XML filtering systems aim to provide fast, on-the-fly matching of XML-encoded data to large numbers of query specifications containing constraints on both structure and content. It is now well accepted that approaches using event-based parsing and Finite State Machines (FSMs) can provide the basis for highly scalable structure-oriented XML filtering systems. The XFilter system [Altinel and Franklin 2000] was the first published FSM-based XML filtering approach. XFilter used a separate FSM per path query and a novel indexing mechanism to allow all of the FSMs to be executed simultaneously during the processing of a document. Building on the insights of the XFilter work, we describe a new method, called "YFilter" that combines all of the path queries into a single Nondeterministic Finite Automaton (NFA). YFilter exploits commonality among queries by merging common prefixes of the query paths such that they are processed at most once. The resulting shared processing provides tremendous improvements in structure matching performance but complicates the handling of value-based predicates.In this paper we first describe the XFilter and YFilter approaches and present results of a detailed performance comparison of structure matching for these algorithms as well as a hybrid approach. The results show that the path sharing employed by YFilter can provide order-of-magnitude performance benefits. We then propose two alternative techniques for extending YFilter's shared structure matching with support for valuebased predicates, and compare the performance of these two techniques. The results of this latter study demonstrate some key differences between shared XML filtering and traditional database query processing. Finally, we describe how the YFilter approach is extended to handle more complicated queries containing nested path expressions.
The integrated stress response (ISR) is a conserved translational and transcriptional program affecting metabolism, memory, and immunity. The ISR is mediated by stress-induced phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) that attenuates the guanine nucleotide exchange factor eIF2B. A chemical inhibitor of the ISR, ISRIB, reverses the attenuation of eIF2B by phosphorylated eIF2α, protecting mice from neurodegeneration and traumatic brain injury. We describe a 4.1-angstrom-resolution cryo-electron microscopy structure of human eIF2B with an ISRIB molecule bound at the interface between the β and δ regulatory subunits. Mutagenesis of residues lining this pocket altered the hierarchical cellular response to ISRIB analogs in vivo and ISRIB binding in vitro. Our findings point to a site in eIF2B that can be exploited by ISRIB to regulate translation.
Cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC) have well documented immunomodulatory effects in vitro, but not following oral administration in humans. Here we show that oral co-administration of cannabinoids with lipids can substantially increase their intestinal lymphatic transport in rats. CBD concentrations in the lymph were 250-fold higher than in plasma, while THC concentrations in the lymph were 100-fold higher than in plasma. Since cannabinoids are currently in clinical use for the treatment of spasticity in multiple sclerosis (MS) patients and to alleviate nausea and vomiting associated with chemotherapy in cancer patients, lymphocytes from those patients were used to assess the immunomodulatory effects of cannabinoids. The levels of cannabinoids recovered in the intestinal lymphatic system, but not in plasma, were substantially above the immunomodulatory threshold in murine and human lymphocytes. CBD showed higher immunosuppressive effects than THC. Moreover, immune cells from MS patients were more susceptible to the immunosuppressive effects of cannabinoids than those from healthy volunteers or cancer patients. Therefore, administering cannabinoids with a high-fat meal or in lipid-based formulations has the potential to be a therapeutic approach to improve the treatment of MS, or indeed other autoimmune disorders. However, intestinal lymphatic transport of cannabinoids in immunocompromised patients requires caution.
Initiation, progression, and completion of the cell cycle are regulated by various cyclin-dependent kinases (CDKs), which are thus critical for cell growth. Tumour development is closely associated with genetic alteration and deregulation of CDKs and their regulators, suggesting that inhibitors of CDKs may be useful anticancer therapeutics. Indeed, early results suggest that transformed and normal cells differ in their requirement for e.g. cyclin/CDK2 and that it may be possible to develop novel antineoplastic agents devoid of the general host toxicity observed with conventional cystostatic drugs. Numerous active-site inhibitors of CDKs have been studied; the main limitation with these ATP antagonists is kinase specificity for CDKs. However, screening of compound collections, as well as rational design based on enzyme-ligand complex crystal structures, are now yielding pre-clinical candidates, particularly certain purine and flavonoid analogues, with impressive potency and selectivity. Natural CDK inhibitors (CKIs), e.g. the tumour suppressor gene products p16 INK4 , p21 WAF1 , and p27 KIP1 , form the starting point for the design of mechanism-based CDK inhibitors. A number of these small proteins have been dissected and inhibitory lead peptides amenable to peptidomimetic development have been identified. Conversion of these peptides into pharmaceutically useful molecules is greatly aided by the recent elucidation of CKI/CDK crystal and solution structures. Additional interaction sites on CDKs being exploited for the purposes of inhibitor design include: phosphorylation/dephosphorylation sites, macromolecular substrate binding site, CKS regulatory subunit binding sites, cyclin-binding site, cellular localisation domain, and destruction box. Finally, progress has recently been made in the application of antisense technology in order to target CDK activity.
Cdk9 is a key elongation factor for RNA transcription and functions by phosphorylating the C-terminal domain of RNA polymerase II. Here we present direct evidence that cdk9 is important for cancer cell survival and describe the characterization of the potent cdk9 inhibitor CDKI-73 in primary human leukemia cells. CDKI-73 induced caspase-dependent apoptosis that was preceded by dephosphorylation of cdk9 and serine 2 of RNA polymerase II. CDKI-73 was more potent than the pan-cdk inhibitor flavopiridol and showed >200-fold selectivity against primary leukemia cells when compared with normal CD34+ cells. Furthermore, CDKI-73 was equipotent in poor prognostic sub-groups of leukemia patients and showed cytotoxic synergy with the nucleoside analog fludarabine. The Mechanism of synergy was associated with CDKI-73-mediated transcriptional inhibition of MCL1 and XIAP that was maintained when used in combination with fludarabine. Our data present a strong rationale for the development of cdk9 inhibitors such as CDKI-73 as anticancer therapeutics.
Following the adoption of basic temporal features in the SQL:2011 standard, there has been a tremendous interest within the database industry in supporting bi-temporal features, as a significant number of real-life workloads would greatly benefit from efficient temporal operations. However, current implementations of bi-temporal storage systems and operators are far from optimal. In this paper, we present the Bi-temporal Timeline Index, which supports a broad range of temporal operators and exploits the special properties of an in-memory column store database system. Comprehensive performance experiments with the TPC-BiH benchmark show that algorithms based on the Bi-temporal Timeline Index outperform significantly both existing commercial database systems and state-of-the-art data structures from research.
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