Solvent Effects on Metal Complexation with Crown Ethers from Liquid to Supercritical Fluids (DE-FG07-98ER 149 13)

The purpose of this project is to study the salvation effects of metal-crown ether complexation in different solvents. It has been suggested in the literature that supercritical fluid carbon dioxide (SF-CO2) is a tunable solvent because its salvation environment can be varied with the fluid density. In this project, spectroscopic techniques including nuclear magnetic resonance (NMR) and Fourier Transform Infrared (FTIR) were used to evaluate salvation effects of metal crown complexation in organic solvents and in SF-CO2. In most solvent extraction systems, water is often involved in the extraction processes. We have carried out extensive studies of water-crown ether interactions in different solvents and in SF-CO2 using NMR and FTIR techniques. Water molecules can be attached to crown ethers through hydrogen bonding of H-0-H to the oxygen atoms of crown ether cavities. This type of interaction is like a Lewis acid-Lewis base complexation. During the course of this project, we noticed that some CO2 soluble Lewis base such as tri-n-butyl-phosphate (TBP) can also form such Lewis acid-Lewis base complexes with water and other inorganic acids including nitric acid and hydrochloric acid. Inorganic acids (e.g. nitric acid) are normally not soluble in SF-CO2. However, because TBP is highly soluble in SF-CO2, an inorganic acid bound to TBP via hydrogen bonding becomes CO2 soluble. This Lewis acid-Lewis base complex approach provides a method of introducing inorganic acids into supercritical fluid CO2 for chemical reactions

Analysis of telephone network traffic based on a complex user network

The traffic in telephone networks is analyzed in this paper. Unlike the classical traffic analysis where call blockings are due to the limited channel capacity, we consider here a more realistic cause for call blockings which is due to the way in which users are networked in a real-life human society. Furthermore, two kinds of user network, namely, the fully-connected user network and the scale-free network, are employed to model the way in which telephone users are connected. We show that the blocking probability is generally higher in the case of the scale-free user network, and that the carried traffic intensity is practically limited not only by the network capacity but also by the property of the user network.Comment: 17 pages, 9 figures, accepted for Physica

Intelligent tracking control of a DC motor driver using self-organizing TSK type fuzzy neural networks

[[abstract]]In this paper, a self-organizing Takagi–Sugeno–Kang (TSK) type fuzzy neural network (STFNN) is proposed. The self-organizing approach demonstrates the property of automatically generating and pruning the fuzzy rules of STFNN without the preliminary knowledge. The learning algorithms not only extract the fuzzy rule of STFNN but also adjust the parameters of STFNN. Then, an adaptive self-organizing TSK-type fuzzy network controller (ASTFNC) system which is composed of a neural controller and a robust compensator is proposed. The neural controller uses an STFNN to approximate an ideal controller, and the robust compensator is designed to eliminate the approximation error in the Lyapunov stability sense without occurring chattering phenomena. Moreover, a proportional-integral (PI) type parameter tuning mechanism is derived to speed up the convergence rates of the tracking error. Finally, the proposed ASTFNC system is applied to a DC motor driver on a field-programmable gate array chip for low-cost and high-performance industrial applications. The experimental results verify the system stabilization and favorable tracking performance, and no chattering phenomena can be achieved by the proposed ASTFNC scheme.[[notice]]補正完畢[[incitationindex]]SCI[[booktype]]紙本[[booktype]]電子

Multi-system neurological disease is common in patients with OPA1 mutations

Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal ‘dominant optic atrophy plus’ variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44–6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08–4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment

NPEPPS Is a Druggable Driver of Platinum Resistance

There is an unmet need to improve the efficacy of platinum-based cancer chemotherapy, which is used in primary and metastatic settings in many cancer types. In bladder cancer, platinum-based chemotherapy leads to better outcomes in a subset of patients when used in the neoadjuvant setting or in combination with immunotherapy for advanced disease. Despite such promising results, extending the benefits of platinum drugs to a greater number of patients is highly desirable. Using the multiomic assessment of cisplatin-responsive and -resistant human bladder cancer cell lines and whole-genome CRISPR screens, we identified puromycin-sensitive aminopeptidase (NPEPPS) as a driver of cisplatin resistance. NPEPPS depletion sensitized resistant bladder cancer cells to cisplatin in vitro and in vivo. Conversely, overexpression of NPEPPS in sensitive cells increased cisplatin resistance. NPEPPS affected treatment response by regulating intracellular cisplatin concentrations. Patient-derived organoids (PDO) generated from bladder cancer samples before and after cisplatin-based treatment, and from patients who did not receive cisplatin, were evaluated for sensitivity to cisplatin, which was concordant with clinical response. In the PDOs, depletion or pharmacologic inhibition of NPEPPS increased cisplatin sensitivity, while NPEPPS overexpression conferred resistance. Our data present NPEPPS as a druggable driver of cisplatin resistance by regulating intracellular cisplatin concentrations.</p

Histone Chaperone NAP1 Mediates Sister Chromatid Resolution by Counteracting Protein Phosphatase 2A

Chromosome duplication and transmission into daughter cells requires the precisely orchestrated binding and release of cohesin. We found that the Drosophila histone chaperone NAP1 is required for cohesin release and sister chromatid resolution during mitosis. Genome-wide surveys revealed that NAP1 and cohesin co-localize at multiple genomic loci. Proteomic and biochemical analysis established that NAP1 associates with the full cohesin complex, but it also forms a separate complex with the cohesin subunit stromalin (SA). NAP1 binding to cohesin is cell-cycle regulated and increases during G2/M phase. This causes the dissociation of protein phosphatase 2A (PP2A) from cohesin, increased phosphorylation of SA and cohesin removal in early mitosis. PP2A depletion led to a loss of centromeric cohesion. The distinct mitotic phenotypes caused by the loss of either PP2A or NAP1, were both rescued by their concomitant depletion. We conclude that the balanced antagonism between NAP1 and PP2A controls cohesin dissociation during mitosis

The BAF complex inhibitor pyrimethamine reverses HIV-1 latency in people with HIV-1 on antiretroviral therapy

Reactivation of the latent HIV-1 reservoir is a first step toward triggering reservoir decay. Here, we investigated the impact of the BAF complex inhibitor pyrimethamine on the reservoir of people living with HIV-1 (PLWH). Twenty-eight PLWH on suppressive antiretroviral therapy were randomized (1:1:1:1 ratio) to receive pyrimethamine, valproic acid, both, or no intervention for 14 days. The primary end point was change in cell-associated unspliced (CA US) HIV-1 RNA at days 0 and 14. We observed a rapid, modest, and significant increase in (CA US) HIV-1 RNA in response to pyrimethamine exposure, which persisted throughout treatment and follow-up. Valproic acid treatment alone did not increase (CA US) HIV-1 RNA or augment the effect of pyrimethamine. Pyrimethamine treatment did not result in a reduction in the size of the inducible reservoir. These data demonstrate that the licensed drug pyrimethamine can be repurposed as a BAF complex inhibitor to reverse HIV-1 latency in vivo in PLWH, substantiating its potential advancement in clinical studies.</p

Treatment Outcomes of Patients With Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis According to Drug Susceptibility Testing to First- and Second-line Drugs: An Individual Patient Data Meta-analysis

The clinical validity of drug susceptibility testing (DST) for pyrazinamide, ethambutol, and second-line antituberculosis drugs is uncertain. In an individual patient data meta-analysis of 8955 patients with confirmed multidrug-resistant tuberculosis, DST results for these drugs were associated with treatment outcome