Understanding Surface Hopping Algorithms And Their Applications In Condensed Phase Systems

While electron transfer plays an important role in a variety of fields, our understanding of electron transfer relies heavily on quantum mechanics. Given the high computational cost of quantum mechanics calculations and the limits of a computer\u27s capability nowadays, the straightforward use of the Schrodinger equation is extremely limited by the dimensionality of the system, which has spurred the advent of many approximate methods. As a mixed quantum-classical approach, fewest-switches surface hopping (FSSH) can treat many nuclei as classical particles while retaining the quantum nature of electrons. However appealing, though, FSSH has some notable drawbacks: FSSH suffers from over-coherence (in addition to its inability to capture presumably rare nuclear quantum effects). Here, in this thesis, we revisit the issue of decoherence from the perspective of entropy, unraveling the nature of the erroneous coherence associated with FSSH trajectories and further justifying the improvements made by the recently proposed augmented-FSSH. Going beyond traditional Tully-style surface hopping technique, we also study new flavors of surface hopping that treat a manifold of electronic states to capture dynamics near metal surfaces. Moreover, we highlight how surface hopping can be used to study electrochemistry and we thoroughly benchmark the surface hopping algorithms against mean-field approaches. This thesis captures 4 years of research which has successfully analyzed the guts of the surface hopping approach for nonadiabatic dynamics both in solution and at a metal surface

Dynamic Studies of Scaffold-dependent Mating Pathway in Yeast

The mating pathway in \emph{Saccharomyces cerevisiae} is one of the best understood signal transduction pathways in eukaryotes. It transmits the mating signal from plasma membrane into the nucleus through the G-protein coupled receptor and the mitogen-activated protein kinase (MAPK) cascade. According to the current understandings of the mating pathway, we construct a system of ordinary differential equations to describe the process. Our model is consistent with a wide range of experiments, indicating that it captures some main characteristics of the signal transduction along the pathway. Investigation with the model reveals that the shuttling of the scaffold protein and the dephosphorylation of kinases involved in the MAPK cascade cooperate to regulate the response upon pheromone induction and to help preserving the fidelity of the mating signaling. We explored factors affecting the dose-response curves of this pathway and found that both negative feedback and concentrations of the proteins involved in the MAPK cascade play crucial role. Contrary to some other MAPK systems where signaling sensitivity is being amplified successively along the cascade, here the mating signal is transmitted through the cascade in an almost linear fashion.Comment: 36 pages, 9 figure

Post-translational regulation of RORγt—A therapeutic target for the modulation of interleukin-17-mediated responses in autoimmune diseases

AbstractRetinoic acid-related orphan receptor gamma t (RORγt) is a nuclear receptor, which is selectively expressed by various lymphocytes. RORγt is critical for the development of secondary and tertiary lymphoid organs, and for the thymic development of the T cell lineage. RORγt has been extensively studied as the master transcription factor of IL-17 expression and Th17 cells, which are strongly associated with various inflammatory and autoimmune conditions. Given its essential role in promoting pro-inflammatory responses, it is not surprising that the expression of RORγt is tightly controlled. By its nature as a nuclear receptor, RORγt activity is also regulated in a ligand-dependent manner, which makes it an attractive drug target. In addition, multiple post-translational mechanisms, including post-translational modifications, such as acetylation and ubiquitinylation, as well as interactions with various co-factors, modulate RORγt function. Here we attempt a comprehensive review of the post-translational regulation of RORγt, an area that holds the potential to transform the way we target the RORγt/IL-17 pathway, by enabling the development of safe and highly selective modulators of RORγt activity

High -density lipoprotein cholesterol as a predictor for diabetes mellitus

Background: Diabetes is a prevalent chronic disease around the world. To evaluate the risk of diabetes comprehensively, we developed a score model for risk prediction with HDL-C as a protective factor. Methods: We extracted physical examination data of 2728 individuals. The data contain 18 demographic and clinical variables. To identify the statistical significant feature variables, the backward stepwise logistic regression was used based on the data of the “exploratory population”. To ascertain the cutoff value of the selected variables, we used the Youden index. Then we assigned each variable level a score according to the estimated regression model coefficients and then calculated the individual’s total score. We gained the cutoff value for the total score through the Youden Index and stratified the total score into four levels. We employed the data of “validation population” to test the performance of the score model based on the area under the ROC curve. Results: Age, LDL-C, HDL-C, BMI, family history of diabetes, diastolic blood pressure and TCHO were selected as statistically significant variables. The diabetes risk score range varied from 0 to 17. The risk level categorized by the total score was low, middle, high and extremely high, with a score range of 0-2, 3-7, 8-12 and 13-17, respectively. Conclusions: The score model based on physical examination data is an efficient and valuable tool to evaluate and monitor the potential diabetes risk for both healthy and unhealthy people at an individual level

Efficacy and safety of tetramethylpyrazine phosphate on pulmonary hypertension: study protocol for a randomized controlled study

Background: Tetramethylpyrazine (TMP), an active ingredient in the traditional Chinese herbal medicine Rhizoma Chuanxiong, has been used clinically for the prevention and treatment of cardiovascular disease. The benefits of TMP are largely attributed to its anti-oxidative and vasodilative properties. However, the efficacy of TMP in the treatment of pulmonary hypertension (PH) is unknown. We hypothesized that TMP may have a therapeutic effect in patients with PH. Methods/design: A randomized, single-blinded, clinical study with a TMP treatment group and a control group will be conducted to evaluate the efficacy and safety of TMP intervention in patients with PH. The recruitment target is 120 subjects meeting the following criteria: (i) at rest and at sea level, mean pulmonary artery pressure above 20 mmHg and pulmonary capillary wedge pressure below 15 mmHg; (ii) type 1 or 4 PH in the stable phase; (iii) age 15-70 years; (iv) 6-min walk distance between 100 and 450 m; (v) World Health Organization (WHO) functional classification of pulmonary hypertension of II, III, or IV. Subjects will be assigned randomly into two groups at a ratio of 1:2 (control:TMP). Both groups will receive routine treatment, and the treatment group will also receive oral TMP (100 mg) three times a day for 16 weeks. All patients will be followed up for 4, 8, 12, and 16 weeks; symptoms and patient compliance will be recorded. Discussion: We aimed to determine the efficacy and safety of TMP for the treatment of PH.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

IL-22–producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis

IL-22 plays an important role in mucosal epithelial cell homeostasis. Using a dextran sodium sulfate-induced mouse model of acute colitis, we observed an IL-23–dependent up-regulation of IL-22 in the middle and distal colon at the onset of epithelial cell damage. This heightened IL-22 correlated with an influx of innate immune cells, suggesting an important role in colonic epithelial protection. Freshly isolated colon-infiltrating neutrophils produced IL-22 contingent upon IL-23 signaling, and IL-22 production was augmented by TNF-α. Importantly, the depletion of neutrophils resulted in diminished IL-22 levels in the colon, and the transfer of IL-22–competent neutrophils to Il22a-deficient mice protected the colonic epithelium from dextran sodium sulfate-induced damage. In addition, IL-22–producing neutrophils targeted colonic epithelial cells to up-regulate the antimicrobial peptides, RegIIIβ and S100A8. This study establishes a role for neutrophils in providing IL-22–dependent mucosal epithelial support that contributes to the resolution of colitis

Covalently immobilized lipase on a thermoresponsive polymer with an upper critical solution temperature as an efficient and recyclable asymmetric catalyst in aqueous media

This work was financially supported by the National Natural Science Foundation of China (Grant No. 21203102), the Tianjin Municipal Natural Science Foundation (Grant No. 14JCQNJC06000), China Scholarship Council (Grant No. 201606200087), MOE (IRT13R30) and 111 Project (B12015).A thermoresponsive lipase catalyst with an upper critical solution temperature (UCST) of about 26 °C was exploited by covalent immobilization of an enzyme, Pseudomonas cepacia lipase (PSL), onto poly(acrylamide-co-acrylonitrile) via glutaraldehyde coupling. The experimental conditions for the PSL immobilization were optimized. The immobilized PSL was much more stable for wide ranges of temperature and pH than the free PSL. The material was also evaluated as an asymmetric catalyst in the kinetic resolution of racemic α-methylbenzyl butyrate at 55 °C in an aqueous medium and exhibited high catalytic performance and stability. Up to 50% conversion and 99.5% product enantiomeric excess were achieved, thus providing highly pure enantiomers. More importantly, this biocatalyst could be easily recovered by simple decantation for reuse based on temperature-induced precipitation. It showed good reusability and retained 80.5% of its original activity with a well reserved enantioselectivity in the 6th cycle. This work would shed light on the future development of new UCST-type enzyme catalysts.PostprintPeer reviewe

LILRB1 blockade enhances bispecific T cell engager antibody-induced tumor cell killing by effector CD8+ T cells

Elicitation of tumor cell killing by CD8+ T cells is an effective therapeutic approach for cancer. In addition to using immune checkpoint blockade to reinvigorate existing but unresponsive tumor-specific T cells, alternative therapeutic approaches have been developed, including stimulation of polyclonal T cell cytolytic activity against tumors using bispecific T cell engager (BiTE) molecules that simultaneously engage the TCR complex and a tumor-associated Ag. BiTE molecules are efficacious against hematologic tumors and are currently being explored as an immunotherapy for solid tumors. To understand mechanisms regulating BiTE molecule­–mediated CD8+ T cell activity against solid tumors, we sought to define human CD8+ T cell populations that efficiently respond to BiTE molecule stimulation and identify factors regulating their cytolytic activity. We find that human CD45RA+CCR7− CD8+ T cells are highly responsive to BiTE molecule stimulation, are enriched in genes associated with cytolytic effector function, and express multiple unique inhibitory receptors, including leukocyte Ig-like receptor B1 (LILRB1). LILRB1 and programmed cell death protein 1 (PD1) were found to be expressed by distinct CD8+ T cell populations, suggesting different roles in regulating the antitumor response. Engaging LILRB1 with its ligand HLA-G on tumor cells significantly inhibited BiTE molecule–induced CD8+ T cell activation. Blockades of LILRB1 and PD1 induced greater CD8+ T cell activation than either treatment alone. Together, our data suggest that LILRB1 functions as a negative regulator of human CD8+ effector T cells and that blocking LILRB1 represents a unique strategy to enhance BiTE molecule therapeutic activity against solid tumors