Recent work suggests that DNA replication origins are regulated by the number of multiple mini‐chromosome maintenance (MCM) complexes loaded. Origins are defined by the loading of MCM – the replicative helicase which initiates DNA replication and replication kinetics determined by origin's location and firing times. However, activation of MCM is heterogeneous; different origins firing at different times in different cells. Also, more MCMs are loaded in G1 than are used in S phase. These aspects of MCM biology are explained by (...) the observation that multiple MCMs are loaded at origins. Having more MCMs at early origins makes them more likely to fire, effecting differences in origin efficiency that define replication timing. Nonetheless, multiple MCM loading raises new questions, such as how they are loaded, where these MCMs reside at origins, and how their presence affects replication timing. In this review, we address these questions and discuss future avenues of research. (shrink)

The regulatory mechanism which ensures that eukaryotic chromosomes replicate precisely once per cell cycle is a basic and essential cellular property of eukaryotes. This fundamental aspect of DNA replication is still poorly understood, but recent advances encourage the view that we may soon have a clearer picture of how this regulation is achieved. This review will discuss in particular the role of proteins in the minichromosome maintenance (MCM) family, which may hold the key to understanding how DNA is replicated once, (...) and only once, per cell cycle. (shrink)

Eukaryotic DNA replication initiates at multiple origins. In early fly and frog embryos, chromosomal replication is very rapid and initiates without sequence specificity. Despite this apparent randomness, the spacing of these numerous initiation sites must be sufficiently regular for the genome to be completely replicated on time. Studies in various eukaryotes have revealed that there is a strict temporal separation of origin “licensing” prior to S phase and origin activation during S phase. This may suggest that replicon size must be (...) already established at the licensing stage. However, recent experiments suggest that a large excess of potential origins are assembled along chromatin during licensing. Thus, a regular replicon size may result from the selection of origins during S phase. We review single molecule analyses of origin activation and other experiments addressing this issue and their general significance for eukaryotic DNA replication. BioEssays 25:116–125, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Myc‐driven tumorigenesis involves a non‐transcriptional role for Myc in over‐activating replicative Cdc45‐MCM‐GINS (CMG) helicases. Excessive stimulation of CMG helicases by Myc mismanages CMG function by diminishing the number of reserve CMGs necessary for fidelity of DNA replication and recovery from replicative stresses. One potential outcome of these events is the creation of DNA damage that alters genomic structure/function, thereby acting as a driver for tumorigenesis and tumor heterogeneity. Intriguingly, another potential outcome of this Myc‐induced CMG helicase over‐activation is the creation (...) of a vulnerability in cancer whereby tumor cells specifically lack enough unused reserve CMG helicases to recover from fork‐stalling drugs commonly used in chemotherapy. This review provides molecular and clinical support for this provocative hypothesis that excessive activation of CMG helicases by Myc may not only drive tumorigenesis, but also confer an exploitable “reserve CMG helicase vulnerability” that supports developing innovative CMG‐focused therapeutic approaches for cancer management. (shrink)

During each school semester, students face an onslaught of material to be learned. Students work hard to achieve initial mastery of the material, but when they move on, the newly learned facts, concepts, and skills degrade in memory. Although both students and educators appreciate that review can help stabilize learning, time constraints result in a trade-off between acquiring new knowledge and preserving old knowledge. To use time efficiently, when should review take place? Experimental studies have shown benefits to long-term retention (...) with spaced study, but little practical advice is available to students and educators about the optimal spacing of study. The dearth of advice is due to the challenge of conducting experimental studies of learning in educational settings, especially where material is introduced in blocks over the time frame of a semester. In this study, we turn to two established models of memory—ACT-R and MCM—to conduct simulation studies exploring the impact of study schedule on long-term retention. Based on the premise of a fixed time each week to review, converging evidence from the two models suggests that an optimal review schedule obtains significant benefits over haphazard (suboptimal) review schedules. Furthermore, we identify two scheduling heuristics that obtain near optimal review performance: (a) review the material from μ-weeks back, and (b) review material whose predicted memory strength is closest to a particular threshold. The former has implications for classroom instruction and the latter for the design of digital tutors. (shrink)

Minichromosome maintenance (Mcm) proteins are well‐known for their functions in DNA replication. However, their roles in chromosome segregation are yet to be reviewed in detail. Following the discovery in 1984, a group of Mcm proteins, known as the ARS‐nonspecific group consisting of Mcm13, Mcm16‐19, and Mcm21‐22, were characterized as bonafide kinetochore proteins and were shown to play significant roles in the kinetochore assembly and high‐fidelity chromosome segregation. This review focuses on the structure, function, and evolution of this group of Mcm (...) proteins. Our in silico analysis of the physical interactors of these proteins reveals that they share non‐overlapping functions despite being copurified in biochemically stable complexes. We have discussed the contrasting results reported in the literature and experimental strategies to address them. Taken together, this review focuses on the structure‐function of the ARS‐nonspecific Mcm proteins and their evolutionary flexibility to maintain genome stability in various organisms. (shrink)

In this review I describe research conducted in my laboratory concerning implicit mood-congruent memory (MCM) bias in clinical depression. MCM is the tendency for depressed individuals to retrieve more unpleasant information from memory than nondepressed controls, and may be an important maintenance mechanism in depression. MCM has been studied frequently with explicit memory tests, but relatively few studies have investigated MCM using implicit memory tests. I describe several implicit memory studies which show that: (a) an implicit MCM bias does not (...) appear to exist when perceptually driven tests are used; (b) implicit memory bias can be found when conceptually driven tests are used, but (c) not all conceptually driven tests show implicit MCM bias. I conclude that conceptual processing is necessary, but is not sufficient for demonstrating implicit memory bias in depression. Future studies should investigate specific components of conceptual elaboration that support implicit memory bias in depression. (shrink)

The purpose of this essay is to critically review the design of methods for ethically robust forms of technology appraisal in the regulation of research and innovation in synthetic biology. It will focus, in particular, on the extent to which cost‐benefit analysis offers a basis for informing decisions about which technological pathways to pursue and which to discourage. A further goal is to consider what (if anything) the precautionary principle might offer in enabling better decisions. And this, in turn, raises (...) questions about why mention of precaution can excite accusations of unscientific bias or irrational, “anti‐innovation” extremism. What does the polarized debate tell us about the politics around synthetic biology? In seeking more rigorous, timely, and practical ways to govern these remarkable new technologies, what might we be missing?The sophistication, diversity, and scope of synthetic biology may seem to make it a rather idiosyncratic area for exploring these general issues. It may seem to be a special case, with the bewildering pace of change amplifying the difficulties. But at root, some of the trickiest issues are just specific instances of familiar and long‐standing conundrums in the governance of science and technology. The basic challenge is how to weigh up, for a wide range of potential options, the various pros and cons, as viewed from divergent perspectives, and find a way to justify the best course of action on behalf of society as a whole. This is the central problem addressed by a number of techniques in CBA. On the face of it, synthetic biology seems to present just one more application of these well‐established and self‐confident prescriptive methods.But there do emerge several obstinate, even prohibitive, difficulties for CBA. Although they are well acknowledged by the scholarly literature on and around this topic, they are often sidelined in practice. Yet all are central to the case for applying the concept of precaution to a field like synthetic biology. This essay will briefly explore multicriteria mapping, an appraisal method for exploring contrasting perspectives on emerging technologies, as one practical way to address them. The essay focuses on MCM, not because it presents any sort of panacea for appraisal, but because it is illustrative of the concrete implications of precaution. Setting out even just one among potentially many practical alternative methods at least refutes the last‐ditch argument that CBA is the only operational choice. (shrink)

Preparing for and responding to public health emergencies involving medical countermeasures raise often complex legal challenges and questions among response stakeholders at the local, state, and federal levels. This includes concerns about emergency legal authorities, liability, emergency use of regulated medical products, and regulations that might enhance or hinder public health response goals. In this article, lawyers from the U.S. Department of Health and Human Services’ Office of the General Counsel , Centers for Disease Control and Prevention , and Food (...) and Drug Administration discuss federal legal tools that are critical to enhancing MCM legal preparedness for public health emergencies, with an emphasis on the legal mechanisms that can be used to facilitate the emergency use of countermeasures. Specifically, the authors describe the Public Readiness and Emergency Preparedness Act and Emergency Use Authorization authority, outlining the conditions under which these tools can be utilized and providing examples of how they have supported both pre-event and intra-event activities. (shrink)

User location prediction in location-based social networks can predict the density of people flow well in terms of intelligent transportation, which can make corresponding adjustments in time to make traffic smooth, reduce fuel consumption, reduce greenhouse gas emissions, and help build a green cycle low-carbon transportation green system. This paper proposes a Markov chain position prediction model based on multidimensional correction. Firstly, extract corresponding information from the user’s historical check-in position sequence as a position-position conversion map. Secondly, the influence of (...) check-in period, space distance, and other factors on the position prediction is linearly weighted and merged with the position prediction of the n-order Markov chain to construct MDC-MCM. Finally, we conduct a comprehensive performance evaluation of MDC-MCM using the dataset collected from Brightkite. Experimental results show that compared with other advanced location prediction technologies, MDC-MCM achieves better location prediction results. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:RUSSEL:rS ANTI-COMMUNIST RHETORIC BEFORE AND AFTER STALIN'S DEATH STEPHEN HAYHURST History / Copenhagen International School Copenhagen, Denmark 1100 A communist regimes collapse in Eastern Europe, and the rhetoric of the Cold War is at last abandoned, it seems an appropriate time to examine an aspect of Bertrand Russell's political life and thought which has not been as well documented as, for example, his activities in the First World War (...) or the 1960s. In the decade following the end of the Second World War Russell could, with some justification, be accused of contributing to Cold War mistrust, and even of playing the role of a "Cold War Warrior". Between 1945 and 1953 not only was Russell, as he himself later admitted, well entrenched as part of the "Establishment", but he was also actively involved in denouncing Communism, Stalin, the Soviet Union, and at times even the Russian people. Russell's Cold War invective intruded into his private letters, newspaper and magazine articles, public lectures and some of his books during this period. For example, What is Freedom? and What is Democracy?, whilst not the best remembered of Russell's books, are illustrative of his vehement hatred of Stalin's regime, and are of especial interest because they underwent small but significant revisions after Stalin's death. This brief survey of Russell's anti-Stalinism is, by necessity, highly selective, and has intentionally focussed on some of Russell's more extreme statements. A much more comprehensive study would be necessary to analyze the overall significance of Russell's anti-Stalinism. Russell's political thought in the years immediately after the end of the Second World War is dominated by what has been called his "preventative war phase". His proposal that the Soviet Union should be ru II: the Journal of the Bertrand Russell Archives McM rer University Libraty Press n.s. II (summer 1991): 67-81 ISSN 0031>-01631 68 STEPHEN HAYHURST pressured into signing the Baruch Plan for the international control of nuclear weapons, was made on at least twelve separate occasions between 1945 and 1949 and was, he later confessed, "the worst thing" he ever said.I This episode, characterized by controversy, proposals, denials and counter-denials, and reasonably well discussed by both critics and commentators, has direct relevance to Russell's anti-communist rhetoric.2 His prescient awareness of the staggering implications of nuclear weapons led him to demand, within two weeks of the destruction of Hiroshima, the urgent implementation of some procedure of international control.3 Since the First World War Russell had always maintained a vigorous belief in the long-term necessity of world government. Although this internationalism had been a central component of Russell's political thought, it had remained at least until 1945, at the level of a political ideal rather than a concrete proposal. In his more pessimistic moods, Russell had maintained that it would only arise through American hegemony, and at all times he had argued that a world government would only be effective if it possessed a monopoly ofweapons.4 Suddenly with the development of the atomic bomb, conditions had changed. Until 1949 the United States had a monopoly of this new monstrous weapon. Despite his very mixed views about both American political ideology and practice, Russell now clearly looked to the United States for international leadership. From the outset he accepted that international control of the bomb may not arise voluntarily. In October 1945 he wrote, "I think a world government supremely important, and I do not expect to see it established without I The twelve occasions are set out in I. F. Stone, "Bertrand Russell as a Moral Force in World Politics", Russell, n.s. I (1981): 7-25. Interview by Cedric Belfrage in the National Guardian, New York, 8, no. 35 (18 June 1956): 6. 2 Clark: D. P. Lackey, "Russell's Contribution to the Study of Nuclear Weapons Policy", Russell, n.s. 4 (1984): 243-52; Alan Ryan, Bertrand Russell, a Political Lift (London: Allen Lane the Penguin P., 1988): Stone, "Bertrand Russell as a Moral Force in World Politics~'. l "The Bomb and Civilization", Forward. Glasgow, 39, no. 33 (18 Aug. 1945): I, 3... (shrink)

The regulation of DNA replication is a fascinating biological problem both from a mechanistic angle—How is replication timing regulated?—and from an evolutionary one—Why is replication timing regulated? Recent work has provided significant insight into the first question. Detailed biochemical understanding of the mechanism and regulation of replication initiation has made possible robust hypotheses for how replication timing is regulated. Moreover, technical progress, including high‐throughput, single‐molecule mapping of replication initiation and single‐cell assays of replication timing, has allowed for direct testing of (...) these hypotheses in mammalian cells. This work has consolidated the conclusion that differential replication timing is a consequence of the varying probability of replication origin initiation. The second question is more difficult to directly address experimentally. Nonetheless, plausible hypotheses can be made and one—that replication timing contributes to the regulation of chromatin structure—has received new experimental support. (shrink)