새로운 낮은 스큐의 클락 분배망 설계 방법

이성철,신현철 대한전자공학회 2004 電子工學會論文誌-SD (Semiconductor and devices) Vol.41 No.5

현재의 반도체 공정은 Deep Sub- Micmn (DSM)으로 발전하면서, 선폭이 줄어들고 구동 주파수가 높아지고 있다. 이로 인해 clock source로부터 clock을 필요로 하는 각 단자(sink)까지의 '지연시간의 최대 차'로 정의되어지는 clock skew가 회로의 속도 향상에 있어 중요 제약요소가 되고 있다. 또한 이를 얼마나 줄이느냐 하는 것은 동기식 회로 설계에 있어 중요한 문제가 되고 있다. 따라서 낮은 clock skew를 위한 배선 기술에 대해 많은 연구들이 이루어지고 있다. 본 논문에서는 clock skew를 줄이기 위한 방법으로서 새로운 Advanced clock Tree Generation(ACTG) 방법을 개발하였다. ACTG는 2단계의 계층적 routing을 통해 최적의 clock tree를 구성한다. 본 논문에서 제안하는 알고리즘을 C 언어로 프로그램하여 구현하 후 벤치마크 테스트 데이터에 대하여 실험한 결과, 주어진 skew 범위를 만족시키면서 지연 시간을 감소시키는 효과를 얻을 수 있었다. The clock skew is one of the major constraints for high-speed operation of synchronous integrated circuits. In this paper, we propose a hierarchical partitioning based clock network design algorithm called Advanced Clock Tree Generation (ACTG). Especially new effective partitioning and refinement techniques have been developed in which the capacitance and edge length to each sink are considered from the early stage of clock design. Hierarchical structures obtained by parhtioning and refinement are utilized for balanced clock routing. We use zero skew routing in which Elmore delay model is used to estimate the delay. An overlap avoidance routing algorithm for clock tree generation is proposed. Experimental results show significant improvement over conventional methods.

Circadian Clock Genes, PER1 and PER2, as Tumor Suppressors

Beomseok Son(손범석),Hyunhee Do(도현희),EunGi Kim(김은기),BuHyun Youn(윤부현),Wanyeon Kim(김완연) 한국생명과학회 2017 생명과학회지 Vol.27 No.10

암을 포함한 다양한 인간의 질병 발생이 circadian clock 유전자의 변형된 발현 양상과 깊은 연관관계를 나타내고 있다. 세포 주기와 세포 성장은 circadian rhythm과 연결되어 있으며, 이를 조절하는 clock 유전자의 비정상적인 발현은 결국 종양 발생과 암의 발달을 유발하게 된다. Circadian clock에 관한 분자적 기전은 다수의 clock activator와 clock repressor의 통합적인 조절에 따른 전사 및 번역이 포함된 음성피드백 고리로 구성되어 있다. 이러한 circadian rhythm의 자동조절 기전에 의해 전체 유전체의 약 10~15%가 전사 수준에서 영향받는 것으로 나타났다. 많은 clock 유전자들 중, Period 1 (Per1)과 Period 2 (Per2)는 clock repressor 유전자로 정상적인 생리적 리듬을 조절하는 것에 기여한다. PER1과 PER2는 cyclin, CDK, CKI를 포함하는 세포 주기 조절자의 발현에 관여함이 밝혀졌으며, 다양한 암에서 PER1과 PER2의 발현 감소가 보고되었다. 따라서, 본 논문에서는 PER1과 PER2의 circadian rhythm에서의 분자적 기능과 종양 발생과 관련된 PER1과 PER2의 하위 표적인자에 대해 살펴보고, 암 치료를 위한 새로운 치료 표적과 암의 예후를 예측하기 위한 분자 지표로써의 PER1과 PER2의 가능성에 대해 서술하고자 한다. Disruptive expression patterns of the circadian clock genes are highly associated with many human diseases, including cancer. Cell cycle and proliferation is linked to a circadian rhythm; therefore, abnormal clock gene expression could result in tumorigenesis and malignant development. The molecular network of the circadian clock is based on transcriptional and translational feedback loops orchestrated by a variety of clock activators and clock repressors. The expression of 10~15% of the genome is controlled by the overall balance of circadian oscillation. Among the many clock genes, Period 1 (Per1) and Period 2 (Per2) are clock repressor genes that play an important role in the regulation of normal physiological rhythms. It has been reported that PER1 and PER2 are involved in the expression of cell cycle regulators including cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors. In addition, correlation of the down-regulation of PER1 and PER2 with development of many cancer types has been revealed. In this review, we focused on the molecular function of PER1 and PER2 in the circadian clock network and the transcriptional and translational targets of PER1 and PER2 involved in cell cycle and tumorigenesis. Moreover, we provide information suggesting that PER1 and PER2 could be promising therapeutic targets for cancer therapies and serve as potential prognostic markers for certain types of human cancers.

Effect of Resveratrol, a SIRT1 Activator, on the Interactions of the CLOCK/BMAL1 Complex

박인성,이율,김희대,김경진 대한내분비학회 2014 Endocrinology and metabolism Vol.29 No.3

Background: In mammals, the CLOCK/BMAL1 heterodimer is a key transcription factor complex that drives the cyclic expression of clock-controlled genes involved in various physiological functions and behavioral consequences. Recently, a growing number of studies have reported a molecular link between the circadian clock and metabolism. In the present study, we explored the regulatory effects of SIRTUIN1 (SIRT1), an NAD+-dependent deacetylase, on CLOCK/BMAL1-mediated clock gene expression. Methods: To investigate the interaction between SIRT1 and CLOCK/BMAL1, we conducted bimolecular fluorescence complementation (BiFC) analyses supplemented with immunocytochemistry assays. BiFC experiments employing deletion-specific mutants of BMAL1 were used to elucidate the specific domains that are necessary for the SIRT1-BMAL1 interaction. Additionally, luciferase reporter assays were used to delineate the effects of SIRT1 on circadian gene expression. Results: BiFC analysis revealed that SIRT1 interacted with both CLOCK and BMAL1 in most cell nuclei. As revealed by BiFC assays using various BMAL1 deletion mutants, the PAS-B domain of BMAL1 was essential for interaction with SIRT1. Activation of SIRT1 with resveratrol did not exert any significant change on the interaction with the CLOCK/BMAL1 complex. However, promoter analysis using Per1-Luc and Ebox-Luc reporters showed that SIRT1 significantly downregulated both promoter activities. This inhibitory effect was intensified by treatment with resveratrol, indicating a role for SIRT1 and its activator in CLOCK/BMAL1-mediated transcription of clock genes. Conclusion: These results suggest that SIRT1 may form a regulatory complex with CLOCK/BMAL1 that represses clock gene expression, probably via deacetylase activity.

Regulation of Arabidopsis Circadian Clock by De-Etiolated 1 (DET1) Possibly via Histone 3 Acetylation (H3Ac)

Hae-Ryong Song(송해룡) 한국생명과학회 2012 생명과학회지 Vol.22 No.8

자기 현가적(self-sustaining) 조절 장치인 생체시계는 24시간 주기의 생체리듬을 조절하며 또한 생물체로 하여금 매일 변화하는 자연환경의 외부 신호를 인지할 수 있도록 해준다. 생체시계 유전자의 발현 조절은 전사/해독의 역환류 기작을 통해 이루어진다. 애기장대 LATE ELONGATED HYPOCOTYL (LHY)와 CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1)는 아침에 최고조로 발현되며 해독된 LHY and CCA1는 저녁에 최고로 발현되는 TIMING OF CAB EXPRESSION1 (TOC1)의 발현을 억제한다. TOC1단백질은 LHY와 CCA1 발현을 촉진시킴으로써 생체시계의 핵심 진자(oscillator)를 형성한다. 동물에서 생체시계의 주요 전사 인자인CLOCK은 아세틸화효소활성 기능을 가지며, 이는 생체시계의 기능 유지에 아세틸화의 중요함을 의미한다. 하지만 애기장대 생체시계에 아세틸화를 담당하는 인자에 대한 정보는 현재 보고된 바가 없다. 본 연구에서 DET1 (De-Etiolated1)는 암조건하에서 애기장대 생체시계 관련 핵심인자 중 하나인 LHY발현을 억제하는데 필요하며 이의 억제는 H3Ac 조절을 통해 이루어짐을 증명하였다. 하지만 LHY 아세틸화를 담당하는 효소의 발굴 및 이들 효소와 DET1과의 연결을 찾는 문제는 여전히 미재로 남아있다. The circadian clock is a self-sustaining 24-hour timekeeper that allows organisms to anticipate daily-changing environmental time cues. Circadian clock genes are regulated by a transcriptional-translational feedback loop. In Arabidopsis, LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1) transcripts are highly expressed in the morning. Translated LHY and CCA1 proteins repress the expression of the TIMING OF CAB EXPRESSION 1 (TOC1) transcripts, which peaks in the evening. The TOC1 protein elevates the expression of the LHY and CCA1 transcripts, forming a negative feedback loop that is believed to constitute the oscillatory mechanism of the clock. In mammals, the transcription factor protein CLOCK, which is a central component of the circadian clock, was reported to have an intrinsic histone acetyltransferase (HAT) activity, suggesting that histone acetylation is important for core clock mechanisms. However, little is known about the components necessary for the histone acetylation of the Arabidopsis clock-related genes. Here, I report that DET1 (De-Etiolated1) functions as a negative regulator of a key component of the Arabidopsis circadian clock gene LHY in constant dark phases (DD) and is required for the down-regulation of LHY expression through the acetylation of histone 3 (H3Ac). However, the HATs directly responsible for the acetylation of H3 within LHY chromatin need to be identified, and a link connecting the HATs and DET1 protein is still absent.

안전하지 않은 I/O핀 노이즈 환경에서 MCU 클럭 보호를 위한 자동 온칩 글리치 프리 백업 클럭 변환 기법

안중현(Joonghyun An),윤지애(Jiae Youn),조정훈(Jeonghun Cho),박대진(Daejin Park) 대한전자공학회 2015 전자공학회논문지 Vol.52 No.12

Induction of Two Mammalian PER Proteins is Insufficient to Cause Phase Shifting of the Peripheral Circadian Clock

Lee, Joon-Woo,Cho, Sang-Gil,Cho, Jun-Hyung,Kim, Han-Gyu,Bae, Ki-Ho The Korean Society for Integrative Biology 2005 Integrative biosciences Vol.9 No.3

Most living organisms exhibit the circadian rhythm in their physiology and behavior. Recent identification of several clock genes in mammals has led to the molecular understanding of how these components generate and maintain the circadian rhythm. Many reports have implicated the photic induction of either mPer1 or mPer2 in the hypothalamic region called the suprachiasmatic nucleus (SCN) to phase shift the brain clock. It is now established that peripheral tissues other than the brain also express these clock genes and that the clock machinery in these tissues work in a similar way to the SCN clock. To determine the role of the two canonical clock genes, mPer1 and mPer2, in the peripheral clock shift, stable HEK293EcR cell lines that can be induced and stably express these proteins were prepared. By regulating the expression of these proteins, it could be shown that induction of the clock genes, either mPer1 or mPer2 alone is not sufficient to cause clock phase shifting in these cells. Our real-time PCR analysis on these cells indicates that the induction of mPER proteins dampens the expression of the clock-specific transcription factor mBmal1. Altogether, our present data suggest that mPer1 and mPer2 may not function in clock shift or take part in differential roles on the peripheral circadian clock.

Low Latency Synchronization Scheme Using Prediction and Avoidance of Synchronization Failure in Heterochronous Clock Domains

Sung-Gun Song,Seong-Mo Park,Jeong-Gun Lee,Myeong-Hoon Oh 대한전자공학회 2015 Journal of semiconductor technology and science Vol.15 No.2

For the performance-efficient integration of IPs on an SoC utilizing heterochronous multi-clock domains, we propose a synchronization scheme that causes low latency overhead when data are crossing clock boundaries. The proposed synchronization scheme is composed of a clock predictor and a synchronizer. The clock predictor of a sender clock domain produces a predicted clock that is used in a receiver clock domain to detect possible synchronization failures in advance. When the possible synchronization failures are detected, a synchronizer at the receiver delays data-capture times to avoid the possible synchronization failures. From the simulation of the proposed scheme through SPICE modeling using a Chartered 0.18 mm CMOS process, we verified the functionalities and timing behavior of the clock predictor and the synchronizer. The simulation results show that the clock predictor produces a predicted clock before a synchronization failure, and the synchronizer samples data correctly using the predicted clock.

Dependence and independence of the root clock on the shoot clock in Arabidopsis

이홍길,서필준 한국유전학회 2018 Genes & Genomics Vol.40 No.10

Temporal and spatial compartmentalization of biological processes is facilitated by tissue-specific uncoupled circadian clocks in plants. However, interactions among tissue-specific circadian clocks have not been well established. The primary objective of this study was to describe both organ-specific circadian behaviors and centralized actions of the root clock. We analyzed transcript accumulation of circadianly-oscillating genes in roots and shoots. Expression of many clock components was different in roots and shoots. In particular, evening-expressed clock components were highly expressed in roots and likely play important roles in oscillation of the root clock. Consistent with this, the root and shoot clocks responded differentially to circadian gene mutations. The root clock was even dampened in gi-2 mutant. Circadian clocks basically oscillate in an organ-specific manner in plants, but the root clock also requires shoot-derived signals for organism-level coordination of circadian activity.

Low Latency Synchronization Scheme Using Prediction and Avoidance of Synchronization Failure in Heterochronous Clock Domains

Song, Sung-Gun,Park, Seong-Mo,Lee, Jeong-Gun,Oh, Myeong-Hoon The Institute of Electronics and Information Engin 2015 Journal of semiconductor technology and science Vol.15 No.2

For the performance-efficient integration of IPs on an SoC utilizing heterochronous multi-clock domains, we propose a synchronization scheme that causes low latency overhead when data are crossing clock boundaries. The proposed synchronization scheme is composed of a clock predictor and a synchronizer. The clock predictor of a sender clock domain produces a predicted clock that is used in a receiver clock domain to detect possible synchronization failures in advance. When the possible synchronization failures are detected, a synchronizer at the receiver delays data-capture times to avoid the possible synchronization failures. From the simulation of the proposed scheme through SPICE modeling using a Chartered $0.18{\mu}m$ CMOS process, we verified the functionalities and timing behavior of the clock predictor and the synchronizer. The simulation results show that the clock predictor produces a predicted clock before a synchronization failure, and the synchronizer samples data correctly using the predicted clock.

Readjustment of circadian clocks by exercise intervention is a potential therapeutic target for sleep disorders: a narrative review

이광준,홍광석,박종훈,박원일 한국운동영양학회 2024 Physical Activity and Nutrition (Phys Act Nutr) Vol.28 No.2

[Purpose] Circadian clocks are evolved endogenous biological systems that communicate with environmental cues to optimize physiological processes, such as the sleep-wake cycle, which is nearly related to quality of life. Sleep disorders can be treated using pharmacological strategies targeting melatonin, orexin, or core clock genes. Exercise has been widely explored as a behavioral treatment because it challenges homeostasis in the human body and affects the regulation of core clock genes. Exercise intervention at the appropriate time of the day can induce a phase shift in internal clocks. Although exercise is a strong external time cue for resetting the circadian clock, exercise therapy for sleep disorders remains poorly understood. [Methods] This review focused on exercise as a potential treatment for sleep disorders by tuning the internal circadian clock. We used scientific paper depositories, including Google Scholar, PubMed, and the Cochrane Library, to identify previous studies that investigated the effects of exercise on circadian clocks and sleep disorders. [Results] The exercise-induced adjustment of the circadian clock phase depended on exercise timing and individual chronotypes. Adjustment of circadian clocks through scheduled morning exercises can be appropriately prescribed for individuals with delayed sleep phase disorders. Individuals with advanced sleep phase disorders can synchronize their internal clocks with their living environment by performing evening exercises. Exercise-induced physiological responses are affected by age, sex, and current fitness conditions. [Conclusion] Personalized approaches are necessary when implementing exercise interventions for sleep disorders.