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Aim: Tumor cells adapt to hypoxic microenvironments by releasing the key transcription factor HIF-1α, which promotes angiogenesis, glycolytic phenotype, metastasis and erythropoiesis, allowing proliferation amid low oxygen levels. Therefore, therapeutic targeting of HIF-1α represents a viable strategy for cancer therapy. Methods & Results: The authors synthesized a series of novel tetrahydroquinazoline derivatives in six steps and demonstrated that their development had a unique ability to suppress HIF-1α expression through proteasomal degradation. Conclusion: Among these compounds, CDMP-TQZ (8bf) exhibited the highest antiproliferative potency in human cancer cells, in part through downregulation of HIF-1α.

● BACKGROUND: To study the effect of inferior rectus muscle recession on intraocular pressure (IOP) in thyroid eye disease (TED) patients with ocular hypertension.● METHODS: This is a retrospective, observational case series. The medical records of patients with ocular hypertension, despite use of antiglaucoma medications, and restrictive myopathy secondary to thyroid eye disease who underwent inferior rectus muscle recession from January 1, 2016 through December 31, 2021 were reviewed and analyzed retrospectively. Seven eyes from six patients met the criteria and were included in this study. All patients were examined at Taichung Veterans General Hospital, a tertiary referral center. The main outcome measure was IOP readings obtained before and after surgery in both primary gaze (hypotropia) and upgaze (or attempted upgaze).● RESULTS: A statistically significant decrease in IOP in primary gaze (hypotropia) and upgaze (or attempted upgaze) was noted after inferior rectus muscle recession. The median IOP before surgery was 24.0 mmHg in primary gaze and 30.5 mmHg in upgaze. After strabismus surgery, the median IOP after one week was 18.0 mm Hg in primary gaze and 20.0 mmHg in upgaze; the median IOP one month after surgery was 15.0 mmHg in primary gaze and 16.5 mmHg in upgaze; the median IOP 3 months after surgery was 12.5 mmHg in primary gaze and 13.5 mmHg in upgaze; the median IOP 12 months after surgery was 15.5 mmHg in primary gaze (overall P = .001) and 17.0 mmHg in upgaze (overall P = .001). All eyes were treated with three to four antiglaucoma medications before the surgery. Four eyes discontinued all preoperative medications within 3 months after the surgery. The other three eyes kept using preoperative medications.● CONCLUSIONS: Inferior rectus muscle recession resulted in a significant and sustained reduction in IOP in patients with ocular hypertension and restrictive myopathy secondary to thyroid eye disease.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has severely affected human lives around the world as well as the global economy. Therefore, effective treatments against COVID-19 are urgently needed. Here, we screened a library containing Food and Drug Administration (FDA)-approved compounds to identify drugs that could target the SARS-CoV-2 main protease (Mpro), which is indispensable for viral protein maturation and regard as an important therapeutic target. We identified anti-malarial drug tafenoquine (TFQ), which is approved for radical cure of Plasmodium vivax and malaria prophylaxis, as a top candidate to inhibit Mpro protease activity. The crystal structure of SARS-CoV-2 Mpro in complex with TFQ revealed that TFQ noncovalently bound to and reshaped the substrate binding pocket of Mpro by altering the loop region (residues 139-144) near the catalytic Cys145, which could block the catalysis of its peptide substrates. We also found that TFQ inhibited human transmembrane protease serine 2 (TMPRSS2). Furthermore, one TFQ derivative, compound 7, showed a better therapeutic index than TFQ on TMPRSS2, and may therefore inhibit the infectibility of SARS-CoV-2, including that of several mutant variants. These results suggest new potential strategies to block infection of SARS-CoV-2 and rising variants.

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) induces the unfolded protein response (UPR), which acts through various mechanisms to reduce ER stress. While the UPR has been well studied for its effects on the ER, its impact on the Golgi is less understood. The Golgi complex receives transport vesicles from the endosome through two types of tethering factors: long coiled-coil golgin and the multisubunit Golgi-associated retrograde protein (GARP) complex. Here, we report that ER stress increases the phosphorylation of golgin Imh1 to maintain the GARP-mediated recycling of the SNAREs Snc1 and Tlg1. We also identify a specific function of the Golgi affected by ER stress and elucidate a homeostatic response to restore this function, which involves both an Ire1-dependent and a MAP kinase Slt2/ERK2-dependent mechanism. Furthermore, our findings advance a general understanding of how two different types of tethers act cooperatively to mediate a transport pathway.

Hypoxia-inducible factor (HIF)-1α is a key transcription factor that contributes to aggressive and drug-resistant phenotypes in tumor cells under hypoxic conditions. Therefore, targeting HIF-1α represents a promising therapeutic strategy for cancer drug development. In the present study, we designed, synthesized, and evaluated a new series of biarylquinoline derivatives as potential HIF-1α inhibitors based on structure-activity relationship. Among these derivatives, compound 7f represents the optimal agent with IC

The yeast cell wall integrity (CWI) MAPK pathway is a signaling cascade function in maintaining cell wall integrity under stressful environmental conditions. Recently, the activity and signaling of Slt2p (Mpk1p) MAP kinase has been shown to control assembly of the processing body (P-body) upon cell wall stresses, implicating its posttranscriptional role in decay of cell wall mRNAs. However, how Slt2p MAP kinase directly regulates the stability of cell wall transcripts during cell wall stress remains unclear. Here, we reported that the RNA-binding protein Rbp1p (Ngr1p) is a downstream effector and target of Slt2p MAP kinase during activation of the cell wall stress signaling cascade. In addition to the well-defined target mitochondrial porin mRNA, we found that Rbp1p also negatively regulates the stability of a subset of Slt2p-regulated cell wall transcripts. Deletion ofRBP1increases the level of cell wall transcripts and partially suppresses the hypersensitivity of theslt2Δdeletion strain to cell wall damage. Slt2p is necessary for cell wall stress-induced stabilization of cell wall transcripts. Deletion ofRBP1compromises the destabilization of cell wall transcripts inslt2Δmutants under cell wall stress. Notably, C-terminal deleted Slt2p impairs its function in promoting turnover of the Rbp1p protein and fails to stabilize cell wall transcripts, although it can complement the growth defect of theslt2Δstrain upon cell wall stress. Altogether, our results demonstrate that MAP kinase Slt2p attenuates CWI mRNA decay in response to cell wall damage by downregulating the activity of the RNA-binding protein Rbp1p.

Background: A growing body of evidence suggests that Hsp70, which is overexpressed in human breast tumors, plays a role in tumorigenesis and tumor progression in breast cancer as well as in its aggressive phenotypes. Hsp70 constitutes a potential therapeutic target in the treatment of this disease. Methods: We developed a new series of rhodacyanine-based Hsp70 inhibitors, represented by compounds 1 and 6, in which the cationic pyridin-1-ium or thiazol-3-ium ring of existing Hsp70 inhibitors (e.g., JG-40 and JG-98) was replaced by a corresponding benzo- fused N-heterocycle. Results: Several lines of evidence suggest that these benzo-fused derivatives may exert their antitumor activities, in part, by targeting Hsp70. These putative inhibitors displayed differential antiproliferative efficacy against breast cancer cells (IC50 as low as 0.25 μM) versus nontumorigenic MCF-10A breast epithelial cells (IC50 ≥ 5 μM). This was correlated with the corresponding Hsp70 expression levels. Using a protein refolding assay, we confirmed that these agents effectively inhibited the chaperone activity of Hsp70. Moreover, these inhibitors effectively suppressed the expression of well-known oncogenic client proteins of Hsp70’s, including FoxM1, HuR, and Akt, which paralleled their antiproliferative efficacy. Supporting the established role of Hsp70 in regulating protein refolding, these derivatives induced autophagy, as manifested by the conversion of LC3B-I to LC3B-II. Notably, these putative Hsp70 inhibitors did not cause a compensatory elevation in Hsp90 expression, contrasting with the previously reported effects of Hsp90 inhibitors on Hsp70 upregulation. Conclusion: Together with the finding that compounds 1 and 6 showed improved microsomal stability, these results suggest the translational potential of these putative Hsp70 inhibitors to foster new strategies for cancer therapy. However, whether these benzo-fused rhodacyanines act on kinases or other targets remains unclear. It is currently under investigation.

Transdermal drug delivery is a convenient route to transport pharmaceuticals. However, its application is limited to a few compounds. Microneedle (MN) patches have demonstrated a high efficiency for delivering poorly permeable drugs and gained significant attention due to the advantages of being painless and convenient for patients as well as providing efficient delivery. This study presents dissolvable polyvinylpyrrolidone (PVP)-based MNs that do not require needle removal while providing the rapid release of encapsulated insulin. PVP with two molecular weights, PVP10 and PVP360, were used to fabricate the needle portion of the MNs, and PVP360/sodium carboxymethyl cellulose (CMC) was used for preparation of the backing layer. The detailed characteristics and in vitro skin penetration capability of a series of PVP360/PVP10 MNs were analyzed. The penetration depths of PVP MNs were evaluated using optical coherence tomography. The PVP360/PVP10 = 1:3 MN patch was chosen for ex vivo and in vivo studies. Ex vivo drug release profiles show that the permeation efficiency of Lissamine green B (LGB)- and fluorescein isothiocyanate-labeled BSA (FITC-BSA)-loaded PVP MN patches was much higher than the groups of patches without MNs. Furthermore, to estimate the feasibility of PVP MNs for diabetes treatment, insulin-loaded PVP MN patches were administered to diabetic mice to evaluate glycemic control. The relative pharmacologic availability revealed that the MN patch has an immediate and effective effect on hypoglycemic administration. This study demonstrates that dissolvable PVP MNs may serve as a promising device to deliver macromolecules or protein drugs for efficient transdermal drug delivery.

Postoperative hearing improvement is one of the main expectations for patients receiving tympanoplasty. The capacity to predict postoperative hearing may help to counsel a patient properly and avoid untoward expectations. It is difficult to predict postoperative hearing without knowing the disease process in the middle ear, which can only be assessed intraoperatively. However, the duration and extent of the underlying pathologies may represent in bone-conduction threshold and air-bone gap. Here in patients undergoing tympanoplasty without ossiculoplasty, we sorted and separated the surgery dates into the first group to build the predicting models and the second group to test the predictions. There were 87 and 30 ears, respectively. No specific enrollment or exclusion criteria were based on underlying pathologies such as the perforation size of the tympanic membrane or the middle ear conditions. The results show that bone-conduction threshold and air-bone gap together predicted air-conduction threshold after the surgery, including each frequency of 0.5k, 1k, 2k, and 4k Hz. The discrepancies between the predictions and recordings did not differ among these four frequencies. Of the variance in mean postoperative air-conduction threshold, 56.7% was linearly accounted for by these two preoperative predictors in this sample. The results suggest a trend that, the higher the frequency, the larger the part was accounted for by these two preoperative predictors. These together may help a surgeon to estimate frequency-specific hearing outcome after the surgery, answer patients’ questions with quantitative statistics, and counsel patients with proper expectations.

Web news provides a direct and efficient way to construct large text corpora. The creation of text data requires an understanding of HTML code and the preparation of customized parsing rules to identify text content in a webpage. Typically, parsing rules are written manually and cannot be applied to pages with different layouts. In this study, we present a web news extraction system that is based on a text detection framework. The proposed method scans the input HTML page and creates text statistics as a projection profile. Then, text block identification is applied to determine a set of content candidates. To filter noise, text verification determines whether a given text block can be included with content. We evaluate the proposed approach with the L3S-GN1 corpus and 3506 multilingual news data items randomly sampled from 325 websites (15 geographic regions and 11 distinct languages). We also compare the proposed method to 23 well-known state-of-the-art techniques. The experimental results show that the proposed method outperforms the second best method (NReadability) by 7.30% in the macro F-measure rate and is 16.91 times faster than NReadability. In terms of the perfect rate, the proposed method demonstrates 46.38% accuracy, whereas the Boilerpipe algorithm demonstrates only 21.54% accuracy. The proposed method is very useful for constructing a multilingual corpus because it requires no language-specific processing component.

Web news provides a quick and convenient means to create collections of large documents. The creation of a web news corpus has typically required the construction of a set of HTML parsing rules to identify content text. In general, these parsing rules are written manually and treat different web pages differently. We address this issue and propose a news content recognition algorithm that is language and layout independent. Our method first scans a given HTML document and roughly localizes a set of candidate news areas. Next, we apply a designed scoring function to rank the best content. To validate this approach, we evaluate the systems performance using 1092 items of multilingual web news data covering 17 global regions and 11 distinct languages. We compare these data with nine published content extraction systems using standard settings. The results of this empirical study show that our method outperforms the second-best approach (Boilerpipe) by 6.04 and 10.79 % with regard to the relative micro and macro F-measures, respectively. We also apply our system to monitor online RSS news distribution. It collected 0.4 million news articles from 200 RSS channels in 20 days. This sample quality test shows that our method achieved 93 % extraction accuracy for large news streams.

Background Global cerebral ischemia triggers neurodegeneration in the hippocampal CA1 region, but the mechanism of neuronal death remains elusive. The epsilon isoform of protein kinase C (PKCε) has recently been identified as a master switch that controls the nucleocytoplasmic trafficking of ATF2 and the survival of melanoma cells. It is of interest to assess the role of PKCε–ATF2 signaling in neurodegeneration. Results Phosphorylation of ATF2 at Thr-52 was reduced in the hippocampus of PKCε null mice, suggesting that ATF2 is a phosphorylation substrate of PKCε. PKCε protein concentrations were significantly reduced 4, 24, 48 and 72 h after transient global cerebral ischemia, resulting in translocation of nuclear ATF2 to the mitochondria. Degenerating neurons staining positively with Fluoro-Jade C exhibited cytoplasmic ATF2. Conclusions Our results support the hypothesis that PKCε regulates phosphorylation and nuclear sequestration of ATF2 in hippocampal neurons during ischemia-induced neurodegeneration.

This paper is the first to investigate the effect of industrial penetration (geographic concentration of industries) and internet intensity (the proportion of enterprises that uses the internet) for Taiwan manufacturing firms, and analyses whether the relationships are substitutes or complements. The sample observations are based on a unique set of data, namely 153,081 manufacturing plants, and covers 26 two-digit industry categories and 358 geographical townships in Taiwan. The Heckman sample selection model is used to accommodate sample selectivity for unobservable data for firms that use the internet. The empirical results from Heckman’s two-stage estimation show that: (1) a higher degree of industrial penetration will not affect the probability that firms will use the internet, but it will affect the total expenditure on internet intensity; (2) for two-digit SIC (Standard Industrial Classification) industries, industrial penetration generally decreases the total expenditure on internet intensity; and, (3) industrial penetration and internet intensity are substitutes.

Most of the researches on text categorization are focus on using bag of words. Some researches provided other methods for classification such as term phrase, Latent Semantic Indexing, and term clustering. Term clustering is an effective way for classification, and had been proved as a good method for decreasing the dimensions in term vectors. The authors used hierarchical term clustering and aggregating similar terms. In order to enhance the performance, they present a modify indexing with terms in cluster. Their test collection extracted from Chinese NETNEWS, and used the Centroid-Based classifier to deal with the problems of categorization. The results had shown that term clustering is not only reducing the dimensions but also outperform than bag of words. Thus, term clustering can be applied to text classification by using any large corpus, its objective is to save times and increase the efficiency and effectiveness. In addition to performance, these clusters can be considered as conceptual knowledge base, and kept related terms of real world.

Semi-supervised machine learning methods have the features of both, integrating labeled and unlabeled training data. In most structural problems, such as natural language processing and image processing, developing labeled data for a specific domain requires considerable amount of human resources. In this paper, we present a cluster-based method to fuse labeled training and unlabeled raw data. We design a top-down divisive clustering algorithm that ensures maximal information gain in the use of unlabeled data via clustering similar words. To implement this idea, we design a top-down iterative K -means clustering algorithm to merge word clusters. Differently, the derived term groups are then encoded as new features for the supervised learners in order to improve the coverage of lexical information. Without additional training data or external materials, this approach yields state-of-the-art performance on the shallow parsing and base-chunking benchmark datasets (94.50 and 93.12 in F ( β ) rates).

Modern information technologies and Internet services are suffering from the problem of selecting and managing a growing amount of textual information, to which access is often critical. Machine learning techniques have recently shown excellent performance and flexibility in many applications, such as artificial intelligence and pattern recognition. Question answering (QA) is a method of locating exact answer sentences from vast document collections. This paper presents a machine learning-based question-answering framework, which integrates a question classifier, simple document/passage retrievers, and the proposed context-ranking models. The question classifier is trained to categorize the answer type of the given question and instructs the context-ranking model to re-rank the passages retrieved from the initial retrievers. This method provides flexible features to learners, such as word forms, syntactic features, and semantic word features. The proposed context-ranking model, which is based on the sequential labeling of tasks, combines rich features to predict whether the input passage is relevant to the question type. We employ TREC-QA tracks and question classification benchmarks to evaluate the proposed method. The experimental results show that the question classifier achieves 85.60% accuracy without any additional semantic or syntactic taggers, and reached 88.60% after we employed the proposed term expansion techniques and a predefined related-word set. In the TREC-10 QA task, by using the gold TREC-provided relevant document set, the QA model achieves a 0.563 mean reciprocal rank (MRR) score, and a 0.342 MRR score is achieved after using the simple document and passage retrieval algorithms.

To determine the ratio of IGFBP3:IGF-1 in normal and diabetic human tears, and in telomerase-immortalized human corneal epithelial cells (hTCEpi) cultured under elevated glucose conditions and to correlate these changes with total and phosphorylated levels of IGF-1R. Tear samples were collected noninvasively from diabetic subjects and non-diabetic controls; corneal sensitivity was assessed using a Cochet-Bonnet Aesthesiometer. Conditioned media were collected following culture of hTCEpi cells in normal (5 mM) and elevated (25 mM) glucose conditions; mannitol was used as an osmotic control. IGFBP3, IGF-1, and phosphorylated IGF-1R levels were assessed by ELISA. IGFBP3 and IGF-1R mRNA were assessed by real-time polymerase chain reaction (PCR). Total and phosphorylated IGF-1R expression in whole cell lysates was assessed by western blot. There was a 2.8-fold increase in IGFBP3 in diabetic tears compared to non-diabetic controls (P=0.006); IGF-1 levels were not significantly altered. No difference in corneal sensitivity was detected between groups. The concentration of IGFBP3 in tears was independent of IGF-1. Consistent with human tear measurements in vivo, IGFBP3 secretion was increased 2.2 fold (P

This study characterized the expression and subcellular localization of the IGF-1R in human corneal epithelial cells. Using a human telomerase-immortalized corneal epithelial cell line, IGF-1R expression and localization was assayed by immunofluorescence and subcellular fractionation followed by western blot. IGF-1R expression was confirmed in primary cultured human corneal epithelial cells. Nuclear localization was assessed under basal and IGF-1 stimulated culture conditions; phosphorylation status of the receptor in response to IGF-1 was demonstrated by western blot. IGF-1R:E-cadherin interactions were detected by immunofluorescence and co-immunoprecipitation of whole cell lysates. The results of this study demonstrated that IGF-1R localized predominantly to the nucleus and in a perinuclear cap pattern which co-localized with the Golgi complex in proliferating corneal epithelial cells. There was no difference in nuclear localization between primary or telomerized cell lines. Subcellular fractionation confirmed IGF-1Rα- and β-subunit localization in soluble and chromatin-bound nuclear fractions. Neither growth factor withdrawal nor IGF-1 stimulation altered nuclear IGF-1R. At points of cell-cell contact, IGF-1R co-localized with E-cadherin; co- immunoprecipitation assays confirmed the presence of an IGF-1R:E-cadherin complex. Importantly, this is the first report to identify IGF-1R in the nucleus and complexed with E-cadherin at points of cell-cell contact in corneal epithelial cells. Nuclear trafficking appeared to be independent of ligand-mediated events at the plasma membrane. The identification of IGF-1R in the nucleus and complexed with E-cadherin suggests novel regulatory functions outside the canonical ligand-induced endocytosis signaling pathway.

Automatic Chinese text classification is an important and a well-known technology in the field of machine learning. The first step for solving Chinese text categorization problems is to tokenize the Chinese words from a sequence of non-segmented sentences. However, previous literatures often employ a Chinese word tokenizer that was trained with different sources and then perform the conventional text classification approaches. However, these taggers are not perfect and often provide incorrect word boundary information. In this paper, we propose an N-gram-based language model which takes word relations into account for Chinese text categorization without Chinese word tokenizer. To prevent from out-of-vocabulary, we also propose a novel smoothing approach based on logistic regression to improve accuracy. The experimental result shows that our approach outperforms traditional methods at least 11% on micro-average F-measure.

In this paper, we present a robust passage retrieval algorithm to extend the conventional text question answering (Q/A) to videos. Users interact with our videoQ/A system through natural language queries, while the top-ranked passage fragments with associated video clips are returned as answers. We compare our method with five of the high-performance ranking algorithms that are portable to different languages and domains. The experiments were evaluated with 75.3 h of Chinese videos and 253 questions. The experimental results showed that our method outperformed the second best retrieval model (language models) in relatively 1.43% in mean reciprocal rank (MRR) score and 11.36% when employing a Chinese word segmentation tool. By adopting the initial retrieval results from the retrieval models, our method yields an improvement of at least 5.94% improvement in MRR score. This makes it very attractive for the Asia-like languages since the use of a well-developed word tokenizer is unnecessary.

Papillomavirus E2 proteins are critical regulatory proteins that function in replication, genome segregation, and viral transcription, including control of expression of the viral oncogenes, E6 and E7. Sumoylation is a post-translational modification that has been shown to target and modulate the function of many transcription factors, and we now demonstrate that E2 proteins are sumoylated. Both bovine and human papillomavirus E2 proteins bind to the SUMO conjugation enzyme, Ubc9, and using in vitro and E. coli sumoylation systems, these E2 proteins were readily modified by SUMO proteins. In vivo experiments further confirmed that E2 can be sumoylated by SUMO1, SUMO2, or SUMO3. Mapping studies identified lysine 292 as the principal residue for covalent conjugation of SUMO to HPV16 E2, and a lysine 292 to arginine mutant showed defects for both transcriptional activation and repression. The expression levels, intracellular localization, and the DNA-binding activity of HPV16 E2 were unchanged by this K292R mutation, suggesting that the transcriptional defect reflects a functional contribution by sumoylation at this residue. This study provides evidence that sumoylation has a role in the regulation of papillomavirus E2, and identifies a new mechanism for the modulation of E2 function at the post-translational level.

Video question answering aims to pinpoint answers in response to user's specified questions. However, most question answering technologies involve in integrating rich specific external knowledge such as syntactic parsers, which are often unavailable for many languages. In this paper, we present a new string pattern matching-based passage ranking algorithm for extending traditional text Q/A toward videoQ/A. Users interact with our videoQ/A system through natural language questions whereas our system returns three sentence-length passages with corresponding video clips as answers. We collect 45GB Discovery videos and 253 Chinese questions for evaluation. The experimental results showed that our method outperformed six top-performed ranking models. It is 7.39% better than the second best method (language model-based) in relatively MRR score and 6.12% in precision rate. Besides, we also show that the use of a trained Chinese word segmentation tool did decrease the overall videoQ/A performance where most ranking algorithms dropped at least 10% in relatively MRR, precision, and answer pattern recall rates.

Automatic text chunking aims to recognize grammatical phrase structures in natural language text. Text chunking provides downstream syntactic information for further analysis, which is also an important technology in the area of text mining (TM) and natural language processing (NLP). Existing chunking systems make use of external knowledge, e.g. grammar parsers, or integrate multiple learners to achieve higher performance. However, the external knowledge is almost unavailable in many domains and languages. Besides, employing multiple learners does not only complicate the system architecture, but also increase training and testing time costs. In this paper, we present a novel phrase chunking model based on the proposed mask method without employing external knowledge and multiple learners. The mask method could automatically derive more training examples from the original training data, which significantly improves system performance. We had evaluated our method in different chunking tasks and languages in comparison to previous studies. The experimental results show that our method achieves state of the art performance in chunking tasks. In two English chunking tasks, i.e., shallow parsing and base-chunking, our method achieves 94.22 and 93.23 in F"("@b"="1") rates. When porting to Chinese, the F"("@b"="1") rate is 92.30. Also, our chunker is quite efficient. The complete chunking time of a 50K-words is less than 10s.

Taiwan has been hailed as a world leader in the development of global innovation and industrial clusters for the past decade. This paper investigates the effects of industrial agglomeration on the use of the internet and internet intensity for Taiwan manufacturing firms, and analyses whether the relationships between industrial agglomeration and total expenditure on internet usage for industries are substitutes or complements. The sample observations are based on 153,081 manufacturing plants, and covers 26 2-digit industry categories and 358 geographical townships in Taiwan. The Heckman selection model is used to adjust for sample selectivity for unobservable data for firms that use the internet. The empirical results from two-stage estimation show that: (1) for the industry overall, a higher degree of industrial agglomeration will not affect the probability that firms will use the internet, but will affect the total expenditure on internet usage; and (2) for 2-digit industries, industrial agglomeration generally decreases the total expenditure on internet usage, which suggests that industrial agglomeration and total expenditure on internet usage are substitutes.

Neural stem/progenitor cells (NSPCs) are a possible candidate for advancing development and lineage control in neural engineering. Differentiated protocols have been developed in this field to generate neural progeny and to establish neural networks. However, continued refinement is required to enhance differentiation specificity and prevent the generation of unwanted cell types. In this study, we fabricated a niche-modulated system to investigate surface effects on NSPC differentiation by the formation of polyelectrolyte multilayer (PEM) films governed by electrostatic interactions of poly-l-glutamine acid as a polyanion and poly-l-lysine as a polycation. The serum- and chemical agent-free system provided a clean and clear platform to observe in isolation the interaction between surface niche and stem cell differentiation. We found that NSPCs were inducible on PEM films of up to eight alternating layers. In addition, neurite outgrowth, neuron percentage, and synaptic function were regulated by layer number and the surface charge of the terminal layer. The average process outgrowth length was over 500μm on PLL/PLGA(n=7.5) only after 3 days of culture. Moreover, the quantity and quality of the differentiated neurons were enhanced as the number of layers increased, especially when the terminal layer was poly-l-lysine. Our results achieve important targets of neural engineering, including long processes, large neural network size, and large amounts of functional neurons. Our methodology for nanoscale control of material deposition can be successfully applied for surface modification, neural niche modulation, and neural engineering applications.

Purpose The aim of this study was to establish a relationship between hypoxic stress and the expression of ΔNp63α in an established rabbit contact lens model and in cultured corneal epithelial cells. Methods New Zealand white rabbits were fit in one eye with either a non-oxygen transmissible or hyper-oxygen-permeable rigid contact lens for 24 hrs of wear; the contralateral eye was used as a control. All the rabbits underwent a bilateral nictitating membranectomy to facilitate lens retention. ΔNp63α expression was analyzed by immunofluorescence and western blot. Telomerase-immortalized human corneal epithelial cells (hTCEpi) were grown in serum-free media and treated with the hypoxia-mimetic cobalt chloride to simulate hypoxia for 6 hrs (short term) or 24 hrs (prolonged). Transcriptional activity and protein levels were assessed using luciferase reporter assays, reverse transcription polymerase chain reaction, and western blot. Cell viability was assessed by live/dead assay. Results Compared with the non-lens wearing eye, 24 hrs of non-oxygen transmissible lens wear in vivo decreased ΔNp63α protein levels in both the limbal and central corneal epithelium; this decrease was not found in the hyper-oxygen transmissible lens group. In hTCEpi cells in vitro, hypoxia increased the activity of the ΔN promoter but reduced the levels of ΔNp63α mRNA after 24 hrs of prolonged culture. Similarly, ΔNp63α expression levels were unaffected from short-term exposure but decreased after 24 hrs. Live/dead assay confirmed the presence of viable cells after CoCl2 treatment at 6- and 24-hr time points. Cells treated for 24 hrs were viable but were smaller and rounded with signs of membrane blebbing, consistent with early stages of apoptosis. Conclusions Hypoxic stress induced by either prolonged wear of a nonoxygen transmissible lens in vivo or hypoxic-mimic conditions by cobalt chloride in vitro downregulates ΔNp63α in the corneal epithelium. The loss of ΔNp63α in response to hypoxic stress may contribute to the disruption of normal renewal mechanisms reported with low oxygen transmissible contact lens wear and prolonged eyelid closure.

Isothiocyanates (ITCs) derived from cruciferous vegetables induce apoptosis in cancer cells. We demonstrate that certain naturally occurring ITCs selectively deplete mutant p53 but not the wild-type and do so via a transcription-independent mechanism. Direct p53 binding followed by conformational changes appears to be a mechanism by which mutant p53 is depleted. Structure-activity relationship studies (SARs) using naturally occurring and synthetic ITCs show that depletion is influenced by the ITC side-chain moiety. Furthermore, we show that cells with p53 mutations are more sensitive to cytotoxicity induced by phenethyl isothiocyanate (PEITC) than those with the wild-type protein. 2,2-Diphenylethyl ITC, a synthetic ITC, is one of the most potent depletors of mutant p53 studies and induces apoptosis to the greatest extent in mutant p53 breast cancer cells. Collectively, this study shows that mutant p53 depletion may be an important novel target for cancer chemoprevention and therapy by natural and synthetic ITCs.

It is conceivable that stimulating proteasome activity for rapid removal of misfolded and oxidized proteins is a promising strategy to prevent and alleviate aging-related diseases. Sulforaphane (SFN), an effective cancer preventive agent derived from cruciferous vegetables, has been shown to enhance proteasome activities in mammalian cells and to reduce the level of oxidized proteins and amyloid β-induced cytotoxicity. Here, we report that SFN activates heat shock transcription factor 1-mediated heat shock response. Specifically, SFN-induced expression of heat shock protein 27 (Hsp27) underlies SFN-stimulated proteasome activity. SFN-induced proteasome activity was significantly enhanced in Hsp27-overexpressing cells but absent in Hsp27-silenced cells. The role of Hsp27 in regulating proteasome activity was further confirmed in isogenic REG cells, in which SFN-induced proteasome activation was only observed in cells stably overexpressing Hsp27, but not in the Hsp27-free parental cells. Finally, we demonstrated that phosphorylation of Hsp27 is irrelevant to SFN-induced proteasome activation. This study provides a novel mechanism underlying SFN-induced proteasome activity. This is the first report to show that heat shock response by SFN, in addition to the antioxidant response mediated by the Keap1-Nrf2 pathway, may contribute to cytoprotection.

Kernel methods such as support vector machines (SVMs) have attracted a great deal of popularity in the machine learning and natural language processing (NLP) communities. Polynomial kernel SVMs showed very competitive accuracy in many NLP problems, like part-of-speech tagging and chunking. However, these methods are usually too inefficient to be applied to large dataset and real time purpose. In this paper, we propose an approximate method to analogy polynomial kernel with efficient data mining approaches. To prevent exponential-scaled testing time complexity, we also present a new method for speeding up SVM classifying which does independent to the polynomial degree d. The experimental results showed that our method is 16.94 and 450 times faster than traditional polynomial kernel in terms of training and testing respectively.

Several phrase chunkers have been proposed over the past few years. Some state-of-the-art chunkers achieved better performance via integrating external resources, e.g., parsers and additional training data, or combining multiple learners. However, in many languages and domains, such external materials are not easily available and the combination of multiple learners will increase the cost of training and testing. In this paper, we propose a mask method to improve the chunking accuracy. The experimental results show that our chunker achieves better performance in comparison with other deep parsers and chunkers. For CoNLL-2000 data set, our system achieves 94.12 in F rate. For the base-chunking task, our system reaches 92.95 in F rate. When porting to Chinese, the performance of the base-chunking task is 92.36 in F rate. Also, our chunker is quite efficient. The complete chunking time of a 50K words document is about 50 seconds.

In this paper, we propose a three-step multilingual dependency parser, which generalizes an efficient parsing algorithm at first phase, a root parser and post-processor at the second and third stages. The main focus of our work is to provide an efficient parser that is practical to use with combining only lexical and part-of-speech features toward language independent parsing. The experimental results show that our method outperforms Maltparser in 13 languages. We expect that such an efficient model is applicable for most languages.

p53 mutations occur in more than 50% of all human tumor. Mutant p53 is incapable of activating downstream target genes necessary for cell cycle arrest and apoptosis. Phenethyl isothiocyanate (PEITC), a cruciferous vegetable-derived compound, has been shown to possess anti-cancer property by causing cell growth arrest or apoptosis in tumor cell lines and animal models. Recently, we have found that PEITC can selectively reduce mutant p53, but not wild type protein levels in a variety of tumor cell lines. Here, we demonstrate that PEITC can increase sequence specific DNA binding of p53 in NSCLC H596 cells expressing mutant p53 and induce the expression of p53-dependent target proteins, such as p21 and Noxa. Similar effects were observed in human glioblastoma T98G cells which also express mutant p53. H596 cells incubated with sulforaphane (SFN), another widely studied ITC compound with much weaker cytotoxicity, showed no increased specific DNA binding of p53. In addition, PEITC induced p53-responsive p21 and Noxa promoter luciferase activity. Blocking mutant p53 protein expression with shRNA in T98G cells entirely prevented p21 protein induction triggered by PEITC. Immunoprecipitation studies with conformation-specific p53 antibodies (Pab1620 and Pab240) show that treatment with PEITC alters mutant p53 to wild type conformation in H596 cells. Currently, we are investigating the significance of function restoration to mutant p53 by phenethyl isothiocyanate in the regulation of apoptosis by PEITC or other conventional chemotherapeutic drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1629.

The stability of papillomavirus E2 proteins is regulated by proteasomal degradation, and regulation of degradation could contribute to the higher expression levels of E2 proteins observed in suprabasal layers of differentiated skin. We have recently shown that the E2 proteins are modified by sumoylation [Wu Y-C, Roark AA, Bian X-L, Wilson, VG (2008) Virol 378:329–338], and that sumoylation levels are up-regulated during keratinocyte differentiation [Deyrieux AF, Rosas-Acosta G, Ozbun MA, Wilson VG (2007) J Cell Sci 120:125–136]. These observations, coupled with the known ability of sumoylation to prevent proteasomal degradation of certain proteins, suggested that this modification might contribute to stabilizing E2 proteins in suprabasal keratinocytes. Conditions that increased overall sumoylation were found to increase the intracellular amounts of the HPV11, 16, and 18 E2 proteins. No effect of sumoylation was seen on E2 transcripts, and the increased levels of E2 proteins resulted from a greatly increased half-life for the E2 proteins. In vitro studies confirmed that sumoylation could block the proteasomal degradation of the 16E2 protein. Interestingly, this stabilization effect was indirect as it did not require sumoylation of 16E2 itself and must be acting through sumoylation of a cellular target(s). This sumoylation-dependent, indirect stabilization of E2 proteins is a novel process that may couple E2 levels to changes in the cellular environment. Specifically, our results suggest that the levels of papillomavirus E2 protein could be up-regulated in differentiating keratinocytes in response to the increased overall sumoylation that accompanies differentiation.