore,we demonstrate the capability of the nanodevice for specificmiRNAimagingboth in living cells and in vivo based on the“dual keys”(overexpressed ATP and APE1 in tumors)priming mode.Therefore,this work illustrates a simple biosensing methodology with great potential for precise imaging of tumor biomarkers in clinical diagnosis and therapeutic evaluation.

Enzymatically controlled DNA tetrahedron nanoprobes for specific imaging of ATP in tumor

Intracellular ATP is an emerging biomarker for cancer early diagnosis because it is a key messenger for regulating the proliferation and migration of cancer cells.However,the conventional ATP biosensing strat-egy is often limited by the undesired on-target off-tumor interference.Here,we reported a novel strategy to design enzymatically controlled DNA tetrahedron nanoprobes(En-DT)for biosensing and imaging ATP in tumor cells.The En-DT was designed via rational engineering of structure-switching aptamers with the incorporation of an enzyme-activatable site and further conjugation on the DNA tetrahedron.The En-DT could be catalytically activated by apurinic/apyrimidinic endonuclease 1(APE1)in cancer cells,but they did not respond to ATP in normal cells,thereby enabling cancer-specific ATP biosensing and imaging in vitro and in vivo with improved tumor specificity.This strategy would facilitate the precise detection of a broad range of biomarker in tumors and may promote the development of smart probes for cancer diagnosis.

用于肿瘤血管栓塞治疗的智能型DNA纳米机器人

恶性肿瘤(癌症)是危害人类健康的一大杀手.肿瘤的快速增殖高度依赖于肿瘤血管的形成及血液供应,因此堵塞肿瘤血管饿死肿瘤细胞成为继放化疗、手术及免疫治疗之后的又一有效治疗策略.凝血酶(thrombin)可以高效地激活血小板并将纤维蛋白原转化为纤维蛋白,进而诱导血栓形成.而游离的凝血酶在血液中的半衰期很短,并且会引起非特异性的血栓形成,造成健康组织的损伤,大大地限制了该分子在肿瘤栓塞治疗中的应用.寻求可以将凝血酶精准递送到肿瘤组织局部的新方法,实现特异性肿瘤血管栓塞成为亟待解决的难题. DNA纳米折纸技术的快速发展使这一问题得以解决.本团队近期构建了智能响应性纳米机器人,将凝血酶精准高效地递送到肿瘤局部,诱导血栓形成,实现高效抑制肿瘤生长和转移的目的.本文将对该领域近年来的国内外研究进展和本实验室的研究成果进行简单概述,并对该技术领域的发展方向和前景提出一定的展望.

Impact of environmental factors on gastric cancer:A review of the scientific evidence,human prevention and adaptation

Globally,gastric cancer(GC) ranks fifth in prevalence and third in fatalities,and shows a distinct geographical distribution in morbidity and mortality.Such a spatial pattern indicates that environmental factors could be an important contributor to GC.We reviewed a total of 135 relevant peer-reviewed articles and other literature published 1936-2019 to investigate the scientific evidence concerning the effects of environmental factors on GC worldwide.Environmental factors affect GC from the aspects of water,soil,air,radiation,and geology.Risk factors identified include water type,water pollution,water hardness,soil type,soil pollution,soil element content,climate change,air pollution,radiation,altitude,latitude,topography,and lithology;and most of them have an adverse impact on GC.Furthermore,we found that their effects followed five common rules:(1) the leading environmental factors that affect GC incidence and mortality vary by region,(2) the same environmental factors may have different effects on GC in different regions,(3) some different environmental factors have similar effects on GC in essence,(4) different environmental factors often interact to have combined or synergistic effects on GC,and(5)environmental factors can affect human factors to have an impact on GC.Environmental factors have a great impact on GC.Human beings may prevent GC by controlling carcinogenic factors,screening high-risk populations and providing symptomatic and rehabilitative treatments.Furthermore,adaptation measures are recommended to reduce GC risk on private and public levels.Future studies should transcend existing empirical studies to develop causal relationship models and focus on vulnerable population analysis.

Palynological constraints on the age of the Mississippi Valley-type Changdong Pb-Zn deposit,Sanjiang belt,West China

Mississippi Valley-type(MVT)Pb-Zn deposits serve as the world’s major supply of Pb-Zn resources.However,the age constraint of MVT Pb-Zn deposits has long been a big challenge,due to the lack of minerals that are unequivocally related to ore deposition and that can be used for radioisotopic dating.Here we show sporopollens can provide useful chronological information on the Changdong MVT Pb-Zn deposit in the Simao basin,Sanjiang belt,West China.The Pb-Zn ores in the Changdong deposit are hosted by internal sediments in paleo-karst caves of meteoric origin.Sphalerite and galena occur as replacements of carbonate minerals and void infillings in the internal sediments.The relations suggest that the Pb-Zn mineralization occurred after the deposition of the internal sediments.A palynological assemblage mainly composed of angiosperm pollen dominated by Castanea,Quercus,and Carya and fern spores dominated by Polypodiaceae,Pteris,and Athyriaceae was identified.These pollen and spores place the ore-hosting internal sediments and the Changdong paleo-karst at early to middle Oligocene.Consequently,the Changdong Pb-Zn deposit must have formed after the early Oligocene(~34 Ma).These age constraints,together with the geological characteristics,indicate that the Changdong Pb-Zn deposit is a paleo-karst-controlled MVT deposit related to fold-thrust systems in the Sanjiang belt.The Changdong deposit is similar to other MVT Pb-Zn deposits in the northern part of the Sanjiang belt,making it possible to extend this Pb-Zn belt 500 km further to the South.Results presented here highlights the potential of sporopollens in dating the age of MVT deposits related to paleo-karst formation in young orogenic belts.

Extracellular ATP-activated hybridization chain reaction for accurate and sensitive detection of cancer cells

Accurate and sensitive detection of caner cells is of significant importance for early diagnosis and treat-ment of cancer.Here,we developed an extracellular ATP-dctivated hybridization chain reaction(HCR)amplification strategy to meet this purpose.This strategy relies on three DNA probes,Apt-trigger,H1-AТP aptamer duplex and hairpin H2.The Apt-trigger probe consists of two com sequence for specific recognition of the target cells.and a trigger sequence for the HCR assembly.Theроnents:an aptamer duplex structure of H1-ATP aptamer causes the tochold in hairpin H1 to be hidden,preventing the strand-ent displacement reaction between haipin H1 and Apt-trigger.Upon activation with ATP the ATP aptamer will blnd to ATP to dissoci iate from hairpin H1,thus leading to an Apt-trigger-induced strand-displacement reaction and subsequent HCR with hairpin H2 on the target cell surface.Benefiting from aptamer recogni-tion and ATP-activated HCR amplification,this strategy can not only perform sensitive quantitative anal-ysis with a detection limit of 25 cells in 200 ul.of binding buffer,but also show desirable specificity and accuracy for identifylng target cells from control cells and mixed cell samples,Imporantly,this method retains stable and good perfor mance for target cell detection in 10%fetal bovine ser rum,den onstrating great potential for clinical diagnosis in complex biological matrices.Furthermore,this strategy can be adapted to detect various types of cancer cells by changing the corresponding aptamer sequence.