Miracle-dz/UniFAR-FTUs huggingface dataset:
NAD-Dependent Isocitrate Dehydrogenase Mutants of Arabidopsis Suggest the Enzyme Is Not Limiting for Nitrogen Assimilation1[C]

NAD-dependent isocitrate dehydrogenase (IDH) is a tricarboxylic acid cycle enzyme that produces 2-oxoglutarate, an organic acid required by the glutamine synthetase/glutamate synthase cycle to assimilate ammonium. Three Arabidopsis (Arabidopsis thaliana) IDH mutants have been characterized, corresponding to an insertion into a different IDH gene (At5g03290, idhv; At4g35260, idhi; At2g17130, idhii). Analysis of IDH mRNA and protein show that each mutant lacks the corresponding gene products. Leaf IDH activity is reduced by 92%, 60%, and 43% for idhv, idhi, and idhii, respectively. These mutants do not have any developmental or growth phenotype and the reduction of IDH activity does not impact on NADP-dependent isocitrate dehydrogenase activity. Soil-grown mutants do not exhibit any alterations in daytime sucrose, glucose, fructose, citrate, ammonium, and total soluble amino acid levels. However, gas chromatography-mass spectrometry metabolic profiling analyses indicate that certain free amino acids are reduced in comparison to the wild type. These data suggest that IDH activity is not limiting for tricarboxylic acid cycle functioning and nitrogen assimilation. On the other hand, liquid culture-grown mutants give a reduced growth phenotype, a large increase in organic acid (citrate is increased 35-fold), hexose-phosphate, and sugar content, whereas ammonium and free amino acids are moderately increased with respect to wild-type cultures. However, no significant changes in 2-oxoglutarate levels were observed. Under these nonphysiological growth conditions, pyridine nucleotide levels remained relatively constant between the wild-type and the idhv line, although some small, but significant, alterations were measured in idhii (lower NADH and higher NADPH levels). On the other hand, soil-grown idhv plants exhibited a reduction in NAD and NADPH content.
Association of inflammatory bowel disease with ankylosing spondylitis and rheumatoid arthritis: A nationwide population-based study

Abstract Objectives: Tantalizing connections between autoimmune rheumatic diseases (ARDs) and inflammatory bowel disease (IBD) have become evident with regard to their genetic and immunologic background. However, the association between these two disease entities remains unclear. The aim of this study is to investigate the association between each ARD and IBD. Methods: A nationwide population-based cross-sectional study was performed using the Korean National Health Insurance Claims database. The data of patients with IBD and age- and sex-matched controls between 2009 and 2013 were collected from the database. The prevalence of ARDs, including systemic lupus erythematosus (SLE), inflammatory myositis (polymyositis and dermatomyositis), systemic sclerosis (SSc), Sjögren’s syndrome (SjS), ankylosing spondylitis (AS), and rheumatoid arthritis (RA), was determined. The associations between each ARD and IBD were analyzed using multivariate logistic regression models. Results: A total of 40,843 IBD patients (28,197 patients with ulcerative colitis and 12,646 with Crohn’s disease) and 122,529 controls were enrolled. The nonstratified analysis revealed that patients with IBD had significant risk of being concomitantly affected by AS (odds ratio [OR] 5.140, 95% confidence interval [95% CI] 4.069–6.492) and RA (OR: 3.474, 95% CI: 2.671–4.519) after adjusting for age and sex. No significant association was observed between IBD and other ARDs including SLE, inflammatory myositis, SSc, and SjS. Conclusion: IBD is significantly associated with AS and RA in the large-scaled population-based study. This result suggests that etiopathogenesis of IBD might be shared with AS and RA.
A random thinning model with a latent factor for improvement of top-down credit risk assessment

Abstract We introduce a credit portfolio risk model within the “top-down approach” and then demonstrate applicability of our model to practical credit risk management via some empirical studies using some historical data on down-grades of Japanese firms. Specifically we present a simple random thinning model with some latent factor so as to explain the fact that downgrades are observed in some sub-portfolio much more or much less than expected naively.
Consideration of patient preferences and challenges in storage and access of pharmacogenetic test results

Purpose: Pharmacogenetic testing is one of the primary drivers of personalized medicine. The use of pharmacogenetic testing may provide a lifetime of benefits through tailoring drug dosing and selection of multiple medications to improve therapeutic outcomes and reduce adverse responses. We aimed to assess public interest and concerns regarding sharing and storage of pharmacogenetic test results that would facilitate the reuse of pharmacogenetic data across a lifetime of care.Methods: We conducted a random-digit-dial phone survey of a sample of the US public.Results: We achieved an overall response rate of 42% (n = 1139). Most respondents indicated that they were extremely or somewhat comfortable allowing their pharmacogenetic test results to be shared with other doctors involved in their care management (90% ± 2.18%); significantly fewer respondents (74% ± 3.27%) indicated that they were extremely or somewhat comfortable sharing results with their pharmacist (P < 0.0001). Conclusion: Patients, pharmacists, and physicians will all be critical players in the pharmacotherapy process. Patients are supportive of sharing pharmacogenetic test results with physicians and pharmacists and personally maintaining their test results. However, further study is needed to understand which options are needed for sharing, appropriate storage, and patient education about the relevance of pharmacogenetic test results to promote consideration of this information by other prescribing practitioners.
Imaging end points for monitoring neuroprotection in Parkinson's disease

In this review, the potential role of positron emission tomography and single‐photon emission computed tomography as biological markers for following the progression of Parkinson's disease (PD) is discussed, and their value for assessing the efficacy of putative neuroprotective agents in PD is considered. It is concluded that functional imaging provides a valuable adjunct to clinical assessment when judging the efficacy of neuroprotective approaches to PD. Ann Neurol 2003;53: (suppl 3)S110–S119
Did Gause Have a Yeast Infection?

We planned to develop predator–prey models using Paramecium and yeast, but they have not been empirically examined since work by Gause in the 1930s. Therefore, we evaluated if Paramecium aurelia ingests and grows on eight yeasts. Recognising that it ingested yeasts but could not grow, we assessed if it might grow on other yeasts, by empirically parameterising a predator–prey model that relies on ingestion, not growth. Simulations were compared to P. aurelia‐yeast time‐series data, from Gause. We hypothesised that if the model simulated predator–prey dynamics that mimicked the original data, then possibly P. aurelia could grow on yeast; simulations did not mimic the original data. Reviewing works by Gause exposed two issues: experiments were undoubtedly contaminated with bacteria, allowing growth on bacteria, not yeast; and the population cycle data cannot be considered a self‐sustaining time series, as they were manipulated by adding yeast and ciliates. We conclude that past and future work should not rely on this system, for either empirical or theoretical evaluations. Finally, although we show that P. aurelia, P. caudatum, Euplotes patella, and Blepharisma sp. cannot grow on yeast, Tetrahymena pyriformis and Colpidium striatum can; these may provide models to explore predator–prey dynamics.
Cloning, Sequencing, and Expression of a 24-kDa Ca2+-binding Protein Activating Photoreceptor Guanylyl Cyclase (*)

Two vertebrate photoreceptor-specific membrane guanylyl cyclases, RetGC-1 and RetGC-2, are activated by a soluble 24-kDa retinal protein, p24, in a Ca2+-sensitive manner (Dizhoor, A. M., Lowe, D. G., Olshevskaya, E. V., Laura, R. P., and Hurley, J. B.(1994) Neuron 12, 1345-1352; Lowe, D. G. , Dizhoor, A. M. , Liu, K. , Gu, O. , Laura, R. , Lu, L. , and Hurley, J. B. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 5535-5539). The primary structure of bovine p24 has been derived from peptide sequencing and from its cDNA. p24 is a new EF-hand-type Ca2+-binding protein, related but not identical to another guanylyl cyclase-activating protein, GCAP (Palczewski, K., Subbaraya, I., Gorczyca, W. A., Helekar, B. S., Ruiz, C. C., Ohguro, H. Huang, J., Zhao, X., Crabb, J. W., Johnson, R. S., Walsh, K. A., Gray-Keller, M. P., Detwiler, P. B., and Baehr, W.(1994) Neuron 13, 395-404) and other members of the recoverin family of Ca2+-binding proteins. Antibodies against a truncated fusion protein and against a p24-specific synthetic peptide specifically recognize retinal p24 on immunoblot. Both antibodies inhibit activation of photoreceptor membrane guanylyl cyclase by purified p24. p24 is found only in retina, and it copurifies with outer segment membranes. Immunocytochemical analysis shows that it is present in rod photoreceptor cells. An immobilized antibody column was used to purify p24 from a heat-treated retinal extract. Purified p24 appears on SDS-polyacrylamide gel electrophoresis as a homogenous protein not contaminated with GCAP, and it activates photoreceptor guanylyl cyclase in vitro at submicromolar concentrations. Ca2+ inhibits this activation with an EC50 near 200 nM and a Hill coefficient of 1.7. Recombinant p24 expressed in 293 cells effectively stimulates photoreceptor guanylyl cyclase. These findings demonstrate that p24, like GCAP, imparts Ca2+ sensitivity to photoreceptor membrane guanylyl cyclase. We propose that p24 be referred to as GCAP-2 and that GCAP be referred to as GCAP-1.
Immunologic Control of Human T-Cell Leukemia Virus Type I and Adult T-Cell Leukemia

Host T-cell responses to human T-cell leukemia virus type I (HTLV-I) control the expansion of HTLV-I-infected cells and are determinants of the equilibrium proviral load in vivo. Insufficient T-cell responses are regarded as an immunologic risk factor for adult T-cell leukemia (ATL) because they allow increased proviral loads, which represent an epidemiologic risk factor for ATL. ATL cells from approximately half of ATL cases retain the ability to express HTLV-I Tax, a major target antigen of HTLV-I-specific cytotoxic T-lymphocytes (CTL), whereas Tax-specific CTL in ATL patients are inactive. Tax-specific CTL responses are strongly activated after hematopoietic stem cell transplantation in some ATL patients in long-term remission, indicating that HTLV-I Tax is expressed in vivo rather than being silent, and that the donor-derived T-cell system can recognize it. These findings strongly suggest that reactivation of Tax-specific CTL by vaccines may be promising for prophylaxis of ATL in the high-risk group of HTLV-I carriers and for therapy of ATL in patients whose tumor cells are capable of expressing Tax.
Automated Selection of DAB-labeled Tissue for Immunohistochemical Quantification

The increased use of immunohistochemistry (IHC) in both clinical and basic research settings has led to the development of techniques for acquiring quantitative information from immunostains. Staining correlates with absolute protein levels and has been investigated as a clinical tool for patient diagnosis and prognosis. For these reasons, automated imaging methods have been developed in an attempt to standardize IHC analysis. We propose a novel imaging technique in which brightfield images of diaminobenzidene (DAB)-labeled antigens are converted to normalized blue images, allowing automated identification of positively stained tissue. A statistical analysis compared our method with seven previously published imaging techniques by measuring each one's agreement with manual analysis by two observers. Eighteen DAB-stained images showing a range of protein levels were used. Accuracy was assessed by calculating the percentage of pixels misclassified using each technique compared with a manual standard. Bland-Altman analysis was then used to show the extent to which misclassification affected staining quantification. Many of the techniques were inconsistent in classifying DAB staining due to background interference, but our method was statistically the most accurate and consistent across all staining levels.
Evolution of HIV-1 Genotype in Plasma RNA and Peripheral Blood Mononuclear Cells Proviral Dna after Interruption and Resumption of Antiretroviral Therapy

Background Structured antiretroviral therapy interruption (TI) is discouraged because of poorer AIDS and non-AIDS-related outcomes, but is often inevitable in clinical practice. Certain strategies could reduce the emergence of resistance mutations related to TI. Methods A total of 106 HIV-1-infected patients on stable HAART with undetectable plasma viral load were randomized to therapy continuation (n=50) or CD4+ T-cell-guided TI (n=56). Staggered interruption involved stopping non-nucleoside reverse transcriptase inhibitors (NNRTIs) 7 days before the nucleoside backbone. Genotypic resistance testing (GRT) was performed on proviral DNA from peripheral blood mononuclear cells (PBMCs) at baseline and before each TI, and on plasma RNA after each TI. Results At baseline, GRT on PBMCs detected mutations in nine patients and only two major mutations were identified. GRT on plasma samples performed after TIs showed nucleoside reverse transcriptase inhibitors (NRTI), NNRTI and protease inhibitor major resistance associated mutations in 10/56, 3/46 and 1/8 patients receiving these drugs, respectively. Only in two patients had the same mutations been observed in GRT on PBMCs at baseline. Three patients presented virological failure after resumption of therapy, all receiving NNRTIs. In one of them, resistance mutations detected at failure had been also observed previously in GRT on plasma after TI. Conclusions Staggered interruption of NNRTIs 7 days before the nucleoside backbone does not avoid resistance emergence completely, but does not necessarily lead to virological failure after treatment resumption. Plasma HIV-1 RNA genotype after the interruption and the patient's treatment history seem to be more useful than baseline proviral DNA genotype to assess the risk of virological failure after restarting therapy.
A Mixed Monte Carlo and Partial Differential Equation Variance Reduction Method for Foreign Exchange Options Under the Heston–Cox–Ingersoll–Ross Model

In this paper, we consider the valuation of European and path-dependent options in foreign exchange markets when the currency exchange rate evolves according to the Heston model combined with the Cox-Ingersoll-Ross (CIR) dynamics for the stochastic domestic and foreign short interest rates. The mixed Monte Carlo/partial differential equation method requires that we simulate only the paths of the squared volatility and the two interest rates, while an "inner" Black-Scholes-type expectation is evaluated by means of a partial differential equation. This can lead to a substantial variance reduction and complexity improvements under certain circumstances depending on the contract and the model parameters. In this work, we establish the uniform boundedness of moments of the exchange rate process and its approximation, and prove strong convergence of the latter in Lρ (ρ ⩾ 1). Then, we carry out a variance reduction analysis and obtain accurate approximations for quantities of interest. All theoretical contributions can be extended to multi-factor short rates in a straightforward manner. Finally, we illustrate the efficiency of the method for the four-factor Heston-CIR model through a detailed quantitative assessment.
Chemokine/CD4 receptor density ratios correlate with HIV replication in lymph node and peripheral blood of HIV-infected individuals

ObjectivesLymphoid tissue is a major reservoir for virus replication in HIV-infected subjects. The relationship of CCR5 and CXCR4 coreceptor density and HIV replication in peripheral blood mononuclear cells (PBMC) and lymph node (LN) mononuclear cells (LNMC) of HIV-infected subjects was examined. MethodsPBMC and cervical LNMC from 12 HIV-infected patients were examined for virological and immunological parameters including chemokine receptor density, HIV plasma and cellular viral load, coreceptor usage and CD38/HLA-DR expression. ResultsThe number of CCR5 and CXCR4 molecules on CD4 lymphocytes in the LN were significantly higher than in PBMC. In contrast the number of CD4 molecules/CD4 T cell was higher in PBMC than in LNMC. The CXCR4/CD4 and CCR5/CD4 ratios in the LN were significantly higher than in the PBMC. This was associated with a cellular viral load in the LN that was ~110-fold higher than in PBMC. The absolute number of coreceptor molecules per cell did not correlate with the viral load. However, the CCR5/CD4 and CXCR4/CD4 ratios in the LN positively correlated with HIV cellular and plasma RNA. Characterization of the viral isolates suggested an association between clinical isolates using a distinct coreceptor and the upregulation of the corresponding chemokine receptor. ConclusionsThe ratios of chemokine receptors to CD4 molecules in CD4 T cells from LN is higher than in PBMC and may account for the relative difference in cellular viral load in these compartments. Additionally, the coreceptor/CD4 ratios, particularly in the lymphoid tissue, were highly related to HIV replication.
Simple adaptive controlߞA stable direct model reference adaptive control methodology - brief survey

Abstract In spite of successful proofs of stability and even successful demonstrations of performance, the use of Model Reference Adaptive Control (MRAC) methodologies in practical real world systems has met a rather strong resistance from practitioners and has remained very limited. Apparently, the practitioners have a hard time understanding the conditions for stable operations of adaptive control systems under realistic operational environments. Besides, it is difficult to measure the robustness of adaptive control system stability when compared with the common measure of phase margin and gain margin that is utilized by present, mainly LTI, controllers. This paper attempts to revisit the fundamental qualities of the common gradient-based MRAC methodology and to show that some of its basic drawbacks have been addressed and eliminated within the so-called Simple Adaptive Control methodology. Sufficient conditions that guarantee stability are clearly stated and lead to similarly clear proofs of stability and to successful and stable applications of SAC.
Zhang Neural Network for Linear Time-Varying Equation Solving and its Robotic Application

Different from gradient-based neural networks, a special kind of recurrent neural network has been proposed by Zhang et al for real-time matrix inversion. In this paper, we generalize such a design method to solving online a set of linear time-varying equations. In comparison with gradient-based neural networks, the resultant Zhang neural network for time-varying equation solving is designed based on a vector-valued error function, instead of a scalar-valued error function. It is depicted in an implicit dynamics, instead of an explicit dynamics. Furthermore, Zhang neural network globally exponentially converges to the exact solution of linear time-varying equations. Simulation results, including the application to robot kinematic control, substantiate the theoretical analysis and demonstrate the efficacy of Zhang neural network on linear time-varying equation solving, especially when using a power-sigmoid activation function.
Evaluation of Biolog for identification of members of the family Micrococcaceae

The Biolog Identification System (Biolog, Inc., Hayward, Calif.) was challenged at two separate laboratories with 113 coded isolates, including 33 type strains of staphylococci, 5 strains of Micrococcus spp. , and 1 strain of Stomatococcus mucilaginosus. Test parameters between the sites were controlled as much as possible. Discrepancies were arbitrated by using conventional biochemicals. Overall accuracies (correct to the species level) upon initial testing were 47.7 and 59.3%, respectively, at the two laboratories. After repeat testing of isolates generating "no identification" responses or errors, the overall accuracies increased to 69.0 and 74.3% at the two sites, respectively, revealing no significant difference in the final results at the two laboratories (78 of 113 versus 84 of 113; P > 0.05). Error rates were 7.1% at one site and 9.7% at the other. The Biolog is not yet accurate enough to serve as a primary method for identifying staphylococci.
The Application of Membrane Vesicles for Cancer Therapy

Cancer, a leading cause of death globally, is projected to become more prevalent in coming years due to increasing life expectancy. Among possible treatment options, the use of biomarkers especially has shown great potential as a gateway to personalized medicine, and in turn, great promise for improved diagnosis, prognosis and treatment of cancer and other diseases. However, the use of biomarkers in cancer therapeutics has thus far exhibited mild success, at best. The most common tool used for biomarker discovery is plasma proteomics due to the accessibility of blood samples and the rapid development of highly sensitive proteomics technologies. However, other body fluids such as urine may also be a reservoir for important marker proteins. Extracellular membrane vesicles ranging in diameter of 30-1000 nm and originating from various cellular origins have been increasingly recognized for their participation in a variety of both normal and pathological cellular processes. Regardless of their cell type of origin these membrane bound vesicles or exosomes provide a protected and controlled internal microenvironment outside the cell for metabolic objectives of the host cell to be carried out at a distance from the host cell. They are also believed to be instrumental in cell-cell and cellextracellular communication. Moreover, while knowledge of exosome biogenesis and physiological relevance remains limited, accumulating evidence suggests that their bioactivity may be clinically applicable in cancer therapeutics. One recent work suggests that the use of exosomes in immunotherapy may prime the immune system to recognize and kill cancer cells and thus could form a viable basis for the development of novel cancer vaccines. This chapter will review current knowledge pertaining to exosomes, describe possible uses of exosomes in immunotherapy, and address challenges and future directions in bringing exosome-based cancer vaccines or immunotherapies closer to clinical reality.