Inhibition of PLK4 remodels histone methylation and activates the immune response via the cGAS-STING pathway in TP53-mutated AML.

Acute myeloid leukemia (AML) with TP53 mutation is one of the most lethal cancers and portends an extremely poor prognosis. Based on in silico analyses of druggable genes and differential gene expression in TP53-mutated AML, we identified pololike kinase 4 (PLK4) as a novel therapeutic target and examined its expression, regulation, pathogenetic mechanisms, and therapeutic potential in TP53-mutated AML. PLK4 expression was suppressed by activated p53 signaling in TP53 wild-type AML and was increased in TP53-mutated AML cell lines and primary samples. Short-term PLK4 inhibition induced DNA damage and apoptosis in TP53 wild-type AML. Prolonged PLK4 inhibition suppressed the growth of TP53-mutated AML and was associated with DNA damage, apoptosis, senescence, polyploidy, and defective cytokinesis. A hitherto undescribed PLK4/PRMT5/EZH2/H3K27me3 axis was demonstrated in both TP53 wild-type and mutated AML, resulting in histone modification through PLK4-induced PRMT5 phosphorylation. In TP53-mutated AML, combined effects of histone modification and polyploidy activated the cGAS-STING pathway, leading to secretion of cytokines and chemokines and activation of macrophages and T cells upon coculture with AML cells. In vivo, PLK4 inhibition also induced cytokine and chemokine expression in mouse recipients, and its combination with anti-CD47 antibody, which inhibited the "don't-eat-me" signal in macrophages, synergistically reduced leukemic burden and prolonged animal survival. The study shed important light on the pathogenetic role of PLK4 and might lead to novel therapeutic strategies in TP53-mutated AML.

Interlacing Infills for Multi-Material Fused Filament Fabrication Using Layered Depth Material Images.

One major concern regarding multi-material additive manufacturing (MMAM) is the strength at the interface between materials. Based on the observation of how nature puts materials together, this paper hypothesizes that overlapping and interlacing materials with each other enhance the interface bonding strength. To test this hypothesis, this research develops a new slicing framework that can efficiently identify the multi-material regions and develop interlaced infills. Based on a ray-tracing technology, we develop layered depth material images (LDMI) to process the material information of digital models for toolpath planning. Each sample point in the LDMI has an associated material and geometric properties that are used to recover the material distribution in each slice. With this material distribution, this work generates an interlocking joint and an interlacing infill in the regions with multiple materials. The experiments include comparisons between similar materials and different materials. Tensile tests have shown that our proposed infill outperforms the interlocking joint in all cases. Fractures occur even outside the interlacing area, meaning that the joint is at least as strong as the materials. The experimental results verify the enhancement of interface strength by overlapping and interlacing materials. In addition, existing computational tools have limitations in full use of material information. To the best of our knowledge, this is the first time a slicer can process overlapped material regions and create interlacing infills. The interlacing infills improve the bonding strength, making the interface no longer the weakest area. This enables MMAM to fabricate truly functional parts. In addition, the new LDMI framework has rich information on geometry and material, and it allows future research in multi-material modeling.

Regulation of proton partitioning in kinase-activating acute myeloid leukemia and its therapeutic implication.

Gain-of-function kinase mutations are common in AML and usually portend an inferior prognosis. We reported a novel mechanism whereby kinase mutants induced intracellular alkalization characteristic in oncogenesis. Thirteen kinases were found to activate sodium/hydrogen exchanger (NHE1) in normal hematopoietic progenitors, of which FLT3-ITD, KRASG12D, and BTK phosphorylated NHE1 maintained alkaline intracellular pH (pHi) and supported survival of AML cells. Primary AML samples with kinase mutations also showed increased NHE1 phosphorylation and evidence of NHE1 addiction. Amiloride enhanced anti-leukemic effects and intracellular distribution of kinase inhibitors and chemotherapy. Co-inhibition of NHE1 and kinase synergistically acidified pHi in leukemia and inhibited its growth in vivo. Plasma from patients taking amiloride for diuresis reduced pHi of leukemia and enhanced cytotoxic effects of kinase inhibitors and chemotherapy in vitro. NHE1-mediated intracellular alkalization played a key pathogenetic role in transmitting the proliferative signal from mutated-kinase and could be exploited for therapeutic intervention in AML.

Analysis and Design of Lattice Structures for Rapid-Investment Casting.

This paper aims to design lattice structures for rapid-investment casting (RIC), and the goal of the design methodology is to minimize casting defects that are related to the lattice topology. RIC can take full advantage of the unprecedented design freedom provided by AM. Since design for RIC has multiple objectives, we limit our study to lattice structures that already have good printability, i.e., self-supported and open-celled, and improve their castability. To find the relationship between topological features and casting performance, various lattice topologies underwent mold flow simulation, finite element analysis, casting experiments, and grain structure analysis. From the results, the features established to affect casting performance in descending order of importance are relative strut size, joint number, joint valence, and strut angle distribution. The features deemed to have the most significant effect on tensile and shear mechanical performance are strut angle distribution, joint number, and joint valence. The practical application of these findings is the ability to optimize the lattice topology with the end goal of manufacturing complex lattice structures using RIC. These lattice structures can be used to create lightweight components with optimized functionality for various applications such as aerospace and medical.

Folding photopolymerized origami sheets by post-curing.

The paper presents a novel manufacturing approach to fabricate origami based on 3D printing utilizing digital light processing. Specifically, we propose to leave part of the model uncured during the printing step, and then cure it in the post-processing step to set the shape in a folded configuration. While the cured regions in the first step try to regain their unfolded shape, the regions cured in the second step attempt to keep their folded shape. As a result, the final shape is obtained when both regions' stresses reach equilibrium. Finite element analysis is performed in ANSYS to obtain the stress distribution on common hinge designs, demonstrating that the square-hinge has a lower maximum principal stress than elliptical and triangle hinges. Based on the square-hinge and rectangular cavity, two variables-the hinge width and the cavity height-are selected as principal variables to construct an empirical model with the final folding angle. In the end, experimental verification shows that the developed method is valid and reliable to realize the proposed deformation and 3D development of 2D hinges.

Numerical assessment of directional energy performance for 3D printed midsole structures.

Energy can be represented in the form of deformation obtained by the applied force. Energy transfer is defined in physics as the energy is moved from one place to another. To make the energy transfer functional, energy should be moved into the right direction. If it is possible to make a better use of the energy in the right direction, the energy efficiency of the structure can be enhanced. This idea leads to the concept of directional energy transfer (DET), which refers to transferring energy from one direction to a specific direction. With the recent development of additive manufacturing and topology optimization, complex structures can be applied to various applications to enhance performances, like a wheel and shoe midsole. While many works are related to structural strength, there is limited research in optimization for energy performance. In this study, a theoretical approach is proposed to measure the directional energy performance of a structure, which can be used to measure the net energy in an intended direction. The purpose is to understand the energy behavior of a structure and to measure if a structure is able to increase energy in the desired direction.

Styling Evolution for Tight-Fitting Garments.

We present an evolution method for designing the styling curves of garments. The procedure of evolution is driven by aesthetics-inspired scores to evaluate the quality of styling designs, where the aesthetic considerations are represented in the form of streamlines on human bodies. A dual representation is introduced in our platform to process the styling curves of designs, based on which robust methods for realizing the operations of evolution are developed. Starting from a given set of styling designs on human bodies, we demonstrate the effectiveness of set evolution inspired by aesthetic factors. The evolution is adaptive to the change of aesthetic inspirations. By this adaptation, our platform can automatically generate new designs fulfilling the demands of variations in different human bodies and poses.

Efficient optimization of common base domains for cross parameterization.

Given a set of corresponding user-specified anchor points on a pair of models having similar features and topologies, the cross parameterization technique can establish a bijective mapping constrained by the anchor points. In this paper, we present an efficient algorithm to optimize the complexes and the shape of common base domains in cross parameterization for reducing the distortion of the bijective mapping. The optimization is also constrained by the anchor points. We investigate a new signature, Length-Preserved Base Domain (LPBD), for measuring the level of stretch between surface patches in cross parameterization. This new signature well balances the accuracy of measurement and the computational speed. Based on LPBD, a set of metrics are studied and compared. The best ones are employed in our domain optimization algorithm that consists of two major operators, boundary swapping and patch merging. Experimental results show that our optimization algorithm can reduce the distortion in cross parameterization efficiently.

Fast query for exemplar-based image completion.

In this paper, we present a fast algorithm for filling unknown regions in an image using the strategy of exemplar-matching. Unlike the original exemplar-based method using exhaustive search, we decompose exemplars into the frequency coefficients and select fewer coefficients which are the most significant to evaluate the matching score. We have also developed a local gradient-based algorithm to fill the unknown pixels in a query image block. These two techniques bring the ability of input with varied dimensions to the fast query of similar image exemplars. The fast query is based upon a search-array data structure, and can be conducted very efficiently. Moreover, the evaluation of search-arrays runs in parallel maps well on the modern graphics hardware with graphics processing units (GPU). The functionality of the approach has been demonstrated by experimental results on real photographs.