Potent bromodomain and extraterminal domain inhibitor JAB-8263 suppresses MYC expression and exerts anti-tumor activity in colorectal cancer models

BACKGROUND The overexpression of the MYC gene plays an important role in the occurrence,development and evolution of colorectal cancer(CRC).Bromodomain and extraterminal domain(BET)inhibitors can decrease the function BET by recognizing acetylated lysine residues,thereby downregulating the expression of MYC.AIM To investigate the inhibitory effect and mechanism of a BET inhibitor on CRC cells.METHODS The effect of the BET inhibitor JAB-8263 on the proliferation of various CRC cell lines was studied by CellTiter-Glo method and colony formation assay.The effect of JAB-8263 on the cell cycle and apoptosis of CRC cells was studied by propidium iodide staining and Annexin V/propidium iodide flow assay,respectively.The effect of JAB-8263 on the expression of c-MYC,p21 and p16 in CRC cells was detected by western blotting assay.The anti-tumor effect of JAB-8263 on CRC cells in vivo and evaluation of the safety of the compound was predicted by constructing a CRC cell animal tumor model.RESULTS JAB-8263 dose-dependently suppressed CRC cell proliferation and colony formation in vitro.The MYC signaling pathway was dose-dependently inhibited by JAB-8263 in human CRC cell lines.JAB-8263 dose-dependently induced cell cycle arrest and apoptosis in the MC38 cell line.SW837 xenograft model was treated with JAB-8263(0.3 mg/kg for 29 d),and the average tumor volume was significantly decreased compared to the vehicle control group(P<0.001).The MC38 syngeneic murine model was treated with JAB-8263(0.2 mg/kg for 29 d),and the average tumor volume was significantly decreased compared to the vehicle control group(P=0.003).CONCLUSION BET could be a potential effective drug target for suppressing CRC growth,and the BET inhibitor JAB-8263 can effectively suppress c-MYC expression and exert anti-tumor activity in CRC models.

Jianpi Gushen Huayu decoction ameliorated diabetic nephropathy through modulating metabolites in kidney,and inhibiting TLR4/NF-κB/NLRP3 and JNK/P38 pathways

BACKGROUND Jianpi Gushen Huayu Decoction(JPGS)has been used to clinically treat diabetic nephropathy(DN)for many years.However,the protective mechanism of JPGS in treating DN remains unclear.AIM To evaluate the therapeutic effects and the possible mechanism of JPGS on DN.METHODS We first evaluated the therapeutic potential of JPGS on a DN mouse model.We then investigated the effect of JPGS on the renal metabolite levels of DN mice using non-targeted metabolomics.Furthermore,we examined the effects of JPGS on c-Jun N-terminal kinase(JNK)/P38-mediated apoptosis and the inflammatory responses mediated by toll-like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB)/NOD-like receptor family pyrin domain containing 3(NLRP3).RESULTS The ameliorative effects of JPGS on DN mice included the alleviation of renal injury and the control of inflammation and oxidative stress.Untargeted metabolomic analysis revealed that JPGS altered the metabolites of the kidneys in DN mice.A total of 51 differential metabolites were screened.Pathway analysis results indicated that nine pathways significantly changed between the control and model groups,while six pathways significantly altered between the model and JPGS groups.Pathways related to cysteine and methionine metabolism;alanine,tryptophan metabolism;aspartate and glutamate metabolism;and riboflavin metabolism were identified as the key pathways through which JPGS affects DN.Further experimental validation showed that JPGS treatment reduced the expression of TLR4/NF-κB/NLRP3 pathways and JNK/P38 pathway-mediated apoptosis related factors.CONCLUSION JPGS could markedly treat mice with streptozotocin(STZ)-induced DN,which is possibly related to the regulation of several metabolic pathways found in kidneys.Furthermore,JPGS could improve kidney inflammatory responses and ameliorate kidney injuries in DN mice via the TLR4/NF-κB/NLRP3 pathway and inhibit JNK/P38 pathwaymediated apoptosis in DN mice.

p-a-SiC:H降低晶体硅异质结太阳能电池寄生损失的研究

使用宽带隙的p型氢化非晶硅碳(p-a-SiC:H)薄膜作为晶体硅异质结(SHJ)太阳能电池的窗口层,使用时域有限差分法(FDTD)模拟证明,p-a-SiC:H不仅能明显降低窗口层的短波寄生吸收损失,而且可以减少SHJ太阳能电池的反射损失,从而增强SHJ太阳能电池的光谱响应。实验结果也证明,使用优化的p-a-SiC:H窗口层可以提升SHJ太阳能电池的短路电流(J_(sc))达1.4 mA/cm^(2),电池光电转化效率达到了21.8%。这主要是由于p-a-SiC:H低的寄生吸收以及使用p-a-SiC:H窗口层降低了SHJ太阳能电池的反射损失所致。

Anticancer therapeutic strategies for targeting mutant p53-Y220C

The tumor suppressor p53 is a transcription factor with a powerful antitumor activity that is controlled by its negative regulator murine double minute 2(MDM2,also termed HDM2 in humans)through a feedback mechanism.At the same time,TP53 is the most frequently mutated gene in human cancers.Mutant p53 proteins lose wild-type p53 tumor suppression functions but acquire new oncogenic properties,among which are deregulating cell proliferation,increasing chemoresistance,disrupting tissue architecture,and promoting migration,invasion and metastasis as well as several other pro-oncogenic activities.The oncogenic p53 mutation Y220C creates an extended surface crevice in the DNA-binding domain destabilizing p53 and causing its denaturation and aggregation.This cavity accommodates stabilizing small molecules that have therapeutic values.The development of suitable small-molecule stabilizers is one of the therapeutic strategies for reactivating the Y220C mutant protein.In this review,we summarize approaches that target p53-Y220C,including reactivating this mutation with small molecules that bind Y220C to the hydrophobic pocket and developing immunotherapies as the goal for the near future,which target tumor cells that express the p53-Y220C neoantigen.

MD Simulations of the P53 oncoprotein structure: the effect of the Arg273→His mutation on the DNA binding domain

A comparative molecular dynamics (MD) simulation study was performed on the p53 oncoprotein to investigate the effect of the Arg273His (R273H) mutation on the p53→DNA Binding Domain (DBD). The two p53 dimer structures of the wild-type and mutant Arg273His (R273H) were simulated with the same thermodynamic and environmental parameters. The obtained results demonstrate that the induced Arg273His mutation has a considerable effect on the p53→DNA close contact interaction and changes the picture of hydrogen formation. The Arg273His mutation, in some cases, destroys the existing native hydrogen bond, but, in other cases, forms a strong p53→DNA hydrogen bond, which is not proper for the native protein. The MD simulation results illustrate some molecular mechanism of the conformational changes of the Arg273His key amino acid residue in the p53→DNA binding domain, which might be important for the understanding of the physiological functioning of the p53 protein and the origin of cancer.

一般有界区域上高维变权p-Laplacian问题保号解的存在性

研究一般有界区域上高维变权p-Laplacian方程-div(φ_(p)▽(u))=γm(x)f(u),u(x)=0,x∈∂Ω保号解的存在性.其中Ω是R^(N)上的一个有界且在其边界上光滑的区域,m(x)∈C(Ω),γ是一个参数,f∈C(ℝ,ℝ),对于s≠0满足sf(s)>0.当满足f_(0)■(0,∞)或f_(∞)(0,∞)(其中f_(0)=lim|s|→0 f(s)/φ_(p)(s),f_(∞)=lim|s|→∞f(s)/φ_(p)(s)),且γ≠0属于一定区间时,本文研究上述高维p-Laplacian方程保号解的存在性.我们用全局分歧技巧和连通序列集取极限的方法获得主要结果.

基于自对偶MDS码的P置换研究

P置换的设计是分组密码设计中的一个重要课题。一直以来,利用编码理论中的MDS码可以设计出许多性质优良的P置换。本文讨论了线性码中的自对偶MDS码,基于这种码,我们可以设计出性质比一般MDS码更好的P线性置换。文中我们给出了一种基于自对偶的广义RS码的线性置换的构造方法。

去铁胺(DFO)诱导骨髓增生异常综合征(MDS)细胞株SKM-1的P15^(INK4B)基因去甲基化

目的探讨铁螯合剂去铁胺(deferoxamine,DFO)诱导骨髓增生异常综合征(myelodysplastic syndrome,MDS)细胞株SKM-1的P15INK4B基因去甲基化作用。方法以枸橼酸铁铵(ferric ammonium citrate,FAC)和DFO处理SKM-1细胞,按不同铁负荷分成3组:对照组、FAC组和FAC+DFO组,分别检测不同铁负荷组细胞内可变铁池(labile ironpool,LIP)、细胞内活性氧类(reactive oxygen species,ROS)、P15INK4B基因甲基化状态、P15INK4B基因mRNA表达情况、细胞增殖(CFSE的平均荧光强度MFI)、细胞早期凋亡率以及细胞周期。结果与对照组相比,FAC组的LIP(64.04%±2.12%vs.1.45%±0.65%)、ROS(45.57%±1.18%vs.33.38%±12.96%)、细胞增殖MFI(23.01%±5.20%vs.51.67%±1.61%)明显升高,P15INK4B基因mRNA表达水平(0.72±0.08 vs.1)和细胞早期凋亡率(13.97%±2.25%vs.22.53%±1.76%)明显减少,差异均有统计学意义(P<0.05);与FAC组相比,FAC+DFO组的LIP(8.34%±4.21%vs.64.04%±2.12%)、ROS(34.39%±2.12%vs.45.57%±1.18%)、细胞增殖MFI(37.34%±6.61%vs.23.01%±5.20%)明显减少,P15INK4B基因mRNA表达水平(1.50±0.15 vs.0.72±0.08)和细胞早期凋亡率(55.07%±1.30%vs.13.97%±2.25%)明显升高,差异均有统计学意义(P<0.05);3组细胞周期的差异无统计学意义。结论 DFO可使LIP和ROS降低,诱导铁过载的SKM-1细胞P15INK4B基因去甲基化,使其mRNA重新表达,并可抑制铁过载的SKM-1细胞增殖,促进其凋亡。

基于P波位移增长特征的矩震级时域估算方法

震时震级估计是地震预警(EEW)系统的关键环节之一,通过有限记录的幅值和频率成分与震级的统计关系实现震源规模快速估计。然而统计方法未采用客观表征地震能量的物理量,对震源破裂传播过程考虑不足,不能直接量化地震矩。在地震场景应用中,EEW系统存在震级估算结果离散,大震震级低估等问题。为实时量化地震破裂能量,推导了中、小地震P波位移波形参数(位移峰值P_(d)和峰值时刻t_(pd))与地震矩的理论关系,并通过日本地震的震源时间函数库验证。采用日本K-net台网记录,分析近场强震动记录P波位移增长特征,尝试从P_(d)曲线中提取特征参数P_(d)和t_(pd),构建预测矩震级的新参数Pdt。离线数据的矩震级估算结果表明,构造参数Pdt能够可靠地预测地震的矩震级,优于经典预警震级参数P_(d)。该时域矩震级估算方法为EEW系统的地震能量评估提供了新的思路。

柱型苹果MdCoLBD1/2基因生物信息学及SNP分析

柱型苹果(Columnar apple)是苹果株型育种的珍贵资源。利用同源基因克隆方法,以柱型苹果‘威塞克旭’一年生枝上休眠期芽cDNA为模板,克隆得到了LOB DOMAIN家族(LBD)的2个同源基因,命名为MdCoLBD1/2,分别编码195和240个氨基酸。该基因有LBD家族的典型结构域,如C盒、GAS盒、亮氨酸拉链(Leu zipper)结构以及LOB Domain区域等。MdCoLBD1/2分别定位于第10条染色体Chr10:18985568..19005801和MdCoLBD2Chr10:18985594..19005850区间。MdCoLBD1/2与白梨、葡萄、草莓、椰子、梅、核桃的氨基酸的相似性均在60%以上。聚类分析表明MdCoLBD1和白梨、梅、草莓亲缘关系较近,MdCoLBD2与葡萄、核桃亲缘关系较近,MdCoLBD1/2与亚洲棉、陆地棉的聚类关系均较远。通过测序分析了MdCoLBD1/2基因在30个不同类型材料中的碱基序列差异,得到MdCoLBD1有8个碱基差异位点,MdCoLBD2有5个碱基差异位点。

THE EQUIVALENT CHARACTERIZATION OF F(p,q,s)SPACE ON BOUNDED SYMMETRIC DOMAINS OF Cn

LetΩ be a bounded symmetric domain in Cn. The purpose of this article is to define and characterize the general function space F（p, q, s） on Ω. Characterizing functions in the F（p, q, s） space is a work of considerable interest nowadays. In this article, the authors give several equivalent descriptions of the functions in the F（p, q, s） space on Ω in terms of fractional differential operators. At the same time, the authors give the relationship between F（p, q, s） space and Bloch type space on Ω too.

基于MD5的P2SP信息认证

C/S模式具有较好的可管理性和稳定性,但不能自适应客户数量的变化;P2P模式可自动适应网络规模的变化,但可管理较差。P2SP模式融合了C/S和P2P两者的技术优势,可以提高信息服务的质量,同时控制系统的成本。通过分析P2SP的结构,应用MD5算法给出了P2SP模式下的信息认证模型。

Long noncoding RNA X-inactive specific transcript regulates NLR family pyrin domain containing 3/caspase-1-mediated pyroptosis in diabetic nephropathy

BACKGROUND NLRP3-mediated pyroptosis is recognized as an essential modulator of renal disease pathology.Long noncoding RNAs(lncRNAs)are active participators of diabetic nephropathy(DN).X inactive specific transcript(XIST)expression has been reported to be elevated in the serum of DN patients.AIM To evaluate the mechanism of lncRNA XIST in renal tubular epithelial cell(RTEC)pyroptosis in DN.METHODS A DN rat model was established through streptozotocin injection,and XIST was knocked down by tail vein injection of the lentivirus LV sh-XIST.Renal metabolic and biochemical indices were detected,and pathological changes in the renal tissue were assessed.The expression of indicators related to inflammation and pyroptosis was also detected.High glucose(HG)was used to treat HK2 cells,and cell viability and lactate dehydrogenase(LDH)activity were detected after silencing XIST.The subcellular localization and downstream mechanism of XIST were investigated.Finally,a rescue experiment was carried out to verify that XIST regulates NLR family pyrin domain containing 3(NLRP3)/caspase-1-mediated RTEC pyroptosis through the microRNA-15-5p(miR-15b-5p)/Toll-like receptor 4(TLR4)axis.RESULTS XIST was highly expressed in the DN models.XIST silencing improved renal metabolism and biochemical indices and mitigated renal injury.The expression of inflammation and pyroptosis indicators was significantly increased in DN rats and HG-treated HK2 cells;cell viability was decreased and LDH activity was increased after HGtreatment. Silencing XIST inhibited RTEC pyroptosis by inhibiting NLRP3/caspase-1. Mechanistically,XIST sponged miR-15b-5p to regulate TLR4. Silencing XIST inhibited TLR4 by promotingmiR-15b-5p. miR-15b-5p inhibition or TLR4 overexpression averted the inhibitory effect ofsilencing XIST on HG-induced RTEC pyroptosis.CONCLUSIONSilencing XIST inhibits TLR4 by upregulating miR-15b-5p and ultimately inhibits renal injury inDN by inhibiting NLRP3/caspase-1-mediated RTEC pyroptosis.

Anti-P-selectin lectin-EGF domain monoclonal antibody inhibits the maturation of human immature dendritic cells

Dendritic cells(DCs) are professinal antigen-presenting cells with the ability to initiate primary Tcell responses. While it iswell known that inflammatory stimuli induce the functional maturation of immature DCs, whether adhesion molecule selectins regulate DCmaturation is poorly understood. Using anti-P-selectin lectin-EGF domain monoclonal antibody (PsL-EGFmAb) that blocks the adhesionof P-, E-, and L-selectin, we demonstrate herein that selectins play important role in stimulating functional maturation of immature DCs.Immature DCs are generated from human cord blood CD34+hematopoietic stem/progenitor cells that were cultured in the presence of stemcell factor, Fms-like tyrosine-kinase-3 ligand, granulocyte-macrophage colony stimulating factor, and transform growth factor-β1. Whenstimulated with tumor necrosis factor-alpha(TNF-α), immature DCs differentiated into mature DCs, producing increased levels of costim-ulatory molecules and interleukin (IL)-12 and obtaining the ability to potently activate naive Tcells. Interestingly, in contrast to matureDCs derived from TNF-α-induced immature DC cultures without PsL-EGFmAb, immature DCs treated with PsL-EGFmAb for7 days werecompletely blocked their maturation, as evidenced by decreased expression of costimulatory molecules CD80, CD86, and CD83, inhibi-ted production of IL-12, and inability to activate naive Tcellsin vitro. Thus, blockade of selectins using PsL-EGFmAb will prove to bea valuable tool for the study of the molecuar mechanisms of DC maturation, as well as for the prevention and treatment of DC-mediated au-toimmunity.

A refined Frequency Domain Decomposition tool for structural modal monitoring in earthquake engineering

Output-only structural identification is developed by a refined Frequency Domain Decomposition（rFDD） approach, towards assessing current modal properties of heavy-damped buildings（in terms of identification challenge）, under strong ground motions. Structural responses from earthquake excitations are taken as input signals for the identification algorithm. A new dedicated computational procedure, based on coupled Chebyshev Type Ⅱ bandpass filters, is outlined for the effective estimation of natural frequencies, mode shapes and modal damping ratios. The identification technique is also coupled with a Gabor Wavelet Transform, resulting in an effective and self-contained time-frequency analysis framework. Simulated response signals generated by shear-type frames（with variable structural features） are used as a necessary validation condition. In this context use is made of a complete set of seismic records taken from the FEMA P695 database, i.e. all 44 ＂Far-Field＂（22 NS, 22 WE） earthquake signals. The modal estimates are statistically compared to their target values, proving the accuracy of the developed algorithm in providing prompt and accurate estimates of all current strong ground motion modal parameters. At this stage, such analysis tool may be employed for convenient application in the realm of Earthquake Engineering, towards potential Structural Health Monitoring and damage detection purposes.

Kronecker函数环对PvMD的一个新刻画

设R是整环,若R是整闭的,则R是Prüfer整环当且仅当Kr(R,b)是平坦R[X]-模;当且仅当Kr(R,b)是平坦R-模(Aaderson D F,Bobbs D E.J Pure Appl Algebra,1989,61:107-122.).给出这一定理在w-版本下的陈述形式,即若R是整闭整环,则R是P v MD当且仅当Kr(R,v c)是w(R[X])-平坦R[X]-模;当且仅当Kr(R,v c)是w-平坦R-模.

时空域与τ-p域预测反褶积压制多次波方法对比研究

预测反褶积是地震数据处理中广泛使用的方法,兼具参数设置简单和运行速度快等特点,正因如此,很多处理人员往往对两种方法影响参数、计算效率、保幅性等问题未进行深入研究,最终导致处理效果不够理想。本文通过对比时空域预测反褶积和τ-p域预测反褶积方法,阐述了两种方法的基本原理,分析了两种方法的主要影响参数,并分析对比两种方法的频谱变化、保幅效果等。研究证明,两种方法都具有相对保幅性,时空域预测反褶积主要影响参数为预测步长和算子长度。而τ-p域预测反褶积由于公式近似数值离散,会在τ-p正、反变换过程中带来假频,同时该方法深受τ-p域最大道数、采样间隔及最大频率等参数影响,在处理时需要更多实验反复论证参数有效性。实际数据结果表明,时空域预测反褶积计算效率是τ-p域预测反褶积的1.5倍,相对保幅性更好;而τ-p域预测反褶积在去除多次波效果、拓宽频带、提高低频、高频信息方面要优于时空域预测反褶积。本文研究方法对从业者方法选择和参数设置极具借鉴价值,对实际资料处理中提高去多次波效果、拓宽频带和保幅处理方面具有实际应用价值。

P2P Model Based on Isolated Broadcast Domains

Resource location is the most important issue for Peer-to-Peer (P2P) system and flooding is the fundamental mechanism for unstructured P2P systems. Redundant messages will exponential growth with flooding scope increasing which severely influences the scalability of the system. In this paper, a new P2P model based on isolated broadcast domains is given to reduce the amount of redundant messages by limiting the radius of messages transmitted. Analysis and experiments show that this model can guarantee coverage of nodes and significantly reduce the amount of redundant messages generated.

Axonal growth inhibitors and their receptors in spinal cord injury:from biology to clinical translation

Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.

Characterization of functional domains of human p100 protein interacting with signal transducer and activator of transcription-6 (STAT-6)

In the present study, the interaction of human p100 protein with signal transducer and activator of transcription-6 (STAT-6) was investigated. It was proved that the staphylococcal nuclease (SN)-like and tudor (TD) domains containing in p100 protein acting as a adaptor to recruit STAT-6 to the basal transcription machinery, enhanced the STAT-6 mediated transcription activity. The interaction between STAT-6 and the p100 protein was mediated by the full-length of the SN-like domain, whereas individual fragments of SN-like domain showed no binding activity to STAT-6. In line with these results, the SN-like domain was directly engaged in the enhancement of STAT-6 mediated activation of gene transcription in vivo. Yet the TD domain had no ability to increase the transcription activation, but it was still required for the sufficient activation of transcription.