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The increasing availability of Chinese language materials and other materials of Chinese authorship in North American libraries are posing major complications for cataloging which lead to retrieval problems, as exemplified by Chinese personal names and titles in this study. These complications include: the intricate nature of the Chinese script along with the extensive use of the traditional and simplified Chinese characters, and the application of variant romanizatlon schemes. includine Pinyin. Proposed solutions to improve access to Chinese language materials include: providing more access points in Pinyin form, establishing standards for international practice in romanizing Chinese personal names and in publishing the order of the family and given names of all authors, and linking cataloging authority files with OPACs.

As next-generation electronic packages continue to dictate smaller devices and more functionality, package-on-package (POP) configurations have started to gain popularity in the SMT industry. These stacked package devices enable board space savings, simplified system design, enhanced performance, and lower pin count. Although POPs are experiencing rapid growth for certain applications such as mobile handsets, digital cameras, PDAs, and MP3 players, concerns over POP drop test and thermal cycling performance reliability issues have been raised. Recently, the electronics industry has gathered a great deal of POP reliability data to help optimize the POP manufacturing and application process. A number of studies and tests have been conducted to investigate the board-level reliability of POPs in relation to drop test and thermal cycling performance. The test conditions have examined packages manufactured with and without underfill and have also analyzed the impact of different underfill dispensing patterns (i.e. full underfill, cornerbond and edgebond) However, few papers discuss the effects of the underfilling strategy — such as undefilling the bottom component only or underfilling both top and bottom components, or the effects of solder alloy choice on the reliability of POP packaging. In this paper, the effects of underfill dispensing type and POP ball alloy type on the reliability of POP devices during drop testing and thermal cycle testing were evaluated. It was found that both underfill dispensing type and alloy type have a profound effect on POP reliability. The study results revealed that underfilling only the bottom component seems to have no significant contribution to POP drop test reliability. Underfilling both the top and bottom components yields better drop test performance than underfilling only the bottom component. In addition, the SAC105 (98.5%Sn + 1.0%Ag + 0.5%Cu) bump alloy shows better drop test performance than the SAC305 (96.5%Sn + 3.0%Ag + 0.5%Cu) alloy.

Anorexia and weight loss are part of the wasting syndrome of late-stage cancer, are a major cause of morbidity and mortality in cancer, and are thought to be cytokine mediated. Macrophage inhibitory cytokine-1 (MIC-1) is produced by many cancers. Examination of sera from individuals with advanced prostate cancer showed a direct relationship between MIC-1 abundance and cancer-associated weight loss. In mice with xenografted prostate tumors, elevated MIC-1 levels were also associated with marked weight, fat and lean tissue loss that was mediated by decreased food intake and was reversed by administration of antibody to MIC-1. Additionally, normal mice given systemic MIC-1 and transgenic mice overexpressing MIC-1 showed hypophagia and reduced body weight. MIC-1 mediates its effects by central mechanisms that implicate the hypothalamic transforming growth factor-beta receptor II, extracellular signal-regulated kinases 1 and 2, signal transducer and activator of transcription-3, neuropeptide Y and pro-opiomelanocortin. Thus, MIC-1 is a newly defined central regulator of appetite and a potential target for the treatment of both cancer anorexia and weight loss, as well as of obesity.

During V(D)J recombination, the RAG proteins create DNA hairpins at the V, D, or J coding ends, and the structure-specific nuclease Artemis is essential to open these hairpins prior to joining. Artemis also is an endonuclease for 5′ and 3′ overhangs at many DNA double strand breaks caused by ionizing radiation, and Artemis functions as part of the nonhomologous DNA end joining pathway in repairing these. All of these activities require activation of the Artemis protein by interaction with and phosphorylation by the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). In this study, we have identified a region of the Artemis protein involved in the interaction with DNA-PKcs. Furthermore, the biochemical and functional analyses of C-terminally truncated Artemis variants indicate that the hair-pin opening and DNA overhang endonucleolytic features of Artemis are triggered by DNA-PKcs in two modes. First, autoinhibition mediated by the C-terminal tail of Artemis is relieved by phosphorylation of this tail by DNA-PKcs. Thus, C-terminally truncated Artemis derivatives imitate DNA-PKcs-activated wild type Artemis protein and exhibit intrinsic hairpin opening activity. Second, DNA-PKcs may optimally configure 5′ and 3′ overhang substrates for the endonucleolytic function of Artemis.

Neurodegenerative diseases such as Huntington's disease, ischemia, and Alzheimer's disease (AD) are major causes of death. Recently, metabotropic glutamate receptors (mGluRs), a group of seven-transmembrane-domain proteins that couple to G-proteins, have become of interest for studies of pathogenesis. Group I mGluRs control the levels of second messengers such as inositol 1,4,5-triphosphate (IP3), Ca2+ ions and cAMP. They elicit the release of arachidonic acid via intracellular Ca2+ mobilization from intracellular stores such as mitochondria and endoplasmic reticulum. This facilitates the release of glutamate and could trigger the formation of neurofibrillary tangles, a pathological hallmark of AD. mGluRs regulate neuronal injury and survival, possibly through a series of downstream protein kinase and cysteine protease signaling pathways that affect mitochondrially mediated programmed cell death. They may also play a role in glutamate-induced neuronal death by facilitating Ca(II) mobilization. Hence, mGluRs have become a target for neuroprotective drug development. They represent a pharmacological path to a relatively subtle amelioration of neurotoxicity because they serve a modulatory rather than a direct role in excitatory glutamatergic transmission.

GABA(A) receptor sites were characterised in cerebral cortex tissue samples from deceased neurologically normal infants who had come to autopsy during the third trimester of pregnancy. Pharmacological parameters were obtained from homogenate binding studies which utilised the 'central-type' benzodiazepine ligands [H-3]diazepam and [H-3]flunitrazepam, and from the GABA activation of [H-3]diazepam binding. It was found that the two radioligands behaved differently during development. The affinity of [H-3]flunitrazepam for its binding site did not vary significantly between preparations, whereas the [H-3]diazepam K-D showed marked regional and developmental variations: infant tissues showed a distinctly lower affinity than adults for this ligand. The density of [H-3]flunitrazepam binding sites increased similar to35% during the third trimester to reach adult levels by term, whereas [H-3]diazepam binding capacity declined slightly but steadily throughout development. The GABA activation of [H-3]diazepam binding was less efficient early in the trimester, in that the affinity of the agonist was significantly lower, though it rose to adult levels by term. The strength of the enhancement response increased to adult levels over the same time-frame. The results strongly suggest that the subunit composition of cortical GABA(A) sites changes significantly during this important developmental stage. (C) 2002 Elsevier Science B.V. All rights reserved.

Microglia are the resident innate immune cells of the CNS. Given their important role in maintaining brain homeostasis it is not surprising that an increasing number of microglia-related genes have been associated with neurodegenerative diseases such as Alzheimer's disease (AD) including CD33 as well as TREM2. The study of microglia dysfunction in AD is limited by access to these cells in the central nervous system. A number of in vitro differentiation protocols exist for converting monocytes to microglia-like cells, leveraging the plasticity of immune cells. However a deeper understanding of the distinctiveness of microglia among myeloid cells is only just beginning to emerge, and therefore validating these in vitro systems has been challenging. A unique microglia signature has been recently described which may be taken advantaged of to characterize these cells and examine markers with strong implications in the specific functions of microglia. Our data demonstrates that using a human monocyte-derived microglia-like protocol with polarizing cytokines leads to increased expression of these unique microglia signature genes, suggesting that we now have a tool to address genetically driven changes in expression levels. Specifically, we see an increase in mRNA expression of PROS1, GAS6, GPR34, CD39, C1QA and TGFBR1 (all p b 0.001) in microglia-like cells compared to monocytes. We also observe an increase in TREM2 surface protein expression in the microglia-like cells relative to monocytes (p = 0.001). Using these cells, we can now assess the functional consequences of known AD susceptibility loci in microglialike cells from genotyped subjects. To this end we have confirmed that the AD-associated SNP, rs3865444, leads to differential CD33 protein surface expression on microglia-like cells (p b 0.0001).

Background Annotation of a set of genes is often accomplished through comparison to a library of labelled gene sets such as biological processes or canonical pathways. However, this approach might fail if the employed libraries are not up to date with the latest research, don't capture relevant biological themes or are curated at a different level of granularity than is required to appropriately analyze the input gene set. At the same time, the vast biomedical literature offers an unstructured repository of the latest research findings that can be tapped to provide thematic sub-groupings for any input gene set. Methods Our proposed method relies on a gene-specific text corpus and extracts commonalities between documents in an unsupervised manner using a topic model approach. We automatically determine the number of topics summarizing the corpus and calculate a gene relevancy score for each topic allowing us to eliminate non-specific topics. As a result we obtain a set of literature topics in which each topic is associated with a subset of the input genes providing directly interpretable keywords and corresponding documents for literature research. Results We validate our method based on labelled gene sets from the KEGG metabolic pathway collection and the genetic association database (GAD) and show that the approach is able to detect topics consistent with the labelled annotation. Furthermore, we discuss the results on three different types of experimentally derived gene sets, (1) differentially expressed genes from a cardiac hypertrophy experiment in mice, (2) altered transcript abundance in human pancreatic beta cells, and (3) genes implicated by GWA studies to be associated with metabolite levels in a healthy population. In all three cases, we are able to replicate findings from the original papers in a quick and semi-automated manner. Conclusions Our approach provides a novel way of automatically generating meaningful annotations for gene sets that are directly tied to relevant articles in the literature. Extending a general topic model method, the approach introduced here establishes a workflow for the interpretation of gene sets generated from diverse experimental scenarios that can complement the classical approach of comparison to reference gene sets.

Tanshinone IIA (TIIA), a purified compound and an active component of Salvia miltiorrhiza (DanShen) has previously been shown to induce apoptosis on several human cancer cell lines. In the current study, we studied the cytotoxic effect of TIIA on a megakaryocytic leukemic cell line CHRF-288. First, we tested the cytotoxic effect of TIIA on CHRF-288 cells by Trypan blue assay and the cell viability was reduced to 80.8% after 72hrs of TIIA treatment (30ug/ml). Using Annexin V/PI staining and flow cytometry, we confirmed that TIIA induced apoptosis on CHRF-288 cells in a dose dependent manner. At the concentrations of 1, 3, 10 and 30ug/ml, the early apoptosis cells proportion showed a stepwise increment of 11.8±1.2%, 13.2±2.8%, 16.3±0.8% and 22.4±1.5% at 72 hrs respectively. This was verified by Caspase 3 assay which showed the activation of Caspase 3 increased from 5.1% to 16.2% after 10ug/ml of TIIA treatment. Activation of Caspase 3 implied the involvement of common apoptotic pathway. Then, we studied the mechanisms of apoptosis. Using JC-1 assay, we found that the depolarized cells increased from 9.06% to 16.6% after 10ug/ml TIIA treatment suggestive the involvement of intrinsic apoptotic pathway. To further determine the molecular mechanisms involved in the pro-apoptosis effect, Microarray studies using Affymetrix 133 plus genechips were conducted to identify the genes that were differentially expressed after TIIA treatment. Several groups of genes involved in apoptosis, calcium regulation and cell cycle checkpoints were found to be differentially expressed after the treatment. The differential expressions of these genes were validated using quantitative PCR. The most significantly upregulated genes (5.9±0.333 folds) was TNF Receptor Super-Family 9 (TNFRSF9). In addition, Receptor Interacting Protein Kinase (RIPK), a protein that likely interacts with TNFRSF9, was upregulated to 1.7±0.167 folds. And lastly, Jun, a transcriptional factor of TNFRSF9 was up-regulated to 1.7±0.03 folds. Since TNF and RIPK1 both involve in caspase-8 activation, this was suggestive of the activation of external apoptotic pathway. Our findings suggested that TIIA could induce significant apoptosis on mekakaryoctic leukemic cells via both intrinsic and extrinsic apoptotic pathways. Its role in treating this poor prognostic leukemia deserves further exploration.

The TGF-b superfamily cytokine MIC-1/GDF15 circulates in the blood of healthy humans. Its levels rise substantially in cancer and other diseases and this may sometimes lead to development of an anorexia/cachexia syndrome. This is mediated by a direct action of MIC1/GDF15 on feeding centres in the hypothalamus and brainstem. More recent studies in germline gene deleted mice also suggest that this cytokine may play a role in physiological regulation of energy homeostasis. To further characterize the role of MIC-1/GDF15 in physiological regulation of energy homeostasis in man, we have examined diurnal and food associated variation in serum levels and whether variation in circulating levels relate to BMI in human monozygotic twin pairs. We found that the within twin pair differences in serum MIC-1/GDF15 levels were significantly correlated with within twin pair differences in BMI, suggesting a role for MIC-1/GDF15 in the regulation of energy balance in man. MIC-1/GDF15 serum levels altered slightly in response to a meal, but comparison with variation its serum levels over a 24hour period suggested that these changes are likely to be due to bimodal diurnal variation which can alter serum MIC-1/GDF15 levels by about plus or minus 10% from the mesor. The lack of a rapid and substantial postprandial increase in MIC-1/GDF15 serum levels suggests that MIC1/GDF15 is unlikely to act as a satiety factor. Taken together, our findings suggest that MIC-1/GDF15 may be a physiological regulator of energy homeostasis in man, most probably due to actions on long-term regulation of energy homeostasis., published_or_final_version