GR-389 Molecular Dynamics and Protein-Protein Interactions (PPIs) on SARS-CoV-2 coronavirus

The objective of this comparative analysis is to study the behavior of the Original, alpha, beta, gamma, delta, and omicron variants of SARS-CoV-2 coronavirus under conditions that resemble the human body. To achieve this, we conducted Molecular Dynamics simulations for all variants in the same environment. Additionally, we conducted salt bridge and hydrogen bond analyses to further investigate the behavior of the SARS-CoV-2 variants. These analyses allowed us to examine the interactions between amino acid residues and to determine the stability of the protein structures. By integrating these analyses with our Molecular Dynamics simulations, we were able to gain a comprehensive understanding of the behavior of each variant in a human-like environment. This information could be crucial in developing effective treatments and vaccines against COVID-19. Overall, our study provides valuable insights into the molecular dynamics and protein-protein interactions of the SARS-CoV-2 variants and highlights the importance of further research in this area to combat the ongoing pandemic

Convergence of flow-based generative models via proximal gradient descent in Wasserstein space

Flow-based generative models enjoy certain advantages in computing the data generation and the likelihood, and have recently shown competitive empirical performance. Compared to the accumulating theoretical studies on related score-based diffusion models, analysis of flow-based models, which are deterministic in both forward (data-to-noise) and reverse (noise-to-data) directions, remain sparse. In this paper, we provide a theoretical guarantee of generating data distribution by a progressive flow model, the so-called JKO flow model, which implements the Jordan-Kinderleherer-Otto (JKO) scheme in a normalizing flow network. Leveraging the exponential convergence of the proximal gradient descent (GD) in Wasserstein space, we prove the Kullback-Leibler (KL) guarantee of data generation by a JKO flow model to be $O(\varepsilon^2)$ when using $N \lesssim \log (1/\varepsilon)$ many JKO steps ($N$ Residual Blocks in the flow) where $\varepsilon$ is the error in the per-step first-order condition. The assumption on data density is merely a finite second moment, and the theory extends to data distributions without density and when there are inversion errors in the reverse process where we obtain KL-$W_2$ mixed error guarantees. The non-asymptotic convergence rate of the JKO-type $W_2$-proximal GD is proved for a general class of convex objective functionals that includes the KL divergence as a special case, which can be of independent interest

FP-PET: Large Model, Multiple Loss And Focused Practice

This study presents FP-PET, a comprehensive approach to medical image segmentation with a focus on CT and PET images. Utilizing a dataset from the AutoPet2023 Challenge, the research employs a variety of machine learning models, including STUNet-large, SwinUNETR, and VNet, to achieve state-of-the-art segmentation performance. The paper introduces an aggregated score that combines multiple evaluation metrics such as Dice score, false positive volume (FPV), and false negative volume (FNV) to provide a holistic measure of model effectiveness. The study also discusses the computational challenges and solutions related to model training, which was conducted on high-performance GPUs. Preprocessing and postprocessing techniques, including gaussian weighting schemes and morphological operations, are explored to further refine the segmentation output. The research offers valuable insights into the challenges and solutions for advanced medical image segmentation

Optimal treatment of ceftazidime-avibactam and aztreonam-avibactam against bloodstream infections or lower respiratory tract infections caused by extensively drug-resistant or pan drug-resistant (XDR/PDR) Pseudomonas aeruginosa

ObjectiveTo evaluate the efficacy of ceftazidime-avibactam (CZA) and aztreonam-avibactam (AZA) against bloodstream infections (BSIs) or lower respiratory tract infections (LRTIs) – caused by extensive drug-resistant or pan drug-resistant (XDR/PDR) Pseudomonas aeruginosa.MethodThe two-fold dilution method was used to determine the minimum inhibitory concentrations (MICs) of CZA/AZA against XDR/PDR P. aeruginosa. Whole-genome sequencing was used to analyze the resistance determinants of each isolate. Monte Carlo simulations (MCSs) were used to evaluate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of each CZA/AZA dosing regimen via traditional infusion (TI)/optimized two-step-administration therapy (OTAT).ResultsWe found that XDR/PDR P. aeruginosa may carry some rare MBLs (e.g.: IND-6, SLB-1, THIN-B). P. aeruginosa isolates producing IMP-45, VIM-1, or VIM-2 were inhibited by AZA at a concentration of 2 to 8 mg/L. All isolates producing IND-6 plus other serine β-lactamases were high-level resistant to CZA/AZA (MICs >64 mg/L). All simulated dosing regimens of CZA/AZA against BSIs-causing XDR/PDR P. aeruginosa achieved 100% PTA when the MIC was ≤32 mg/L.ConclusionAZA has been considered as an option for the treatment of infections caused by XDR/PDR P. aeruginosa producing IMP-45, VIM-1, or VIM-2. OTAT with sufficient pharmacodynamic exposure may be an optimal treatment option for XDR/PDR P. aeruginosa with a high-level MIC of CZA/AZA

Functional examination of novel kisspeptin phosphinic peptides

Kisspeptins acting on their cognate G protein-coupled receptor, kisspeptin receptor, play important roles in the suppression of cancer cell metastasis and regulation of the reproductive system, and therefore are important for therapeutic intervention. All native functional human kisspeptins (kisspeptin-54, kisspsptin-14 and kisspeptin-13) share the 10 amino acids of kisspeptin-10 at their C-terminus (45–54). However, they are inactivated rapidly by matrix metalloproteinases (MMPs) through the cleavage of the peptide bond between glycine51 and leucine52, which limits their clinical applications. Development of MMP-resistant analogues of kisspeptins may provide better therapeutic outputs. In the present study, two kisspeptin phosphinic peptides were designed and synthesized, and their ability to induce phosphorylation of ERK1/2 through kisspeptin receptor and their inhibition on MMP-2 and MMP-9 whose activity correlates with cancer metastasis were assessed. The results showed that one analogue, phosphinic kisspeptin R isomer (PKPR), exhibited kisspeptin receptor-agonistic activity and also inhibitory activity on MMP-2, indicating that PKPR may serve as a lead for the further development of kisspeptin analogues for therapeutic purpose

BONE MORPHOGENETIC PROTEIN-2 AND COLLAGEN TYPE 1 FROM DIFFERENT SOURCES OF DEMINERALIZED DENTINE MATRIX: RELEASE KINETIC AND CHEMOTAXIS POTENTIAL FOR OSTEOPROGENITOR CELLS

Objective: To investigate the release of bone morphogenetic protein-2 (BMP-2) and collagen type I proteins (COL1) from different sources ofdemineralized dentine matrix (DDM) and their chemotaxis to mouse osteoprogenitor cells.Methods: The release kinetic of BMP-2 and COL1 was measured from custom-made DDM (CMDDM) and commercially available DDM (CADDM).Using Urist physicochemical method, CMDDM was collected from the extracted teeth in a certified dental clinic. Levels of BMP-2 and COL1 releasedwere measured at days 1, 2, 3, 5, 7, 9, 11, and 13. Next, mouse osteoprogenitor cells, MC3T3-E1, were cultured with a variety of materials as follows:CMDDM, CADDM, Bio-Oss®, and blank control in transwell system. The number of cell migration was determined by crystal violet staining to explorechemotaxis of different DDMs to mouse osteoprogenitor cells.Results: BMP-2 was detected at 588.32 ± 14.53 pg/ml from 5 g of CMDDM. In the release kinetic assay, the concentration of BMP-2 in the CMDDMgroup increased rapidly and peaked at 113.9 pg/ml on day 5, almost four times higher than that of CADDM. The release of COL1 showed similarpattern in both CMDDM and CADDM; however, the amount was significantly higher in the CMDDM group. In cell culture experiment, the number ofmigrated MC3T3-E1 was ranked as the highest in CMDDM, followed by CADDM and Bio-Oss® (p<0.05).Conclusion: CMDDM released BMP-2 and COL1 greater than CADDM, which can induce more osteoblast-like cell migration. These results demonstrateda release kinetic of proteins and osteoinductivity of CMDDM, which supports a benefit of using autogenous bone graft

Photo-Mediated Ultrasound Therapy for the Treatment of Corneal Neovascularization in Rabbit Eyes

Purpose: Corneal neovascularization (CNV) is the invasion of new blood vessels into the avascular cornea, leading to reduced corneal transparency and visual acuity, impaired vision, and even blindness. Current treatment options for CNV are limited. We developed a novel treatment method, termed photo-mediated ultrasound therapy (PUT), that combines laser and ultrasound, and we tested its feasibility for treating CNV in a rabbit model. Methods: A suture-induced CNV model was established in New Zealand White rabbits, which were randomly divided into two groups: PUT and control. For the PUT group, the applied light fluence at the corneal surface was estimated to be 27 mJ/cm2 at 1064-nm wavelength with a pulse duration of 5 ns, and the ultrasound pressure applied on the cornea was 0.43 MPa at 0.5 MHz. The control group received no treatment. Red-free photography and fluorescein angiography were utilized to evaluate the efficiency of PUT. Safety was evaluated by histology and immunohistochemistry. For comparison with the PUT safety results, conventional laser photocoagulation (LP) treatment was performed with standard clinical parameters: 532-nm continuous-wave (CW) laser with 0.1-second pulse duration, 450-mW power, and 75-µm spot size. Results: In the PUT group, only 1.8% ± 0.8% of the CNV remained 30 days after treatment. In contrast, 71.4% ± 7.2% of the CNV remained in the control group after 30 days. Safety evaluations showed that PUT did not cause any damage to the surrounding tissue. Conclusions: These results demonstrate that PUT is capable of removing CNV safely and effectively in this rabbit model. Translational Relevance: PUT can remove CNV safely and effectively

Photo-Mediated Ultrasound Therapy for the Treatment of Corneal Neovascularization in Rabbit Eyes

Purpose: Corneal neovascularization (CNV) is the invasion of new blood vessels into the avascular cornea, leading to reduced corneal transparency and visual acuity, impaired vision, and even blindness. Current treatment options for CNV are limited. We developed a novel treatment method, termed photo-mediated ultrasound therapy (PUT), that combines laser and ultrasound, and we tested its feasibility for treating CNV in a rabbit model. Methods: A suture-induced CNV model was established in New Zealand White rabbits, which were randomly divided into two groups: PUT and control. For the PUT group, the applied light fluence at the corneal surface was estimated to be 27 mJ/cm2 at 1064-nm wavelength with a pulse duration of 5 ns, and the ultrasound pressure applied on the cornea was 0.43 MPa at 0.5 MHz. The control group received no treatment. Red-free photography and fluorescein angiography were utilized to evaluate the efficiency of PUT. Safety was evaluated by histology and immunohistochemistry. For comparison with the PUT safety results, conventional laser photocoagulation (LP) treatment was performed with standard clinical parameters: 532-nm continuous-wave (CW) laser with 0.1-second pulse duration, 450-mW power, and 75-µm spot size. Results: In the PUT group, only 1.8% ± 0.8% of the CNV remained 30 days after treatment. In contrast, 71.4% ± 7.2% of the CNV remained in the control group after 30 days. Safety evaluations showed that PUT did not cause any damage to the surrounding tissue. Conclusions: These results demonstrate that PUT is capable of removing CNV safely and effectively in this rabbit model. Translational Relevance: PUT can remove CNV safely and effectively