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This paper explores the impact of international diversification on the decision to hold conference calls. In addition, we examine the mitigating roles of legal environment and agency problems in holding conference calls. Using a sample drawn from Taiwan, we find that greater corporate internationalization (INT) is associated with a higher likelihood of holding conference calls. We also find that firms are more likely to conduct conference calls when companies invest in a higher proportion of common law countries. We also find that the positive association between the likelihood of holding conference calls and corporate INT is less pronounced when the control divergence of controlling owners increases.

Museums in Taiwan have developed various digital archives, but few people have visited these digital archives. Therefore, this study designed a digital archaeology game for high school students to play. Based on the concept of ''learning for playing'' (i.e., players who want to win will study more), the digital archaeology game contest aims at attracting students to visit the natural science digital museum. In the game, researchers (players) reorient the artifacts, structures and architectures through excavation and assemblages to understand the world of natural science based on the saliency-based model. To examine whether this game prompts learners to visit the natural science digital museum to acquire knowledge, 80 students from three high schools were recruited and grouped into 40 pairs to compete against each other. After the contest, questionnaires were collected and analyzed using confirmatory factor analysis with structural equation modeling. The results indicated that the research participants' gameplay self-efficacy affected their perceived hedonic values and was mediated by the perceived ease of playing the game increased their intention to visit the digital archives of the natural science museum. The implications of this study could be used for promotion of digital archives or other digital museums.

PurposeThe purpose of this paper is to investigate the impact of corporate internationalization, governance structures, and legal protections on the foreign earnings response coefficient (FERC). The FERC is a measure of the value‐relevance of foreign earnings.Design/methodology/approachData were collected on 3,653 Taiwanese firms which had overseas investments. The authors examined the impact of the site of their overseas investments and the nature of the legal code of the investee country on the investor perceptions of firms' reported foreign and domestically‐generated earnings. Also examined was the impact of corporate governance arrangements (e.g. the difference between the owners' cash flow and voting rights) on the same components of the firms' earnings.FindingsThe empirical findings suggest that an aggressive internationalization strategy (foreign direct investment) has positive effects on the value relevance of foreign earnings, but that this strategy is impacted by the firm's own corporate governance arrangements and the target of its overseas investment efforts. While foreign investments bring about growth and profits, they expose the investors to the risk of expropriation by investee countries and corporate insiders.Originality/valueThe importance of the findings is that they should help regulatory agencies – and firms themselves – to better understand factors that can promote the global expansion of domestic enterprises.

This research aims to develop an artificial intelligence (AI) estimator for the coating touch panel (TP) film. The AI estimator could estimate the transmittance of touch panel (TP) with different layers coating. It also could be used for helping the technician precisely set the relevant control parameters of evaporator in advance so that the optical quality of TP film could fit the customers request. In order to catch the unknown relationship between the films transmittance and its all possible influencing factors, the neural network (NN) is taken as the AI tool. In other words, a fast and precise intelligent manufacturing mechanism for TP evaporation process is expected to be developed and this intelligent mechanism could be practically used in the real industrial applications.

This research aims to estimate the optical property of touch panel (TP) with different layers coating. The neural network (NN) model is used to catch the complex relationship among the chromatic aberration, i.e. L. a. b. values, and their relevant influencing factors. An artificial intelligent (AI) estimator is expected to be developed so that the optical property of TP decoration film with different layers coating could be precisely estimated before the evaporation process is taken. Such an AI estimator can help the technician to set the control parameters of evaporator in advance and make the films optical property could fit the customers request. From the simulation results shown, the estimations of chromatic aberration of TP film are very accurate. In other words, such an AI estimator is possibly to be developed and it is quite promising and potential in the real industrial applications.

Chronic heart failure (HF) is a major health problem throughout the world. Gender has significant effects on the pathophysiology of HF. Low levels of free testosterone are independently associated with increased chronic HF symptoms and mortality. Cardiac fibrosis plays a pivotal role in structural remodeling in HF. Transforming growth factor (TGF)-β, angiotensin II and oxidative stress contribute to the activity/extent of cardiac fibrosis. Androgen deficiency can up-regulate TGF-β expression under angiotensin II stimulation in vivo. In this review, we summarized the potential mechanisms accounting for the effects of androgen on cardiac fibrosis through regulating fibrocytes activity under TGF, which can explain wound healing and cardiac fibrosis in male with acute myocardial injury and chronic HF.

This paper investigates the impact of outside directors on firm performance during legal transitions and examines how the roles of family business and director compensation influence board efficacy. By using Taiwanese listed companies as our sample, the empirical results show that outside directors who are appointed by legal mandate have less positive impacts on firm performance than outside directors appointed voluntarily. Family business weakens the positive impact of outside director on firm performance. The evidence further suggests that director compensation contributes to firm performance, particularly when outside directors are voluntarily appointed. The findings provide western managers with an understanding of how the typical Chinese family business affects board independence. We also demonstrate and incorporate the cultural and the ownership characteristics into the analysis to present a country-specific pattern that should be informative for foreign investors who are concerned about the quality of corporate governance in East Asia.

This study investigates the effects of intermetallics (IMCs) on the single-joint shear strength of 50 μm diameter Cu pillar bumps joined with Sn–4.0%Ag–0.5%Cu (SAC405) solder caps. The correlations between the shear strength of the Cu pillar bumps and the IMCs aged at 180 °C for 150, 300, 500, and 750 h are studied. Microstructure characterization reveals that the Cu 6 Sn 5 morphology transforms from scallop-type to planar-type after 150 h of aging. Void formations are observed at the Cu 3 Sn/Cu interface after 300 h of aging and the amount of void formations increases with aging time. The shear test result shows that the shear strength decreases with aging time. Although the void formations did contribute to the deterioration of the solder joint strength, the main contributing factor was the planarization of the Cu 6 Sn 5 morphology through the aging process. The failure modes of the solder joint are also discussed in this study.

Eight trigrams (BaGua) is a philosophy that has played an essential role in Chinese life. The purpose of the present study is to extend the theory to organizational problem-solving, so that individuals can engage in creative problem solving and justification to discover the most effective approaches. Questionnaires were returned by 259 research and development managers, and were analyzed using the SEM statistical method. The results indicate that the interaction among each trigram in the model of BaGua was significantly correlated. Most of the hypotheses were supported. The more an individual interacted with others, with data and with devices, the higher the problem sensitivity and evaluation performance. Despite the finding that the Tui trigram was not significantly related to the Ken trigram, all other trigram elements significantly affected each other. This finding is discussed in terms of the confirmatory situation and the conceptualization of epistemology in problem-solving.

Protein modification is an extremely important post-translational regulation that adjusts the physical and chemical properties, conformation, stability and activity of a protein; thus altering protein function. Due to the high throughput of mass spectrometry (MS)-based methods in identifying site-specific post-translational modifications (PTMs), dbPTM (http://dbPTM.mbc.nctu.edu.tw/) is updated to integrate experimental PTMs obtained from public resources as well as manually curated MS/MS peptides associated with PTMs from research articles. Version 3.0 of dbPTM aims to be an informative resource for investigating the substrate specificity of PTM sites and functional association of PTMs between substrates and their interacting proteins. In order to investigate the substrate specificity for modification sites, a newly developed statistical method has been applied to identify the significant substrate motifs for each type of PTMs containing sufficient experimental data. According to the data statistics in dbPTM, >60% of PTM sites are located in the functional domains of proteins. It is known that most PTMs can create binding sites for specific protein-interaction domains that work together for cellular function. Thus, this update integrates protein–protein interaction and domain–domain interaction to determine the functional association of PTM sites located in protein-interacting domains. Additionally, the information of structural topologies on transmembrane (TM) proteins is integrated in dbPTM in order to delineate the structural correlation between the reported PTM sites and TM topologies. To facilitate the investigation of PTMs on TM proteins, the PTM substrate sites and the structural topology are graphically represented. Also, literature information related to PTMs, orthologous conservations and substrate motifs of PTMs are also provided in the resource. Finally, this version features an improved web interface to facilitate convenient access to the resource.

Rhodopseudomonas palustris (R. palustris) is a purple nonsulfur anoxygenic phototrophic bacterium with metabolic versatility and is able to grow under photoheterotrophic and chemoheterotrophic states. It has uses in carbon management, carbon recycling, hydrogen generation, and lipid production; therefore, it has the potential for bioenergy production and biodegradation. This study is the first to identify the phosphoproteome of R. palustris including 100 phosphopeptides from 54 phosphoproteins and 74 phosphopeptides from 42 phosphoproteins in chemoheterotrophic and photoheterotrophic growth conditions, respectively. In the identified phosphoproteome, phosphorylation at the threonine residue, Thr487, of pyruvate phosphate dikinase (PPDK, RPA1051) was found to participate in the regulation of carbon metabolism. Here, we show that PPDK enzyme activity is higher in photoheterotrophic growth, with Thr487 phosphorylation as a possible mediator. Under the same photoheterotrophic conditions, R. palustris with overexpressed wild-type PPDK showed an enhanced accumulation of total lipids than those with mutant PPDK (T487V) form. This study reveals the role of the PPDK in the production of biodiesel material, lipid content, with threonyl-phosphorylation as one of the possible regulatory events during photoheterotrophic growth in R. palustris.

Purpose: The minimal clinically important difference (MCID) of 6MWT used to monitor the change of disease severity or evaluate the outcomes is still debated. The purpose of this study was to evaluate the effect of 6MWT MCID used in target population of chronic obstructive pulmonary disease (COPD). Methods: Systematic review was used in this study. Electronic databases including CINAHL, Cochrane Library, and PubMed/MEDLINE were retrieved for relevant articles which published before November 2015. Keywords included chronic obstructive pulmonary disease, minimal clinically important difference, exercise tolerance, and 6-minute walk test. A total of 65 articles that matched the search criteria were extracted. After screening the topics and deleting repetitions, 3 articles were selected for further analysis. One study is the randomized controlled trial (RCT), and two study are the systematic review. Results: The findings recommend the 6MWT is an objective assessment tool of disease severity and outcome evaluations, and invest effort to examine the cut-point value of 6MWT for the effectiveness of Pulmonary rehabilitation exercise training is 25 to 48 meters. Conclusion: The 6-min walking test (6MWT) is a valid and reliable assessment tool for exercise tolerance in patients with COPD. With anticipation, this article might provide the recommendations of MCID of 6MWT for clinical health care providers and researchers conducting the evaluation of interventional outcomes and effectiveness in patients with COPD.

Background: Regular exercise improves psychological and physiological functioning in patients with COPD; and exercise self-regulatory efficacy (Ex-SRE) has been shown to be important for adherence to regular exercise. However, a valid and reliable instrument to measure exercise self-regulatory efficacy in Chinese patients with COPD is lacking. Purpose: The purpose of this study is to determine semantic equivalenceand preliminary test the psychometric properties of a Chinese version of Self-Regulatory Efficacy Scale(Ex-SRES-Chinese). Methods: The Ex-SRES-Chinese was established through Beaton et al.9s recommended guidelines. The reliability and validity of the determined Ex-SRES-Chinese was tested on a group of patients with COPD (n = 76) in Taiwan. Results: The rigorous translation and appraisal process were repeated to translate and culturally adapt Ex-SRES into Chinese, until semantic equivalence of each question between English and Chinese was agreedand accepted by an advisory committee. The overall content validity index of determined Ex-SRES-Chinese was 0.875. The Ex-SRES-Chinese demonstrated excellent internal reliability (Cronbach9s alpha 0.92) and construct validity (correlation with weekly exercise time [ r = 0.67; P r = 0.29; P r = 0.26; P Conclusion: The Ex-SRES-Chinese demonstrated excellent semantic equivalency and initial psychometric properties, and is a short, easily administrated exercise self-regulatory efficacy measure.

Background: Biofeedback combined with pulmonary rehabilitative exercise program (BF-PR) has been used to facilitate COPD patients9 adherence of regular exercise, but it is important to explore how participants experienced and perceived participation. Aims: To explore COPD participants9 self-awareness on their psychological and physiological changes after BF-PR. Methods: Twelve COPD patients, who completed the 4-week BF-PR,were received two in-depth interviews at the time of right after completed the training program and 6 months after. The transcripts were analyzed by the method of content analysis. Results: Six themes identified from participants9 self-disclosure at the time right after the training were identified, which were (1) the initiative motivation of participating; (2) special experiences via engaging the training program, (3) positive progressing in health status; (4) driving the healthy behaviors; (5) expanding exercise benefits; (6) the additive effects of biofeedback training. At 6 months after the training, five themes were refined, which were (1) sustaining the positive progressing in physiological and psychological impacts from the program; (2) further engaging in healthy behaviors; (3) wanting to maintain the exercise effects; (4) perceived the factors to maintain the regular exercise; (5) perceived barriers to maintain the regular exercise. Conclusion: After received the BF-PR, patients with COPD experienced their own positive changes, and willing to execute healthy behaviors and establish their own way to maintain the regular exercise.

We reported an integrated platform to explore serum protein variant pattern in cancer and its utility as a new class of biomarker panel for diagnosis. On the model study of serum amyloid A (SAA), we employed nanoprobe-based affinity mass spectrometry for enrichment, identification and quantitation of SAA variants from serum of 105 gastric cancer patients in comparison with 54 gastritis patients, 54 controls, and 120 patients from other cancer. The result revealed surprisingly heterogeneous and most comprehensive SAA bar code to date, which comprises 24 SAA variants including SAA1- and SAA2-encoded products, polymorphic isoforms, N-terminal–truncated forms, and three novel SAA oxidized isotypes, in which the variant-specific peptide sequence were also confirmed by LC-MS/MS. A diagnostic model was developed for dimension reduction and computational classification of the 24 SAA-variant bar code, providing good discrimination (AUC = 0.85 ± 3.2E−3) for differentiating gastric cancer group from gastritis and normal groups (sensitivity, 0.76; specificity, 0.81) and was validated with external validation cohort (sensitivity, 0.71; specificity, 0.74). Our platform not only shed light on the occurrence and modification extent of under-represented serum protein variants in cancer, but also suggested a new concept of diagnostic platform by serum protein variant profile. This article is protected by copyright. All rights reserved

Crosslinking of B-cell receptor (BCR) sets off an apoptosis programme, but the underlying pathways remain obscure. Here we decipher the molecular mechanisms bridging B-cell activation and apoptosis mediated by post-translational modification (PTM). We find that O-GlcNAcase inhibition enhances B-cell activation and apoptosis induced by BCR crosslinking. This proteome-scale analysis of the functional interplay between protein O-GlcNAcylation and phosphorylation in stimulated mouse primary B cells identifies 313 O-GlcNAcylation-dependent phosphosites on 224 phosphoproteins. Among these phosphoproteins, temporal regulation of the O-GlcNAcylation and phosphorylation of lymphocyte-specific protein-1 (Lsp1) is a key switch that triggers apoptosis in activated B cells. O-GlcNAcylation at S209 of Lsp1 is a prerequisite for the recruitment of its kinase, PKC-β1, to induce S243 phosphorylation, leading to ERK activation and downregulation of BCL-2 and BCL-xL. Thus, we demonstrate the critical PTM interplay of Lsp1 that transmits signals for initiating apoptosis after BCR ligation., B cell receptor (BCR) activation can trigger signalling causing apoptosis in order to eliminate auto-reactive B cells. Here the authors show that the O-GlcNAcylation and phosphorylation of lymphocyte-specific protein-1 are involved in a switch that regulates the initiation of apoptosis induced by BCR cross-linking.

Metabolic syndrome (MetS) has been reported to cause considerable psychoneuroimmunology (PNI) disturbances such as, psychological distress, autonomic nervous imbalance, and impaired immune function. Associations among these psychoneuroimmunology (PNI) factors and their integrated effects with MetS and risk components of MetS necessitate further exploration.This study investigated associations among psychoneuroimmunological factors, their integrated effects with MetS and risk components of MetS.This was a cross-sectional study. Participants were recruited from two health management centers at a medical center in Northern Taiwan. Demographics and data on psychological distress (e.g., perceived stress and depression) were collected using self-reported questionnaires. Heart rate variability (HRV) and C-reactive protein values (CRP) were measured to evaluate participants' autonomic nervous function and immune reaction. The risk components of MetS (e.g., elevated blood pressure, impaired fasting glucose, dyslipidemia, and abdominal obesity) were identified according to the Taiwan-specific definition of MetS and were determined based on participants' health examination profiles.A total of 345 participants with complete data were included for data analysis. Compared with healthy controls, participants with MetS exhibited higher depression scores (11.2±8.5 vs. 8.7±7.0), higher CRP values (2.1±2.5 vs. 0.7±1.0), and lower HRV (total power: 758.7±774.9 vs. 1064.4±1075.0). However, perceived stress in participants with MetS did not significantly differ from that of their healthy counterparts (p0.05). Univariate analyses indicated that associations among psychoneuroimmunological factors and MetS risk components were statistically heterogeneous: a) perceived stress and depression were significantly associated only with high blood glucose (p0.05); b) CRP was significantly associated with all MetS risk components (p0.05); and c) HRV was significantly associated with high triglycerides and high fasting blood glucose (p0.05). Multivariate analysis indicated that the integrated effects of depression, CRP, and HRV were significantly associated with MetS (p0.01) after controlling for age and education level.Higher depression scores, higher CRP values, and lower HRV are independently and additively associated with MetS and risk components of MetS. Accordingly, a multidisciplinary approach to alleviating psychological distress, immune dysfunction, and autonomic nervous imbalance is recommended for promoting well-being in people with subclinical metabolic abnormalities or MetS to minimize downstream health consequences.

Rationale Despite advances in mass spectrometry (MS)-based identification, effective phosphopeptide enrichment is a prerequisite towards comprehensive phosphoproteomic analysis. Based on the different binding affinities and coordination geometries of the Ti(4+) and Fe(3+) ions with the phosphate group, we report a complementary metal-directed immobilized metal ion affinity chromatography (IMAC) method to increase the identification coverage of a phosphoproteome. Methods Phosphopeptides from standard phosphoproteins and Raji B cells were enriched from Ti(4+)-IMAC and Fe(3+)-IMAC methods, followed by matrix-assisted laser desorption/ionization (MALDI) MS and Orbitrap MS analysis. Optimal enrichment specificity was achieved by selection of acid structure/concentration and organic solvent to compete with non-phosphopeptides. The effect of the metal ion and the chelating compound was evaluated by the comparison of the characteristics of enriched phosphopeptides between Ti(4+)-IMAC, Fe(3+)-IMAC and TiO(2) methods. Results To address the low enrichment specificity of the Ti(4+)-IMAC method, a simple one-step acid/solvent controlled IMAC method was developed with significantly improved specificity (88%) and recovery (93%). The most striking discovery is that the optimal Ti(4+)-IMAC and Fe(3+)-IMAC methods have low overlapping percentage (10%) among the 2905 enriched phosphopeptides from Raji cells, comprised of the distinct characteristics including hydrophobicity, amino acid compositions, and frequency of multiple phosphorylation of the phosphopeptides. Conclusions The reported Fe(3+)-IMAC and Ti(4+)-IMAC methods can complementarily enrich acidic and basic phosphopeptides to effectively increase the identification coverage of an heterogeneous phosphoproteome (twice than the single approach). Given the reproducibility and low sample loss, the combination of our enrichment strategy with a quantitative technique could be feasible for quantitative phosphoproteomics.

SummaryThe synthesis of dTDP is unique because there is a requirement for thymidylate kinase (TMPK). All other dNDPs including dUDP are directly produced by ribonucleotide reductase (RNR). We report the binding of TMPK and RNR at sites of DNA damage. In tumor cells, when TMPK function is blocked, dUTP is incorporated during DNA double-strand break (DSB) repair. Disrupting RNR recruitment to damage sites or reducing the expression of the R2 subunit of RNR prevents the impairment of DNA repair by TMPK intervention, indicating that RNR contributes to dUTP incorporation during DSB repair. We identified a cell-permeable nontoxic inhibitor of TMPK that sensitizes tumor cells to doxorubicin in vitro and in vivo, suggesting its potential as a therapeutic option.

We describe an improved version of the data-independent acquisition (DIA) computational analysis tool DIA-Umpire, and show that it enables highly sensitive, untargeted, and direct (spectral library-free) analysis of DIA data obtained using the Orbitrap family of mass spectrometers. DIA-Umpire v2 implements an improved feature detection algorithm with two additional filters based on the isotope pattern and fractional peptide mass analysis. The targeted re-extraction step of DIA-Umpire is updated with an improved scoring function and a more robust, semiparametric mixture modeling of the resulting scores for computing posterior probabilities of correct peptide identification in a targeted setting. Using two publicly available Q Exactive DIA datasets generated using HEK-293 cells and human liver microtissues, we demonstrate that DIA-Umpire can identify similar number of peptide ions, but with better identification reproducibility between replicates and samples, as with conventional data-dependent acquisition. We further demonstrate the utility of DIA-Umpire using a series of Orbitrap Fusion DIA experiments with HeLa cell lysates profiled using conventional data-dependent acquisition and using DIA with different isolation window widths.

Membrane proteins are crucial targets for cancer biomarker discovery and drug development. However, in addition to the inherent challenges of hydrophobicity and low abundance, complete membrane proteome coverage of clinical specimen is usually hindered by the requirement of large amount of starting materials. Toward comprehensive membrane proteomic profiling for small amounts of samples (10 μg), we developed high-pH reverse phase (Hp-RP) combined with stop-and-go extraction tip (StageTip) technique, as a fast (∼15 min.), sensitive, reproducible, high-resolution and multiplexed fractionation method suitable for accurate quantification of the membrane proteome. This approach provided almost 2-fold enhanced detection of peptides encompassing transmembrane helix (TMH) domain, as compared with strong anion exchange (SAX) and strong cation exchange (SCX) StageTip techniques. Almost 5000 proteins (∼60% membrane proteins) can be identified in only 10 μg of membrane protein digests, showing the superior sensitivity of the Hp-RP StageTip approach. The method allowed up to 9- and 6-fold increase in the identification of unique hydrophobic and hydrophilic peptides, respectively. The Hp-RP StageTip method enabled in-depth membrane proteome profiling of 11 lung cancer cell lines harboring different EGFR mutation status, which resulted in the identification of 3983 annotated membrane proteins. This provides the largest collection of reference peptide spectral data for lung cancer membrane subproteome. Finally, relative quantification of membrane proteins between Gefitinib-resistant and -sensitive lung cancer cell lines revealed several up-regulated membrane proteins with key roles in lung cancer progression.

To enhance the detection sensitivity of target clinical protein biomarkers, a simple and rapid nanoprobe-based immuno-affinity mass spectrometry assay employing biocompatible monodisperse magnetic nanoparticles (MNPs) is reported herein. The MNPs were synthesized via a streamlined protocol that includes (a) fabrication of core MNPs using the thermal decomposition method to minimize aggregation, (b) surface protection by gold coating (MNP@Au) and surfactant coating using MNP@IGEPAL to improve hydrophilicity, and lastly, (c) oriented functionalization of antibodies to maximize immuno-affinity. The enrichment performances of the monodisperse MNPs for the C-reactive protein (CRP) serum biomarker were then evaluated and compared with aggregated magnetic nanoparticles synthesized from the conventional co-precipitation method (MNP(CP)). The detection sensitivity for CRP at an extremely low amount of serum sample (1 μL) was enhanced ∼19- and ∼15-fold when monodisperse MNP@Au and MNP@IGEPAL, respectively, were used. Furthermore, the detection sensitivity of CRP by this approach (1 ng mL(-1), S/N = 3) provided a 1000-fold sensitivity enhancement to the clinical cut-off (1 μg mL(-1)) of CRP. We supposed that these observed improvements are due to the enhanced nanoparticle dispersibility and size uniformity which eliminated completely other non-specific binding of high-abundance serum proteins. Most interestingly, the enrichment efficiency correlates more closely with the MNP dispersibility than the ligand density. Our investigation revealed the critical role of MNP dispersibility, as well as provided mechanistic insight into its impact on immunoaffinity enrichment and detection of CRP in one drop of serum sample. This strategy offers an essential advantage over the other methods by providing a simple and facile biofunctionalization protocol while maintaining excellent solvent dispersibility of MNPs.

Human mesenchymal stromal cells (hMSCs) are promising candidates for cell therapy and tissue regeneration. Knowledge of the molecular mechanisms governing hMSC commitment into osteoblasts is critical to the development of therapeutic applications for human bone diseases. Because protein phosphorylation plays a critical role in signaling transduction network, the purpose of this study is to elucidate the phosphoproteomic changes in hMSCs during early osteogenic lineage commitment. hMSCs cultured in osteogenic induction medium for 0, 1, 3, and 7 days were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Surprisingly, we observed a dramatic loss of protein phosphorylation level after 1 day of osteogenic induction. Pathways analysis of these reduced phosphoproteins exhibited a high correlation with cell proliferation and protein synthesis pathways. During osteogenic differentiation, differentially expressed phosphoproteins demonstrated the dynamic alterations in cytoskeleton at the early stages of differentiation. The fidelity of our quantitative phosphoproteomic analyses were further confirmed by Western blot analyses, and the changes from protein expression or its phosphorylation level were distinguished. In addition, several ion channels and transcription factors with differentially expressed phosphorylation sites during osteogenic differentiation were identified and may serve as potentially unexplored transcriptional regulators of the osteogenic phenotype of hMSCs. Taken together, our results have demonstrated the dynamic changes in phosphoproteomic profiles of hMSCs during osteogenic differentiation and unraveled potential candidates mediating the osteogenic commitment of hMSCs. The findings in this study may also shed light on the development of new therapeutic targets for metabolic bone diseases such as osteoporosis and osteomalacia.

Background To identify novel serological biomarkers for human colorectal cancer (CRC), we analyzed CRC tissues using gel-assisted digestion and isobaric tags with related and absolute quantitation (iTRAQ) labeling mass spectrometry (MS). By comparing pairs of tumor tissues and matched normal tissues, we discovered the SEC61β with expression changes 3.3-fold and a marginal statistical significance ( p = 0.052) previously. Methods SEC61β expression in CRC tissues was further analyzed by western blotting and immunohistochemistry. We next assessed the putative diagnostic value of the SEC61β autoantibody as a serum marker. Results Using western blotting analysis, SEC61β expression was increased 1.9-fold in tumor tissues. Immunohistochemical analysis of 64 CRC specimens showed that SEC61β was positively detected in 64% of the tumors, but weakly or not detected in > 80% of the adjacent nontumor epithelial cells. Western blot analysis with plasma samples showed that the sensitivity and specificity of the SEC61β autoantibody from patients with CRC were 79% and 75%, respectively. Importantly, the results of the SEC61β autoantibody for early detection of colorectal cancer revealed a higher sensitivity of 77% than the carcinoembryonic antigen (CEA) assay. Conclusions Measurement of SEC61β autoantibody levels may provide an alternative detection indicator for CRC, particularly among early-stage patients.

Research highlights? This paper presents the estimations of ammonia concentration by using neural network (NN) models. ? The shear horizontal surface acoustic wave (SH-SAW) devices coated with L-glutamic acid hydrochloride and polyaniline (PANI) film, respectively, were applied as the ammonia sensors. ? The signal sensed by SH-SAW sensors were implemented by using different NN models for the estimation of ammonia concentration. ? A reliable and superior neural network SAW identifier is expected to be found for effectively overcoming the interference of humidity in ammonia detection.Display Omitted This paper presents the estimations of ammonia concentration by using neural network (NN) models. The shear horizontal surface acoustic wave (SH-SAW) devices coated with L-glutamic acid hydrochloride and polyaniline (PANI) film, respectively, were applied as the ammonia sensors. The data sensed by SH-SAW sensors were implemented by using different NN models. A reliable and superior neural network SAW identifier is expected to be found for effectively overcoming the interference of humidity in ammonia detection.

The derivation of induced pluripotent stem cells (iPSCs) requires not only efficient reprogramming methods, but also reliable markers for identification and purification of iPSCs. Here, we demonstrate that surface markers, epithelial cells adhesion molecule (EpCAM) and epithelial cadherin (E-cadherin) can be used for efficient identification and/or isolation of reprogrammed mouse iPSCs. By viral transduction of Oct4, Sox2, Klf4 and n- or c-Myc into mouse embryonic fibroblasts, we observed that the conventional mouse embryonic stem cell (mESC) markers, alkaline phosphatase (AP) and stage-specific embryonic antigen 1 (SSEA1), were expressed in incompletely reprogrammed cells that did not express all the exogenous reprogramming factors or failed to acquire pluripotent status even though exogenous reprogramming factors were expressed. EpCAM and E-cadherin, however, remained inactivated in these cells. Expression of EpCAM and E-cadherin correlated with the activation of Nanog and endogenous Oct4, and was only seen in the successfully reprogrammed iPSCs. Furthermore, purification of EpCAM-expressing cells at late reprogramming stage by FACS enriched the Nanog-expressing cell population suggesting the feasibility of selecting successful reprogrammed mouse iPSCs by EpCAM expression. We have thus identified new surface markers that can efficiently identify successfully reprogrammed iPSCs and provide an effective means for iPSC isolation.

This paper presents the chromatic aberration identification of touch panel (TP) decoration film by using nearly equivalent neural network (NN) model. This model is expected to adequately catch the complex relationship between the chromatic aberration and its possible influencing factors during the evaporation process of TP decoration film. Then, an intelligent estimator for the chromatic aberration of TP film could be developed automatically. Based on this estimator, the technician could set the control parameters of evaporation process in advance and make the quality of chromatic aberration of TP could meet the customer’s required.

OBJECTIVES: To examine the combined effect of healthy behaviors on the development of functional disability in an elderly cohort. DESIGN: Prospective cohort study. SETTING: Taiwan Longitudinal Study in Aging from 1989, 1993, 1996, 1999, and 2003. PARTICIPANTS: A national sample of 1,940 men and 1,247 women aged 60 and older without functional disability at baseline. MEASUREMENTS: Functional disability was defined as difficulty with activities of daily living: taking a bath or walking 200 to 300 m. Time to functional disability was the age at midpoint between the first occurrence of disability onset in the survey year and prior survey year. Considering that the onset of disability is probably a precursor of death, for those who died without disability, time to disability onset was set at the midpoint between the last follow-up and death year. Four healthy behaviors were measured: not smoking, moderate alcohol consumption, regular exercise, and sleeping 6 to 8 hours per day. A Cox proportional hazards model with time-dependent covariates was used to analyze the association between age at the first functional disability and prior healthy behavior, after controlling for sex, time-varying disease status, marital status, and education. RESULTS: Healthy behaviors were linked to the onset of functional disability. Participants who performed one or more healthy behaviors were 15% to 75% less likely to be disabled than those who performed none. CONCLUSION: In the population studied, healthy behaviors were associated with lower incidence of functional disability. As the number of healthy behaviors increased, the likelihood of disability decreased.

Summary: S-glutathionylation, the reversible protein posttranslational modification (PTM) that generates a mixed disulfide bond between glutathione and cysteine residue, critically regulates protein activity, stability and redox regulation. Due to its importance in regulating oxidative/nitrosative stress and balance in cellular response, a number of methods have been rapidly developed to study S-glutathionylation, thus expanding the dataset of experimentally determined glutathionylation sites. However, there is currently no database dedicated to the integration of all experimentally verified S-glutathionylation sites along with their characteristics or structural or functional information. Thus, the dbGSH database has been created to integrate all available datasets and to provide the relevant structural analysis. As of January 31, 2014, dbGSH has manually collected >2200 experimentally verified S-glutathionylated peptides from 169 research articles using a text-mining approach. To solve the problem of heterogeneity of the data collected from different sources, the sequence identity of the reported S-glutathionylated peptides is mapped to UniProtKB protein entries. To delineate the structural correlations and consensus motifs of these S-glutathionylation sites, the dbGSH database also provides structural and functional analyses, including the motifs of substrate sites, solvent accessibility, protein secondary and tertiary structures, protein domains and gene ontology. Availability and implementation: dbGSH is now freely accessible at http://csb.cse.yzu.edu.tw/dbGSH/. The database content is regularly updated with new data collected by the continuous survey of research articles. Contact: francis@saturn.yzu.edu.tw or yujuchen@gate.sinica.edu.tw Supplementary information: Supplementary Data are available at Bioinformatics online.

S-nitrosylation, a post-translational modification of cysteine residues induced by nitric oxide, mediates many physiological functions. Due to the labile nature of S-nitrosylation, detection by mass spectrometry (MS) is challenging. Here, we developed an S-alkylating labeling strategy using the irreversible biotinylation on S-nitrosocysteines for site-specific identification of the S-nitrosoproteome by LC-MS/MS. Using COS-7 cells without endogenous nitric oxide synthase, we demonstrated that the S-alkylating labeling strategy substantially improved the blocking efficiency of free cysteines, minimized the false-positive identification caused by disulfide interchange, and increased the digestion efficiency for improved peptide identification using MS analyses. Using this strategy, we identified total 586 unique S-nitrosylation sites corresponding to 384 proteins in S-nitroso-N-acetylpenicillamine (SNAP)/l-cysteine-treated mouse MS-1 endothelial cells, including 234 previously unreported S-nitrosylated proteins. When the topologies of 84 identified transmembrane proteins were further analyzed, their S-nitrosylation sites were found to mostly face the cytoplasmic side, implying that S-nitrosylation occurs in the cytoplasm. In addition to the previously known acid/basic motifs, the ten deduced consensus motifs suggested that combination of local hydrophobicity and acid/base motifs in the tertiary structure contribute to the specificity of S-nitrosylation. Moreover, the S-nitrosylated cysteines showed preference on beta-strand, having lower relative surface accessibility at the S-nitrosocysteines.

In this paper, the predictions of optoelectronic attributes of Light-Emitting Diode (LED) chip, including luminous intensity, wavelength and forward voltage by using neural network were presented. The simulated data was measured by Electrical Luminescence (EL) technique. The well-trained neural models were used to predict the optoelectronic attributes of LED chip in its epitaxy growth stage in advance. These predicted results could provide the necessary information for the process engineer to adjust the control parameters of epitaxy growth accurately and then ensure the LED chip to be in conformance with the requested quality.

The aim of this study was to uncover the membrane protein profile differences between colorectal carcinoma and neighboring normal mucosa from colorectal cancer patients. Information from cellular membrane proteomes can be used not only to study the roles of membrane proteins in fundamental biological processes, but also to discover novel targets for improving the management of colorectal cancer patients. We used solvent extraction and a gel-assisted digestion method, together with isobaric tags with related and absolute quantitation (iTRAQ) reagents to label tumoral and adjacent normal tissues in a pairwise manner (n = 8). For high-throughput quantification, these digested labeled peptides were combined and simultaneously analyzed using LC-MS/MS. Using the shotgun approach, we identified a total of 438 distinct proteins from membrane fractions of all eight patients. After comparing protein expression between cancerous and corresponding normal tissue, we identified 34 upregulated and eight downregulated proteins with expression changes greater than twofold (Student's t-test, P < 0.05). Among these, the overexpression of well-established biomarkers such as carcinoembryonic antigens (CEACAM5, CEACAM6), as well as claudin-3, HLA class I histocompatibility antigen A-1, tapasin and mitochondrial solute carrier family 25A4 were confirmed by western blotting. We conclude that gel-assisted digestion and iTRAQ labeling MS is a potential approach for uncovering and comparing membrane protein profiles of tissue samples that has the potential to identify novel biomarkers.

This paper investigates the relationship between business group factors and affiliated firm innovation in terms of patents granted. We examine the following factors for business groups: group affiliation, group diversification, inside ownership, and family ties. In emerging markets, business groups act not only as an internal capital market, but also as a platform for resource sharing among affiliates. We use Taiwan's business groups as a research sample to investigate how these group factors affect affiliated firms' innovation. The findings indicate that firms that are affiliated with business groups innovate better than their unaffiliated counterparts. Group diversification and family ties have positive effects on firm innovation, while inside ownership has no significant positive effect. Our study contributes to the innovation literature by shedding light on business group factors and firm innovation.

In this paper, an artificial intelligent (AI) analyzer for mechanical properties of rolled steel bar by using neural networks was proposed. Based on the learning capability of neural network, the nonlinear and complex relationships among the steel bar's properties, the billet compositions and the control parameters of manufacture could be automatically developed. Such an AI analyzer could help the technician to precisely set the related control parameters on the bar rolling process. Not only the quality of steel bar could be improved, the production cost of the bar could also be greatly reduced.

Autism is a childhood-onset neurodevelopmental disorder with a strong genetic basis in its etiology. Conventional karyotype analysis has revealed that chromosomal structural aberrations such as translocation, inversion, deletion, and duplication play a role in causing autism spectrum disorders (ASD). In addition, recent array-based comparative genomic hybridization (array CGH) studies discovered that submicroscopic deletion and duplication of DNA segments also contributed significantly to the genetic etiology of ASD. Together, these studies indicate that genomic rearrangement is an important genetic mechanism of ASD. Using karyotyping analysis and array CGH technology, we identified a subtelomeric deletion of approximately 6.8 Mb at 4q35.1-35.2 and a terminal deletion of approximately 2.4 Mb at 8p23.2-pter in two autistic boys, respectively. These two deletions were further validated using fluorescent in situ hybridization and real-time quantitative polymerase chain reaction, and their breakpoints were delineated using high-resolution array CGH. The 4q deletion is a rare de novo mutation, while the transmission of 8p deletion is unknown, because the father of the patient was unavailable for study. These two deletions are rare mutations and were not found in the additional 282 patients with ASD and in the 300 control subjects in our population. The identification of these two chromosomal deletions contribute to our understanding of the genetic basis of ASD, and the haploinsufficiency of several genes located at the deleted regions of chromosome 8p and 4q may contribute to the clinical phenotypes of autism.

In this study, we present a fully automated tool, called IDEAL-Q, for label-free quantitation analysis. It accepts raw data in the standard mzXML format as well as search results from major search engines, including Mascot, SEQUEST, and X!Tandem, as input data. To quantify as many identified peptides as possible, IDEAL-Q uses an efficient algorithm to predict the elution time of a peptide unidentified in a specific LC-MS/MS run but identified in other runs. Then, the predicted elution time is used to detect peak clusters of the assigned peptide. Detected peptide peaks are processed by statistical and computational methods and further validated by signal-to-noise ratio, charge state, and isotopic distribution criteria (SCI validation) to filter out noisy data. The performance of IDEAL-Q has been evaluated by several experiments. First, a serially diluted protein mixed with Escherichia coli lysate showed a high correlation with expected ratios and demonstrated good linearity (R(2) = 0.996). Second, in a biological replicate experiment on the THP-1 cell lysate, IDEAL-Q quantified 87% (1,672 peptides) of all identified peptides, surpassing the 45.7% (909 peptides) achieved by the conventional identity-based approach, which only quantifies peptides identified in all LC-MS/MS runs. Manual validation on all 11,940 peptide ions in six replicate LC-MS/MS runs revealed that 97.8% of the peptide ions were correctly aligned, and 93.3% were correctly validated by SCI. Thus, the mean of the protein ratio, 1.00 +/- 0.05, demonstrates the high accuracy of IDEAL-Q without human intervention. Finally, IDEAL-Q was applied again to the biological replicate experiment but with an additional SDS-PAGE step to show its compatibility for label-free experiments with fractionation. For flexible workflow design, IDEAL-Q supports different fractionation strategies and various normalization schemes, including multiple spiked internal standards. User-friendly interfaces are provided to facilitate convenient inspection, validation, and modification of quantitation results. In summary, IDEAL-Q is an efficient, user-friendly, and robust quantitation tool. It is available for download.

This paper presents a passive auto-focus camera control system which can easily achieve the function of auto-focus with no necessary of any active component (e.g., infrared or ultrasonic sensor) in comparison with the conventional active focus system. To implement the technique we developed, the hardware system including the adjustable lens with CMOS sensor and servo motor, an 8051 image capture micro-controller, a field programmable gate array (FPGA) sharpness measurement circuit, a pulse width modulation (PWM) controller, and a personal digital assistant (PDA) image displayer was constructed. The discrete wavelet transformation (DWT), the morphology edge enhancement sharpness measurement algorithms, and the self-organizing map (SOM) neural network were used in developing the control mechanism of the system. Compared with other passive auto-focus methods, the method we proposed has the advantages of lower computational complexity and easier hardware implementation.

Chemokines orchestrate leukocyte migration toward sites of inflammation and infection and target leukocytes via chemokine receptors such as CCR6, a subfamily of the seven-transmembrane G-protein-coupled receptors. Lipid rafts are cholesterol and sphingolipid-enriched liquid-ordered membrane microdomains thought to serve as scaffolding platforms for signal transduction. To globally understand the dynamic changes of proteins within lipid rafts upon CCR6 activation in T cells, we quantitatively analyzed the time-dependent changes of lipid raft proteome using our recently reported membrane proteomics strategy combining gel-assisted digestion, iTRAQ labeling and LC-MS/MS. To our knowledge, the error-free identification of 852 proteins represents the first data set of the raft proteome in T cells upon chemokine receptor activation, including 354 previously annotated raft proteins and 85 dynamically recruited proteins that are potential raft-associated proteins. The temporal profiles revealed that many proteins involved in the actin cytoskeleton rearrangement are actively recruited into lipid rafts upon CCR6 activation. We further confirmed the proteomics results by Western blotting and used small interfering RNA-mediated knockdown to evaluate their roles upon CCR6 activation. In sum, we employed quantitative proteomic strategy to analyze raft proteome and identified many molecules actively involved in the control of actin assembly and disassembly regulating CCR6 activation-induced cell migration.

Aluminum chlorohydrate (Al2(OH)5Cl · 2H2O, ACH) is an active ingredient in many antiperspirants and deodorants formulation to reduce the body odors (mainly sweat) through interaction with apocrine sweat glands to produce insoluble aluminum hydroxide and free chloride, which then plugs the sweat gland that stops the flow of sweat to the skins surface. We demonstrated here an one drop (50 mL) electrochemical sensing of the ACH using an in-built three screen-printed electrodes assembly containing Ag as working and pseudo reference and carbon as counter electrode system (AgSPE). The free Cl � ion librated from ACH/H2O reaction was detected at AgSPE surface at 0.072 V vs. pseudo Ag reference electrode system in pH 2 phosphate solution by Cyclic voltammetric Technique. Under optimal working condition the AgSPE shows a linear calibration plot in the window of 30 - 2000 ppm of ACH with sensitivity and regression values of 0.104 mA/ppm and 0.998 respectively. Calculated detection limit is 3.03 ppm. RSD values of intra- and interassays were 0.19% and 2.79% respectively. Finally, real sample (antiperspirant deodorant lotions) assays were successfully demonstrated with results comparable to the predicted values.

Transcription factor activating enhancer-binding protein 4 (AP-4) is a basic helix-loop-helix protein that binds to E-box elements. AP-4 has received increasing attention for its regulatory role in cell growth and development, including transcriptional repression of the human homolog of murine double minute 2 (HDM2), an important oncoprotein controlling cell growth and survival, by an unknown mechanism. Here we demonstrate that AP-4 binds to an E-box located in the HDM2-P2 promoter and represses HDM2 transcription in a p53-independent manner. Incremental truncations of AP-4 revealed that the C-terminal Gln/Pro-rich domain was essential for transcriptional repression of HDM2. To further delineate the molecular mechanism(s) of AP-4 transcriptional control and its potential implications, we used DNA-affinity purification followed by complementary quantitative proteomics, cICAT and iTRAQ labeling methods, to identify a previously unknown E-box-bound AP-4 protein complex containing 75 putative components. The two labeling methods complementarily quantified differentially AP-4-enriched proteins, including the most significant recruitment of DNA damage response proteins, followed by transcription factors, transcriptional repressors/corepressors, and histone-modifying proteins. Specific interaction of AP-4 with CCCTC binding factor, stimulatory protein 1, and histone deacetylase 1 (an AP-4 corepressor) was validated using AP-4 truncation mutants. Importantly, inclusion of trichostatin A did not alleviate AP-4-mediated repression of HDM2 transcription, suggesting a previously unidentified histone deacetylase-independent repression mechanism. In contrast, the complementary quantitative proteomics study suggested that transcription repression occurs via coordination of AP-4 with other transcription factors, histone methyltransferases, and/or a nucleosome remodeling SWI·SNF complex. In addition to previously known functions of AP-4, our data suggest that AP-4 participates in a transcriptional-regulating complex at the HDM2-P2 promoter in response to DNA damage.

This paper compares the availability characteristics between three different systems with reboot delay and standby switching failures. Three systems are studied under the assumption that the time-to-failure and the time-to-repair of the primary and standby units are exponentially and generally distributed, respectively. The reboot times are assumed to be exponentially distributed with parameter @b. It is assumed that there is a significant probability q of a switching failure. Using the supplementary variable technique, we develop the explicit expressions for the steady-state availability, Av, for three configurations and perform comparative analysis for three various repair time distributions, such as exponential, gamma, and uniform. Under the cost/benefit criterion, comparisons are made based on assumed numerical values given to the distribution parameters, and to the cost of the primary and standby units.

Infecting about one-half of the global human population, Helicobacter pylori is well established as the primary cause of gastritis, duodenal ulcer, and gastric cancer. Currently there is no clear information regarding if and how host cells interact with H. pylori , and if such interactions are dependent on the type of gastric disease. Using fluorescently labeled fucose-containing glycoconjugates, we provide evidence observing both the uptake of l -fucose from gastric cancer cells to H. pylori and that human α- l -fucosidase 2 (FUCA2) is secreted only under coculture conditions (i.e., host cells infected with H. pylori ). Upon depletion of FUCA2 by RNA interference and detection of translocated CagA (a virulence factor of H. pylori ) in host cells, FUCA2 was found to be essential for H. pylori adhesion, in particular to the gastric cancer- and duodenal ulcer-specific strains. Additionally FUCA2 was shown to significantly enhance the expression of Lewis x antigen in H. pylori , which is critical for bacterial cell adhesion in the pathogenesis and defense strategy to escape host surveillance. These findings not only demonstrate an important connection between FUCA2 and the adhesion, growth, and pathogenicity of H. pylori , but also support the idea that FUCA2 is a potential target for clinical diagnosis and therapeutic intervention of H. pylori -related diseases.

In this paper, an artificial intelligent mechanism for the decision of control parameters of touch panel film printing was developed. This mechanism is capable of providing the accurate information for the control parameters of the film printing, so that the technician could make a good setting work for the real-line manufacturing operation of touch panel film. Thus, this system not only can help the technician to improve the efficiency on the work of film printing, but also can reduce the cost caused by the defective products for the company. In our study, this intelligent system was constructed by using quantum neural network. It can automatically display the proper value of each control parameter needed for the film printing when the thickness of film is determined.

Discrepancies always exist between the dynamic properties predicted by a finite element model and those measured directly from the structure. In this study, a direct method based on the orthogonality constraints is proposed for updating the mass and stiffness matrices of the structure first using a single set of modal data. This method hinges on replacement of the modal vector of concern by the modal matrix in computing the correction matrices to solve the problem of insufficient known conditions. Such a method is then extended and applied in a consecutive manner to update the structural model for each of the first few modes that are experimentally made available. In the numerical studies, it was demonstrated that for buildings of the shear type, the natural frequencies predicted by the updated model agree well with the measured ones for those modes that are experimentally made available, while the rest modes remain basically untouched. The approach proposed herein is simple, accurate and robust, which sh...

Isotope labeling combined with liquid chromatography–mass spectrometry (LC–MS) provides a robust platform for analyzing differential protein expression in proteomics research. We present a web service, called MaXIC-Q Web (http://ms.iis.sinica.edu.tw/MaXIC-Q_Web/), for quantitation analysis of large-scale datasets generated from proteomics experiments using various stable isotope-labeling techniques, e.g. SILAC, ICAT and user-developed labeling methods. It accepts spectral files in the standard mzXML format and search results from SEQUEST, Mascot and ProteinProphet as input. Furthermore, MaXIC-Q Web uses statistical and computational methods to construct two kinds of elution profiles for each ion, namely, PIMS (projected ion mass spectrum) and XIC (extracted ion chromatogram) from MS data. Toward accurate quantitation, a stringent validation procedure is performed on PIMSs to filter out peptide ions interfered with co-eluting peptides or noise. The areas of XICs determine ion abundances, which are used to calculate peptide and protein ratios. Since MaXIC-Q Web adopts stringent validation on spectral data, it achieves high accuracy so that manual validation effort can be substantially reduced. Furthermore, it provides various visualization diagrams and comprehensive quantitation reports so that users can conveniently inspect quantitation results. In summary, MaXIC-Q Web is a user-friendly, interactive, robust, generic web service for quantitation based on ICAT and SILAC labeling techniques.

HOXD gene cluster maps to chromosome 2q31 and plays a key role in embryonic limb morphogenesis. Mutations of the HOXD13 and HOXD10 genes have been found to be associated with digital and limb malformations. In addition, dysregulation of HOXD gene cluster has been proposed to account for the limb abnormalities in patients with chromosome 2q rearrangements. In this report, we investigated a three-generation family presenting clinical phenotypes of duplication of great toes, tapering fingers, and clinodactyly of the fifth finger in both hands, which were transmitted in a dominant fashion in this family. We identified and validated an interstitial microdeletion of approximately 3.4 Mb at chromosome 2q31.1-31.2 by array-based comparative genomic hybridization, fluorescence in situ hybridization, and real-time quantitative polymerase chain reaction that cosegregates with the clinical phenotypes in this family. The microdeletion removes 30 labeled genes including the entire HOXD gene cluster, suggesting that the digital abnormalities of this family may be attributed to the haploinsufficiency of the HOXD gene cluster. The delineation of the microdeletion region may contribute to the genotype-phenotype correlation study in patients with genomic rearrangements of the long arm of chromosome 2 and helps to understand the pathogenesis of haploinsufficiency of the HOXD gene cluster.