Miracle-dz/UniFAR-FTUs huggingface dataset:
NDRG2 acts as a negative regulator downstream of androgen receptor and inhibits the growth of androgen-dependent and castration-resistant prostate cancer

Castration resistance is a major issue during castration therapy for prostate cancer and thus more effective treatment are needed for castration-resistant prostate cancer (CRPC). NDRG2 (N-Myc downstream regulated gene 2), a recently identified tumor suppressor, was previously shown to inhibit the proliferation and invasion of prostate cancer, but whether NDRG2 is involved in CRPC remains to be known. Because androgen receptor (AR) axis plays an important role in castration resistance, we evaluate the role of NDRG2 in AR signaling and CRPC. Immunohistochemistry examination of prostate cancer tissues demonstrated that the expression of NDRG2 is negatively correlated with that of AR and c-Myc. Furthermore, AR negatively regulates NDRG2, as well as alters levels of c-Myc and prostate specific antigen (PSA). Forced expression of NDRG2 significantly inhibits the in vitro growth of androgen-dependent and castration-resistant prostate cancer cells; this was accompanied by alterations in PSA, but not by those of AR and c-Myc. Finally, by mimicking castration therapy in a xenograft mouse model, we showed that lentivirus-mediated NDRG2 overexpression efficiently overcomes castration resistance. Thus, by acting as a negative regulator downstream of AR, NDRG2 may emerge as a potential therapy molecule for CRPC.
District Competition in Japan’s 2014 Election: The Roles of Nominations, Incumbency, and Dual Listing

Duverger’s Law expects two-party competition in single member districts (SMDs), but evidence from mixed member systems is less consistent with these theoretical expectations. Rather than simply focusing on whether Japan’s most recent House of Representatives election converges toward Duvergerian equilibrium, this article focuses on three factors within Japan. In particular, how do the roles of major party nominations, incumbency, and dual-listing shape district competition vis-à-vis Duverger? Empirical results find that the lack of a Democratic Party of Japan candidate decreases the effective number of candidates, while the lack of a Liberal Democratic Party candidate, multiple incumbents, and dual-listing correlates with an increased number of candidates. The results suggest that often ignored underlying effects of Japan’s mixed system influences its consistency with theoretical expectations.
Perverse market rewards for meeting or beating earnings expectations*

Abstract Approximately 47 (43) percent of the observations in our sample receive negative (positive) market rewards when they meet (miss) earnings expectations. We define these phenomena as perverse market rewards (PMR). We find that the likelihood of PMR is increased when (i) firms use earnings and/or expectations management; (ii) earnings growth is negative (positive) when earnings expectations are met (missed); and (iii) ownership by transient (dedicated) institutional investors is high when earnings expectations are met (missed). In addition, we find that, when earnings expectations are met (missed), PMR appears to be an indicator of bad (good) future stock performance. Our study demonstrates that gratuitous participation in the ‘numbers game’ does not always result in the desired market rewards.
Identification of the Yeast Mitochondrial Transporter for Oxaloacetate and Sulfate*

Saccharomyces cerevisiae encodes 35 members of the mitochondrial carrier family, including the OAC protein. The transport specificities of some family members are known, but most are not. The function of the OAC has been revealed by overproduction inEscherichia coli, reconstitution into liposomes, and demonstration that the proteoliposomes transport malonate, oxaloacetate, sulfate, and thiosulfate. Reconstituted OAC catalyzes both unidirectional transport and exchange of substrates. In S. cerevisiae, OAC is in inner mitochondrial membranes, and deletion of its gene greatly reduces transport of oxaloacetate sulfate, thiosulfate, and malonate. Mitochondria from wild-type cells swelled in isoosmotic solutions of ammonium salts of oxaloacetate, sulfate, thiosulfate, and malonate, indicating that these anions are cotransported with protons. Overexpression of OAC in the deletion strain increased greatly the [35S]sulfate/sulfate and [35S]sulfate/oxaloacetate exchanges in proteoliposomes reconstituted with digitonin extracts of mitochondria. The main physiological role of OAC appears to be to use the proton-motive force to take up into mitochondria oxaloacetate produced from pyruvate by cytoplasmic pyruvate carboxylase.
Analysis of change in the presence of informative censoring: application to a longitudinal clinical trial of progressive renal disease

The rate of change in a continuous variable, measured serially over time, is often used as an outcome in longitudinal studies or clinical trials. When patients terminate the study before the scheduled end of the study, there is a potential for bias in estimation of rate of change using standard methods which ignore the missing data mechanism. These methods include the use of unweighted generalized estimating equations methods and likelihood‐based methods assuming an ignorable missing data mechanism. We present a model for analysis of informatively censored data, based on an extension of the two‐stage linear random effects model, where each subject's random intercept and slope are allowed to be associated with an underlying time to event. The joint distribution of the continuous responses and the time‐to‐event variable are then estimated via maximum likelihood using the EM algorithm, and using the bootstrap to calculate standard errors. We illustrate this methodology and compare it to simpler approaches and usual maximum likelihood using data from a multi‐centre study of the effects of diet and blood pressure control on progression of renal disease, the Modification of Diet in Renal Disease (MDRD) Study. Sensitivity analyses and simulations are used to evaluate the performance of this methodology in the context of the MDRD data, under various scenarios where the drop‐out mechanism is ignorable as well as non‐ignorable. Copyright © 2001 John Wiley & Sons, Ltd.
Nuclear‐targeted minicircle to enhance gene transfer with non‐viral vectors in vitro and in vivo

To develop more efficient non‐viral vectors, we have previously described a novel approach to attach a nuclear localisation signal (NLS) to plasmid DNA, by generating a fusion protein between the tetracycline repressor protein TetR and an SV40 NLS peptide (TetR‐NLS). The high affinity of TetR for the DNA sequence tetO is used to bind the NLS to DNA. We have now investigated the ability of this system displaying the SV40 NLS or HIV‐1 TAT peptide to enhance nuclear import of a minimised DNA construct more suitable for in vivo gene delivery: a minicircle.
Induction of c‐fos and c‐jun mRNA at the M/G1 border is required for cell cycle progression

The proto‐oncogenes c‐fos and c‐jun have been shown in numerous model systems to be induced within minutes of growth factor stimulation, during the G0/G1 transition. In this report we use the mitotic shake‐off procedure to generate a population of highly synchronized Swiss 3T3 cells. We show that both of these immediate‐early, competence genes are also induced during the M/G1 transition, immediately after completion of mitosis. While c‐fos mRNA levels drop to undetectable levels within 2 hr after division, c‐jun mRNA levels are maintained at a basal level which is ∼ 30% maximum throughout the remainder of G1. In order to access the functional significance of these patterns of c‐fos and c‐jun expression, antisense oligodeoxynucleotides specific to c‐fos or c‐jun were added to either actively growing Swiss 3T3 cells or mitotically synchronized cells, and their ability to inhibit DNA synthesis and cell division determined. Our results show that treatment of Swiss 3T3 cells with either c‐fos or c‐jun antisense oligodeoxynucleotides, while actively growing, during mitosis, or in early G1, results in a reduction in ability to enter S and subsequently divide. This was also true if Swiss 3T3 cells were treated during mid‐G1 with c‐jun antisense oligodeoxynucleotides. These results demonstrate that the regulation of G1 progression following mitosis is dependent upon the expression and function of the immediate‐early, competence proto‐oncogenes c‐fos and c‐jun. © 1994 Wiley‐Liss, Inc.
Maternal and Fetal Plasma Concentrations of Ritodrine

Previous studies using other β -adrenergic drugs for tocolysis suggest that if treatment fails and the patient delivers shortly after the therapy is discontinued, there is a direct correlation between neonatal drug concentration and major neonatal complications. In the present study, the disposition of ritodrine was studied in 28 maternal-infant pairs in whom intravenous ritodrine had been administered for clinical indications. The fetal to maternal ratio of ritodrine was 1.17 ± 0.48. The concentration of ritodrine in both maternal and umbilical vein was found to vary inversely with the length of time the drug was discontinued before delivery. A stepwise multilinear regression revealed that the maternal ritodrine dose in the 24 hours before delivery and the drug discontinuance to delivery interval were both independently related to umbilical vein ritodrine concentrations. When combined, the two variables explained 52% of the variance in umbilical vein ritodrine levels. The frequency of respiratory distress syndrome was increased in the neonates in whom umbilical vein ritodrine was greater than 10 ng/mL, compared with the groups with umbilical vein levels ranging from 3.0 to 10.0 ng/mL. However, neonates with the highest ritodrine concentration were also of lower gestational age (29.4 versus 33.5 weeks, P <0.5) and thus, had greater inherent risk of prematurity-related complications. (
Involvement of M1-muscarinic acetylcholine receptors, protein kinase C and mitogen-activated protein kinase in the effect of huperzine A on secretory amyloid precursor protein-&agr;

This study is to explore the involvement of muscarinic acetylcholine receptors/protein kinase C cascade and the mitogen-activated protein kinase pathway in the effect of huperzine A on the secretory amyloid precursor protein-&agr;. Upregulation of secretory amyloid precursor protein-&agr; by huperzine A was attenuated by muscarinic acetylcholine receptor antagonist (specifically by M1-muscarinic acetylcholine receptor antagonist), and markedly blocked (−37.7%) by protein kinase C inhibitor as well. Meanwhile, huperzine A can activate the phosphorylation of mitogen-activated protein kinase and, accordingly, partly restored PD98059-decreased secretory amyloid precursor protein-&agr; secretion. In addition, huperzine A largely inhibited (−55.4%) acetylcholinesterase activity of the cell line. Our results suggest that activated M1-muscarinic acetylcholine receptor/protein kinase C pathway and mitogen-activated protein kinase signaling are involved in the process of huperzine A enhancing the secretory amyloid precursor protein-&agr; secretion.
Precipitation Drivers of Cropping Frequency in the Brazilian Cerrado: Evidence and Implications for Decision-Making

AbstractThe Amazon basin has been subjected to unprecedented rates of land-use change over the past several decades, primarily as a result of the expansion of agriculture. Enhanced rain forest conservation efforts toward the end of the twentieth century slowed deforestation of the Amazon but, in turn, increased demand for land repurposing in the adjacent Cerrado (savanna) region, where conservation regulations are less strict. To maintain or increase yields while minimizing the need for additional land, agricultural producers adopted a form of intensification in which two rain-fed crops are planted within a single growing season (double cropping). Using 10 years (August 2002 to July 2012) of MODIS and TRMM data, it is demonstrated that there exists a threshold growing season rainfall amount (1759 mm) for double cropping. But more nuanced is the relationship between observable precipitation information available to farmers at the time of planting decision and the choice to “double crop” in a given year. An.
Effects of lasofoxifene and bazedoxifene on B cell development and function

The third generation selective estrogen receptor modulators lasofoxifene (las) and bazedoxifene (bza) are indicated for treatment of postmenopausal osteoporosis. 17β‐Estradiol (E2) and the second generation SERM raloxifene (ral) have major effects on the immune system, particularly on B cells. Treatment with E2 or ral inhibits B lymphopoiesis and treatment with E2, but not ral, stimulates antibody production. The effects of las and bza on the immune system have not been studied. Therefore, the aim of this study was to investigate their role in B cell development, maturation, and function. C57BL/6 mice were sham‐operated or ovariectomized (ovx) and treated with vehicle, E2, ral, las, or bza. All substances increased total bone mineral density in ovx mice, as measured by peripheral quantitative computed tomography. In uterus, bza alone lacked agonistic effect in ovx mice and even acted as an antagonist in sham mice. As expected, E2 decreased B cell numbers at all developmental stages from pre‐BI cells (in bone marrow) to transitional 1 (T1) B cells (in spleen) and increased marginal zone (MZ) B cells as determined by flow cytometry. However, treatment with las or bza only decreased the last stages of bone marrow B cell development and splenic T1 B cells, but had no effect MZ B cells. E2 increased antibody‐producing cells quantified by ELISPOT, but las or bza did not. In conclusion, las and bza differ from E2 by retaining normal number of cells at most B cell stages during B lymphopoiesis and maturation and by not increasing antibody‐producing cells.
Determinants Of Financial Inclusion In Bangladesh: Dynamic Gmm & Quantile Regression Approach

ABSTRACT:Financial Inclusion has been recently acknowledged as a key enabler for reducing poverty and improving prosperity. However, more than 50% adults of the poorest households are still unbanked globally. According to IMF (2016), 45% people of Bangladesh are out of formal financial services. High interest rate, vast rural population and low literacy rate are among the prominent factors that restrained the government and the World Bank joint initiatives to reach universal financial access. Researchers have reasons to believe, there are certain other factors that remain unnoticed by the policy maker and which in turn, probably affecting their ability to formulate effective policy. The quest to identify these factors materialize this study. In this study, the determinants of financial inclusion have been clustered in two broad areas: bank specific factors and macroeconomic factors. Then, econometrically try to analyse which group of factors has more influence in determining the level of financial inclusion in a country. In the study, static model like, random effects and dynamic panel models like, generalized methods of moments (GMM) methodologies have been applied. Data from 25 banks: 18 conventional and 7 Islamic banks operating in Bangladesh during the period 2005–2014, is collected to analyze the role of both types of banks in financial inclusion. For robustness, this study also employs Quantile regression approach. The study found that, on the supply side, the size of a bank, its efficiency, and the interest rate it charges has a directs impact on financial inclusion. Where on the demand side, literacy rate is positively and age dependency ratio is negatively related to financial inclusion. In addition to that, quantile regression analysis found that bank size has a significant impact on both deposit collection and loans & advances disbursement of a bank. The study can be beneficial for both government and bank authorities in developing their policy decisions to ensure more inclusive financial system. Setting the loan interest rate close to international level and extending the branch facilities can encourage excluded population to use formal financial services. Finally, the study also signifies that, by developing human capital developing country countries can improve their financial market participation and therefore can foster economic growth.
Higher Serum Vitamin D3 Levels Are Associated with Better Cognitive Test Performance in Patients with Alzheimer’s Disease

Background/Aims: Recent studies suggest that vitamin D metabolites may be important for preserving cognitive function via specific neuroprotective effects. No large studies have examined the association between vitamin D status and cognition. Methods: In this cross-sectional study, we analyzed the serum 25-hydroxyvitamin D3 levels and Mini-Mental State Examination (MMSE) test scores of 225 older outpatients who were diagnosed as having probable Alzheimer’s disease (AD). In addition to the 25-hydroxyvitamin D3 levels, we analyzed the serum vitamin B1, B6 and B12 levels. Results: An association was found between MMSE test scores and serum 25-hydroxyvitamin D3 levels, with a β-coefficient of 0.05 (p = 0.01). Vitamin-D-sufficient patients had significantly higher MMSE scores as compared to vitamin-D-insufficient ones. No association was found with the other serum vitamin levels. Conclusions: These data support the idea that a relationship exists between vitamin D status and cognition in patients with probable AD. However, given the cross-sectional design of this study, no causality can be concluded. Further prospective studies are needed to specify the contribution of vitamin D status to the onset and course of cognitive decline and AD.
An analysis of allelic variation in the ABCA4 gene.

PURPOSE To assess the allelic variation of the ATP-binding transporter protein (ABCA4). METHODS A combination of single-strand conformation polymorphism (SSCP) and automated DNA sequencing was used to systematically screen this gene for sequence variations in 374 unrelated probands with a clinical diagnosis of Stargardt disease, 182 patients with age-related macular degeneration (AMD), and 96 normal subjects. RESULTS There was no significant difference in the proportion of any single variant or class of variant between the control and AMD groups. In contrast, truncating variants, amino acid substitutions, synonymous codon changes, and intronic variants were significantly enriched in patients with Stargardt disease when compared with their presence in subjects without Stargardt disease (Kruskal-Wallis P < 0.0001 for each variant group). Overall, there were 2480 instances of 213 different variants in the ABCA4 gene, including 589 instances of 97 amino acid substitutions, and 45 instances of 33 truncating variants. CONCLUSIONS Of the 97 amino acid substitutions, 11 occurred at a frequency that made them unlikely to be high-penetrance recessive disease-causing variants (HPRDCV). After accounting for variants in cis, one or more changes that were compatible with HPRDCV were found on 35% of all Stargardt-associated alleles overall. The nucleotide diversity of the ABCA4 coding region, a collective measure of the number and prevalence of polymorphic sites in a region of DNA, was found to be 1.28, a value that is 9 to 400 times greater than that of two other macular disease genes that were examined in a similar fashion (VMD2 and EFEMP1).
Development of an optimized hyaluronic acid-based lipidic nanoemulsion co-encapsulating two polyphenols for nose to brain delivery

Abstract The development of mucoadhesive lipidic nanoemulsion based on hyaluronic acid, co-encapsulating two polyphenols (resveratrol and curcumin) for the transnasal treatment of neurodegenerative diseases was attempted in the current manuscript. Nanoemulsions were prepared by the spontaneous emulsification method, and were characterized for their particle size, zeta potential, mucoadhesive strength and morphology. The selected formula was tested for its antioxidant potential, in vitro and ex vivo release of the two polyphenols, safety on nasal mucosa and in vivo quantification of the two drugs in rat brains. Its stability was tested by monitoring the change in particle size, zeta potential, drugs' content and antioxidant potential upon storage for 3 months. The optimized hyaluronic acid based nanoemulsion formula displayed a particle size of 115.2 ± 0.15 and a zeta potential of −23.9 ± 1.7. The formula displayed a spherical morphology and significantly higher mucoadhesive strength compared to its non mucoadhesive counterpart. In addition, the nanoemulsion was able to preserve the antioxidant ability of the two polyphenols and protect them from degradation. Diffusion controlled release of the two drugs was achievable till 6 hours, with an ex vivo flux across sheep nasal mucosa of 2.86 and 2.09 µg/cm2hr for resveratrol and curcumin, respectively. Moreover, the mucoadhesive nanoemulsion was safe on nasal mucosa and managed to increase the amounts of the two polypehnols in the brain (about 7 and 9 folds increase in AUC0–7 h for resveratrol and curcumin, respectively). Hyaluronic acid based lipidic nanoemulsion proved itself as a successful carrier enhancing the solubility, stability and brain targetability of polyphenols.
Using Modafinil to Treat Fatigue in Parkinson Disease: A Double-Blind, Placebo-Controlled Pilot Study

Background: Fatigue is a major nonmotor symptom in Parkinson disease (PD). It is associated with reduced activity and lower quality of life. Objective: To determine if modafinil improves subjective fatigue and physical fatigability in PD. Methods: Nineteen PD patients who reported significant fatigue in the Multidimensional Fatigue Inventory (MFI) participated in this 8-week study. Subjects took their regular medications and were randomly assigned to the treatment group (9 subjects, modafinil 100-mg capsule BID) or placebo group (10 subjects). We used the MFI to measure subjective fatigue and used finger tapping and intermittent force generation to evaluate physical fatigability. Subjects also completed the Epworth Sleepiness Scale (ESS) and the Center of Epidemiological Study-Depression Scale. Results: There were no significant differences at baseline and at 1 month in finger tapping and ESS between the modafinil and placebo groups. At 2 months, the modafinil group had a higher tapping frequency (P < 0.05), shorter dwell time (P < 0.05), and less fatigability in finger tapping and tended to have lower ESS scores (P < 0.12) than the placebo group. However, there was no difference between groups over time for any dimension of the MFI. Conclusions: This small study demonstrated that although modafinil may be effective in reducing physical fatigability in PD, it did not improve fatigue symptoms.