Miracle-dz/UniFAR-FTUs huggingface dataset:
Functional classification of DNA variants by hybrid minigenes: Identification of 30 spliceogenic variants of BRCA2 exons 17 and 18

Mutation screening of the breast cancer genes BRCA1 and BRCA2 identifies a large fraction of variants of uncertain clinical significance (VUS) whose functional and clinical interpretations pose a challenge for genomic medicine. Likewise, an increasing amount of evidence indicates that genetic variants can have deleterious effects on pre-mRNA splicing. Our goal was to investigate the impact on splicing of a set of reported variants of BRCA2 exons 17 and 18 to assess their role in hereditary breast cancer and to identify critical regulatory elements that may constitute hotspots for spliceogenic variants. A splicing reporter minigene with BRCA2 exons 14 to-20 (MGBR2_ex14-20) was constructed in the pSAD vector. Fifty-two candidate variants were selected with splicing prediction programs, introduced in MGBR2_ex14-20 by site-directed mutagenesis and assayed in triplicate in MCF-7 cells. Wild type MGBR2_ex14-20 produced a stable transcript of the expected size (1,806 nucleotides) and structure (V1-[BRCA2_exons_14–20]–V2). Functional mapping by microdeletions revealed essential sequences for exon recognition on the 3’ end of exon 17 (c.7944-7973) and the 5’ end of exon 18 (c.7979-7988, c.7999-8013). Thirty out of the 52 selected variants induced anomalous splicing in minigene assays with >16 different aberrant transcripts, where exon skipping was the most common event. A wide range of splicing motifs were affected including the canonical splice sites (15 variants), novel alternative sites (3 variants), the polypyrimidine tract (3 variants) and enhancers/silencers (9 variants). According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), 20 variants could be classified as pathogenic (c.7806-2A>G, c.7806-1G>A, c.7806-1G>T, c.7806-1_7806-2dup, c.7976+1G>A, c.7977-3_7978del, c.7977-2A>T, c.7977-1G>T, c.7977-1G>C, c.8009C>A, c.8331+1G>T and c.8331+2T>C) or likely pathogenic (c.7806-9T>G, c.7976G>C, c.7976G>A, c.7977-7C>G, c.7985C>G, c.8023A>G, c.8035G>T and c.8331G>A), accounting for 30.8% of all pathogenic/likely pathogenic variants of exons 17–18 at the BRCA Share database. The remaining 8 variants (c.7975A>G, c.7977-6T>G, c.7988A>T, c.7992T>A, c.8007A>G, c.8009C>T, c.8009C>G, and c.8072C>T) induced partial splicing anomalies with important ratios of the full-length transcript (≥70%), so that they remained classified as VUS. Aberrant splicing is therefore especially prevalent in BRCA2 exons 17 and 18 due to the presence of active ESEs involved in exon recognition. Splicing functional assays with minigenes are a valuable strategy for the initial characterization of the splicing outcomes and the subsequent clinical interpretation of variants of any disease-gene, although these results should be checked, whenever possible, against patient RNA.
Immune Regulation by Self-Reactive T Cells is Antigen Specific1

Immune regulation plays an important role in the establishment and maintenance of self-tolerance. Nevertheless, it has been difficult to conclude whether regulation is Ag specific because studies have focused on polyclonal populations of regulatory T cells. We have used in this study a murine transgenic model that generates self-reactive, regulatory T cells of known Ag specificity to determine their capacity to suppress naive T cells specific for other Ags. We show that these regulatory cells can regulate the responses of naive T cells with the same TCR specificity, but do not inhibit T cell proliferation or differentiation of naive T cells specific for other Ags. These results demonstrate that immune regulation may be more Ag specific than previously proposed.
The Influence of Plasma Albumin Concentration on the Analysis Methodology of Free Valproic Acid by Ultrafiltration and Its Application to Therapeutic Drug Monitoring

Background: Free drug analysis is increasingly becoming popular in therapeutic drug monitoring (TDM). Centrifugal ultrafiltration (CF-UF) is the primary method to separate free drug from that of bound drug. However, the volume ratio of ultrafiltrate to sample solution (Vu/Vs) affects the accuracy of CF-UF, which highly depends on the different plasma conditions. Plasma protein concentrations in patients are different from those observed in healthy subjects, and there are also significant differences among patients with different diseases. Only very few studies have reported on the effect of protein concentration on the analysis methodology of free drug by CF-UF. Methods: In this study, valproic acid was used as the representative drug, and plasma samples with different albumin concentrations were analyzed by CF-UF and hollow fiber centrifugal ultrafiltration (HFCF-UF). Results: There was no significant difference of free drug concentrations by HFCF-UF and CF-UF when plasma albumin concentrations ranged 40–60 g/L. However, at low albumin concentrations (<40 g/L), a considerable difference was detected, and the difference was increased with the decrease of plasma albumin concentration. When the albumin concentration was as low as 10 g/L, the free drug concentration was 17.3 mcg/mL by CF-UF, whereas it was 10.2 mcg/mL by HFCF-UF. Conclusions: The accuracy of free drug measurement by CF-UF was albumin concentration dependent. However, such an effect was not observed when samples were prepared by HFCF-UF, which was more suitable for TDM of plasma samples from different patients. Therefore, this method could be readily applied to the measurement of free valproic acid plasma concentrations for TDM in patients.
Development of Managerial Competence through Knowledge Management in Small Industries in West Java

The research focuses on the gaps of the capability of managerial competence among small industry holders at the province of West Java. It specifically aims to identify the factors influencing managerial competence capability and formulate an appropriate managerial competence profile for small business holders in West Java province. This research was conducted with the quantitative approach by using survey method and data analysis technique of MSA (Measure of Sampling Adequacy) factors analysis, based on Bartlett’s test of sphericity. Research population includes all of small and middle industry holders in West Java Province (198.478 small industry business). Through the cluster random sampling, 400 respondents were taken as the research sample representing four regions: Sukabumi Regency, Purwakarta Regency, Cirebon Regency and Bandung Regency. The results show there are three major factors influencing managerial competence capability, namely technical skill, human relations skill, and conceptual skill. The three factors are the embodiment of knowledge management.
A Theory of Diagnosability of Digital Systems

The problem of automatic fault diagnosis of systems decomposed into a number of interconnected units is considered by using a simplified version of the diagnostic model introduced by Preparata et al. The model used in this paper is supposed to be a realistic representation of systems where each unit has a considerable computational capability. For any system of n units whose set of testing links is given, necessary and sufficient conditions for t-diagnosability are presented in both cases of one-step diagnosis and diagnosis with repair, and it is shown that the procedure for diagnosis with repair has very small complexity. The problem of optimal assignment of testing links in order to achieve a given diagnosability is also considered and classes of optimal t-diagnosable systems are presented for arbitrary values of t in both cases of one-step diagnosis and diagnosis with repair.
Launch on a High Note: How Prefunding Affects Crowdfunding Outcomes

In an increasingly competitive crowdfunding market, entrepreneurs are seeking out new ways to improve their likelihood of success. This is one of the reasons for the emergence of prefunding platforms, which help entrepreneurs to raise awareness of their forthcoming fund-raising projects. Using data from an online crowdfunding platform, we show that opting for prefunding prior to fund-raising significantly increases the likelihood of a campaign meeting its fund-raising goal. We also find that prefunding projects transition to the fund-raising stage with a higher number of backers, and a higher contribution size on the first day of funding when compared to non-prefunding projects. This strong head-start on the first day of solicitation then enhances a project’s ability to garner funds over the fund-raising window, thus increasing the likelihood of eventual success. Moreover, when entrepreneurs proactively update information about their projects and actively engage with followers during the prefunding period, their campaigns are more likely to launch with a higher number of backers and higher contribution size. Our study has important implications for both entrepreneurs and crowdfunding platforms.
PENGARUH RASIO KEUANGAN TERHADAP KEBIJAKAN DIVIDEN DENGAN GOOD CORPORATE GOVERNANCE SEBAGAI VARIABEL INTERVENING

ABSTRACT The purpose of this research is to prove the influence profitability (ROA), leverage (DER), liquidity (CR), and growth (TAG) to the dividend policy (DPR) by considering good corporate governance (CGPI ) as the intervening variable. The population is all companies which are ranked by the Indonesian Institute for Corporate Governance (IICG) in 2010-2014 periods. The samples are 8 companies which have been selected by using purposive sampling method. The data analysis has been done by using multiple linear regressions to identify the independent variables which give influence to the dependent variable and path analysis is to detect the indirect influence through good corporate governance. The result of the F test shows that all independent variables give significant influence to the dividend policy through the implementation of good corporate governance. The result of t-test shows that profitability, liquidity, growth, and good corporate governance do not give significant influence to the dividend policy whereas the leverage gives significant influence to the dividend policy. It has been found from the result of the path analysis that the implementation of good corporate governance is not proven to give influence as the intervening variable. Keywords: Profitability, leverage, liquidity, growth, good corporate governance, dividend payout ratio.
Preliminary Report on Informed Consent for Mental Capacity Assessments

RÉSUMÉ La présente étude avait pour but d'étudier le consentement éclairé, c'est-à-dire donné en connaissance de cause, et la capacité intellectuelle. Dix-sept patients qui avaient été aiguillés à la Competency Clinic (clinique d'évaluation de la capacité intellectuelle) du Baycrest Centre for Geriatric Care ont été interrogés à la suite de leur évaluation. Les réponses qu'ils ont données relativement aux questions entourant les raisons et les conséquences possibles de l'évaluation indiquent une variation de la compréhension et de la capacité de donner un consentement éclairé. Les résultats sont analysés afin de déterminer si le niveau peu élevé de consentement éclairé convient dans les cas où les autres capacités sont déjà remises en question. ABSTRACT The goal of the study was to investigate the issue of informed consent for mental capacity. Seventeen clients referred to the Competency Clinic at the Baycrest Centre for Geriatric Care were interviewed after the assessment had been completed. Their responses to questions regarding the reasons for and possible consequences of the assessment indicated a range of understanding and of capacity to give informed consent. The results are discussed in terms of the appropriateness of having a fairly low threshold for informed consent in situations where other capacities are already in question.
Frequent BCOR aberrations in extranodal NK/T‐Cell lymphoma, nasal type

Extranodal natural killer/T cell lymphoma (ENKTL) is a rare subtype of lymphoma. Recurrent mutations in the JAK‐STAT pathway, recently reported in ENKTL cases, are interesting in terms of both pathogenesis and inhibitor therapy. However, the frequencies of these mutations are low and variable among reports, and other pathognomonic mutations in ENKTL remain to be elucidated. In the present study, targeted capture sequencing of 602 cancer‐related genes from 25 frozen ENKTL samples was performed, 11 of which were matched to normal samples. Several recurrent somatic mutations involving BCOR (32%), TP53 (16%), DDX3X (12%), FAT4 (8%), NRAS (8%), MLL3 (12%), and MIR17HG (8%) were identified. The pattern of BCOR aberrations (1 nonsense and 5 frame‐shift mutations, a mutation leading to a splicing error, and gene loss) suggested that loss of function of BCOR was the functionally important outcome of such changes. The literature was reviewed and the public data on BCOR aberrations was reanalyzed and it was found that the aberrations were frequently found in myeloid neoplasms, but, interestingly, were highly specific to ENKTL among lymphoid malignancies. Given the high frequency and pattern of aberration, BCOR is likely to play an important role in ENKTL pathogenesis as a tumor suppressor gene. © 2016 Wiley Periodicals, Inc.
A Comparison of Naive and Experienced Bidders in Common Value Offer Auctions: A Laboratory Analysis

Experiments compare bidding behavior of experienced business executives in the construction contract industry with that of student subjects in efforts to identify differences in behavior between "naive" and "expert" subjects. Qualitatively similar behavior is reported across subject pools as in both cases (1) bidders suffer from the "winner's curse"; (2) increasing the number of bidders exacerbates the winner's curse; and (3) public information reducing uncertainty in cost estimates has the perverse effect (relative to Nash equilibrium bidding theory) of increasing the offer price in the presence of a winner's curse. Copyright 1989 by Royal Economic Society.
Government Intervention in SMEs E-Commerce Adoption

This study investigates the role of government in the adoption and diffusion of e-commerce in small and medium size enterprises. Institutional involvement, and especially the role of government, has historically been determinant in the adoption and diffusion of technological innovations. King, Gurbaxani, Kraemer, McFarlan, Raman, and Yap’s (1994) framework of institutional factors in information technology innovation is used to analyze what is actually done and what SMEs would like to be done regarding government intervention to foster the adoption and diffusion of e-commerce. The findings show that the government could mostly influence adoption and diffusion through knowledge deployment, subsidies, and mobilization and that a convergence between companies’ wishes and government initiatives is starting taking place.
Impact of Gender on Customer Satisfaction for Service Quality: A Case Study of Hyper Stores

Satisfaction of customers is an integral part for the success of the business. Customer satisfaction is based on perceived service quality. Service quality is a comparison of expectations with performance. Customer satisfaction is based on perceived service quality. Service quality is a crucial factor for the triumph of the business firm. This study is an attempt to examine the impact of gender on satisfaction level of customers for service quality in hyper stores. All the relevant data has been collected through a sample survey of 70 customers purchasing goods from hyper stores in South West Delhi. Sample was drawn by convenient sampling. Retail Service Quality Scale was used as measurement instrument. It was developed by Dabholkar, Thrope and Rentz (1996). Likert’s five point scale was used to rate all the variables. A survey was conducted to verify the hypothesis and research framework. Statistical techniques such as mean, standard deviation and ttest were used. Major Findings exhibit that there is no significant difference between male and female customers for different variables of service quality in hyper stores.
Examination of Decision Factors in the Process of Buying Kitchen Furniture Using Conjoint Analysis

The aim of this research was to determine the relative importance of three factors relevant for buying wooden kitchen furniture in Croatia and Slovenia. A survey was made of 172 potential kitchen buyers: 138 in person at two largest furniture stores in Croatia and Slovenia, and 34 online. A conjoint analysis revealed that respondents were more concerned about the manufacturer and design than the price of the kitchen furniture. For all demographic groups, the lower price kitchen furniture was preferable. Only three demographic groups (3545 years of age, elementary school or less, and unemployed) preferred the classic kitchen furniture design, while all other groups preferred the modern design. For the manufacturer, differences were found among most sociodemographic categories.
Impact of enterprise resource planning on management control system and accountants' role

The advancement of information and communication technologies (ICTs) changes not only people’s lives, but also the way businesses operate. Enterprise resource planning (ERP) is one example how technology transforms business from a labour-to a machine-intensive process and improves organizational control. The purposes of this study are to examine the effectiveness of ERP system implementation on the management control system and identify the changes in accountants’ roles with the implementation of ERP systems. Two companies, one from construction and one in property development activities in Malaysia, were selected, and triangulated data-collection techniques of observation, document analysis, and interviews were employed. This study found that the ERP system is an excellent device for a formal management control system as it helps companies identify wastage at the earliest possible time. In terms of accountants’ role, the ERP improved their work significantly as they can dedicate more time to financial analysis and decision making compared to data entry previously. JEL Classification : M100, M150, M410
Long-term outcomes of complete vascular ring division in children: a 36-year experience from a single institution.

Objectives Complete vascular rings are rare and cause tracheoesophageal compression. Following surgical division, some patients have persisting tracheomalacia. We aim to assess the long-term outcomes of complete vascular ring division. Methods All patients (n = 132) who underwent surgical division of a complete vascular ring between 1978 and 2014 were identified from the hospital database and retrospectively reviewed. Results Complete vascular rings consisted of a double aortic arch (n = 80), right aortic arch with an aberrant subclavian artery and left ligamentum arteriosum (n = 50), right aortic arch with mirror image branching and left ligamentum arteriosum (n = 1), and a left aortic arch with right descending aorta and right ligamentum arteriosum (n = 1). Kommerell's diverticulum was identified in 10 patients. Preoperative tracheomalacia was identified via bronchoscopy in 25 patients. Concomitant tracheal reconstruction was not performed in any patient. Kommerell's diverticulum was resected in 1 patient. The hospital mortality rate was 1.5% (2/132). There were no late deaths. The overall survival rate was 98.3 ± 1.2% (95% CI: 93.4, 99.6) at 20 years. Postoperatively, persistent tracheal compression was reported in 3 patients, and tracheomalacia in 16 patients. The rate of freedom from reoperation was 88.6 ± 4.0% (95% CI: 77.9, 94.3) at 20 years. No patient required tracheal surgery during the follow-up period. Follow-up was 92% (121/132) complete, with a median follow-up of 11.4 years (range 44 days to 36 years). At the last follow-up, 7 patients had mild tracheomalacia. Conclusions Outcomes of division of a complete vascular ring are excellent. Tracheomalacia often improves following division of the vascular ring. Respiratory symptoms following complete vascular ring division are uncommon.
Credit Risk, Market Risk, Operational Risk and Liquidity Risk on Profitability of Banks in Indonesia

This study examines the effect of credit risk, market risk, operational risk, and liquidity risk on profitability of banks listed on the Indonesia Stock Exchange in 2010-2014. The method used is descriptive and verification methods, with a sample of 30 banks and using multiple regression analysis. The results showed that credit risk does not partially affect profitability. Market risk, operational risk, and liquidity risk partially have positive effect on profitability. It simultaneously shows that credit risk, market risk, operational risk and liquidity risk have effect on the profitability of banks amounted to 67.1%. Improvement of Non-Performing Loan, Net Interest Margin, Operating Expenses to Operating Income Ratio, and Loan to Deposit Ratio will increase the Profitability.
Meta-Analytic Framework for Sparse K-Means to Identify Disease Subtypes in Multiple Transcriptomic Studies

Disease phenotyping by omics data has become a popular approach that potentially can lead to better personalized treatment. Identifying disease subtypes via unsupervised machine learning is the first step toward this goal. In this article, we extend a sparse K-means method toward a meta-analytic framework to identify novel disease subtypes when expression profiles of multiple cohorts are available. The lasso regularization and meta-analysis identify a unique set of gene features for subtype characterization. An additional pattern matching reward function guarantees consistent subtype signatures across studies. The method was evaluated by simulations and leukemia and breast cancer datasets. The identified disease subtypes from meta-analysis were characterized with improved accuracy and stability compared to single study analysis. The breast cancer model was applied to an independent METABRIC dataset and generated improved survival difference between subtypes. These results provide a basis for diagnosis and development of targeted treatments for disease subgroups. Supplementary materials for this article are available online.
Charged Residues in the β2 Subunit Involved in GABAA Receptor Activation*

Fast synaptic inhibition in the mammalian central nervous system is mediated primarily via activation of the γ-aminobutyric acid type A receptor (GABAA-R). Upon agonist binding, the receptor undergoes a structural transition from the closed to the open state. This transition, known as gating, is thought to be associated with a sequence of conformational changes originating at the agonist-binding site, ultimately resulting in opening of the channel. Using site-directed mutagenesis and several different GABAA-R agonists, we identified a number of highly conserved charged residues in the GABAA-R β2 subunit that appear to be involved in receptor activation. We then used charge reversal double mutants and disulfide trapping to investigate the interactions between these flexible loops within the β2 subunit. The results suggest that interactions between an acidic residue in loop 7 (Asp146) and a basic residue in pre-transmembrane domain-1 (Lys215) are involved in coupling agonist binding to channel gating.