Developing and validating a new comprehensive glucose-insulin pharmacokinetics and pharmacodynamics model

Type 2 diabetes has reached epidemic proportions worldwide. The resulting increase in chronic and costly diabetes related complications has potentially catastrophic implications for healthcare systems, and economics and societies as a whole. One of the key pathological factors leading to type 2 diabetes is insulin resistance (IR), which is the reduced or impaired ability of the body to make use of available insulin to maintain safe glucose concentrations in the bloodstream. It is essential to understand the physiology of glucose and insulin when investigating the underlying factors contributing to chronic diseases such as diabetes and cardiovascular disease. For many years, clinicians and researchers have been working to develop and use model-based methods to increase understanding and aid therapeutic decision support. However, the majority of practicable tests cannot yield more than basic metrics that allow only a threshold-based assessment of the underlying disorder. This thesis gives an overview on several dynamic model-based methodologies with different clinical applications in assessing glycaemia via measuring effects of treatment or medication on insulin sensitivity. Other tests are clinically focused, designed to screen populations and diagnose or detect the risk of developing diabetes. Thus, it is very important to observe sensitivity metrics in various clinical and research settings

The mechanism of NLRP3 inflammasome activation and its pharmacological inhibitors

NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) is a cytosolic pattern recognition receptor (PRR) that recognizes multiple pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Once activated, NLRP3 initiates the inflammasome assembly together with the adaptor ASC and the effector caspase-1, leading to caspase-1 activation and subsequent cleavage of IL-1β and IL-18. Aberrant NLRP3 inflammasome activation is linked with the pathogenesis of multiple inflammatory diseases, such as cryopyrin­associated periodic syndromes, type 2 diabetes, non-alcoholic steatohepatitis, gout, and neurodegenerative diseases. Thus, NLRP3 is an important therapeutic target, and researchers are putting a lot of effort into developing its inhibitors. The review summarizes the latest advances in the mechanism of NLRP3 inflammasome activation and its pharmacological inhibitors

DLX3 Inhibits the Proliferation of Human Dental Pulp Cells Through Inactivation of Canonical Wnt/β-Catenin Signaling Pathway

Homeodomain gene Distal-less-3 (Dlx3) plays an important role during tooth development. Our previous studies indicate that DLX3 inhibits proliferation of human dental pulp cells (hDPCs). However, the mechanism of DLX3 regulating proliferation of hDPCs and maintaining the quiescence of the cells remain unknown. Given the importance of canonical Wnt signaling in the proliferation of dental pulp cell and tooth development, we hypothesized that DLX3 inhibited proliferation of hDPCs through inactivation of canonical Wnt signaling. With overexpression or knock-down of DLX3 in primary hDPCs, we found DLX3 down regulated canonical Wnt signaling and its downstream target genes. And when the DLX3 overexpressed-cells were treated with lithium chloride, the proliferation inhibition by DLX3 was reversed. We also found that DLX3 enhanced the expression of DKK1 and the reduced proliferation of hDPCs by DLX3 was reversed with knock-down of DKK1. Furthermore, luciferase reporter assay and chromatin immunoprecipitation assay showed DLX3 was able to bind to Dkk1 promoter region from nucleotides (nt) -1656 to -1245, and stimulated Dkk1 promoter activity. Mutagenesis studies further revealed two DLX3 responsive elements in Dkk1 promoter. Taken together, our data indicate that DLX3 inhibits proliferation of hDPCs via inactivation of Wnt/β-catenin signaling pathway by directly binding to Dkk1 promoter and increasing its expression

Provably Efficient CVaR RL in Low-rank MDPs

We study risk-sensitive Reinforcement Learning (RL), where we aim to maximize the Conditional Value at Risk (CVaR) with a fixed risk tolerance $\tau$. Prior theoretical work studying risk-sensitive RL focuses on the tabular Markov Decision Processes (MDPs) setting. To extend CVaR RL to settings where state space is large, function approximation must be deployed. We study CVaR RL in low-rank MDPs with nonlinear function approximation. Low-rank MDPs assume the underlying transition kernel admits a low-rank decomposition, but unlike prior linear models, low-rank MDPs do not assume the feature or state-action representation is known. We propose a novel Upper Confidence Bound (UCB) bonus-driven algorithm to carefully balance the interplay between exploration, exploitation, and representation learning in CVaR RL. We prove that our algorithm achieves a sample complexity of $\tilde{O}\left(\frac{H^7 A^2 d^4}{\tau^2 \epsilon^2}\right)$ to yield an $\epsilon$-optimal CVaR, where $H$ is the length of each episode, $A$ is the capacity of action space, and $d$ is the dimension of representations. Computational-wise, we design a novel discretized Least-Squares Value Iteration (LSVI) algorithm for the CVaR objective as the planning oracle and show that we can find the near-optimal policy in a polynomial running time with a Maximum Likelihood Estimation oracle. To our knowledge, this is the first provably efficient CVaR RL algorithm in low-rank MDPs.Comment: The first three authors contribute equally and are ordered randoml

Femtosecond visualization of oxygen vacancies in metal oxides.

Oxygen vacancies often determine the electronic structure of metal oxides, but existing techniques cannot distinguish the oxygen-vacancy sites in the crystal structure. We report here that time-resolved optical spectroscopy can solve this challenge and determine the spatial locations of oxygen vacancies. Using tungsten oxides as examples, we identified the true oxygen-vacancy sites in WO2.9 and WO2.72, typical derivatives of WO3 and determined their fingerprint optoelectronic features. We find that a metastable band with a three-stage evolution dynamics of the excited states is present in WO2.9 but is absent in WO2.72. By comparison with model bandstructure calculations, this enables determination of the most closely neighbored oxygen-vacancy pairs in the crystal structure of WO2.72, for which two oxygen vacancies are ortho-positioned to a single W atom as a sole configuration among all O─W bonds. These findings verify the existence of preference rules of oxygen vacancies in metal oxides

Mutagenesis of Murine Cytomegalovirus Using a Tn3-Based Transposon

AbstractA transposon derived from Escherichia coli Tn3 was introduced into the genome of murine cytomegalovirus (MCMV) to generate a pool of viral mutants. We analyzed three of the constructed recombinant viruses that contained the transposon within the M25, M27, and m155 open reading frames. Our studies provide the first direct evidence to suggest that M25 and M27 are not essential for viral replication in mouse NIH 3T3 cells. Studies in cultured cells and Balb/c mice indicated that the transposon insertion is stable during viral propagation both in vitro and in vivo. Moreover the virus that contained the insertion mutation in M25 exhibited a titer similar to that of the wild-type virus in the salivary glands, lungs, livers, spleens, and kidneys of the Balb/c mice that were intraperitoneally infected with these viruses. These results suggest that M25 is dispensable for viral growth in these organs and the presence of the transposon sequence in the viral genome does not significantly affect viral replication in vivo. The Tn3-based system can be used as a mutagenesis approach for studying the function of MCMV genes in both tissue culture and in animals

Perbandingan Harga Energi dari Sumber Energi Baru Terbarukan dan Fosil

PERBANDINGAN HARGA ENERGI DARI SUMBER ENERGI BARU TERBARUKAN DAN FOSIL. Transportasi biaya rendah untuk orang dan barang sangat penting untuk kesejahteraan ekonomi bangsa. Hingga kini jika harga minyak naik, biaya transportasi otomatis akan mengikuti dan sebagian rakyat menderita akibat melambungnya harga makanan dan barang-barang lainnya. Hampir 100 persen kebutuhan energi transportasi negara Indonesia didukung oleh minyak. Sementara biaya di sektor energi terutama listrik, di negara maju yang juga berperan signifikan untuk mendukung transportasi, jauh lebih stabil dan dapat diprediksi. Kebutuhan energi yang begitu tinggi di sektor transportasi cenderung memaksa manusia untuk mengupayakan sumber dan sarana energi dalam bentuk lain seperti listrik atau hydrogen yang dapat menyamai atau melebihi kinerja bahan bakar minyak. Makalah ini bertujuan untuk menganalisis perbandingan keekonomian harga energi dari sumber EBT dan fosil untuk melihat sejauh mana peluang keekonomian beberapa jenis energi dapat memainkan peran signifikan di sektor transportasi dan dampak selanjutnya di dalam sistem energi. Metodologi yang digunakan adalah penelusuran pustaka dan perhitungan langsung pada bahan atau sumber energi terkait. Dari hasil analisis diperoleh bahwa akan semakin dibutuhkan peran energi nuklir dan energi tertentu lainnya sebagai sumber energi listrik menimbang aspek keekonomiannya yang relatif lebih baik

Absence of topological Hall effect in Fex_xRh100−x_{100-x} epitaxial films: revisiting their phase diagram

A series of Fe$_x$Rh$_{100-x}$ ($30 \leq x \leq 57$) films were epitaxially grown using magnetron sputtering, and were systematically studied by magnetization-, electrical resistivity-, and Hall resistivity measurements. After optimizing the growth conditions, phase-pure Fe$_{x}$Rh$_{100-x}$ films were obtained, and their magnetic phase diagram was revisited. The ferromagnetic (FM) to antiferromagnetic (AFM) transition is limited at narrow Fe-contents with $48 \leq x \leq 54$ in the bulk Fe$_x$Rh$_{100-x}$ alloys. By contrast, the FM-AFM transition in the Fe$_x$Rh$_{100-x}$ films is extended to cover a much wider $x$ range between 33 % and 53 %, whose critical temperature slightly decreases as increasing the Fe-content. The resistivity jump and magnetization drop at the FM-AFM transition are much more significant in the Fe$_x$Rh$_{100-x}$ films with $\sim$50 % Fe-content than in the Fe-deficient films, the latter have a large amount of paramagnetic phase. The magnetoresistivity (MR) is rather weak and positive in the AFM state, while it becomes negative when the FM phase shows up, and a giant MR appears in the mixed FM- and AFM states. The Hall resistivity is dominated by the ordinary Hall effect in the AFM state, while in the mixed state or high-temperature FM state, the anomalous Hall effect takes over. The absence of topological Hall resistivity in Fe$_{x}$Rh$_{100-x}$ films with various Fe-contents implies that the previously observed topological Hall effect is most likely extrinsic. We propose that the anomalous Hall effect caused by the FM iron moments at the interfaces nicely explains the hump-like anomaly in the Hall resistivity. Our systematic investigations may offer valuable insights into the spintronics based on iron-rhodium alloys.Comment: 9 pages, 10 figures; accepted by Phys. Rev.