• BMB Reports
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• 제51권1호
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• pp.21-26
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• 2018

Delta-like ligand 4 (DLL4) expression in endothelial cells is intimately associated with angiogenic sprouting and vascular remodeling, but the precise mechanism of transcriptional regulation of DLL4 remains incompletely understood. Here, we showed that LIM-domain binding protein 2 (LDB2) plays an important role in regulating basal DLL4 and VEGF-induced DLL4 expression. Knockdown of LDB2 using siRNA enhanced endothelial sprouting and tubular network formation in vitro. Injection of ldb2-morpholino resulted in defective development of intersegmental vessels in zebrafish. Reduction or over-expression of LDB2 in endothelial cells decreased or increased DLL4 expression. LDB2 regulated DLL4 promoter activity by binding to its promoter region and the same promoter region was occupied and regulated by the LMO2/TAL1/GATA2 complex. Interestingly, LDB2 also mediated VEGF-induced DLL4 expression in endothelial cells. The regulation of DLL4 by the LDB2 complex provides a novel mechanism of DLL4 transcriptional control that may be exploited to develop therapeutics for aberrant vascular remodeling.

• 전기전자학회논문지
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• 제21권4호
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• pp.416-419
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• 2017

본 논문에서는 고속 DDR3/DDR4 SDRAM을 위한 새로운 디지털 지연고정루프 (delay-locked loop: DLL)를 제안한다. 제안하는 디지털 DLL은 디지털 지연라인의 boundary switching 문제에 의한 jitter 증가 문제를 제거하기 위하여 위상보간 (phase interpolation) 방식의 파인지연라인 (fine delay line)을 채택하였다. 또한, 제안하는 디지털 DLL은 harmonic lock 문제를 제거하기 위하여 새로운 점진직 검색 (gradual search) 알고리즘을 사용한다. 제안하는 디지털 DLL은 1.1V, 38-nm CMOS DRAM 공정으로 설계되었으며, 0.25-2.0 GHz의 주파수 동작 영역을 가진다. 2.0 GHz에서 1.1 ps의 피크-투-피크 (p-p) 지터를 가지며, 약 13 mW의 전력소모를 가진다.

• BMB Reports
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• 제53권10호
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• pp.533-538
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• 2020

Notch signaling has been identified as a critical pathway in gastric cancer (GC) progression and metastasis, and inhibition of Delta-like ligand 4 (DLL4), a Notch ligand, is suggested as a potent therapeutic approach for GC. Expression of both DLL4 and vascular endothelial growth factor receptor 2 (VEGFR2) was similar in the malignant tissues of GC patients. We focused on vascular endothelial growth factor (VEGF), a known angiogenesis regulator and activator of DLL4. Here, we used ABL001, a DLL4/VEGF bispecific therapeutic antibody, and investigated its therapeutic effect in GC. Treatment with human DLL4 therapeutic antibody (anti-hDLL4) or ABL001 slightly reduced GC cell growth in monolayer culture; however, they significantly inhibited cell growth in 3D-culture, suggesting a reduction in the cancer stem cell population. Treatment with anti-hDLL4 or ABL001 also decreased GC cell migration and invasion. Moreover, the combined treatment of irinotecan with anti-hDLL4 or ABL001 showed synergistic antitumor activity. Both combination treatments further reduced cell growth in 3D-culture as well as cell invasion. Interestingly, the combination treatment of ABL001 with irinotecan synergistically reduced the GC burden in both xenograft and orthotopic mouse models. Collectively, DLL4 inhibition significantly decreased cell motility and stem-like phenotype and the combination treatment of DLL4/VEGF bispecific therapeutic antibody with irinotecan synergistically reduced the GC burden in mouse models. Our data suggest that ABL001 potentially represents a potent agent in GC therapy. Further biochemical and pre-clinical studies are needed for its application in the clinic.

• JSTS:Journal of Semiconductor Technology and Science
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• 제16권4호
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• pp.520-527
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• 2016

A new dual-loop digital delay-locked loop (DLL) using a hybrid (binary + sequential) search algorithm is presented to achieve both wide-range operation and high delay resolution. A new phase-interpolation range selector (PIRS) and a variable successive approximation register (VSAR) algorithm are adopted to resolve the boundary switching and harmonic locking problems of conventional digital DLLs. The proposed digital DLL, implemented in a $0.18-{\mu}m$ CMOS process, occupies an active area of $0.19mm^2$ and operates over a wide frequency range of 0.15-1.5 GHz. The DLL dissipates a power of 11.3 mW from a 1.8 V supply at 1 GHz. The measured peak-to-peak output clock jitter is 24 ps (effective pk-pk jitter = 16.5 ps) with an input clock jitter of 7.5 ps at 1.5 GHz. The delay resolution is only 2.2 ps.

• 한국정보통신학회:학술대회논문집
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• 한국정보통신학회 2012년도 추계학술대회
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• pp.259-262
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• 2012

본 논문에서는 125 MHz 동작 주파수에서 64개 위상의 클럭을 출력하는 지연 고정 루프 (DLL: delay-locked loop)을 제안한다. 제안된 다중 지연 고정 루프는 delay line의 선형성을 개선하기 위해 $4{\times}8$ matrix 구조의 delay line을 사용한다. CMOS multiplexer와 inverter-based interpolator를 이용하여 $4{\times}8$ matrix 기반의 delay line에서 출력된 32개 위상의 클럭으로부터 64개 위상의 클럭을 생성한다. 또한 DLL에서 harmonic lock을 방지하기 위해 클럭의 duty cycle ratio에 무관한 initial phase locking을 위한 회로가 제안된다. 제안된 지연 고정 루프는 1.8 V의 공급전압을 이용하는 $0.18-{\mu}m$ CMOS 공정에서 설계된다. 시뮬레이션된 DLL은 40 MHz에서 200 MHz의 동작 주파수 범위를 가진다. 125 MHz 동작 주파수에서 최악의 위상 오차와 jitter는 각각 +11/-12 ps와 6.58 ps이다.

• 대한전자공학회논문지SD
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• 제40권6호
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• pp.408-420
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• 2003

이 논문에서는 1) 넓은 잠금 범위를 위한 이중 루프 동작과 2) 차세대 패키지 스큐 개선에 대한 전압 발생기와 안티퓨즈 회로를 사용한 프로그래머블 레프리카 딜레이, 두 가지 이점을 갖는 Delay Lock Loop(DLL)을 기술하였다. 이중 루프 동작은 차동 내부 루프 중 하나를 선택하기 위해 외부 클럭과 내부 클럭 사이의 초기 시간차에 대한 정보를 사용한다. 이를 이용하여 더 낮은 주파수로 DLL의 잠금 범위를 증가시킨다. 덧붙여서, 전압발생기와 안티퓨즈 회로를 사용한 프로그래머블 레프리카 딜레이의 결합은 패키지 공정 후에 온-오프 칩 변화로부터 발생하는 외부 클럭과 내부 클럭 사이에 스큐 제거를 해준다. 제안된 DLL은 0.16um 공정으로 제조되었고, 2.3v의 전원 공급과 42㎒ - 400㎒의 넓은 범위에서 동작한다. 측정된 결과는 43psec p-p 지터와 400㎒에서 52㎽를 소비하는 4.71psec 실효치(rms)지터를 보여준다.

• JSTS:Journal of Semiconductor Technology and Science
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• 제14권4호
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• pp.457-462
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• 2014

This letter proposes a low-jitter DLL-based clock generator with two negative feedback loops. The main negative feedback loops suppress the jitter of DLL. The additional negative feedback loops suppress the delay-time variance of each delay stages. Both two negative feedback loops in a DLL results in suppressing the jitter of clock signal further. Measurement results of the DLL-based clock generator with two negative feedback loops fabricated in a one-poly six-metal $0.18{\mu}m$ CMOS process show 5.127-ps rms jitter and 47.6-ps peak-to-peak jitter at 1 GHz.

• JSTS:Journal of Semiconductor Technology and Science
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• 제6권4호
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• pp.264-269
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• 2006

A $0.12GHz{\sim}1.4GHz$ DLL-based clock generator with the capability of multiplied four phase clock generation was designed using a 0.18um CMOS process. An adaptive bandwidth DLL with a regulated supply delay line was used for a multiphase clock generation and a low jitter. An extra phase detector (PD) in a reference DLL solves the problem of the initial VCDL delay and achieves a fast lock time. Twice multiplied four phase clocks were generated at the outputs of four edge combiners, where the timing alignment was achieved using a coarse lock signal and the 10 multiphase clocks with T/8 time difference. Those four clocks were combined one more time using a static XOR circuit. Therefore the four times multiplication was achieved. With a 1.8V supply, the rms jitter of 2.1ps and the peak-to-peak jitter of 14.4ps were measured at 1.25GHz output. The operating range is $0.12GHz{\sim}1.4GHz$. It consumes 57mW and occupies 450*325um2 of die area.

• JSTS:Journal of Semiconductor Technology and Science
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• 제16권4호
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• pp.387-394
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• 2016

This paper presents a fully digital delay locked loop (DLL) that can acquire lock in four clock cycles with a resolution of a 1/4 NAND-delay. The proposed DLL with a multi-dither-free phase detector acquires the initial lock in four clock cycles with 1/2 NAND-delay. Then, it utilizes a multi-dither-free phase detector, a region accumulator, and phase blenders, to improve the resolution to a 1/4 NAND-delay. The region accumulator which continuously steers the control registers and the phase blender, adaptively controls the tracking bandwidth depending on the amount of jitter, and effectively suppresses the dithering jitter. Fabricated in a 65 nm CMOS process, the proposed DLL occupies $0.0432mm^2$, and consumes 3.7 mW from a 1.2-V supply at 2 GHz.

• 전기학회논문지
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• 제56권6호
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• pp.1133-1138
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• 2007

DLLs(Delay Locked Loops) have widely been used in many systems in order to achieve the clock synchronization. A SMD (Synchronous Mirror Delay) structure is used both for skew reduction and for DCC (Duty Cycle Correction). In this paper, a SMD based DLL with DCC using Reduced Delay Lines is proposed in order to reduce the clock skew and correct the duty cycle. The merged structure allows the forward delay array to be shared between the DLL and the DCC, and yields a 25% saving in the number of the required delay cells. The designed chip was fabricated using a $0.25{\mu}m$ 1-poly, 4-metal CMOS process. Measurement results showed the 3% duty cycle error when the input signal ranges from 80% to 20% and the clock frequency ranges from 400MHz to 600MHz. The locking operation needs 3 clock and duty correction requires only 5 clock cycles as feature with SMD structure.