88 resultados para Néhémie (livre de-) 2-5
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An optical modulator is designed and fabricated based on a Si0.75Ge0.25/Si/Si0.5Ge0.5 asymmetrical superlattice structure. The device comprises a p-i-n diode made on the asymmetrical superlattice integrated with a 920-mu m-long Fabry-Perot (F-P) cavity. Parameters of the rib waveguide are designed to satisfy only the fundamental-TE mode transmission. Here, 65 and 40-pm red shifts of the peak resonant were measured under the applied bias of 2.5 and -32.0 V, respectively. The analysis shows that, besides the thermal-optical and plasma dispersion effects, the Pockels effect also contributes to such a peak shift. The corresponding calculated effective Pockels coefficient is about 0.158 pm/V.
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Optimized AlGaN/AlN/GaN high electron mobility transistor (HEMT) with high mobility GaN channel layer structures were grown on 2-in. diameter semi-insulating 6H-SiC substrates by MOCVD. The 2-in. diameter GaN HEMT wafer exhibited a low average sheet resistance of 261.9 Omega/square, with the resistance un-uniformity as low as 2.23%. Atomic force microscopy measurements revealed a smooth AlGaN surface whose root-mean-square roughness is 0.281 nm for a scan area of 5 x 5 mu m. For the single-cell HEMTs device of 2.5-mm gate width fabricated using the materials, a maximum drain current density of 1.31 A/mm, an extrinsic transconductance of 450 mS/mm, a current gain cutoff frequency of 24 GHz and a maximum frequency of oscillation 54 GHz were achieved. The four-cell internally-matched GaN HEMTs device with 10-mm total gate width demonstrated a very high output power of 45.2 W at 8 GHz under the condition of continuous-wave (CW), with a power added efficiency of 32.0% and power gain of 6.2 dB. To our best knowledge, the achieved output power of internally-matched devices are the state-of-the-art result ever reported for X-band GaN-based HEMTs. Crown Copyright (C) 2009 Published by Elsevier Ltd. All rights reserved.
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Unselective regrowth for fabricating 1.5-mu m InGaAsP multiple-quantum well (MQW) distributed-feedback (DFB) buried heterostructure (BH) lasers is developed. The experimental results exhibit superior characteristics, such as a low threshold of 8.5 mA, high slope efficiency of 0.55 mW/mA, circular-like far-field patterns, the narrow line-width of 2.5 MHz, etc. The high performance of the devices effectively proves the feasibility of the new method to fabricate buried heterostructure lasers. (c) 2006 Society of Photo-Optical Instrumentation Engineers.
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Ten-period 5.5 nm Si0.75Ge0.25/10.3 nm Si/2.5 nm Si0.5Ge0.5 trilayer asymmetric superlattice was prepared on Si (001) substrate by ultrahigh vacuum chemical vapor deposition at 500 degrees C. The stability of Mach-Zehnder interferometer was improved by utilizing polarization-maintaining fibers. According to the electro-optic responses of the superlattice with the light polarization along [110] and [-110], respectively, both electro-optic coefficients gamma(13) and gamma(63) of such asymmetric superlattice were measured. gamma(13) and gamma(63) are 2.4x10(-11) and 1.3x10(-11) cm/V, respectively, with the incident light wavelength at 1.55 mu m. (c) 2006 American Institute of Physics.
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为外源5-氨基乙酰丙酸(ALA)在日光温室蔬菜上的应用提供科学依据。【方法】研究了不同浓度ALA处理对日光温室番茄生产的影响。【结果】ALA以及ALA+N叶面施用均明显提高了番茄植株株高、叶绿素相对含量和果实产量,并改善了番茄果实品质;与对照相比,外源ALA各处理植株株高、叶绿素相对含量和单株生物产量均有明显提高,其中D处理(ALA1号肥料第1次2 kg/hm2,第2~4次1 kg/hm2)效果最佳,植株株高、叶绿素相对含量及单株生物产量分别提高27.18%,17.75%和13.93%;外源ALA对番茄果实产量和品质也有明显的提高和改善作用,其中处理B(ALA1号肥料第1次0.5 kg/hm2,第2~4次0.3 kg/hm2)对果实产量效果最明显,处理E(ALA3号肥料第1次2.5 kg/hm2,第2~4次1.5 kg/hm2)对果实品质效果最佳。【结论】处理E(ALA3号肥料第1次2.5 kg/hm2,第2~4次1.5 kg/hm2)既有利于番茄生长发育,又能增加产量并改善品质,为最佳的ALA施用量及方法。
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本论文从2,3'-联吡啶出发,利用两个吡啶环上氮的反应活性差异,选择性合成了单烷基盐1-甲基-2,3,-联吡啶盐、1-甲基-1,一氧-2,3,-联吡啶盐和1'-甲基/节基2,3气联吡啶盐,还原单烷基盐合成了天然生物碱毒黎碱、安那他品和异毒黎碱及其衍生物:对异毒黎碱的合成由还原N,-节基盐后脱节基简化为一步实现还原和脱节基直接得到异毒黎碱。通过用(R)-BINOL和(S)-BINOL对N,-节基异毒黎碱拆分得到了旋光纯的N,-节基异毒黎碱和异毒黎碱,-N,-节基异毒黎碱的旋光度[a]D20:-61.50(c=2.0,乙醇),卜异毒黎碱的旋光度fa]D20:-14.4"(c-1.0,乙醇);将C关异毒黎碱用(RMTPA和(s)MT队衍生为Mosher酞胺,应用Mosllel方法确定了C)异毒黎碱手性中心的绝对构型为R型,即(R)-C)异毒黎碱,同时发现,由(R)一MTPA合成的Mosller酞胺中顺式旋转异构体占优。而通常在环胺的Mosller酞胺中,是反式旋转异构体占优。这一例外被MollteCarlo模型模拟计算结果解释:稀溶液中C卜异毒黎碱的Moshel-酞胺,顺式构型能量上比反式更有利。不对称合成天然生物碱更具有挑战性。对异毒黎碱还原合成中的呱l淀烯类中间体,用BINAP-灿催化体系进行了催化不对称还原的合成研究,氢化N'-节基-1,,4,,5,,6,-四氢一2,3,一联吡陡时得到了最高为21.5%的对映体选择性,而对N'-节基一1,,2',5',6,-四氢-2,3'一联吡陡的氢化则只得到了不超过10.0%的对映体选择性。
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1、喜树碱类衍生物抗HIV构效关系与作用机制研究 喜树碱为传统的抗肿瘤药物。本研究对经过化学结构修饰的喜树碱类衍生物进行抗HIV活性及作用机制的研究,并初步探讨了其抗HIV构效关系。 我们对喜树碱类衍生物A系列化合物A1(喜树碱)、A2(10-羟基喜树碱)及A3(7-羟基喜树碱)进行了抗HIV活性检测。化合物A1和A3有较好的抗HIV-1和抗HIV-2活性,化合物A2没有显示抗HIV活性。表明化合物A1的C-10位上-OH基团修饰可能会降低抗HIV活性,化合物A1的C-7位上-CH2OH基团修饰和C-20位-CH3缺失可能会提高其抗HIV活性。对化合物A3和A1的抗HIV机制研究发现:二者对整合酶有一定的结合活性,对慢性感染H9/HIV-1ⅢB 和Jurkat/HIV-1ⅢB细胞中病毒复制没有抑制活性、不能阻断H9/HIV-1ⅢB与正常细胞间的融合,对重组的HIV-1蛋白酶和逆转录酶没有抑制活性。化合物A1和A3不具有选择性杀伤HIV-1ⅢB慢性感染的H9和Jurkat细胞系的作用。进一步进行化合物A3诱导 H9和H9/HIV-1ⅢB、Jurkat和Jurkat/HIV-1ⅢB的凋亡实验显示,化合物A3诱导感染HIV-1ⅢB和未感染病毒细胞的凋亡没有选择性。据此我们初步认为化合物A3和A1的抗HIV作用可能与抑制整合酶活性有关,该化合物可能还作用于其它靶点。 喜树碱类衍生物B系列中化合物B1为20(S)-O - [-O-( 1'-氧基-2',2',6',6'-四甲基哌啶-4'-丁二酸)]-20-喜树碱酯,化合物B2为20(S)-O - [-N-( 1'-氧基-2',2',6',6'-四甲基-1',2',5',6'-四氢吡啶酰胺)-4'-丙氨酸)]-20-喜树碱酯)。我们对化合物B1和B2进行了抗HIV活性检测。结果显示:化合物B2有较好的抗HIV-1和抗HIV-21、喜树碱类衍生物抗HIV构效关系与作用机制研究 喜树碱为传统的抗肿瘤药物。本研究对经过化学结构修饰的喜树碱类衍生物进行抗HIV活性及作用机制的研究,并初步探讨了其抗HIV构效关系。 我们对喜树碱类衍生物A系列化合物A1(喜树碱)、A2(10-羟基喜树碱)及A3(7-羟基喜树碱)进行了抗HIV活性检测。化合物A1和A3有较好的抗HIV-1和抗HIV-2活性,化合物A2没有显示抗HIV活性。表明化合物A1的C-10位上-OH基团修饰可能会降低抗HIV活性,化合物A1的C-7位上-CH2OH基团修饰和C-20位-CH3缺失可能会提高其抗HIV活性。对化合物A3和A1的抗HIV机制研究发现:二者对整合酶有一定的结合活性,对慢性感染H9/HIV-1ⅢB 和Jurkat/HIV-1ⅢB细胞中病毒复制没有抑制活性、不能阻断H9/HIV-1ⅢB与正常细胞间的融合,对重组的HIV-1蛋白酶和逆转录酶没有抑制活性。化合物A1和A3不具有选择性杀伤HIV-1ⅢB慢性感染的H9和Jurkat细胞系的作用。进一步进行化合物A3诱导 H9和H9/HIV-1ⅢB、Jurkat和Jurkat/HIV-1ⅢB的凋亡实验显示,化合物A3诱导感染HIV-1ⅢB和未感染病毒细胞的凋亡没有选择性。据此我们初步认为化合物A3和A1的抗HIV作用可能与抑制整合酶活性有关,该化合物可能还作用于其它靶点。 喜树碱类衍生物B系列中化合物B1为20(S)-O - [-O-( 1'-氧基-2',2',6',6'-四甲基哌啶-4'-丁二酸)]-20-喜树碱酯,化合物B2为20(S)-O - [-N-( 1'-氧基-2',2',6',6'-四甲基-1',2',5',6'-四氢吡啶酰胺)-4'-丙氨酸)]-20-喜树碱酯)。我们对化合物B1和B2进行了抗HIV活性检测。结果显示:化合物B2有较好的抗HIV-1和抗HIV-2活性,而化合物B1的抗HIV活性差。表明化合物B1的C-4’位-CH2被-NH取代,同时C-3’位-CH3修饰可能会提高其抗HIV活性。对化合物B2的抗HIV机制研究发现,化合物B2对慢性感染H9/HIV-1ⅢB细胞中病毒复制没有抑制活性、不能阻断H9/HIV-1ⅢB与正常细胞间的融合,对HIV-1蛋白酶、重组的HIV-1逆转录酶及整合酶没有抑制活性。化合物B2不具有选择性杀伤HIV-1ⅢB慢性感染的H9细胞系的作用。化合物B2抗HIV的作用机制还需进一步研究。 2、HIV/AIDS患者疱疹病毒感染状况及性病患者的HIV感染状况分析 疱疹病毒是AIDS患者合并感染的常见病原体。引起人类疾病的8种疱疹病毒与HIV感染及AIDS进展、机会性感染、恶性肿瘤密切相关。为了解HIV/AIDS患者人类8型疱疹病毒感染状况,我们检测了30例AIDS患者、40例HIV携带者及70例正常对照的液标本中8型疱疹病毒感染状况。采用ELISA法检测单纯疱疹病毒1型(HSV-1)、单纯疱疹病毒2型(HSV-2)、水痘-带状疱疹病毒(VZV)和巨细胞病毒(CMV);采用PCR法检测EB病毒(EBV)、疱疹病毒6型(HHV-6)、疱疹病毒7型(HHV-7)及疱疹病毒8型(HHV-8)。结果显示,HIV/AIDS患者中HSV-1、HSV-2、VZV、CMV、HHV-6、HHV-8 阳性率均高于健康体检者,其中AIDS患者VZV感染率与HIV携带者有显著性差异;在AIDS患者中多种疱疹病毒共感染普遍存在,必须重视HIV/AIDS患者合并疱疹病毒感染的防治。 性病可促进HIV的传播,了解性病患者的HIV感染状况及临床特征具有重要的意义。在自愿接受HIV咨询检测的基础上,对临床确诊的412例性病患者进行HIV-1/2抗体检测,并对其临床特征进行分析研究。结果显示412例性病患者的HIV检出率为2.9%。性病患者中检出HIV阳性率依次为:尖锐湿疣(6.2%)、生殖器疱疹(4.2%)、梅毒(3.4%)、淋病(1.5%)及非淋菌性尿道炎(1.0%)。83.3%合并感染HIV的性病患者存在多性伴,商业性行为普遍存在,安全套使用率极低现象。感染HIV的尖锐湿疣及生殖器疱疹患者以频繁复发为突出表现,1例合并感染HIV的梅毒患者半年即进展为神经梅毒。性病患者是HIV感染的重要高危人群,危险性行为是其感染HIV和其它性病的主要原因,应该加强性病患者的HIV检测。对临床上频繁复发的尖锐湿疣及生殖器疱疹患者、快速进展的梅毒患者应高度怀疑合并HIV感染的可能。
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The growth,fabrication,and characterization of 0.2μm gate-length AlGaN/GaN HEMTs,with a high mobility GaN thin layer as a channel,grown on (0001) sapphire substrates by MOCVD,are described.The unintentionally doped 2.5μm thick GaN epilayers grown with the same conditions as the GaN channel have a room temperature electron mobility of 741cm2/(V·s) at an electron concentration of 1.52×1016 cm-3.The resistivity of the thick GaN buffer layer is greater than 108Ω·cm at room temperature.The 50mm HEMT wafers grown on sapphire substrates show an average sheet resistance of 440.9Ω/□ with uniformity better than 96%.Devices of 0.2μm×40μm gate periphery exhibit a maximum extrinsic transconductance of 250mS/mm and a current gain cutoff frequency of77GHz.The AlGaN/GaN HEMTs with 0.8mm gate width display a total output power of 1.78W (2.23W/mm) and a linear gain of 13.3dB at 8GHz.The power devices also show a saturated current density as high as 1.07A/mm at a gate bias of 0.5V.
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采用测量反射谱方法确定了低压金属有机化合物气相外延生长的GaAs衬底匹配(Al_xGa_(1-x))_(0.51)In_(0.49)P外延材料的折射率。实验中测量的反射谱波长范围为05-2.5μm。在拟合实验数据过程中采用了单振子模型。折射率数据用于分析应变量子阱GaInP/AlGaInP可见光激光二极管波导,计算出的器件远场图与实验数据吻合很好。
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In this paper we proposed a single ridge waveguide electroabsorption modulated distributed feedback laser (EML) for long-haul high-speed optical fiber communication system. This EML was successfully fabricated by two step metal organic vapor phase epitaxy (MOVPE) including selective area growth (SAG) and helium partially implantation. No obvious changes of the threshold current (< 0.2 mA), extinction ratio (< 0.1 dB), output power (< 0.2 dBm) and isolation resistance were achieved in the preliminary aging test. With 2.5 Gb/s NRZ modulation, no power penalty was observed after the optical signal was transmitted through 280 Km normal single mode fiber.
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5-氟尿嘧啶(5-Fluorouracil, 5-FU)是一种抗代谢药物,广泛用于临床治疗结直肠癌、胃癌、乳腺癌等多种癌症,但其首过代谢显著、亲脂性较低,选择性差、毒副作用大。为克服这些缺点人们对5-FU进行了大量的修饰工作,包括小分子修饰以及与各种载体形成微球、微囊、纳米粒、共价前药等。 环糊精(Cyclodextrin,简称CD),可被结肠中的糖苷酶特异性地降解成小分子糖,而胃和小肠中由于缺乏相应的酶而使环糊精不被降解,这一特性在结肠药物的靶向输送及释放中有重要应用价值。环糊精中含有丰富的羟基,易进行化学修饰,将药物与环糊精通过共价键结合制成前药,使其在胃和小肠中不降解,而在盲结肠中被特异性的酶降解释出药物,达到结肠靶向释药的目的。研究表明,环糊精作为一种前药载体为结肠靶向释药和缓释、控释系统提供了一种有效的手段。 本工作选择5-氟尿嘧啶为模型药物、β-环糊精作为载体,通过中间体5-FU羧酸衍生物的制备及其与β-环糊精的偶联,合成了系列5-FU-β-CD前体药物,并利用紫外、红外、质谱、核磁、元素分析、热分析等手段对其进行结构表征。同时,还研究了前体药物的体外释药性质。具体内容包括: 1. 含有羧基的5-FU衍生物中间体的合成:(5-氟尿嘧啶-1-基)-乙酸(FUAC)、3-(5-氟尿嘧啶-1-基)-丙酸(FUPC)、5-(5-氟尿嘧啶-1-基)-戊酸(FUVC)的合成。 2. 中间体5-FU的羧酸衍生物与β-CD的偶联:分别通过以6-OTs-β-CD为中间体的取代法和活化酯法,合成了第一面取代和第二面取代的5-FU-β-CD大分子前体药物。在二面取代的前体药物制备中,通过改变原料的比例,合成了系列不同取代度(DS)的2-[(5-氟尿嘧啶-1-基)-乙酰基] -β-环糊精结合物。 3. 对上述前体药物进行体外释放研究:分别考察了前体药物在不同pH缓冲溶液中的水解行为及其在小鼠胃肠道人工体液中的酶解行为,并通过UV-Vis及HPLC对前体药物释放情况进行检测分析。 5-Fluorouracil(5-Fu), commonly known as a broad-spectrum antineoplastic drug, has been widely used in the treatment of various kinds of cancer including colon cancer for 40 years. However, this antitumor agent exhibits serious adverse effects, such as their marrow toxicity, gastrointestinal reaction and low selectivity in their clinical use. In order to improve its antitumor activity and reduce its toxicity, the compound was modified in various ways, including the formation of conjugated prodrugs with kinds of carrier, microsphere and nanoparticles etc. Cyclodextrins(CDs) are known to be barely capable of being hydrolyzed and only slightly absorbed in passing through the stomach and small intestine; however they are fermented into small saccharides by colonic microflora and thus absorbed as small saccharides in the large intestine. This biodegradation property of CDs may be useful as a colon-targeting carrier, and thus CD prodrugs may serve as a source of site-specific delivery of drugs to colon. It was demonstrated that prodrugs of CDs can provide a versatile means for construction of not only colon targeted delivery systems, but also delayed release systems. 5-Fluorouracil was taken as a model drug and β-CD as the carrier in this study. Series prodrugs of 5-FU was prepared through the preparation of reactive 5-FU derivatives containing carboxyl group and coupling to hydroxyl groups of CD. The structures of the conjugates were charactered by using IR, UV–vis, ESI-MS, 1H, 13C-NMR spectra, elemental analyses, and thermal analysis. In vitro hydrolysis behavior in aqueous solution and in rat gastrointestinal tract contents of the conjugates were also investigated. The main content of this dissertation includes following aspects: 1. The preparation of 5-FU derivatives containing carboxyl group: 5-Fluorouracil- acetic acid(FUAC)、3-(5-FU-1)-propionic acid (FUPC)、and 5-(5-FU-1)-valeric acid(FUVC). 2. The coupling of 5-FU derivatives to β-CD: 5-FU was selectively conjugated onto the primary or secondary hydroxyl groups of β-CD through an ester linkage, by the substitution of 6-OTs-β-CD and the activated ester method respectively. For the secondary face conjugation, the degree of substitution(DS) can be controlled by changing the mole ratio of the starting materials(FUAC and β-CD). 3. In vitro release behavior of the conjugates in aqueous solution and in rat gastro- intestinal tract contents of the conjugates were investigated, and the reaction was monitored and analyzed by using UV-Vis and HPLC methods.
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利用重离子熔合蒸发反应和在束γ谱学实验方法 ,研究了双奇核184 Au的高自旋态能级结构 .扩展了基于πh9/ 2 ν7/ 2 - [5 14 ]和πi13/ 2 νi13/ 2 2准粒子组态下的转动带能级纲图 ,建立了两个转动带之间以及πh9/ 2 ν7/ 2 - [5 14 ]带与基态的谱学连接 .从而确定了πi13/ 2 νi13/ 2 带能级的自旋和宇称 ,证实了此转动带在低自旋区出现旋称反转 .分析了πi13/ 2 νi13/ 2 带和相邻核转动带的准粒子顺排特征 ,指出此带的第一回弯以及相邻核转动带在低频观测到的顺排异常可能与h9/ 2 质子顺排有关 .
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A 2-kW-class chemical oxygen-iodine laser (COIL) using nitrogen buffer gas has been developed and tested since industrial applications of COIL devices will require the use of nitrogen as the buffer gas. The laser, with a gain length of 11.7 cm, is energized by a square pipe-array jet-type singlet oxygen generator (SPJSOG) and employs a nozzle bank with a designed Mach number of 2.5. The SPJSOG has advantages over the traditional plate-type JSOG in that it has less requirements on basic hydrogen peroxide (BHP) pump, and more important, it has much better operational stability. The SPJSOG without a cold trap and a gas-liquid separator could provide reliable operations for a total gas flow rate up to 450 mmol/s and with a low liquid driving pressure of around 0.7 atm or even lower. The nozzle bank was specially designed for a COIL using nitrogen as the buffer gas. The cavity was designed for a Mach number of 2.5, in order to provide a gas speed and static temperature in the cavity similar to that for a traditional COIL with helium buffer gas and a Mach 2 nozzle. An output power of 2.6 kW was obtained for a chlorine flow rate of 140 mmol/s, corresponding to a chemical efficiency of 20.4%. When the chlorine flow rate was reduced to 115 mmol/s, a higher chemical efficiency of 22.7% was attained. Measurements showed that the SPJSOG during normal operation could provide a singlet oxygen yield Y greater than or equal to 55%, a chlorine utilization U greater than or equal to 85%, and a relative water vapor concentration w = [H2O]/([O-2] + [Cl-2]) less than or equal to 0.1.
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A simple, sensitive, and mild method for the determination of amino compounds based on a condensation reaction with fluorescence detection has been developed. 9-(2-Hydroxyethyl)acridone reacts with coupling agent N,N-carbonyldiimidazole at ambient temperature to form activated amide intermediate 9-(2-acridone)oxyethylcarbonylimidazole (AOCD). The amide intermediate (AOCD) preferably reacts with amino compounds under mild reactions in the presence of 4-(dimethylamino)pyridine (base catalyst) in acetonitrile to give the corresponding sensitively fluorescent derivatives with an excitation maximum lambda(ex) 404 mn and an emission maximum at lambda(em) 440 nm. The labeled derivatives exhibit high stability under reversed-phase conditions. The fluorescence intensities of derivatives in various solvents or at different temperatures were investigated. The method, in conjunction with a gradient elution, offers a baseline resolution of the common amine derivatives on a reversed-phase C-18 column. The LC separation for the derivatized amines shows good reproducibility with acetonitrile-water including 2.5% DMF as mobile phase. The relative standard deviations (n = 6) for each amine derivative are <4.5%. The detection limits (at a signal-to-noise ratio of 3) per injection were 0.16-12.8 ng/mL. Further research for the field of application, based on the AOCD amide intermediate as derivatization reagent, for the determination of free amines in real water samples is achieved.
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A 2.5-D and 3-D multi-fold GPR survey was carried out in the Archaeological Park of Aquileia (northern Italy). The primary objective of the study was the identification of targets of potential archaeological interest in an area designated by local archaeological authorities. The second geophysical objective was to test 2-D and 3-D multi-fold methods and to study localised targets of unknown shape and dimensions in hostile soil conditions. Several portions of the acquisition grid were processed in common offset (CO), common shot (CSG) and common mid point (CMP) geometry. An 8×8 m area was studied with orthogonal CMPs thus achieving a 3-D subsurface coverage with azimuthal range limited to two normal components. Coherent noise components were identified in the pre-stack domain and removed by means of FK filtering of CMP records. Stack velocities were obtained from conventional velocity analysis and azimuthal velocity analysis of 3-D pre-stack gathers. Two major discontinuities were identified in the area of study. The deeper one most probably coincides with the paleosol at the base of the layer associated with activities of man in the area in the last 2500 years. This interpretation is in agreement with the results obtained from nearby cores and excavations. The shallow discontinuity is observed in a part of the investigated area and it shows local interruptions with a linear distribution on the grid. Such interruptions may correspond to buried targets of archaeological interest. The prominent enhancement of the subsurface images obtained by means of multi-fold techniques, compared with the relatively poor quality of the conventional single-fold georadar sections, indicates that multi-fold methods are well suited for the application to high resolution studies in archaeology.