P2X7 Receptor Expression and Signaling on Dendritic Cells and CD4+ T Cells is Not Required but Can Enhance Th17 Differentiation.

The purinergic receptor P2X7 (P2X7R) is important in inflammasome activation and generally considered to favor proinflammatory immune responses. However, there is still a limited understanding of the role of P2X7R signaling in Th cell differentiation, particularly, Th17 differentiation. Herein, the impact of P2X7R signaling on primary Th17 and Th1 cell responses was examined when P2X7R was expressed specifically on dendritic cells (DCs) and CD4+ T cells. Surprisingly, global genetic ablation and pharmacological inhibition of the P2X7R did not affect the generation of Th17 and Th1 development in response to immunization with Complete Freund's Adjuvant and the model antigens, keyhole limpet hemocyanin or OVA. However, in-depth in vitro and in vivo investigations revealed differences in the balance of Th1/Th17 differentiation when P2X7R blockade was restricted to either DCs or CD4+ T cells. In this regard, in vitro DCs treated with a P2X7R agonist released more IL-6 and IL-1ß and induced a more robust Th17 response in mixed leukocyte reactions when compared to controls. To test the hypothesis that P2X7R signaling specifically in DCs enhances Th17 responses in vivo, DC-specific P2X7R deficient chimeras were immunized with CFA and OVA. In this model, the P2X7R expression on DCs decreased the Th1 response without impacting Th17 responses. Following an assessment of CD4+ T cell P2X7R signaling, it was determined that in vitro P2X7R sufficient T cells develop an increased Th17 and suppressed Th1 differentiation profile. In vivo, P2X7R expression on CD4+ T cells had no effect on Th17 differentiation but likewise significantly suppressed the Th1 response, thereby skewing the immune balance. Interestingly, it appears that WT OT-II Th1 cells are more sensitive to P2X7R-induced cell death as evidence by a decrease in cell number and an increase in T cell death. Overall, these studies indicate that in vitro P2X7R signaling does enhances Th17 responses, which suggests that compensatory Th17 differentiation mechanisms are utilized in vivo in the absence of P2X7R signaling.

Online Reconstruction of Complex Networks From Streaming Data.

The problem of reconstructing nonlinear and complex dynamical systems from available data or time series is prominent in many fields, including engineering, physical, computer, biological, and social sciences. Many methods have been proposed to address this problem and their performance is satisfactory. However, none of them can reconstruct network structure from large-scale real-time streaming data, which leads to the failure of real-time and online analysis or control of complex systems. In this article, to overcome the limitations of current methods, we first extend the network reconstruction problem (NRP) to online settings, and then develop a follow-the-regularized-leader (FTRL)-Proximal style method to address the online complex NRP; we refer to it as Online-NR. The performance of Online-NR is validated on synthetic evolutionary game network reconstruction datasets and eight real-world networks. The experimental results demonstrate that Online-NR can effectively solve the problem of online network reconstruction with large-scale real-time streaming data. Moreover, Online-NR outperforms or matches nine state-of-the-art network reconstruction methods.

Elastic and Stretchable Double Network Hydrogel as Printable Ink for High-Resolution Fabrication of Ionic Skin.

A hydrogel that combines both printability and adaptability, high elasticity, and stretchability can provide ideal mechanical properties, and also render complex and accurate construction for ionic skin. However, it is extremely challenging. Here, we propose a colloidal-based double-network (DN) hydrogel as printable inks for high-precision fabrication of ionic skins. Particularly, polyacrylamide (PAAm), as the covalent network that can maintain the long-term material integrity, was combined with gelatin colloidal network to improve the injectability and printability of the resulting DN hydrogels. The DN design cooperatively provides the hydrogels with higher toughness values and deformability than what single colloidal or PAAm network can achieve. Further design of ionic skin based on capacitor microarray was demonstrated to serve as a sensitive and stable capacitor that can respond to external stimuli, thereby allowing to sense the body movements such as finger bending, laugh, and wrist pulse by translating mechanical changes into electric signals. Therefore, this study provides a novel strategy for the design and preparation of high-resolution ionic skins as the wearable sensor.

Skin immunization for effective treatment of multifocal melanoma refractory to PD1 blockade and Braf inhibitors.

BACKGROUND: Despite the remarkable benefits associated with the interventional treatment of melanomas (and other solid cancers) with immune checkpoint and Braf inhibitors (Brafi), most patients ultimately progress on therapy. The presence of multifocal/disseminated disease in patients increases their mortality risk. Hence, the development of novel strategies to effectively treat patients with melanomas that are resistant to anti-PD1 mAb (αPD1) and/or Brafi, particularly those with multifocal/disseminated disease remains a major unmet clinical need. METHODS: Mice developing induced/spontaneous BrafV600E/Pten-/- melanomas were treated by cutaneous immunization with a DNA vaccine encoding the melanoma-associated antigen TRP2, with Brafi or αPD1 alone, or with a combination of these treatments. Tumor progression, tumor-infiltration by CD4+ and CD8+ T cells, and the development of TRP2-specific CD8+ T cells were then monitored over time. RESULTS: Vaccination led to durable antitumor immunity against PD1/Brafi-resistant melanomas in both single lesion and multifocal disease models, and it sensitized PD1-resistant melanomas to salvage therapy with αPD1. The therapeutic efficacy of the vaccine was associated with host skin-resident cells, the induction of a systemic, broadly reactive IFNγ+CD8+ T cell repertoire, increased frequencies of CD8+ TIL and reduced levels of PD1hi/intCD8+ T cells. Extended survival was associated with improved TIL functionality, exemplified by the presence of enhanced levels of IFNγ+CD8+ TIL and IL2+CD4+ TIL. CONCLUSIONS: These data support the use of a novel genetic vaccine for the effective treatment of localized or multifocal melanoma refractory to conventional αPD1-based and/or Brafi-based (immune)therapy.

Improved estimation of motion blur parameters for restoration from a single image.

This paper presents an improved method to estimate the blur parameters of motion deblurring algorithm for single image restoration based on the point spread function (PSF) in frequency spectrum. We then introduce a modification to the Radon transform in the blur angle estimation scheme with our proposed difference value vs angle curve. Subsequently, the auto-correlation matrix is employed to estimate the blur angle by measuring the distance between the conjugated-correlated troughs. Finally, we evaluate the accuracy, robustness and time efficiency of our proposed method with the existing algorithms on the public benchmarks and the natural real motion blurred images. The experimental results demonstrate that the proposed PSF estimation scheme not only could obtain a higher accuracy for the blur angle and blur length, but also demonstrate stronger robustness and higher time efficiency under different circumstances.

Entanglement-Driven Adhesion, Self-Healing, and High Stretchability of Double-Network PEG-Based Hydrogels.

Hydrogels that are capable of wet adhesion and self-healing can enable major advances in a variety of biomedical applications such as tissue regeneration, wound dressings, wearable/implantable devices, and drug delivery. We hereby developed an innovative but simple strategy to achieve adhesive, self-healing, and highly stretchable double-network hydrogels, which were composed of a primary covalent polyethylene glycol diacrylate (PEGDA) network in combination with a noncovalent network of highly diffusive, giant PEG chains. The adhesion to substrates including tissue matrices was instant and repeatable due to the diffusive PEG chains that can spontaneously penetrate and entangle with the substrate network. Combining the intrinsic biocompatibility of PEG and rational design for tuning the hydrogel network properties, we exemplarily demonstrated that this hydrogel can be used as a three-dimensional matrix for cell culture or as a tissue adhesive for wound healing. The in vivo study showed that the hydrogel is capable of effectively triggering skin wound healing with a significantly lower immune response in comparison to commercial tissue adhesives currently used in clinics. Therefore, our study provides new and critical insights into the design strategy to achieve adhesion and rehealability by taking advantages of the entanglement effect from double-network hydrogels and opens up a new avenue for the application of entanglement-driven hydrogels in regenerative medicine.

Melanoma-Induced Reprogramming of Schwann Cell Signaling Aids Tumor Growth.

The tumor microenvironment has been compared with a nonhealing wound involving a complex interaction between multiple cell types. Schwann cells, the key regulators of peripheral nerve repair, have recently been shown to directly affect nonneural wound healing. Their role in cancer progression, however, has been largely limited to neuropathic pain and perineural invasion. In this study, we showed that melanoma activated otherwise dormant functions of Schwann cells aimed at nerve regeneration and wound healing. Such reprogramming of Schwann cells into repair-like cells occurred during the destruction and displacement of neurons as the tumor expanded and via direct signaling from melanoma cells to Schwann cells, resulting in activation of the nerve injury response. Melanoma-activated Schwann cells significantly altered the microenvironment through their modulation of the immune system and the extracellular matrix in a way that promoted melanoma growth in vitro and in vivo. Local inhibition of Schwann cell activity following cutaneous sensory nerve transection in melanoma orthotopic models significantly decreased the rate of tumor growth. Tumor-associated Schwann cells, therefore, can have a significant protumorigenic effect and may present a novel target for cancer therapy. SIGNIFICANCE: These findings reveal a role of the nerve injury response, particularly through functions of activated Schwann cells, in promoting melanoma growth.

Tumor-derived high-mobility group box 1 and thymic stromal lymphopoietin are involved in modulating dendritic cells to activate T regulatory cells in a mouse model.

High-mobility group box 1 (HMGB1) is involved in the tumor-associated activation of regulatory T cells (Treg), but the mechanisms remain unknown. In a mouse tumor model, silencing HMGB1 in tumor cells or inhibiting tumor-derived HMGB1 not only dampened the capacity of tumor cells to produce thymic stromal lymphopoietin (TSLP), but also aborted the tumor-associated modulation of Treg-activating DC. Tumor-derived HMGB1 triggered the production of TSLP by tumor cells. Importantly, both tumor-derived HMGB1 and TSLP were necessary for modulating DC to activate Treg in a TSLP receptor (TSLPR)-dependent manner. In the therapeutic model, intratumorally inhibiting tumor-derived HMGB1 (causing downstream loss of TSLP production) attenuated Treg activation, unleashed tumor-specific CD8 T cell responses, and elicited CD8α+/CD103+DC- and T cell-dependent antitumor activity. These results suggest a new pathway for the activation of Treg involving in tumor-derived HMGB1 and TSLP, and have important implications for incorporating HMGB1 inhibitors into cancer immunotherapy.

Intratumoral delivery of tumor antigen-loaded DC and tumor-primed CD4+ T cells combined with agonist α-GITR mAb promotes durable CD8+ T-cell-dependent antitumor immunity.

The progressive tumor microenvironment (TME) coordinately supports tumor cell expansion and metastasis, while it antagonizes the survival and (poly-)functionality of antitumor T effector cells. There remains a clear need to develop novel therapeutic strategies that can transform the TME into a pro-inflammatory niche that recruits and sustains protective immune cell populations. While intravenous treatment with tumor-primed CD4+ T cells combined with intraperitoneal delivery of agonist anti-glucocorticoid-induced TNF receptor (α-GITR) mAb results in objective antitumor responses in murine early stage disease models, this approach is ineffective against more advanced tumors. Further subcutaneous co-administration of a vaccine consisting of tumor antigen-loaded dendritic cells (DC) failed to improve the antitumor efficacy of this approach. Remarkably, these same three therapeutic agents elicited significant antitumor benefits when the antitumor CD4+ T cells and tumor antigen-loaded DC were co-injected directly into tumors along with intratumoral or intraperitoneal delivery of α-GITR mAb. This latter protocol induced the production of an array of antitumor cytokines and chemokines within the TME, supporting increased tumor-infiltration by antitumor CD8+ T cells capable of mediating tumor regression and extended overall survival.

Mitigate Cascading Failures on Networks using a Memetic Algorithm.

Research concerning cascading failures in complex networks has become a hot topic. However, most of the existing studies have focused on modelling the cascading phenomenon on networks and analysing network robustness from a theoretical point of view, which considers only the damage incurred by the failure of one or several nodes. However, such a theoretical approach may not be useful in practical situation. Thus, we first design a much more practical measure to evaluate the robustness of networks against cascading failures, termed Rcf. Then, adopting Rcf as the objective function, we propose a new memetic algorithm (MA) named MA-Rcf to enhance network the robustness against cascading failures. Moreover, we design a new local search operator that considers the characteristics of cascading failures and operates by connecting nodes with a high probability of having similar loads. In experiments, both synthetic scale-free networks and real-world networks are used to test the efficiency and effectiveness of the MA-Rcf. We systematically investigate the effects of parameters on the performance of the MA-Rcf and validate the performance of the newly designed local search operator. The results show that the local search operator is effective, that MA-Rcf can enhance network robustness against cascading failures efficiently, and that it outperforms existing algorithms.

Multifocus color image sequence fusion based on mean shift segmentation.

This paper presents a region-based technique for fusion of a multifocus color image sequence in the LUV color space. First, mean shift segmentation was applied on the weighted average image of the image sequence to obtain the fusion reference areas. Second, for each segmented area, the well-known modified Laplacian (LAP2) was used as a focus measure to select the clearest parts within the image sequence and then a final image focused with all parts can be generated. Mutual information, QAB/F metric, entropy, standard deviation, image sharpness metric, image contrast metric, average gradient, and spatial frequency were adopted to assess the quality of the fused image. Experiments carried out using standard image sequences from HeliconSoft demonstrated that the results obtained through our technique offer good performance. The proposed technique can be used to extend the depth of field (DOF) of a camera system effectively.