Search

Evidence-based reasoning and critical thinking are two crucial scientific abilities of students, sharing a close relationship with each other—critical thinking is not just randomly refuting but a l...

In this study, an innovative scientific modeling course on concentration cells is designed: First, the demonstrations revealed examples of three different concentration cells. Then, scientific models visualizing the process and principle of cell reactions at the level of microparticulates were introduced to students. Finally, three new concentration cell examples were abstracted from real life, and students were asked to build corresponding new models and explain the phenomenon. During implementation, high school students and undergraduates with only a little background knowledge on concentration cells participated in this course. The effectiveness of the course was evaluated by questionnaire and quiz. The results showed that, by establishing a triple link among macroscopic phenomena, submicroscopic processes, and symbolic representations, most students can directly understand the principles of concentration cell reactions with the help of scientific models. More than 60% of the students successfully constructed the model in the test, and the correct rate (including basically and completely correct) of all of the questions was above 80%. These results prove that this course was helpful for students to master the knowledge of concentration cells and improve the ability of model understanding and construction.

We propose a stability preserved Arnoldi algorithm for matrix exponential in the time domain simulation of large-scale power delivery networks (PDNs), which are formulated as semi-explicit differential-algebraic equations (DAEs). The matrix exponential and vector products (MEVPs) compose the solution of DAEs in multistep integration methods and can be efficiently approximated with the rational Krylov subspace. To produce stable simulation results for the ill-conditioned system from semi-explicit DAEs, the revised Arnoldi algorithm introduces a new structured orthogonalization process to construct the Krylov subspace. We demonstrate the performance of the new algorithm with theoretical proof and experiments. In the computation of MEVPs, we utilize the exponential related $\varphi $ functions to improve the numerical accuracy. We further explore the optimal ratio to confine the spectrum in the rational Krylov subspace. Finally, the transient framework is tested on a group of system-level PDNs, showing that matrix exponential-based algorithms could achieve high efficiency and accuracy.

Background: Treatment of immunologically cold tumors is a major challenge. IL-12 can activates both innate and adaptive immunity to elicit strong antitumor immunity. Nevertheless, the poor pharmacokinetic and severe side effects of IL-12 limit the application. We have recently developed pH-sensitive polymeric micelles loading IL-12 (IL-12/m) that can selective activate in tumor tissues to invigorate immunotherapy and enhance efficacy. Herein, we elucidated the mechanisms behind the enhanced efficacy of IL-12/m and their ability to synergize with immune checkpoint inhibitors (ICIs). Methods: To determine the contribution of the immune cells on the efficacy on IL-12/m, mice bearing orthotopic 4T1 tumor models were treated with anti-CD4 (for depleting CD4+ cells), anti-CD8 (for depleting CD8+ cells), anti-asialo GM1 (for depleting NK cells). The tumor volume was tracked after treatment with IL-12/m. The immune status of the tumors was studied by histology, flow cytometry and RNA-seq after treatment with free IL-12, IL-12/m and their combination with ICIs. The efficacy of the treatments was assessed by following the tumor growth and mice survival. Results: IL-12 can promote the growth and function of T cells to initiate the enhanced anti-tumoral immune reactions. Flow cytometry analysis IL-12/m significantly enhanced tumor infiltration of CD8+ T cells compared to free IL-12. The immune cell depletion study revealed that the depletion of CD8+ cytotoxic T cells, CD4+ T cells and NK cells significantly lessen efficacy of IL-12/m, which is consistent with the biological function of IL-12. The depletion experiment suggests CD8+ cytotoxic T cells are the most important fraction for IL-12/m efficacy. Moreover, immunohistochemistry analysis of 4T1 revealed IL-12/m promoted high infiltration of CD8+ cells and the upregulation of Granzyme B in CD8 + Cells. IL-12/m also increased PD-L1 levels in tumors. The effects of IL-12/m on the TME was further investigated as a monotherapy and in combination with anti-PD-1 antibodies. The combination of IL-12/m with anti-PD-1antibodies presented high CD45+ cells in tumors. Lymphoid cells and T cells were upregulated by IL-12 and the anti-PD-1 antibody combination. The general CD4+ T cells also showed upregulation in the IL-12/m treated groups. While anti-PD-1 monotherapy did not show any suppression on Tregs in the tumor model, the combination of IL-12/m plus anti-PD-1 depleted Tregs. Moreover, IL-12/m increase the presence of Th cells. We then investigated the activation by transcriptome analysis. The heatmap of global gene expression indicated differentiated gene profiles. GOBP and KEGG analysis showed that IL-12/m upregulated the stimulation of proliferation, differentiation and activation of various effector immune cells, differentiation of T cells into Th cells, and T cell activation and T cell receptor signaling pathway. The enhanced the intratumoral immunity of IL-12/m plus ICIs allowed eradicating 4T1 tumors. Conclusions: Systemically injected IL-12/m ensured strong stimulation of antitumor immunity leading to high safety and strong therapeutic outcomes in cold tumor models. The enhanced immune response of IL-12 synergize with checkpoint blockade to eradicate cold tumors. The approach has potential for developing safer and more effective immunotherapies. Citation Format: Horacio Cabral, Pengwen Chen, Koji Nagaoka, Takuya Miyazaki, Kazunori Kataoka, Kazuhiro Kakimi. pH-sensitive polymeric micelles loading IL-12 profoundly inflame the tumor microenvironment to eradicate cold tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB336.

This paper proposes an experiment in which students build microdevices for conveniently electrolyzing water and use image recognition and processing technology to measure the volume of gas generate...

This paper introduces a safe, interesting, convenient, and low-cost experiment. The products of galvanic cells and electrolytic cells are compressed into specimens that are placed on a slide to stretch the metal dendrites in one plane and ensure they are not easily destroyed by external factors. The details and growth process of the metal dendrites can be clearly observed with the naked eye and optical microscopy, which arouses interest from students and allows them to enjoy the beautiful images while obtaining a large amount of macroscopic information. By allowing the students to observe the macroscopic phenomena and the corresponding microscopic changes among the microparticles, it is possible for them to explain the morphological origins and growth rates of the metal dendrites, which deepens their understanding of the reactions that occur in galvanic and electrolytic cells.

Intracellular protein delivery is a powerful strategy for developing innovative therapeutics. Nanocarriers present great potential to deliver proteins inside cells by promoting cellular uptake and overcoming entrapment and degradation in acidic endo/lysosomal compartments. Thus, because cytosolic access is essential for eliciting the function of proteins, significant efforts have been dedicated to engineering nanocarriers with maximal endosomal escape regardless of the cell type. On the other hand, controlling the ability of nanocarriers to escape from the endo/lysosomal compartments of particular cells may offer the opportunity for enhancing delivery precision. To test this hypothesis, we developed pH-sensitive polymeric nanocarriers with adjustable endosomal escape potency for selectively reaching the cytosol of defined cancer cells with dysregulated endo/lysosomal acidification. By loading antibodies against nuclear pore complex in the nanocarriers, we demonstrated the selective delivery into the cytosol and subsequent nucleus targeting of cancer cells rather than non-cancerous cells both in vitro and in vivo. Systemically injected nanocarriers loading anti-c-MYC antibodies suppressed c-MYC in solid tumors and inhibit tumor growth without side effects, confirming the therapeutic potential of our approach. These results indicated that regulating the ability of nanocarriers to escape from endo/lysosomal compartments in particular cells is a practical approach for gaining delivery specificity.

Background: IL-12 is a pro-inflammatory cytokine with antitumor potential that activates both innate and adaptive immunity. However, IL-12 shows poor pharmacokinetics and intolerable toxicities due to unspecific distribution. Herein, we present pH-sensitive polymeric micelles loading IL-12 (IL-12/m) that release fully active IL-12 after sensing intratumoral pH to safely potentiate immunotherapy. Methods: IL-12/m with 40 nm in diameter were prepared by self-assembly in phosphate buffer. The IL-12 release was tested at different pH. The stimulation of IFN-γ release from IL-12 and IL-12/m was studied in mouse splenocytes. Pharmacokinetic, pharmacodynamic, and antitumor activity were studied in immunosuppressed (B16F10 and 4T1) mouse tumor models (staged ≥ 200 mm3) and in a lung metastasis model (4T1). The safety of IL-12 was evaluated by tracing levels of cytokines and blood markers of toxicity. Results: IL-12/m selectively activated at intratumoral pH 6.5, releasing more than 80% of IL-12 in 24 h. While IL-12/m did not induce IFN-γ production in splenocytes, the released IL-12 showed similar activity to native IL-12. In mice, IL-12/m prolonged blood circulation with minimal leakage, yielding a 3-fold longer half-life than IL-12. Moreover, the accumulation in tumor for IL-12/m (7.5%ID/g of tumor) was 3-fold higher compared that of free IL-12, with more than 90% of IL-12/m being activated. The tumors treated with IL-12/m showed 2-3-fold higher levels of IFN-γ, IL-6 and TNF-α than those treated with IL-12, whereas anti-inflammatory IL-10 was 2-fold lower for IL-12/m. In blood and organs, IL-12/m lowered the cytokine levels compared to IL-12. Also, IL-12/m avoided the tachyphylaxis of IL-12 without peak effects of IFN-γ, and the blood markers of toxicity, i.e., BUN, ALT and AST, remained close to control levels, supporting the tumor selective activation of IL-12/m. IL-12/m was efficacious in the B16F10 tumor model (10 µg iv 3 injections every 4 days) as monotherapy, and in combination with anti-PD-1 (10 mg/kg IP 3 injections every 4 days), which led to 6 of 10 complete regressions (CR). IL-12/m was also effective at 1 µg (5 injections every 2 days) against 4T1 tumors. IL-12/m increase the number and activation of CD8+ T cells and NK cells in tumors. The combination of IL-12/m (10 µg iv 3 injections every 4 days) with anti-PD1 and anti-CTLA-4 (both 10 mg/kg IP 3 injections every 4 days) achieve complete CR in a spontaneous model of lung metastasis. Responders showed immunological memory after being rechallenged with fresh tumor cells. Conclusions: IL-12/m, a pH-activated polymeric micelle loading IL-12, masked the activity of IL-12 in healthy tissues, while it unleashed full potency of IL-12 in tumors, improving tolerability and efficacy. IL-12/m presented greater antitumor activity than IL-12 as monotherapy and in combination with immune checkpoint inhibitors. Citation Format: Horacio Cabral, Pengwen Chen, Kazuhiko Kakimi, Kazunori Kataoka, Takuya Miyazaki, Koji Nagaoka. pH-activatable IL-12-loaded polymeric micelles safely enhance antitumor efficacy as monotherapy and in combination with immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2072.

Nano-immunotherapy has high potential to improve cancer patient outcomes, as already demonstrated in triple negative breast cancer with the combination of nanoparticle albumin-bound paclitaxel and the immune checkpoint blocker antibody, atezolizumab. This regimen, however, does not lead to complete cure with median survival lasting less than two years. To increase patient survival, research focuses on repurposing common drugs to modulate the tumor microenvironment (TME), aiming to increase delivery of nanoparticles, antibodies and other drug regimens and improve immunostimulation. These drugs, however, exhibit certain dose-limitations and are associated with adverse effects. Here, taking advantage of the TME reprogramming capabilities of the approved antihistamine drug tranilast, we developed polymeric tranilast-loaded nanoparticles and explored their potential to modulate the TME more efficiently than the free drug. The results were striking as the micellar formulation of tranilast administered in a dose 100 times lower than that of the free drug reported superior reprogramming effects in two syngeneic triple negative breast tumor models. These effects were due to the enhanced intratumoral accumulation and cancer-associated fibroblast uptake of the nanoparticles compared to the free drug. Tranilast micelles were also found to promote significantly the delivery and efficacy of epirubicin micelles, overcome immune checkpoint resistance and induce tumor immunogenicity. Overall, the proposed micelles improved the efficacy of nano-immunotherapy in both breast cancer tumor models leading to complete cure. Furthermore, we employed the non-invasive and clinically applied ultrasound shear wave elastography method to monitor changes in tumor stiffness, which is the first effect caused by the tranilast micelles, and thus to determine an optimal dose-scheduling. Importantly, we found that tumor stiffness before the initiation of nano-immunotherapy was able to predict the efficacy of the treatment providing strong evidence for the potential of shear wave elastography to be used as a biomarker predictive of response. Our findings are very encouraging indicating that a) encapsulation of TME modulating drugs improves their pharmacokinetic properties, while allows for drastic reduction in the dose of administration, b) modulation of the TME can lead to complete cures of nano-immunotherapy in resistant to this therapy breast cancer tumor models, and c) ultrasound shear wave elastography can be employed for optimizing the use of TME modulating agents and for the prediction of tumor response to nano-immunotherapy allowing for optimized treatment protocols. Citation Format: Myrofora Panagi, Fotios Mpekris, Pengwen Chen, Chrysovalantis Voutouri, Yasuhiro Nakagawa, John D. Martin, Tetsuro Hiroi, Hiroko Hashimoto, Genichiro Ishii, Motohiro Kojima, Kazunori Kataoka, Horacio Cabral, Triantafyllos Stylianopoulos. Superior effects of polymeric micelles in reprogramming tumor microenvironment and enhancing nano-immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6381.

Phase retrieval can be expressed as a non-convex constrained optimization problem to identify one phase minimizer one a torus. Many iterative transform techniques have been proposed to identify the minimizer, e.g., relaxed averaged alternating reflections (RAAR) algorithms. In this paper, we present one optimization viewpoint on the RAAR algorithm. RAAR algorithm is one alternating direction method of multipliers with one penalty parameter. Pairing with multipliers (dual vectors), phase vectors on the primal space are lifted to higher dimensional vectors, RAAR algorithm is one continuation algorithm, which searches for local saddles in the primal-dual space. The dual iteration approximates one gradient ascent flow, which drives the corresponding local minimizers in a positive-definite Hessian region. Altering penalty parameters, the RAAR avoids the stagnation of these corresponding local minimizers in the primal space and thus screens out many stationary points corresponding to non-local minimizers.

Alternating projection (AP) of various forms, including the parallel AP (PAP), real-constrained AP (RAP) and the serial AP (SAP), are proposed to solve phase retrieval with at most two coded diffraction patterns. The proofs of geometric convergence are given with sharp bounds on the rates of convergence in terms of a spectral gap condition. To compensate for the local nature of convergence, the null initialization is proposed to produce good-quality initial guess. Numerical experiments show that the null initialization is more accurate than the spectral initialization and that AP converges faster to the true object than other iterative schemes such as the Wirtinger flow (WF). In numerical experiments AP with the null initialization converges globally to the true object.

Ptychography with an unknown mask and object is analyzed for general ptychographic measurement schemes that are strongly connected and possess an anchor. Under a mild constraint on the mask phase, it is proved that the masked object estimate must be the product of a block phase factor and the true masked object. This local uniqueness manifests itself in the phase drift equation that determines the ambiguity at different locations connected by ptychographic shifts. The proposed mixing schemes effectively connects the ambiguity throughout the whole domain such that a distinct ambiguity profile arises and consequently possess the global uniqueness that the block phases have an affine profile and that the object and mask can be simultaneously recovered up to a constant scaling factor and an affine phase factor.

The Fourier-domain Douglas-Rachford (FDR) algorithm is analyzed for phase retrieval with a single random mask. Since the uniqueness of phase retrieval solution requires more than a single oversampled coded diffraction pattern, the extra information is imposed in either of the following forms: 1) the sector condition on the object; 2) another oversampled diffraction pattern, coded or uncoded. For both settings, the uniqueness of projected fixed point is proved and for setting 2) the local, geometric convergence is derived with a rate given by a spectral gap condition. Numerical experiments demonstrate global, power-law convergence of FDR from arbitrary initialization for both settings as well as for 3 or more coded diffraction patterns without oversampling. In practice, the geometric convergence can be recovered from the power-law regime by a simple projection trick, resulting in highly accurate reconstruction from generic initialization.

SPICE (Simulation Program with Integrated Circuit Emphasis) is a widely used circuit simulation framework for integrated circuit designs. The basic skeleton of SPICE time domain simulation was derived from the versions developed in UC Berkeley during the 1970s. In this paper, we report most recent numerical integration methods to improve traditional SPICE time integration schemes, which are based on linear multi-step and low order approximation for the circuit differential equation system. Recently, matrix exponential based time domain simulation algorithms are being developed to address long-term issues in the standard numerical integration methods. We review the related techniques in matrix exponential based approaches and state several distinguished features in challenging simulation problems, such as linear power network analysis and nonlinear circuit system simulation (SPICEDiego). We believe that the matrix exponential approaches can shed new light on the research and development of future circuit simulation algorithmic systems.

Independent component analysis (ICA) has been shown to be useful in many applications. However, most ICA methods are sensitive to data contamination. In this article we introduce a general minimum U-divergence framework for ICA, which covers some standard ICA methods as special cases. Within the U-family we further focus on the γ-divergence due to its desirable property of super robustness for outliers, which gives the proposed method γ-ICA. Statistical properties and technical conditions for recovery consistency of γ-ICA are studied. In the limiting case, it improves the recovery condition of MLE-ICA known in the literature by giving necessary and sufficient condition. Since the parameter of interest in γ-ICA is an orthogonal matrix, a geometrical algorithm based on gradient flows on special orthogonal group is introduced. Furthermore, a data-driven selection for the γ value, which is critical to the achievement of γ-ICA, is developed. The performance, especially the robustness, of γ-ICA is demonstrated through experimental studies using simulated data and image data.

Uniqueness of solution is proved for any ptychographic scheme with a random masks under a minimum overlap condition and local geometric convergence analysis is given for the alternating projection (AP) and Douglas-Rachford (DR) algorithms. DR is shown to possess a unique fixed point in the object domain and for AP a simple criterion for distinguishing the true solution among possibly many fixed points is given. A minimalist scheme, where the adjacent masks overlap 50\% of area and each pixel of the object is illuminated by exactly four illuminations, is conveniently parametrized by the number $q$ of shifted masks in each direction. The lower bound $1-C/q^2$ is proved for the geometric convergence rate of the minimalist scheme, predicting a poor performance with large $q$ which is confirmed by numerical experiments. The twin-image ambiguity is shown to arise for certain Fresnel masks and degrade the performance of reconstruction. Extensive numerical experiments are performed to explore the general features of a well-performing mask, the optimal value of $q$ and the robustness with respect to measurement noise.

We study the performance of optimal mass transport-based methods applied to point-set matching problems. The present study, which is based on the L2 mass transport cost, states that perfect matches always occur when the product of the point-set cardinality and the norm of the curl of the nonrigid deformation field does not exceed some constant. This analytic result is justified by a numerical study of matching two sets of pulmonary vascular tree branch points whose displace- ment is caused by the lung volume changes in the same human subject. The nearly perfect match performance verifies the effectiveness of this mass transport-based approach.

The null vector method, based on a simple linear algebraic concept, is proposed as an initialization method for nonconvex approaches to the phase retrieval problem. For the stylized measurement with random complex Gaussian matrices, a nonasymptotic error bound is derived, stronger than that of the spectral vector method. Numerical experiments show that the null vector method also has a superior performance for the realistic measurement of coded diffraction patterns in coherent diffractive imaging.