Engineering Efferocytosis-Mimicking Nanovesicles to Regulate Joint Anti-Inflammation and Peripheral Immunosuppression for Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation of the synovial joints and the dysfunction of regulatory T cells (Tregs) in the peripheral blood. Therefore, an optimal treatment strategy should aim to eliminate the inflammatory response in the joints and simultaneously restore the immune tolerance of Tregs in peripheral blood. Accordingly, we developed an efferocytosis-mimicking nanovesicle that contains three functional factors for immunomodulating of efferocytosis, including "find me" and "eat me" signals for professional (macrophage) or non-professional phagocytes (T lymphocyte), and "apoptotic metabolite" for metabolite digestion. We showed that efferocytosis-mimicking nanovesicles targeted the inflamed joints and spleen of mice with collagen-induced arthritis, further recruiting and selectively binding to macrophages and T lymphocytes to induce M2 macrophage polarization and Treg differentiation and T helper cell 17 (Th17) recession. Under systemic administration, the efferocytosis-mimicking nanovesicles effectively maintained the pro-inflammatory M1/anti-inflammatory M2 macrophage balance in joints and the Treg/Th17 imbalance in peripheral blood to prevent RA progression. This study demonstrates the potential of efferocytosis-mimicking nanovesicles for RA immunotherapy.

Immunosuppressive microvesicles-mimetic derived from tolerant dendritic cells to target T-lymphocytes for inflammation diseases therapy.

The utilization of extracellular vesicles (EV) in immunotherapy, aiming at suppressing peripheral immune cells responsible for inflammation, has demonstrated significant efficacy in treating various inflammatory diseases. However, the clinical application of EV has faced challenges due to their inadequate targeting ability. In addition, most of the circulating EV would be cleared by the liver, resulting in a short biological half-life after systemic administration. Inspired by the natural microvesicles (MV, as a subset of large size EV) are originated and shed from the plasma membrane, we developed the immunosuppressive MV-mimetic (MVM) from endotoxin tolerant dendritic cells (DC) by a straightforward and effective extrusion approach, in which DC surface proteins were inherited for providing the homing ability to the spleen, while αCD3 antibodies were conjugated to the MVM membranes for specific targeting of T cells. The engineered MVM carried a large number of bioactive cargos from the parental cells, which exhibited a remarkable ability to promote the induction of regulatory T cells (Treg) and polarization of anti-inflammatory M2 macrophages. Mechanistically, the elevated Treg level by MVM was mediated due to the upregulation of miR-155-3p. Furthermore, it was observed that systemic and local immunosuppression was induced by MVM in models of sepsis and rheumatoid arthritis through the improvement of Treg and M2 macrophages. These findings reveal a promising cell-free strategy for managing inflammatory responses to infections or tissue injury, thereby maintaining immune homeostasis.

Ru(ii)/Os(ii)-based carbonic anhydrase inhibitors as photodynamic therapy photosensitizers for the treatment of hypoxic tumours.

Photodynamic therapy (PDT) is a medical technique for the treatment of cancer. It is based on the use of non-toxic molecules, called photosensitizers (PSs), that become toxic when irradiated with light and produce reactive oxygen specious (ROS) such as singlet oxygen (1O2). This light-induced toxicity is rather selective since the physician only targets a specific area of the body, leading to minimal side effects. Yet, a strategy to improve further the selectivity of this medical technique is to confine the delivery of the PS to cancer cells only instead of spreading it randomly throughout the body prior to light irradiation. To address this problem, we present here novel sulfonamide-based monopodal and dipodal ruthenium and osmium polypyridyl complexes capable of targeting carbonic anhydrases (CAs) that are a major target in cancer therapy. CAs are overexpressed in the membrane or cytoplasm of various cancer cells. We therefore anticipated that the accumulation of our complexes in or outside the cell prior to irradiation would improve the selectivity of the PDT treatment. We show that our complexes have a high affinity for CAs, accumulate in cancer cells overexpressing CA cells and importantly kill cancer cells under both normoxic and hypoxic conditions upon irradiation at 540 nm. More importantly, Os(ii) compounds still exhibit some phototoxicity under 740 nm irradiation under normoxic conditions. To our knowledge, this is the first description of ruthenium/osmium-based PDT PSs that are CA inhibitors for the selective treatment of cancers.

Theranostics with photodynamic therapy for personalized medicine: to see and to treat.

Photodynamic Therapy (PDT) is an approved treatment modality, which is presently receiving great attention due to its limited invasiveness, high selectivity and limited susceptibility to drug resistance. Another related research area currently expanding rapidly is the development of novel theranostic agents based on the combination of PDT with different imaging technologies, which allows for both therapy and diagnosis. This combination can help to address issues of suboptimal biodistribution and selectivity through regional imaging, while therapeutic agents enable an effective and personalized therapy. In this review, we describe compounds, whose structures combine PDT photosensitizers with different imaging probes - including examples for near-infrared optical imaging, magnetic resonance imaging (MRI) and nuclear imaging (PET or SPECT), generating novel theranostic drug candidates. We have intentionally focused our attention on novel compounds, which have already been investigated preclinically in vivo in order to demonstrate the potential of such theranostic agents for clinical applications.

Towards Ruthenium(II)-Rhenium(I) Binuclear Complexes as Photosensitizers for Photodynamic Therapy.

The search for new metal-based photosensitizers (PSs) for anticancer photodynamic therapy (PDT) is a fast-developing field of research. Knowing that polymetallic complexes bear a high potential as PDT PSs, in this study, we aimed at combining the known photophysical properties of a rhenium(I) tricarbonyl complex and a ruthenium(II) polypyridyl complex to prepare a ruthenium-rhenium binuclear complex that could act as a PS for anticancer PDT. Herein, we present the synthesis and characterization of such a system and discuss its stability in aqueous solution. In addition, one of our complexes prepared, which localized in mitochondria, was found to have some degree of selectivity towards two types of cancerous cells: human lung carcinoma A549 and human colon colorectal adenocarcinoma HT29, with interesting photo-index (PI) values of 135.1 and 256.4, respectively, compared to noncancerous retinal pigment epithelium RPE1 cells (22.4).

Clinical value of 125I radioactive seed implantation in the treatment of lymph node metastasis of 131I refractory differentiated thyroid cancer.

PURPOSE: To evaluate the clinical value of 1251 seed implantation in the treatment of lymph node metastasis of 111 cases of refractory differentiated thyroid cancer (RAIR-DTC). METHODS AND MATERIALS: From January 2015 to June 2016, 42 patients with RAIR-DTC with lymph node metastasis (14 males and 28 females, median age 49 years) were analyzed retrospectively. After CT-guided 1251 seed implantation, CT was reexamined 2,4,6 months after operation, and the changes of metastatic lymph node size, serum thyroglobulin (Tg) level and complications were compared before or after treatment. Paired-Samples T Test, Methods repetitive measure analysis of variance, Spearman correlation coefficient analysis were used to analyze the data. RESULTS: Among the 42 patients, 2 had complete remission (4.76%), 9 had partial remission (21.43%), 29 had no change (69.05%), and 2 had disease progression (4.76%), with an overall effective rate of 95.24% (40/42). The diameter of lymph node metastasis was (1.39 ± 0.75) cm after treatment and (1.99 ± 0.38) cm before treatment; the diameter of lymph node metastasis was significantly reduced after treatment compared with that before metastasis (t = 5.557, P< 0.01); the serum Tg at 2, 4 and 6 months after treatment were (53.34 ± 14.05) ug/L, (33.17 + 7.61)ug/L and (25.93 ± 10.91)ug/L, respectively, compared with (57.72 ± 15.23)ug/L before treatment, and the differences between serum Tg after treatment and before treatment were all statistically significant (F = 23.612,P<0.05). Except for the diameter of lymph node metastasis (χ2 = 4.524, P<0.05), the patients' age, gender, metastasis site and the number of implanted particles per lesion were not influential factors in the efficacy (χ2 = 0.569-15.884, rs = 0.277, all P>0.05). CONCLUSION: 125I RSIT can significantly alleviate the clinical symptoms of RAIR-DTC patients with LNM, and the LNM lesions size has relevance for the treatment effect. The clinical follow-up time of serum Tg level can be extended to 6 months or even longer.

Multi-depth phase-only hologram optimization using the L-BFGS algorithm with sequential slicing.

We implement a limited-memory Broyden-Fletcher-Goldfarb-Shanno (L-BFGS) optimization of phase-only computer-generated hologram for a multi-depth three-dimensional (3D) target. Instead of computing the full 3D reconstruction of the hologram, we use a novel method using L-BFGS with sequential slicing (SS) for partial evaluation of the hologram during optimization that only computes loss for a single slice of the reconstruction at every iteration. We demonstrate that its ability to record curvature information enables L-BFGS to have good quality imbalance suppression under the SS technique.

The impacts of ambient ozone pollution on China's wheat yield and forest production from 2010 to 2021.

Near-surface ozone causes damages on both crop and forest but their long-term spatiotemporal changes in China have been insufficiently explored, preventing comprehensive policy making with food security and climate targets. Moreover, limitation exists in the current metrics for long-term regional ozone risk assessment, AOT40 (the accumulated hourly ozone over a threshold of 40 ppbv) and PODY (phytotoxic ozone dose over a threshold of Y nmol ozone m-2 PLA s-1), with ignorance of meteorological influence for the former and complicated data collection and calculation procedures for the latter. Here, we developed a new metric for ozone-induced risk on winter wheat, O3MET, which can be easily derived based on ozone concentrations and meteorological variables, and is suitable for long-term assessment of ozone-induced wheat loss at the regional scale. Combining with existing metric for forest (O3RH), we comprehensively quantified the ozone damages on winter wheat yield and forest gross primary production (GPP) for mainland China during 2010-2021, the period with fast growth of ozone level across the country. The annual average losses of wheat yield and forest GPP were estimated at 26.5 Mt and 552.6 TgC, accounting for 17% and 4% of the total yield and GPP without ozone impact, respectively. Heavy dual ozone-induced damages on both wheat and forest were presented in East and South China. The ozone-induced wheat yield loss and forest GPP loss were estimated to increase at a rate of 1.8 Mt/yr and 13.9 TgC/yr for the entire country, respectively, driven mainly by the enhanced ambient ozone level within the research period. Besides ecological impact, the ozone pollution in the developed eastern China resulted in serious health burden as well, thus effective actions on ozone pollution alleviation in the region is crucial for reducing its ecological and health risks simultaneously.

Histone chaperones AtChz1A and AtChz1B are required for H2A.Z deposition and interact with the SWR1 chromatin-remodeling complex in Arabidopsis thaliana.

The histone variant H2A.Z plays key functions in transcription and genome stability in all eukaryotes ranging from yeast to human, but the molecular mechanisms by which H2A.Z is incorporated into chromatin remain largely obscure. Here, we characterized the two homologs of yeast Chaperone for H2A.Z-H2B (Chz1) in Arabidopsis thaliana, AtChz1A and AtChz1B. AtChz1A/AtChz1B were verified to bind to H2A.Z-H2B and facilitate nucleosome assembly in vitro. Simultaneous knockdown of AtChz1A and AtChz1B, which exhibit redundant functions, led to a genome-wide reduction in H2A.Z and phenotypes similar to those of the H2A.Z-deficient mutant hta9-1hta11-2, including early flowering and abnormal flower morphologies. Interestingly, AtChz1A was found to physically interact with ACTIN-RELATED PROTEIN 6 (ARP6), an evolutionarily conserved subunit of the SWR1 chromatin-remodeling complex. Genetic interaction analyses showed that atchz1a-1atchz1b-1 was hypostatic to arp6-1. Consistently, genome-wide profiling analyses revealed partially overlapping genes and fewer misregulated genes and H2A.Z-reduced chromatin regions in atchz1a-1atchz1b-1 compared with arp6-1. Together, our results demonstrate that AtChz1A and AtChz1B act as histone chaperones to assist the deposition of H2A.Z into chromatin via interacting with SWR1, thereby playing critical roles in the transcription of genes involved in flowering and many other processes.

Towards Selective Delivery of a Ruthenium(II) Polypyridyl Complex-Containing Bombesin Conjugate into Cancer Cells.

An increasing number of novel Ru(II) polypyridyl complexes have been successfully applied as photosensitizers (PSs) for photodynamic therapy (PDT). Despite recent advances in optimized PSs with refined photophysical properties, the lack of tumoral selectivity is often a major hurdle for their clinical development. Here, classical maleimide and versatile NHS-activated acrylamide strategies were employed to site-selectively conjugate a promising Ru(II) polypyridyl complex to the N-terminally Cys-modified Bombesin (BBN) targeting unit. Surprisingly, the decreased cell uptake of these novel Ru-BBN conjugates in cancer cells did not hamper the high phototoxic activity of the Ru-containing bioconjugates and even decreased the toxicity of the constructs in the absence of light irradiation. Overall, although deceiving in terms of selectivity, our new bioconjugates could still be useful for advanced cancer treatment due to their nontoxicity in the dark.

Polymersomes with Red/Near-Infrared Emission and Reactive Oxygen Species Generation.

In photodynamic therapy (PDT), the uses of nanoparticles bearing photosensitizers (PSs) can overcome some of the drawbacks of using a PS alone (e.g., poor water solubility and low tumor selectivity). However, numerous nano-formulations are developed by physical encapsulation of PSs through Van der Waals interactions, which have not only a limited load efficiency but also some in vivo biodistribution problems caused by leakage or burst release. Herein, polymersomes made from an amphiphilic block copolymer, in which a PS with aggregation-induced emission (AIE-PS) is covalently attached to its hydrophobic poly(amino acid) block, are reported. These AIE-PS polymersomes dispersed in aqueous solution have a high AIE-PS load efficiency (up to 46% as a mass fraction), a hydrodynamic diameter of 86 nm that is suitable for in vivo applications, and an excellent colloidal stability for at least 1 month. They exhibit a red/near-infrared photoluminescence and ability to generate reactive oxygen species (ROS) under visible light. They are non-cytotoxic in the dark as tested on Hela cells up to concentration of 100 µm. Benefiting from colloidal stability, AIE property and ROS generation capability, such a family of polymersomes can be great candidates for image-guided PDT.

PSR-Nets: Deep neural networks with prior shift regularization for PET/CT based automatic, accurate, and calibrated whole-body lymphoma segmentation.

Lymphoma is a type of lymphatic tissue originated cancer. Automatic and accurate lymphoma segmentation is critical for its diagnosis and prognosis yet challenging due to the severely class-imbalanced problem. Generally, deep neural networks trained with class-observation-frequency based re-weighting loss functions are used to address this problem. However, the majority class can be under-weighted by them, due to the existence of data overlap. Besides, they are more mis-calibrated. To resolve these, we propose a neural network with prior-shift regularization (PSR-Net), which comprises a UNet-like backbone with re-weighting loss functions, and a prior-shift regularization (PSR) module including a prior-shift layer (PSL), a regularizer generation layer (RGL), and an expected prediction confidence updating layer (EPCUL). We first propose a trainable expected prediction confidence (EPC) for each class. Periodically, PSL shifts a prior training dataset to a more informative dataset based on EPCs; RGL presents a generalized informative-voxel-aware (GIVA) loss with EPCs and calculates it on the informative dataset for model finetuning in back-propagation; and EPCUL updates EPCs to refresh PSL and RRL in next forward-propagation. PSR-Net is trained in a two- stage manner. The backbone is first trained with re-weighting loss functions, then we reload the best saved model for the backbone and continue to train it with the weighted sum of the re-weighting loss functions, the GIVA regularizer and the L2 loss function of EPCs for regularization fine-tuning. Extensive experiments are performed based on PET/CT volumes with advanced stage lymphomas. Our PSR-Net achieves 95.12% sensitivity and 87.18% Dice coefficient, demonstrating the effectiveness of PSR-Net, when compared to the baselines and the state-of-the-arts.

Organometallic small molecule kinase inhibitors - direct incorporation of Re and 99mTc into Opaganib®.

[(η5-Cp)ReI(CO)3] was incorporated into the kinase inhibitor Opaganib®. The resulting bioorganometallic complex showed a similar anti-cancer activity to Opaganib® against PC-3 cancer cells. The IC50 value for the kinase SK2 is 30x higher than that of Opaganib®. The 99mTc homologue was synthesized, completing a matched-pair for molecular theranostics.

HoloBlade: an open-hardware spatial light modulator driver platform for holographic displays.

Spatial light modulators (SLMs) are key research tools in several contemporary applied optics research domains. In this paper, we present the argument that an open platform for interacting with SLMs would dramatically increase their accessibility to researchers. We introduce HoloBlade, an open-hardware implementation of an SLM driver-stack, and provide a detailed exposition of HoloBlade's architecture, key components, and detailed design. An optical verification rig is constructed to demonstrate that HoloBlade can provide Fourier imaging capability in a 4f system. Finally, we discuss HoloBlade's future development roadmap and the opportunities that it presents as a research tool for applied optics.

Cost-optimized heterogeneous FPGA architecture for non-iterative hologram generation.

The generation of computer-generated holograms (CGHs) requires a significant amount of computational power. To accelerate the process, highly parallel field-programmable gate arrays (FPGAs) are deemed to be a promising computing platform to implement non-iterative hologram generation algorithms. In this paper, we present a cost-optimized heterogeneous FPGA architecture based on a one-step phase retrieval algorithm for CGH generation. The results indicate that our hardware implementation is 2.5× faster than the equivalent software implementation on a personal computer with a high-end multi-core CPU. Trade-offs between cost and performance are demonstrated, and we show that the proposed heterogeneous architecture can be used in a compact display system that is cost and size optimized.

Predictive search algorithm for phase holography.

We present an algorithm for generating high-quality holograms for computer generated holography: holographic predictive search. This approach is presented as an alternative to traditional holographic search algorithms such as direct search (DS) and simulated annealing (SA). We first introduce the current search-based methods and then introduce an analytical model of the underlying Fourier elements. This is used to make prescient judgments regarding the next iteration of the algorithm. This approach is developed for the case of phase-modulating devices with phase-sensitive reconstructions. When compared to conventional iterative approaches such as DS and SA on a multiphase device, holographic predictive search offered a fivefold improvement in quality as well as up to a 10-fold improvement in convergence time. This comes at the cost of an increased iteration overhead.

Incorporation of 7-dehydrocholesterol into liposomes as a simple, universal and efficient way to enhance anticancer activity by combining PDT and photoactivated chemotherapy.

Cholesterol (CHOL) is an indispensable component of liposomes. Incorporation of 7-dehydrocholesterol (7-DHC) instead of CHOL can efficiently enhance the anticancer activity of photosensitizer-encapsulated liposomes upon irradiation, yielding an IC50 value about half of that of CHOL-based controls. The photo-oxidation of 7-DHC into its endoperoxide form by singlet oxygen may account for the enhanced therapeutic effect, realizing an efficient combination of photodynamic therapy (PDT) and photoactivated chemotherapy.

Fluorination on non-photolabile dppz ligands for improving Ru(ii) complex-based photoactivated chemotherapy.

Ru(ii) polypyridine complexes which can undergo photo-induced ligand dissociation and subsequent DNA covalent binding may potentially serve as photoactivated chemotherapeutic (PACT) agents. In this paper, three fluorinated dppz ligand coordinated Ru(ii) complexes (2-4) containing four monodentate pyridine ligands were studied. All complexes released one pyridine and covalently bound to DNA upon 470 nm irradiation. Compared with the parent complex [Ru(dppz)(py)4]2+ (1), 2-4 displayed enhanced phototoxicity but diminished dark cytotoxicity, more favorable for PACT application. Complex 3 is the most efficient one with IC50 values of about 8 µM toward HeLa and SKOV-3 cell lines, and also has a much higher IC50 value toward normal L-02 cells. Our results indicate that fluorination on the retaining ligand may be an efficient way to improve the drug activity of Ru(ii) PACT agents.

[Prognosis of three-dimension change at middle facial soft tissue with distraction osteogenesis].

PURPOSE: To evaluate the changes in middle facial soft tissue caused by distraction osteogenesis. METHODS: A three-dimensional finite element model was established based on the simulation of a 13-year-old female with skeletal class III malocclusion. Three approaches of osteotomy, namely Le Fort I, Le Fort II and Le Fort III, were simulated and the maxillary complex was advanced by 5mm in the direction of FH plane, functional occlusal plane and functional occlusal plane with deviation of counter-clockwise 10 degrees, respectively, some premeters indicating the contour of the facial soft tissue were evaluated. RESULTS: The three kinds of osteotomy in which different levels of osteotomied maxillary complex area were advanced. Changing in detail is that the nose tip moved forward 1.25 mm, upper lip moved forward 4.9 mm, and the angle of Cm-Sn-U1 tended to increase after Le Fort I osteotomy; and nose tip moved forward 4.9 mm after Le Fort II osteotomy without increase of the angle of Cm-Sn-U1; besides changes that happened after Le Fort II osteotomy, lower eyelid moved forward 2mm after Le Fort III osteotomy. CONCLUSION: By computer surgery simulation using three-dimensional finite element model, we can obtain not only the amount of the three-dimensional change of the facial soft tissue, but also the three-dimensional effected graphics after operations.