• BMB Reports
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• v.51 no.1
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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.

• Journal of IKEEE
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• v.21 no.4
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• pp.416-419
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• 2017

In this paper, we propose a new digital delay-locked loop (DLL) for high-speed DDR3/DDR4 SDRAMs. The proposed digital DLL adopts a fine delay line using phase interpolation to eliminate the jitter increase problem due to the boundary switching problem. In addition, the proposed digital DLL utilizes a new gradual search algorithm to eliminate the harmonic lock problem. The proposed digital DLL is designed with a 1.1 V, 38-nm CMOS DRAM process and has a frequency operating range of 0.25-2.0 GHz. It has a peak-to-peak jitter of 1.1 ps at 2.0 GHz and has a power consumption of about 13 mW.

• BMB Reports
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• v.53 no.10
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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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• v.16 no.4
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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.

• Proceedings of the Korean Institute of Information and Commucation Sciences Conference
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• 2012.10a
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• pp.259-262
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• 2012

This paper describes a delay-locked loop (DLL) that generates a 64-phase clock with the operating frequency of 125MHz. The proposed DLL use a $4{\times}8$ matrix-based delay line to improve the linearity of a delay line. The output clock with 64-phase is generated by using a CMOS multiplex and a inverted-based interpolator from 32-phase clock which is the output clock of the $4{\times}8$ matrix-based delay line. The circuit for an initial phase lock, which is independent on the duty cycle ratio of the input clock, is used to prevent from the harmonic lock of a DLL. The proposed DLL is designed using a $0.18-{\mu}m$ CMOS process with a 1.8 V supply. The simulated operating frequency range is 40 MHz to 200 MHz. At the operating frequency of a 125 MHz, the worst phase error and jitter of a 64-phase clock are +11/-12 ps and 6.58 ps, respectively.

• Journal of the Institute of Electronics Engineers of Korea SD
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• v.40 no.6
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• pp.408-420
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• 2003

This paper describes a Delay Locked Loop (DLL) circuit having two advancements : 1) a dual loop operation for a wide lock-range and 2) programmable replica delays using antifuse circuitry and internal voltage generator for a post-package skew calibration. The dual loop operation uses information from the initial time-difference between reference clock and internal clock to select one of the differential internal loops. This increases the lock-range of the DLL to the lower frequency. In addition, incorporation with the programmable replica delay using antifuse circuitry and internal voltage generator allows for the elimination of skews between external clock and internal clock that occur from on and off-chip variations after the package process. The proposed DLL, fabricated on 0.16m process, operates over the wide range of 42MHz - 400MHz with 2.3v power supply. The measured results show 43psec peak-to-peak jitter and 4.71psec ms jitter consuming 52㎽ at 400MHz.

• JSTS:Journal of Semiconductor Technology and Science
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• v.14 no.4
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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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• v.6 no.4
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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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• v.16 no.4
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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.

• The Transactions of The Korean Institute of Electrical Engineers
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• v.56 no.6
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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.