Single-molecule dynamics reveals cooperative binding-folding in protein recognition

The study of associations between two biomolecules is the key to understanding molecular function and recognition. Molecular function is often thought to be determined by underlying structures. Here, combining a single-molecule study of protein binding with an energy-landscape-inspired microscopic model, we found strong evidence that biomolecular recognition is determined by flexibilities in addition to structures. Our model is based on coarse-grained molecular dynamics on the residue level with the energy function biased toward the native binding structure ( the Go model). With our model, the underlying free-energy landscape of the binding can be explored. There are two distinct conformational states at the free-energy minimum, one with partial folding of CBD itself and significant interface binding of CBD to Cdc42, and the other with native folding of CBD itself and native interface binding of CBD to Cdc42. This shows that the binding process proceeds with a significant interface binding of CBD with Cdc42 first, without a complete folding of CBD itself, and that binding and folding are then coupled to reach the native binding state.

Application-Level Document Caching in the Internet

With the increasing demand for document transfer services such as the World Wide Web comes a need for better resource management to reduce the latency of documents in these systems. To address this need, we analyze the potential for document caching at the application level in document transfer services. We have collected traces of actual executions of Mosaic, reflecting over half a million user requests for WWW documents. Using those traces, we study the tradeoffs between caching at three levels in the system, and the potential for use of application-level information in the caching system. Our traces show that while a high hit rate in terms of URLs is achievable, a much lower hit rate is possible in terms of bytes, because most profitably-cached documents are small. We consider the performance of caching when applied at the level of individual user sessions, at the level of individual hosts, and at the level of a collection of hosts on a single LAN. We show that the performance gain achievable by caching at the session level (which is straightforward to implement) is nearly all of that achievable at the LAN level (where caching is more difficult to implement). However, when resource requirements are considered, LAN level caching becomes much more desirable, since it can achieve a given level of caching performance using a much smaller amount of cache space. Finally, we consider the use of organizational boundary information as an example of the potential for use of application-level information in caching. Our results suggest that distinguishing between documents produced locally and those produced remotely can provide useful leverage in designing caching policies, because of differences in the potential for sharing these two document types among multiple users.

Accelerating Internet Streaming Media Delivery Using Network-Aware Partial Caching

Internet streaming applications are adversely affected by network conditions such as high packet loss rates and long delays. This paper aims at mitigating such effects by leveraging the availability of client-side caching proxies. We present a novel caching architecture (and associated cache management algorithms) that turn edge caches into accelerators of streaming media delivery. A salient feature of our caching algorithms is that they allow partial caching of streaming media objects and joint delivery of content from caches and origin servers. The caching algorithms we propose are both network-aware and stream-aware; they take into account the popularity of streaming media objects, their bit-rate requirements, and the available bandwidth between clients and servers. Using realistic models of Internet bandwidth (derived from proxy cache logs and measured over real Internet paths), we have conducted extensive simulations to evaluate the performance of various cache management alternatives. Our experiments demonstrate that network-aware caching algorithms can significantly reduce service delay and improve overall stream quality. Also, our experiments show that partial caching is particularly effective when bandwidth variability is not very high.

GreenCoop: Cooperative Green Routing with Energy-efficient Servers

Energy-efficient communication has recently become a key challenge for both researchers and industries. In this paper, we propose a new model in which a Content Provider and an Internet Service Provider cooperate to reduce the total power consumption. We solve the problem optimally and compare it with a classic formulation, whose aim is to minimize user delay. Results, although preliminary, show that power savings can be huge: up to 71% on real ISP topologies. We also show how the degree of cooperation impacts overall power consumption. Finally, we consider the impact of the Content Provider location on the total power savings.

Changes in Web Client Access Patterns: Characteristics and Caching Implications

Understanding the nature of the workloads and system demands created by users of the World Wide Web is crucial to properly designing and provisioning Web services. Previous measurements of Web client workloads have been shown to exhibit a number of characteristic features; however, it is not clear how those features may be changing with time. In this study we compare two measurements of Web client workloads separated in time by three years, both captured from the same computing facility at Boston University. The older dataset, obtained in 1995, is well-known in the research literature and has been the basis for a wide variety of studies. The newer dataset was captured in 1998 and is comparable in size to the older dataset. The new dataset has the drawback that the collection of users measured may no longer be representative of general Web users; however using it has the advantage that many comparisons can be drawn more clearly than would be possible using a new, different source of measurement. Our results fall into two categories. First we compare the statistical and distributional properties of Web requests across the two datasets. This serves to reinforce and deepen our understanding of the characteristic statistical properties of Web client requests. We find that the kinds of distributions that best describe document sizes have not changed between 1995 and 1998, although specific values of the distributional parameters are different. Second, we explore the question of how the observed differences in the properties of Web client requests, particularly the popularity and temporal locality properties, affect the potential for Web file caching in the network. We find that for the computing facility represented by our traces between 1995 and 1998, (1) the benefits of using size-based caching policies have diminished; and (2) the potential for caching requested files in the network has declined.

Popularity-Aware GreedyDual-Size Web Proxy Caching Algorithms

Web caching aims to reduce network traffic, server load, and user-perceived retrieval delays by replicating "popular" content on proxy caches that are strategically placed within the network. While key to effective cache utilization, popularity information (e.g. relative access frequencies of objects requested through a proxy) is seldom incorporated directly in cache replacement algorithms. Rather, other properties of the request stream (e.g. temporal locality and content size), which are easier to capture in an on-line fashion, are used to indirectly infer popularity information, and hence drive cache replacement policies. Recent studies suggest that the correlation between these secondary properties and popularity is weakening due in part to the prevalence of efficient client and proxy caches (which tend to mask these correlations). This trend points to the need for proxy cache replacement algorithms that directly capture and use popularity information. In this paper, we (1) present an on-line algorithm that effectively captures and maintains an accurate popularity profile of Web objects requested through a caching proxy, (2) propose a novel cache replacement policy that uses such information to generalize the well-known GreedyDual-Size algorithm, and (3) show the superiority of our proposed algorithm by comparing it to a host of recently-proposed and widely-used algorithms using extensive trace-driven simulations and a variety of performance metrics.

Temporal Locality in Web Request Streams: Sources, Characteristics, and Caching Implications

Temporal locality of reference in Web request streams emerges from two distinct phenomena: the popularity of Web objects and the {\em temporal correlation} of requests. Capturing these two elements of temporal locality is important because it enables cache replacement policies to adjust how they capitalize on temporal locality based on the relative prevalence of these phenomena. In this paper, we show that temporal locality metrics proposed in the literature are unable to delineate between these two sources of temporal locality. In particular, we show that the commonly-used distribution of reference interarrival times is predominantly determined by the power law governing the popularity of documents in a request stream. To capture (and more importantly quantify) both sources of temporal locality in a request stream, we propose a new and robust metric that enables accurate delineation between locality due to popularity and that due to temporal correlation. Using this metric, we characterize the locality of reference in a number of representative proxy cache traces. Our findings show that there are measurable differences between the degrees (and sources) of temporal locality across these traces, and that these differences are effectively captured using our proposed metric. We illustrate the significance of our findings by summarizing the performance of a novel Web cache replacement policy---called GreedyDual*---which exploits both long-term popularity and short-term temporal correlation in an adaptive fashion. Our trace-driven simulation experiments (which are detailed in an accompanying Technical Report) show the superior performance of GreedyDual* when compared to other Web cache replacement policies.

GreedyDual* Web Caching Algorithm: Exploiting the Two Sources of Temporal Locality in Web Request Streams

The relative importance of long-term popularity and short-term temporal correlation of references for Web cache replacement policies has not been studied thoroughly. This is partially due to the lack of accurate characterization of temporal locality that enables the identification of the relative strengths of these two sources of temporal locality in a reference stream. In [21], we have proposed such a metric and have shown that Web reference streams differ significantly in the prevalence of these two sources of temporal locality. These finding underscore the importance of a Web caching strategy that can adapt in a dynamic fashion to the prevalence of these two sources of temporal locality. In this paper, we propose a novel cache replacement algorithm, GreedyDual*, which is a generalization of GreedyDual-Size. GreedyDual* uses the metrics proposed in [21] to adjust the relative worth of long-term popularity versus short-term temporal correlation of references. Our trace-driven simulation experiments show the superior performance of GreedyDual* when compared to other Web cache replacement policies proposed in the literature.

Notes on the Effect of Different Access Patterns on the Intensity of Mistreatment in Distributed Caching Groups

In this report, we extend our study of the intensity of mistreatment in distributed caching groups due to state interaction. In our earlier work (published as BUCS-TR-2006-003), we analytically showed how this type of mistreatment may appear under homogeneous demand distributions. We provided a simple setting where mistreatment due to state interaction may occur. According to this setting, one or more "overactive" nodes generate disproportionately more requests than the other nodes. In this report, we extend our experimental evaluation of the intensity of mistreatment to which non-overactive nodes are subjected, when the demand distributions are not homogeneous.

Synchronized Oscillations During Cooperative Feature Lining in a Cortical Model of Visual Perception

A neural network model of synchronized oscillations in visual cortex is presented to account for recent neurophysiological findings that such synchronization may reflect global properties of the stimulus. In these experiments, synchronization of oscillatory firing responses to moving bar stimuli occurred not only for nearby neurons, but also occurred between neurons separated by several cortical columns (several mm of cortex) when these neurons shared some receptive field preferences specific to the stimuli. These results were obtained for single bar stimuli and also across two disconnected, but colinear, bars moving in the same direction. Our model and computer simulations obtain these synchrony results across both single and double bar stimuli using different, but formally related, models of preattentive visual boundary segmentation and attentive visual object recognition, as well as nearest-neighbor and randomly coupled models.

Synchronized Oscillations During Cooperative Feature Linking in a Cortical Model of Visual Perception

A neural network model of synchronized oscillator activity in visual cortex is presented in order to account for recent neurophysiological findings that such synchronization may reflect global properties of the stimulus. In these recent experiments, it was reported that synchronization of oscillatory firing responses to moving bar stimuli occurred not only for nearby neurons, but also occurred between neurons separated by several cortical columns (several mm of cortex) when these neurons shared some receptive field preferences specific to the stimuli. These results were obtained not only for single bar stimuli but also across two disconnected, but colinear, bars moving in the same direction. Our model and computer simulations obtain these synchrony results across both single and double bar stimuli. For the double bar case, synchronous oscillations are induced in the region between the bars, but no oscillations are induced in the regions beyond the stimuli. These results were achieved with cellular units that exhibit limit cycle oscillations for a robust range of input values, but which approach an equilibrium state when undriven. Single and double bar synchronization of these oscillators was achieved by different, but formally related, models of preattentive visual boundary segmentation and attentive visual object recognition, as well as nearest-neighbor and randomly coupled models. In preattentive visual segmentation, synchronous oscillations may reflect the binding of local feature detectors into a globally coherent grouping. In object recognition, synchronous oscillations may occur during an attentive resonant state that triggers new learning. These modelling results support earlier theoretical predictions of synchronous visual cortical oscillations and demonstrate the robustness of the mechanisms capable of generating synchrony.

A Recurrent Cooperative/Competitive Field for Segmentation of Magnetic Resonance Brain Imagery

The Grey-White Decision Network is introduced as an application of an on-center, off-surround recurrent cooperative/competitive network for segmentation of magnetic resonance imaging (MRI) brain images. The three layer dynamical system relaxes into a solution where each pixel is labeled as either grey matter, white matter, or "other" matter by considering raw input intensity, edge information, and neighbor interactions. This network is presented as an example of applying a recurrent cooperative/competitive field (RCCF) to a problem with multiple conflicting constraints. Simulations of the network and its phase plane analysis are presented.

The political philosophy of Miki Kiyoshi: A close reading of the philosophical foundations of cooperative communitarianism

The thesis is a historical and philological study of the mature political theory of Miki Kiyoshi (1897-1945) focused on Philosophical Foundations of Cooperative Communitarianism (1939), a full translation of which is included. As the name suggests, it was a methodological and normative communitarianism, which critically built on liberalism, Marxism and Confucianism to realise a regional political community. Some of Miki’s Western readers have wrongly considered him a fascist ideologue, while he has been considered a humanist Marxist in Japan. A closer reading cannot support either view. The thesis argues that the Anglophone study of Japanese philosophy is a degenerating research programme ripe for revolution in the sense of returning full circle to an original point. That means returning to the texts, reading them contextually and philologically, in principle as early modern European political theory is read by intellectual historians, such as the representatives of Cambridge School history of political thought. The resulting reading builds critically on the Japanese scholarship and relates it to contemporary Western and postcolonial political theory and the East Asian tradition, particularly neo-Confucianism. The thesis argues for a Cambridge School perspective radicalised by the critical addendum of geo-cultural context, supplemented by Geertzian intercultural hermeneutics and a Saidian ‘return to philology’. As against those who have seen radical reorientations in Miki’s political thought, the thesis finds gradual progression and continuity between his neo-Kantian, existentialist, Marxian anthropology, Hegelian and finally communitarian phases. The theoretical underpinnings are his philosophical anthropology, a structurationist social theory of praxis, and a critique of liberalism, Marxism, nationalism and idealism emphasising concrete as opposed to abstract theory and the need to build on existing cultural traditions to modernise rather than westernise East Asia. This post-Western fusion was imagined to be the beginning of a true and pluralistic universalism.

Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early-stage hodgkin's disease: the H6 twin randomized trials from the european organization for research and treatment of cancer lymphoma cooperative group

info:eu-repo/semantics/published

Development and standardization of solid phase assays for the detection of anti-neutrophil cytoplasmic antibodies (ANCA). A report on the second phase of an international cooperative study on the standardization of ANCA assays

Anti-neutrophil cytoplasmic antibodies (ANCA) are diagnostic markers for systemic vasculitis. They are classically I detected by an indirect immunofluorescence test using normal donor neutrophils as substrate. This assay lacks antigenic specificity and is not quantitative. The 'EC/BCR Project for ANCA Assay Standardization' is an international collaboration study with the aim to develop and standardize solid phase assays for ANCA detection. In this part of the study the isolation and characterization of proteinase-3 and myeloperoxidase, the two main target molecules for ANCA, and the development and standardization of ELISAs with these antigens are described. Six laboratories successfully isolated purified proteinase-3 preparations that could be used. Three of these preparations, together with one myeloperoxidase preparation, were subsequently used for ANCA testing by ELISA. The ELISA technique was standardized in two rounds of testing in the 14 participating laboratories. The coefficient of variation of these new assays decreased from values of approx. 50% in the first round to approx. 20% in the second round. We conclude that purified proteinase-3 and myeloperoxidase can be used in standardized ELISAs for ANCA detection. Whether such procedures offer advantages over the IIF test will be determined in a prospective clinical study.