Genetically Engineered Macrophages Co-Loaded with CD47 Inhibitors Synergistically Reconstruct Efferocytosis and Improve Cardiac Remodeling Post Myocardial Ischemia Reperfusion Injury.

Efferocytosis, mediated by the macrophage receptor MerTK (myeloid-epithelial-reproductive tyrosine kinase), is a significant contributor to cardiac repair after myocardial ischemia-reperfusion (MI/R) injury. However, the death of resident cardiac macrophages (main effector cells), inactivation of MerTK （main effector receptor), and overexpression of "do not eat me" signals (brake signals, such as CD47), collectively lead to the impediment of efferocytosis in the post-MI/R heart. To date, therapeutic strategies targeting individual above obstacles are relatively lacking, let alone their effectiveness being limited due to constraints from the other concurrent two. Herein, inspired by the application research of chimeric antigen receptor macrophages (CAR-Ms) in solid tumors, a genetically modified macrophage-based synergistic drug delivery strategy that effectively challenging the three major barriers in an integrated manner is developed. This strategy involves the overexpression of exogenous macrophages with CCR2 (C-C chemokine receptor type 2) and cleavage-resistant MerTK, as well as surface clicking with liposomal PEP-20 (a CD47 antagonist). In MI/R mice model, this synergistic strategy can effectively restore cardiac efferocytosis after intravenous injection, thereby alleviating the inflammatory response, ultimately preserving cardiac function. This therapy focuses on inhibiting the initiation and promoting active resolution of inflammation, providing new insights for immune-regulatory therapy.

Targeted delivery and ROS-responsive release of Resolvin D1 by platelet chimeric liposome ameliorates myocardial ischemia-reperfusion injury.

Resolvin D1 (RvD1) has been shown to provide effective protection against ischemia-reperfusion injury in multiple vital organs such as the heart, brain, kidney. However, the clinical translational potential of systemic administration of RvD1 in the treatment of ischemia-reperfusion injury is greatly limited due to biological instability and lack of targeting ability. Combining the natural inflammatory response and reactive oxygen species (ROS) overproduction after reperfusion injury, we developed a platelet-bionic, ROS-responsive RvD1 delivery platform. The resulting formulation enables targeted delivery of RvD1 to the injury site by hijacking circulating chemotactic monocytes, while achieving locally controlled release. In a mouse model of myocardial ischemia repefusuin (MI/R) injury, intravenous injection of our formula resulted in the enrichment of RvD1 in the injured area, which in turn promotes clearance of dead cells, production of specialized proresolving mediators (SPMs), and angiogenesis during injury repair, effectively improving cardiac function. This delivery system integrates drug bio-protection, targeted delivery and controlled release, which endow it with great clinical translational value.

Dynamic algorithm for fitness function greatly improves the optimization efficiency of frequency selective surface for better design of radar.

Multiple objectives optimization of frequency selective surface (FSS) structures is challenging in electromagnetic wave filter design. For example, one of the sub-objectives, the sidelobe level (SLL), is critical to directional anti-interference, which is complicated and becomes the bottleneck for radar design. Here, we established a dynamic algorithm for fitness function to automatically adjust the weights of multiple objectives in the optimization process of FSS structures. The dynamic algorithm could efficiently evaluate the achieving probability of sub-objectives according to the statistical analysis of the latest individual distribution so that the fitness function could automatically adjusted to focus on the sub-objective difficult to optimize, such as SLL. Computational results from the dynamic algorithm showed that the efficiency of multi-objective optimization was greatly improved by 213%, as compared to the fixed-weighted algorithm of the fitness function. Specifically for SLL, the efficiency rate increased even better, up to 315%. More interestingly, the FSS structures were most improved while picking median value or golden section value as the reference value. Taken together, the current study indicated that the dynamic algorithm with fitness function might be a better choice for FSS structural optimization with SLL suppression and potentially for the better design of lower SLL radar.

Variation laws and release characteristics of phosphorus on surface sediment of Dongting Lake.

The variation trend and growth rate of P were analyzed by the concentration of the phosphorus fraction on surface sediment of Dongting Lake from 2012 to 2016, to reveal the cumulative effect of P in the actual environment. Meanwhile, the adsorption kinetics and adsorption isotherm were employed to examine the P-release possibility of sediment, which predicts the yearly released sediment phosphorus in Dongting Lake. The actual growth rate of TP (Total Phosphorus) is 53 mg·(kg·year)-1 in East Dongting Lake, 39 mg·(kg·year)-1 in South Dongting Lake, and 29 mg·(kg·year)-1 in West Dongting Lake, while the sum of the phosphorus fraction growth rates has little difference from the rate of TP in sediments of the three areas of Dongting Lake. Furthermore, the Elovich model and the Langmuir crossover-type equations are established to present the adsorption characteristic of sediment in Dongting Lake; the result shows that the sediments play a source role for phosphorus in East and South Dongting Lake from zero equilibrium phosphorus concentration (EPC0) in the present situation, but an adsorption effect on TP is shown in West Dongting Lake. When the conditions of environment change are ignored, the maximum P-sorption level in sediments of East Dongting Lake will reach in 2040 according to the actual growth rate of sediments, while that in West Dongting Lake and South Dongting Lake will be in 2046 and 2061, respectively.

Modified Haybittle-Peto group sequential designs for testing superiority and non-inferiority hypotheses in clinical trials.

In designing an active controlled clinical trial, one sometimes has to choose between a superiority objective (to demonstrate that a new treatment is more effective than an active control therapy) and a non-inferiority objective (to demonstrate that it is no worse than the active control within some pre-specified non-inferiority margin). It is often difficult to decide which study objective should be undertaken at the planning stage when one does not have actual data on the comparative advantage of the new treatment. By making use of recent advances in the theory of efficient group sequential tests, we show how this difficulty can be resolved by a flexible group sequential design that can adaptively choose between the superiority and non-inferiority objectives during interim analyses. While maintaining the type I error probability at a pre-specified level, the proposed test is shown to have power advantage and/or sample size saving over fixed sample size tests for either only superiority or non-inferiority, and over other group sequential designs in the literature.