Interlocked Loops Research Articles

Low cost and high performance double‐node upset resilient latch for low orbit space applications

SummaryThis paper proposes a double‐node upset complete resilient (DNUCR) latch to meet the requirements of low orbit space applications for high robustness, cost‐effectiveness, and high performance. With the help of its interlocked loops with multiple feedbacks consisting of C‐elements (CE), input splitting CEs, 1P‐2N and 2P‐1N elements, and inverters, the proposed DNUCR latch preserves the original data even after the radiation incident. Error injection simulations in Synopsys HSPICE show that the proposed DNUCR latch recovers from all DNUs and can withstand large amount of injected charge. The simulation outcomes further show that the proposed DNUCR latch outperforms existing DNU‐resilient latches in terms of delay, power consumption, and power–delay–area product (PDAP), with an average of 48% reduction in delay, 22% savings in power, and 60% reduction in PDAP. The proposed DNUCR latch is also found to be the best among the existing radiation‐hardened latches in terms of charge‐to‐PDAP ratio.

A triple-node upset self-healing latch for high speed and robust operation in radiation-prone harsh-environment

With continuous advancement in technology, latches have become highly susceptible to radiation induced soft-errors such as multi-node-upsets (MNU). To effectively resilient the MNUs, this work presents a triple-node-upset (TNU) self-healing (TNUSH) latch, which performs robust operation in harsh radiation environment. The TNUSH latch mainly employs Muller C-elements and is segmented as storage cells, feedback interceptors, and the healer, forming multi-feedback interlocked loops to retain the original data after a radiation event. The self-healing capability of the proposed latch is successfully validated by the fault-injection simulation using Synopsys HSPICE. Simulation results show that the proposed latch offers highest speed of operation and has the lowest cost in terms of the power-delay-area-product (PDAP) among the existing TNU resilient latches. The proposed latch saves up to 26.64 % power and 18.47 % area compared to TNU resilient TNURL, and 92.21 % time and 88.33 % PDAP compared to the TNUTL, which is not resilient to TNU. Robustness of the proposed latch against process, voltage, and temperature variation is further assessed by Monte-Carlo simulations.

Implications of styrenic triblock copolymer gel mechanics on midblock bridging fraction

Triblock copolymer gels have garnered considerable scientific interest over the past few decades and are used in a variety of applications including consumer cushioning, pressure-sensitive adhesives, and ballistics gels. While many of their applications rely upon understanding mechanical properties, mechanical studies of block copolymer gels are relatively disjointed with each focusing on specific copolymers, which inherently have a fixed molecular weight and composition. The present study examines the quasistatic mechanical response of styrenic triblock copolymer gels composed of seven unique triblock copolymers at various concentrations. Resultant stress-extension data is fitted with the slip-tube network (STN) theory that describes gel mechanics based upon crosslinked network (Gc) and chain entanglement (Ge) modulus contributions. Collectively, modulus contributions imply that midblock bridging is independent of copolymer identity (i.e., molecular weight and block fraction) and dependent on triblock copolymer concentration via Fb ∝ φABA0.91±0.39 over the concentration range examined (φABA = 0.05–0.39). Gels composed of a complementary diblock-triblock copolymer pair were subsequently analyzed to explore the influence of interlocking loop-loop and loop-bridge pairs within the effective midblock bridging population. These results point to the presence of a physically significant quantity of interlocked loops, but quantitative analysis was inconclusive.

Uncovering the dynamics of a circadian-dopamine model influenced by the light–dark cycle

The neurotransmitter dopamine (DA) is known to be influenced by the circadian timekeeping system in the mammalian brain. We have previously created a single-cell differential equations model to understand the mechanisms behind circadian rhythms of extracellular DA. In this paper, we investigate the dynamics in our model and study different behaviors such as entrainment to the 24-hour light–dark cycle and robust periodicity versus decoupling, quasiperiodicity, and chaos. Imbalances in DA are often accompanied by disrupted circadian rhythms, such as in Parkinson’s disease, hyperactivity, and mood disorders. Our model provides new insights into the links between the circadian clock and DA. We show that the daily rhythmicity of DA can be disrupted by decoupling between interlocked loops of the clock circuitry or by quasiperiodic clock behaviors caused by misalignment with the light–dark cycle. The model can be used to further study how the circadian clock affects the dopaminergic system, and to help develop therapeutic strategies for disrupted DA rhythms.

A Highly Robust and Low-Power Real-Time Double Node Upset Self-Healing Latch for Radiation-Prone Applications

This work presents a single event double node upset (SEDNU) self-healing (DNUSH) latch to meet the high-robustness requirement of the applications used in a harsh radiation environment. The DNUSH latch is based on dual modular redundancy and mainly employs C-elements and inverters, forming multi-feedback interlocked loops to retain the correct data even after the radiation event. The self-healing capability of the proposed latch is successfully shown by the fault injection simulation using Synopsys HSPICE. Simulation results show that the proposed latch can self-heal from all SEDNUs, consumes low power even for high-speed operations, and has the least power-delay-area product (PDAP) compared to the existing SEDNU resilient latches. The proposed latch offers on average 51.25% improvement in speed, 22.67% saving in power consumption, and 59.74% lower PDAP compared to the existing SEDNU resilient latches. In addition, the sensitivity assessment of the proposed latch against the process, voltage, and temperature (PVT) variations are found to be either low or equivalent to the reference latches.

An Esrrb and Nanog Cell Fate Regulatory Module Controlled by Feed Forward Loop Interactions

Cell fate decisions during development are governed by multi-factorial regulatory mechanisms including chromatin remodeling, DNA methylation, binding of transcription factors to specific loci, RNA transcription and protein synthesis. However, the mechanisms by which such regulatory “dimensions” coordinate cell fate decisions are currently poorly understood. Here we quantified the multi-dimensional molecular changes that occur in mouse embryonic stem cells (mESCs) upon depletion of Estrogen related receptor beta (Esrrb), a key pluripotency regulator. Comparative analyses of expression changes subsequent to depletion of Esrrb or Nanog, indicated that a system of interlocked feed-forward loops involving both factors, plays a central part in regulating the timing of mESC fate decisions. Taken together, our meta-analyses support a hierarchical model in which pluripotency is maintained by an Oct4-Sox2 regulatory module, while the timing of differentiation is regulated by a Nanog-Esrrb module.

MazEF Toxin-Antitoxin System-Mediated DNA Damage Stress Response in Deinococcus radiodurans.

Deinococcus radiodurans shows marked resistance to various types of DNA-damaging agents, including mitomycin C (MMC). A type II toxin-antitoxin (TA) system that responds to DNA damage stress was identified in D. radiodurans, comprising the toxin MazF-dr and the antitoxin MazE-dr. The cleavage specificity of MazF-dr, an endoribonuclease, was previously characterized. Here, we further investigated the regulatory role of the MazEF system in the response to DNA damage stress in D. radiodurans. The crystal structure of D. radiodurans MazF (MazF-dr) was determined at a resolution of 1.3 Å and is the first structure of the toxin of the TA system of D. radiodurans. MazF-dr forms a dimer mediated by the presence of interlocked loops. Transcriptional analysis revealed 650 downregulated genes in the wild-type (WT) strain, but not in the mazEF mutant strain, which are potentially regulated by MazEF-dr in response to MMC treatment. Some of these genes are involved in membrane trafficking and metal ion transportation. Subsequently, compared with the WT strain, the mazEF mutant strain exhibited much lower MMC-induced intracellular iron concentrations, reactive oxygen species (ROS), and protein carbonylation levels. These results provide evidence that MazEF-mediated cell death in D. radiodurans might be caused by an increase in ROS accumulation upon DNA damage stress.

Çin'in Zhou Hanedanlığı Döneminde Ritüel ve Müzik Sistemi'nin Yükselişi ve Zayıflaması: Tarihsel Süreçte İnsan ve Medeniyetin Karşılıklı Etkileşimi

Bir toplumun iyi gelişip gelişemeyeceği; o toplumun siyasi, dini, kültürel ve sosyal açıdan tamamlayıcı ve başarılı bir sisteme sahip olup olmadığına bağlıdır. Toplumda böyle bir sistemin formüle edilip gereğince uygulanabilmesinin temel şartı, sistemin kurucusu olan insanın iyi bir tabiata sahip olabilmesiyle alâkalıdır. İnsan karakterinin iyiye eğilim göstermesi ise öncelikle kendi tabiatına yönelik yapacağı içsel gözlem ve sonra da insan doğasının temel kaynağına dair sahip olabildiği doğru anlayışa bağlıdır. Bu prensibin, tarihsel dönem ve kültürel yapı ayırmaksızın tüm toplumlar için geçerli olduğunu söylemek mümkündür. Çin medeniyetine temel oluşturan antik Zhou Hanedanlığı'nda siyasi ve sosyal yaşamı düzenleyen Ritüel ve Müzik Sistemi ve sistemin yönetim ile toplum üzerindeki etkileri, bu prensibi doğrulayan en iyi örneklerden biridir. Çin kültür tarihinin en önemli kaidelerinden biri olan Ritüel ve Müzik Sistemi, temelinde dinsel törenlerden kültürel etkinliklere ve siyasi uygulamalara kadar çok geniş bir yelpazede insanlar arası ilişkileri düzenleyen kaideleri içermiş; müzikse bu kaidelerin belirlenmesi ve uygulanması esnasında çok önemli bir rol üstlenmiştir. Bu makalede, Ritüel ve Müzik Sistemi'nin uygulanış süreci ile sistemin yükselişine ve zayıflamasına neden olan etkenler, insan ve medeniyet arasındaki ilişki perspektifinden ele alınarak incelenmiştir. Bu bağlamda çalışmada öncelikle Zhou Hanedanlığı Ritüel ve Müzik Sistemi'ne temel oluşturan tarihsel süreç; sistemin ortaya çıktığı, ilkel yaşam biçimine en yakın olan Beş Hükümdar Dönemi ile bu dönemi takip eden ve uygarlığın gelişim gösterdiği Xia ve Shang Hanedanlıkları kapsamında ele alınarak değerlendirilmiştir. Zhou Hanedanlığı kurucusu Zhou Gong, Shang Handanlığı'nın yıkılmasının sebeplerinden önemli dersler çıkararak zayıflayan Ritüel ve Müzik Sistemi'ni yeniden düzenlemiş ve Shang Dönemi'nde önemini yitirmiş olan ideal insan, ideal toplum hayalini gerçekleştirmeyi başarmıştır. Ancak, Zhou Hanedanlığı'nın ilerleyen dönemlerinde yönetici tabakasındaki ruhsal yozlaşma sistemin zayıflamasına sebep olmuş, bu da toplumsal düzenin tekrar bozulmasıyla sonuçlanmıştır. Bu dönemde toplumsal karmaşaya çözüm üretmek için ortaya çıkan düşünürler, bozulan sistemin uygulama yöntemlerinden çok, özüne yönelik kapsamlı ve derin eleştiriler getirmişlerdir. Bu bağlamda, çalışmanın devamında Ritüel ve Müzik Sistemi'nin öz ve içeriğine yönelik şu sorulara cevap aranmıştır: Ritüeller ve Müzik arasındaki ideal uyum ve denge ilişkisi nasıldır? İdeal sistemde Ritüel ve Müzik arasındaki önem sıralaması nedir? Doğa, insan, sistem ve toplum arasında birbirini var eden döngü ilişkisi nasıl kurulmuştur? Sistem hangi şartlarda başarılı, hangi şartlarda başarısız olmuştur?

Conserved Conformational Changes in the Regulation of Mycobacterium tuberculosis MazEF-mt1

Toxin-antitoxin (TA) systems, which regulate many important cellular processes, are abundantly present in prokaryotic organisms. MazEF is a common type of TA system implicated in the formation of "persisters cells" of the pathogen Mycobacterium tuberculosis, which contains 10 such systems. However, the exact function and inhibition mode of each MazF protein are not quite understood. Here, we report four high-resolution crystal structures of MazF-mt1 in various forms, including one in complex with MazE-mt1. The toxin displayed two unique interlocked loops that allow the formation of a tight dimer. These loops would open upon interacting with the MazE-mt1 antitoxin mediated by the last two helices of MazE-mt1. With our structure-based design, a mutant that could bind to the antitoxin with an enhanced affinity was produced. Combined crystallographic and biochemical studies further revealed that the binding affinity of MazE-mt1 to MazF-mt1 was mainly attributed to its α3 helical region, while the terminal helix η1 contributes very little or even negatively to the association of the pair, in stark contrast to the MazEF-mt9 system. This study provides structural insight into the binding mode and the inhibition mechanism of the MazE/F-mt1 TA pair, which may reflect the functional differences between different TA systems.

NRF2 regulates core and stabilizing circadian clock loops, coupling redox and timekeeping in Mus musculus.

Diurnal oscillation of intracellular redox potential is known to couple metabolism with the circadian clock, yet the responsible mechanisms are not well understood. We show here that chemical activation of NRF2 modifies circadian gene expression and rhythmicity, with phenotypes similar to genetic NRF2 activation. Loss of Nrf2 function in mouse fibroblasts, hepatocytes and liver also altered circadian rhythms, suggesting that NRF2 stoichiometry and/or timing of expression are important to timekeeping in some cells. Consistent with this concept, activation of NRF2 at a circadian time corresponding to the peak generation of endogenous oxidative signals resulted in NRF2-dependent reinforcement of circadian amplitude. In hepatocytes, activated NRF2 bound specific enhancer regions of the core clock repressor gene Cry2, increased Cry2 expression and repressed CLOCK/BMAL1-regulated E-box transcription. Together these data indicate that NRF2 and clock comprise an interlocking loop that integrates cellular redox signals into tissue-specific circadian timekeeping.

Positive And Negative Feedback Loops Coupled By Common Transcription Activator And Repressor

AbstractDynamical systems consisting of two interlocked loops with negative and positive feedback have been studied using the linear analysis of stability and numerical solutions. Conditions for saddle-node bifurcation were formulated in a general form. Conditions for Hopf bifurcations were found in a few symmetrical cases. Auto-oscillations, when they exist, are generated by the negative feedback repressive loop. This loop determines the frequency and amplitude of oscillations. The positive feedback loop of activation slightly modifies the oscillations. Oscillations are possible when the difference between Hilll’s coefficients of the repression and activation is sufficiently high. The highly cooperative activation loop with a fast turnover slows down or even makes the oscillations impossible. The system under consideration can constitute a component of epigenetic or enzymatic regulation network.

Interlocked loops trigger lineage specification and stable fates in the Drosophila nervous system.

Multipotent precursors are plastic cells that generate different, stable fates at the correct number, place and time, to allow tissue and organ formation. While fate determinants are known to trigger specific transcriptional programs, the molecular pathway driving the progression from multipotent precursors towards stable and specific identities remains poorly understood. Here we demonstrate that, in Drosophila neural precursors, the glial determinant glial cell missing (Gcm) acts as a 'time bomb' and triggers its own degradation once the glial programme is stably activated. This requires a sequence of transcriptional and posttranscriptional loops, whereby a Gcm target first affects the expression and then acetylation of the fate determinant, thus controlling Gcm levels and stability over time. Defective homeostasis between the loops alters the neuron:glia ratio and freezes cells in an intermediate glial/neuronal phenotype. In sum, we identify an efficient strategy triggering cell identity, a process altered in pathological conditions such as cancer.

Novel mechanism of hexamer ring assembly in protein/RNA interactions revealed by single molecule imaging

Many nucleic acid-binding proteins and the AAA+ family form hexameric rings, but the mechanism of hexamer assembly is unclear. It is generally believed that the specificity in protein/RNA interaction relies on molecular contact through a surface charge or 3D structure matching via conformational capture or induced fit. The pRNA of bacteriophage phi29 DNA-packaging motor also forms a ring, but whether the pRNA ring is a hexamer or a pentamer is under debate. Here, single molecule studies elucidated a mechanism suggesting the specificity and affinity in protein/RNA interaction relies on pRNA static ring formation. A combined pRNA ring-forming group was very specific for motor binding, but the isolated individual members of the ring-forming group bind to the motor nonspecifically. pRNA did not form a ring prior to motor binding. Only those RNAs that formed a static ring, via the interlocking loops, stayed on the motor. Single interlocking loop interruption resulted in pRNA detachment. Extension or reduction of the ring circumference failed in motor binding. This new mechanism was tested by redesigning two artificial RNAs that formed hexamer and packaged DNA. The results confirmed the stoichiometry of pRNA on the motor was the common multiple of two and three, thus, a hexamer.

A biomechanical comparison of six different double loop configurations for use in the lateral fabella suture technique

Six different double loop configurations which could be applied to the lateral fabella suture (LFS) technique were subjected to in vitro mechanical testing. Three double loop, single strand and three double loop, double strand configurations were tested. The strongest configuration, with a significantly higher mean ultimate load and load at yield, was the interlocking loop configuration. This is a novel configuration which has not previously been reported. The three double loop, single strand configurations all had higher mean ultimate loads than the double loop, double strand configurations. The double strand group with uneven loop length performed very poorly, with significantly lower mean stiffness and ultimate load than all of the single strand groups. This group also developed unacceptably high levels of elongation during high level cyclic loading.

A Time to Divide: Does the Circadian Clock Control Cell Cycle?

A variety of molecular, genomic and epidemiological evidence has linked cell cycle regulation to circadian rhythms. In a recent issue of Molecular Cell, Koeffler and colleagues show that PER1 sensitizes human cancer cells to ionizing radiation-induced apoptosis. In addition, PER1 expression was found to be downregulated in human tumors, suggesting a tumor suppressor role for the PER1 protein. The significance of PERs, clocks, and cell cycle control is discussed.

Interactivating Feedback Loops within the Mammalian Clock: BMAL1 Is Negatively Autoregulated and Upregulated by CRY1, CRY2, and PER2

Transcriptional regulation appears to be fundamental to circadian oscillations of clock gene expression. These oscillations are believed to control output rhythms. The transcriptional feedback loop and a model of interlocked loops have been proposed as the basis for these oscillations. We characterized the genomic structure of the mouse Bmal1 gene (mBmal1) and defined the mBmal1 promoter region. Transcription of mBmal1 was activated by CRY1, CRY2, and PER2, and was repressed by BMAL1-CLOCK dimers. Therefore, CRY, PER2, and BMAL1-CLOCK play bidirectional roles in transcription when they are at high levels by late day and midnight, respectively. This underlies the opposite phase of BMAL1 compared to CRY and PER. We propose that a BMAL1 negative feedback loop interlocks with the CRY and PER2 negative feedback loop by inter-activation, forming a third positive forward loop. This transcriptional model suggests a molecular basis for the maintenance of stability, persistence, and period of circadian rhythms. The transcriptional potency of CRY is predominant within the mammalian clock, suggesting a clearance mechanism for CRY in period maintenance.

Interconnected feedback loops in the Neurospora circadian system.

In Neurospora crassa, white collar 1 (WC-1), a transcriptional activator and positive clock element, is rhythmically expressed from a nonrhythmic steady-state pool of wc-1 transcript, consistent with posttranscriptional regulation of rhythmicity. Mutations in frq influence both the level and periodicity of WC-1 expression, and driven FRQ expression not only depresses its own endogenous levels, but positively regulates WC-1 synthesis with a lag of about 8 hours, a delay similar to that seen in the wild-type clock. FRQ thus plays dual roles in the Neurospora clock and thereby, with WC-1, forms a second feedback loop that would promote robustness and stability in this circadian system. The existence also of interlocked loops in Drosophila melanogaster and mouse clocks suggests that such interlocked loops may be a conserved aspect of circadian timing systems.