RATIONAL DESIGN, SYNTHESIS, AND CHARACTERIZATION OF NOVEL mPGES-1 INHIBITORS AS NEXT GENERATION OF ANTI-INFLAMMATORY DRUGS

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are currently widely used as fever and pain relief in patients with arthritis and other inflammatory symptoms. NSAIDs effect by inhibiting cyclooxygenase-1 (COX-1) and/or cyclooxygenase-2 (COX-2). COX isozymes (COXs) are key enzymes in the biosynthesis of prostaglandin H2 (PGH2) from arachidonic acid (AA). It is now clear that prostaglandin E2 (PGE2), one of the downstream products of PGH2, is the main mediator in both chronic and acute inflammation. Microsomal prostaglandin E synthase (mPGES-1) is the terminal enzyme of COX-2 in the PGE2 biosynthesis pathway. Different from other two constitutively expressed PGE2 synthase (PGES), mPGES-2 and cPGES, mPGES-1 is induced by pro-inflammatory stimuli and responsible for the production of PGE2 related to inflammation, fever and pain. For these reasons, selective inhibition of mPGES-1 is expected to suppress inflammation induced PGE2 production and, therefore, will exert anti-inflammatory activity while avoid the side effects of COXs inhibitors, such as gastrointestinal (GI) toxicity, and cardiovascular events. A combination of computational and experimental approaches was used to discovery mPGES-1 inhibitors with new scaffolds. The methods used include molecular docking, molecular dynamic simulation, molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculation, and in vitro activity assays. Our large-scale structure-based virtual screening was performed on compounds in the NCI libraries, containing a total of ~260,000 compounds. 7 compounds have been determined for their IC50 values (about 300 nM to 8000 nM). What’s more, these new inhibitors of mPGES-1 identified from virtual screening did not shown significant inhibition against COX isozymes even at substantially high concentrations (e.g. 100 µM). Rational methodology for drug design and organic synthesis were applied to generate three series of mPGES-1 inhibitors with different scaffolds. In total, about 200 compounds were synthesized and tested for their in vitro inhibition against human mPGES-1. Compounds with high potency against human mPGES-1 were further screened for their inhibition against mouse mPGES-1 and selectivity of human mPGES-1 over COXs. Several compounds were identified as submicromolar inhibitors against human mPGES-1 with high selectivity over COXs. In general, we have successfully identified a library of compounds as potent mPGES-1 inhibitors without significant inhibition against COXs. Structure information and in vitro activity evaluation data generated from the virtual screening and the library of compounds will be used to guide future design and synthesis of the mPGES-1 inhibitors

A Measure of Perceived Severity in Organizational Crises: A Multidimensional Scale Development and Validation

This study proposed a definition of perceived crisis severity and created a valid and reliable scale to measure the construct following Churchill’s scale development procedure. The proposed scale, after rigorous pilot testing and exploratory and confirmatory factor analysis, contains 3 factors with 12 items. This study discusses potential applications of the developed measures and provides future research directions

No-Reference Light Field Image Quality Assessment Based on Micro-Lens Image

Light field image quality assessment (LF-IQA) plays a significant role due to its guidance to Light Field (LF) contents acquisition, processing and application. The LF can be represented as 4-D signal, and its quality depends on both angular consistency and spatial quality. However, few existing LF-IQA methods concentrate on effects caused by angular inconsistency. Especially, no-reference methods lack effective utilization of 2-D angular information. In this paper, we focus on measuring the 2-D angular consistency for LF-IQA. The Micro-Lens Image (MLI) refers to the angular domain of the LF image, which can simultaneously record the angular information in both horizontal and vertical directions. Since the MLI contains 2-D angular information, we propose a No-Reference Light Field image Quality assessment model based on MLI (LF-QMLI). Specifically, we first utilize Global Entropy Distribution (GED) and Uniform Local Binary Pattern descriptor (ULBP) to extract features from the MLI, and then pool them together to measure angular consistency. In addition, the information entropy of Sub-Aperture Image (SAI) is adopted to measure spatial quality. Extensive experimental results show that LF-QMLI achieves the state-of-the-art performance

Selective Inhibitors of Human mPGES-1 from Structure-Based Computational Screening

Human mPGES-1 is recognized as a promising target for next generation of anti-inflammatory drugs. Although various mPGES-1 inhibitors have been reported in literature, few have entered clinical trials and none has been proven clinically useful so far. It is highly desired for developing the next generation of therapeutics for inflammation-related diseases to design and discover novel inhibitors of mPGES-1 with new scaffolds. Here, we report the identification of a series of new, potent and selective inhibitors of human mPGES-1 with diverse scaffolds through combined computational and experimental studies. The computationally modeled binding structures of these new inhibitors with mPGES-1 provide some interesting clues for rational design of modified structures of the inhibitors to more favorably bind with mPGES-1

Quality Assessment of Stereoscopic 360-degree Images from Multi-viewports

Objective quality assessment of stereoscopic panoramic images becomes a challenging problem owing to the rapid growth of 360-degree contents. Different from traditional 2D image quality assessment (IQA), more complex aspects are involved in 3D omnidirectional IQA, especially unlimited field of view (FoV) and extra depth perception, which brings difficulty to evaluate the quality of experience (QoE) of 3D omnidirectional images. In this paper, we propose a multi-viewport based fullreference stereo 360 IQA model. Due to the freely changeable viewports when browsing in the head-mounted display (HMD), our proposed approach processes the image inside FoV rather than the projected one such as equirectangular projection (ERP). In addition, since overall QoE depends on both image quality and depth perception, we utilize the features estimated by the difference map between left and right views which can reflect disparity. The depth perception features along with binocular image qualities are employed to further predict the overall QoE of 3D 360 images. The experimental results on our public Stereoscopic OmnidirectionaL Image quality assessment Database (SOLID) show that the proposed method achieves a significant improvement over some well-known IQA metrics and can accurately reflect the overall QoE of perceived images

Physically Plausible Animation of Human Upper Body from a Single Image

We present a new method for generating controllable, dynamically responsive, and photorealistic human animations. Given an image of a person, our system allows the user to generate Physically plausible Upper Body Animation (PUBA) using interaction in the image space, such as dragging their hand to various locations. We formulate a reinforcement learning problem to train a dynamic model that predicts the person's next 2D state (i.e., keypoints on the image) conditioned on a 3D action (i.e., joint torque), and a policy that outputs optimal actions to control the person to achieve desired goals. The dynamic model leverages the expressiveness of 3D simulation and the visual realism of 2D videos. PUBA generates 2D keypoint sequences that achieve task goals while being responsive to forceful perturbation. The sequences of keypoints are then translated by a pose-to-image generator to produce the final photorealistic video.Comment: WACV 202

A Quantitative LC-MS/MS Method for Simultaneous Determination of Cocaine and Its Metabolites in Whole Blood

As new metabolic pathways of cocaine were recently identified, a high performance liquid chromatography tandem mass spectrometry (LC–MS/MS) method was developed to simultaneously determine cocaine and nine cocaine-related metabolites in whole blood samples. One-step solid phase extraction was used to extract all of the ten compounds and corresponding internal standards from blood samples. All compounds and internal standards extracted were separated on an Atlantis T3 (100 Å, 3 μm, 2.1 mm × 150 mm I.D) column and detected in positive ion and high sensitivity mode with multiple reaction monitoring. This method was validated for its sensitivity, linearity, specificity, accuracy, precision, recovery, and stability. All of the ten compounds were quantifiable ranging from the lower limit of quantification (LLOQs) of ∼10 nM (1.9–3.2 ng/ml) to ∼1000 nM (190–320 ng/ml) without any interfering substance. Accuracy and precision were determined, and both of them were within the acceptance criteria of the United States (US) Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. The recovery was above 66.7% for all compounds. Stability tests demonstrated the stability of compounds under different storage conditions in whole blood samples. The method was successfully applied to a pharmacokinetic study with co-administration of cocaine and alcohol in rats

Res-Tuning: A Flexible and Efficient Tuning Paradigm via Unbinding Tuner from Backbone

Parameter-efficient tuning has become a trend in transferring large-scale foundation models to downstream applications. Existing methods typically embed some light-weight tuners into the backbone, where both the design and the learning of the tuners are highly dependent on the base model. This work offers a new tuning paradigm, dubbed Res-Tuning, which intentionally unbinds tuners from the backbone. With both theoretical and empirical evidence, we show that popular tuning approaches have their equivalent counterparts under our unbinding formulation, and hence can be integrated into our framework effortlessly. Thanks to the structural disentanglement, we manage to free the design of tuners from the network architecture, facilitating flexible combination of various tuning strategies. We further propose a memory-efficient variant of Res-Tuning, where the bypass i.e., formed by a sequence of tuners) is effectively detached from the main branch, such that the gradients are back-propagated only to the tuners but not to the backbone. Such a detachment also allows one-time backbone forward for multi-task inference. Extensive experiments on both discriminative and generative tasks demonstrate the superiority of our method over existing alternatives from the perspectives of efficacy and efficiency. Project page: $\href{https://res-tuning.github.io/}{\textit{https://res-tuning.github.io/}}$.Comment: Accepted to NeurIPS 202

Structure-Based Discovery of mPGES-1 Inhibitors Suitable for Preclinical Testing in Wild-Type Mice as a New Generation of Anti-Inflammatory Drugs

Human mPGES-1 is recognized as a promising target for next generation of anti-inflammatory drugs without the side effects of currently available anti-inflammatory drugs, and various inhibitors have been reported in the literature. However, none of the reported potent inhibitors of human mPGES-1 has shown to be also a potent inhibitor of mouse or rat mPGES-1, which prevents using the well-established mouse/rat models of inflammation-related diseases for preclinical studies. Hence, despite of extensive efforts to design and discover various human mPGES-1 inhibitors, the promise of mPGES-1 as a target for the next generation of anti-inflammatory drugs has never been demonstrated in any wild-type mouse/rat model using an mPGES-1 inhibitor. Here we report discovery of a novel type of selective mPGES-1 inhibitors potent for both human and mouse mPGES-1 enzymes through structure-based rational design. Based on in vivo studies using wild-type mice, the lead compound is indeed non-toxic, orally bioavailable, and more potent in decreasing the PGE2 (an inflammatory marker) levels compared to the currently available drug celecoxib. This is the first demonstration in wild-type mice that mPGES-1 is truly a promising target for the next generation of anti-inflammatory drugs

Clinical Potential of an Enzyme-Based Novel Therapy for Cocaine Overdose

It is a grand challenge to develop a truly effective medication for treatment of cocaine overdose. The current available, practical emergence treatment for cocaine overdose includes administration of a benzodiazepine anticonvulsant agent (e.g. diazepam) and/or physical cooling with an aim to relieve the symptoms. The inherent difficulties of antagonizing physiological effects of drugs in the central nervous system have led to exploring protein-based pharmacokinetic approaches using biologics like vaccines, monoclonal antibodies, and enzymes. However, none of the pharmacokinetic agents has demonstrated convincing preclinical evidence of clinical potential for drug overdose treatment without a question mark on the timing used in the animal models. Here we report the use of animal models, including locomotor activity, protection, and rescue experiments in rats, of drug toxicity treatment with clinically relevant timing for the first time. It has been demonstrated that an efficient cocaine-metabolizing enzyme developed in our previous studies can rapidly reverse the cocaine toxicity whenever the enzyme is given to a living rat, demonstrating promising clinical potential of an enzyme-based novel therapy for cocaine overdose as a successful example in comparison with the commonly used diazepam