A panel of multivalent nanobodies broadly neutralizing Omicron subvariants and recombinant.

The emerging Omicron subvariants have a remarkable ability to spread and escape nearly all current monoclonal antibody (mAb) treatments. Although the virulence of SARS-CoV-2 has now diminished, it remains a significant threat to public health due to its high transmissibility and susceptibility to mutation. Therefore, it is urgent to develop broad-acting and potent therapeutics targeting current and emerging Omicron variants. Here, we identified a panel of Omicron BA.1 spike receptor-binding domain (RBD)-targeted nanobodies (Nbs) from a naive alpaca VHH library. This panel of Nbs exhibited high binding affinity to the spike RBD of wild-type, Alpha B.1.1.7, Beta B.1.351, Delta plus, Omicron BA.1, and BA.2. Through multivalent Nb construction, we obtained a subpanel of ultrapotent neutralizing Nbs against Omicron BA.1, BA.2, BF.7 and even emerging XBB.1.5, and XBB.1.16 pseudoviruses. Protein structure prediction and docking analysis showed that Nb trimer 2F2E5 targets two independent RBD epitopes, thus minimizing viral escape. Taken together, we obtained a panel of broad and ultrapotent neutralizing Nbs against Omicron BA.1, Omicron BA.2, BF.7, XBB.1.5, and XBB.1.16. These multivalent Nbs hold great promise for the treatment against SARS-CoV-2 infection and could possess a superwide neutralizing breadth against novel omicron mutants or recombinants.

The short isoform of MS4A7 is a novel player in glioblastoma microenvironment, M2 macrophage polarization, and tumor progression.

BACKGROUND: The unique intracranial tumor microenvironment (TME) contributes to the immunotherapy failure for glioblastoma (GBM), thus new functional protein targets are urgently needed. Alternative splicing is a widespread regulatory mechanism by which individual gene can express variant proteins with distinct functions. Moreover, proteins located in the cell plasma membrane facilitate targeted therapies. This study sought to obtain functional membrane protein isoforms from GBM TME. METHODS: With combined single-cell RNA-seq and bulk RNA-seq analyses, novel candidate membrane proteins generated by prognostic splicing events were screened within GBM TME. The short isoform of MS4A7 (MS4A7-s) was selected for evaluation by RT-PCR and western blotting in clinical specimens. Its clinical relevance was evaluated in a GBM patient cohort. The function of MS4A7-s was identified by in vitro and in vivo experiments. MS4A7-s overexpression introduced transcriptome changes were analyzed to explore the potential molecular mechanism. RESULTS: The main expression product, isoform MS4A7-s, generated by exon skipping, is an M2-specific plasma membrane protein playing a pro-oncogenic role in GBM TME. Higher expression of MS4A7-s correlates with poor prognosis in a GBM cohort. In vitro cell co-culture experiments, intracranial co-injection tumorigenesis assay, and RNA-seq suggest MS4A7-s promotes activation of glioma-associated macrophages' (GAMs) PI3K/AKT/GSK3ß pathway, leading to M2 polarization, and drives malignant progression of GBM. CONCLUSIONS: MS4A7-s, a novel splicing isoform of MS4A7 located on the surface of GAMs in GBM TME, is a predictor of patient outcome, which contributes to M2 polarization and the malignant phenotype of GBM. Targeting MS4A7-s may constitute a promising treatment for GBM.

Assembly-level topology optimization and additive manufacturing of aluminum alloy primary mirrors.

Additive manufacturing can realize complex structures that cannot be achieved by conventional manufacturing methods. At the same time, topology optimization provides more excellent solutions for structural design. In the field of guidance and navigation optics, ultra-lightweight, high rigidity, and high integration are important requirements. Metal mirrors are widely used in this field due to their good processing performance. In this paper, we describe the integrated design and manufacturing of aluminum alloy primary mirror assembly (mirrors and mirror backplane) through the combination of additive manufacturing technology and topology optimization. Compared with the conventional design, it shows better performance.

Optomechanical design of a wide-field auroral imager on Fengyun-3D.

We present the optomechanical design and development of a wide-field auroral imager (WAI) on board the satellite Fengyun-3D. The optomechanical system of the WAI features a combination of a large field of view and a single-axis scanning mechanism. The combination makes the WAI perform better than its counterparts in temporal resolution in a low Earth orbit. In-orbit tests have verified the survival of WAI in the launching vibration and space environment. It has functioned on-orbit since 2018, with a spatial resolution of ∼10km at the nadir point, at a reference height of 110 km above the ionosphere.

Optics ellipticity performance of an unobscured off-axis space telescope.

With the development of astronomy, more and more attention is paid to the survey of dark matter. Dark matter cannot be seen directly but can be detected by weak gravitational lensing measurement. Ellipticity is an important parameter used to define the shape of a galaxy. Galaxy ellipticity changes with weak gravitational lensing and nonideal optics. With our design of an unobscured off-axis telescope, we implement the simulation and calculation of optics ellipticity. With an accurate model of optics PSF, the characteristic of ellipticity is modeled and analyzed. It is shown that with good optical design, the full field ellipticity can be quite small. The spatial ellipticity change can be modeled by cubic interpolation with very high accuracy. We also modeled the ellipticity variance with time and analyzed the tolerance. It is shown that the unobscured off-axis telescope has good ellipticity performance and fulfills the requirement of dark matter survey.

Reprogramming tumor microenvironment with precise photothermal therapy by calreticulin nanobody-engineered probiotics.

Targeted therapies have revolutionized traditional cancer treatments by precisely targeting tumor cells, enhancing efficacy and safety. Despite this advancement, the proportion of cancer patients eligible for such therapies remains low due to the absence of suitable targets. Here, we investigate whether the translocation of the immunogenic cell death (ICD) marker calreticulin (CALR) from the endoplasmic reticulum (ER) to the cell surface following ICD induction can serve as a target for targeted therapies. To target CALR, a nanobody Nb215 identified from a naïve VHH phage library with high binding affinity to both human and mouse CALR was employed to engineer probiotic EcN 1917. Our results demonstrated that CALR nanobody-modified EcN-215 coupled with the photothermal dye indocyanine green (ICG) was able to exert NIR-II imaging-guide photothermal therapy (PTT). Moreover, PTT with EcN-215/ICG can reshape the tumor microenvironment by enhancing the infiltration of CD45+CD3+ T cells and CD11b+F4/80+ macrophages. Furthermore, the antitumor activity of CALR-targeted EcN-215/ICG is synergistically enhanced by blocking CD47-SIRPα axis. Collectively, our study provides a proof of concept for CALR-targeted therapy. Given that CALR translocation can be induced by various anticancer therapies across numerous tumor cell lines, CALR-targeted therapies hold promise as a novel approach for treating multiple types of cancers.

Off-the-shelf CAR-NK cells targeting immunogenic cell death marker ERp57 execute robust antitumor activity and have a synergistic effect with ICD inducer oxaliplatin.

BACKGROUND: Chimeric antigen receptor natural killer (CAR-NK) therapy holds great promise for treating hematologic tumors, but its efficacy in solid tumors is limited owing to the lack of suitable targets and poor infiltration of engineered NK cells. Here, we explore whether immunogenic cell death (ICD) marker ERp57 translocated from endoplasmic reticulum to cell surface after drug treatment could be used as a target for CAR-NK therapy. METHODS: To target ERp57, a VHH phage display library was used for screening ERp57-targeted nanobodies (Nbs). A candidate Nb with high binding affinity to both human and mouse ERp57 was used for constructing CAR-NK cells. Various in vitro and in vivo studies were performed to assess the antitumor efficacy of the constructed CAR-NK cells. RESULTS: We demonstrate that the translocation of ERp57 can not only be induced by low-dose oxaliplatin (OXP) treatment but also is spontaneously expressed on the surface of various types of tumor cell lines. Our results show that G6-CAR-NK92 cells can effectively kill various tumor cell lines in vitro on which ERp57 is induced or intrinsically expressed, and also exhibit potent antitumor effects in cancer cell-derived xenograft and patient-derived xenograft mouse models. Additionally, the antitumor activity of G6-CAR-NK92 cells is synergistically enhanced by the low-dose ICD-inducible drug OXP. CONCLUSION: Collectively, our findings suggest that ERp57 can be leveraged as a new tumor antigen for CAR-NK targeting, and the resultant CAR-NK cells have the potential to be applied as a broad-spectrum immune cell therapy for various cancers by combining with ICD inducer drugs.

Precise Photodynamic Therapy by Midkine Nanobody-Engineered Nanoparticles Remodels the Microenvironment of Pancreatic Ductal Adenocarcinoma and Potentiates the Immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its resistance against chemotherapy and immunotherapy due to its dense desmoplastic and immunosuppressive tumor microenvironment (TME). Traditional photodynamic therapy (PDT) was also less effective for PDAC owing to poor selectivity, insufficient penetration, and accumulation of photosensitizers in tumor sites. Here, we designed a light-responsive novel nanoplatform targeting the TME of PDAC through tumor-specific midkine nanobodies (Nbs), which could efficiently deliver semiconducting polymeric nanoparticles (NPs) to the TME of PDAC and locally produce abundant reactive oxygen species (ROS) for precise photoimmunotherapy. The synthesized nanocomposite can not only achieve multimodal imaging of PDAC tumors (fluorescence and photoacoustic imaging) but also lead to apoptosis and immunogenic cell death of tumor cells via ROS under light excitation, ultimately preventing tumor progression and remodeling the immunosuppressive TME with increased infiltration of T lymphocytes. Combined with a PD-1 checkpoint blockade, the targeted PDT platform showed the best antitumor performance and markedly extended mice survival. Conclusively, this work integrating Nbs with photodynamic NPs provides a novel strategy to target formidable PDAC to achieve tumor suppression and activate antitumor immunity, creating possibilities for boosting efficacy of immunotherapy for PDAC tumors through the combination with precise local PDT.

Cadherin 17 Nanobody-Mediated Near-Infrared-II Fluorescence Imaging-Guided Surgery and Immunotoxin Delivery for Colorectal Cancer.

Surgery and targeted therapy are of equal importance for colorectal cancer (CRC) treatment. However, complete CRC tumor resection remains challenging, and new targeted agents are also needed for efficient CRC treatment. Cadherin 17 (CDH17) is a membrane protein that is highly expressed in CRC and, therefore, is an ideal target for imaging-guided surgery and therapeutics. This study utilizes CDH17 nanobody (E8-Nb) with the near-infrared (NIR) fluorescent dye IRDye800CW to construct a NIR-II fluorescent probe, E8-Nb-IR800CW, and a Pseudomonas exotoxin (PE)-based immunotoxin, E8-Nb-PE38, to evaluate their performance for CRC imaging, imaging-guided precise tumor excision, and antitumor effects. Our results show that E8-Nb-IR800CW efficiently recognizes CDH17 in CRC cells and tumor tissues, produces high-quality NIR-II images for CRC tumors, and enables precise tumor removal guided by NIR-II imaging. Additionally, fluorescent imaging confirms the targeting ability and specificity of the immunotoxin toward CDH17-positive tumors, providing the direct visible evidence for immunotoxin therapy. E8-Nb-PE38 immunotoxin markedly delays the growth of CRC through the induction of apoptosis and immunogenic cell death (ICD) in multiple CRC tumor models. Furthermore, E8-Nb-PE38 combined with 5-FU exerts synergistically antitumor effects and extends survival. This study highlights CDH17 as a promising target for CRC imaging, imaging-guided surgery, and drug delivery. Nanobodies targeting CDH17 hold great potential to construct NIR-II fluorescent probes for surgery navigation, and PE-based toxins fused with CDH17 nanobodies represent a novel therapeutic strategy for CRC treatment. Further investigation is warranted to validate these findings for potential clinical translation.

Effect of additives on sulfur resistance of catalytic filter material during denitrification and synergistic decomposition of 1,2-DCBz.

Modified Mn-Ce/P84 catalytic filter material can be used to achieve high removal efficiency of NOx and 1,2-DCBz in bag-filtering dust precipitator synergistic removal of multiple pollutants. However, the presence of SO2 in the actual industrial flue gas has an adverse impact on the catalytic performance of the catalytic filter material. In this paper, a kind of Mn-Ce catalytic filter material was prepared by the impregnation method, which was modified by Fe, Cu, and Co, respectively. As a result, the sulfur resistance of the catalytic filter material was improved. The change of catalytic activity of the three kinds of modified catalytic filter material at different concentrations was compared in the SO2 flue gas fixed bed system. And the modified catalytic filter materials were characterized by SEM, BET, XPS, XRD, and H2-TPR. When the temperature was over 80 °C, different concentrations of SO2 were injected into the simulated flue gas to test the denitrification activity of the catalytic filter material. The results showed that under the low SO2 concentration of 150 ppm, the denitrification activity and 1,2-DCBz activity of Fe, Co, and Cu-modified filter material were increased, and the sulfur resistance of Fe was better under the flue gas conditions of 300 ppm and 450 ppm SO2. Under the condition of 450 ppm SO2 and 200 °C reaction, 93.4% denitrification efficiency and 96.1% 1,2-DCBz removal efficiency could be achieved by using modified Fe-Mn-Ce catalytic filter material.

A simple liposome-based bionic bacterium for tumor treatment by re-education of tumor-associated microphages in combination with chemotherapy.

Re-education of tumor-associated macrophages (TAMs) into M1-like macrophages (Mφ1) has become one of the aims of tumor immunotherapy. Injection of live bacteria has been applied for this purpose; however, an acute innate immune response might be caused in this progress, and therefore a bacteria-based strategy with great security is needed. In this study, the bacterial walls of Staphylococcus aureus were inserted into the bilayer of liposome to construct liposome-based bionic bacteria (Bio-Bac), and doxorubicin (DOX) was encapsulated to form DOX@Bio-Bac. DOX@Bio-Bac re-educated the THP-1-derived TAMs into Mφ1 in vitro, and subsequently inhibited the migration and invasion of CAL27 cells. In a mouse model of hepatocellular carcinoma with lymphatic metastasis, the re-education of TAMs was proved, and an effective inhibition of tumor growth and metastasis in mice was observed. The liposome-based bionic bacteria constructed in this study provide a new strategy for re-education of TAMs, replacing the bacterial therapy reported previously, and a more effective anti-tumor effect can be obtained by combining the chemotherapy drugs with this bionic bacterium.

Erratum: Effects of Aptamer to U87-EGFRvIII Cells on the Proliferation, Radiosensitivity, and Radiotherapy of Glioblastoma Cells.

[This corrects the article DOI: 10.1016/j.omtn.2018.01.001.].

Beyond canonical PROTAC: biological targeted protein degradation (bioTPD).

Targeted protein degradation (TPD) is an emerging therapeutic strategy with the potential to modulate disease-associated proteins that have previously been considered undruggable, by employing the host destruction machinery. The exploration and discovery of cellular degradation pathways, including but not limited to proteasomes and lysosome pathways as well as their degraders, is an area of active research. Since the concept of proteolysis-targeting chimeras (PROTACs) was introduced in 2001, the paradigm of TPD has been greatly expanded and moved from academia to industry for clinical translation, with small-molecule TPD being particularly represented. As an indispensable part of TPD, biological TPD (bioTPD) technologies including peptide-, fusion protein-, antibody-, nucleic acid-based bioTPD and others have also emerged and undergone significant advancement in recent years, demonstrating unique and promising activities beyond those of conventional small-molecule TPD. In this review, we provide an overview of recent advances in bioTPD technologies, summarize their compositional features and potential applications, and briefly discuss their drawbacks. Moreover, we present some strategies to improve the delivery efficacy of bioTPD, addressing their challenges in further clinical development.

Resveratrol improves cognition and decreases amyloid plaque formation in Tg6799 mice.

Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder of the central nervous system that causes severe cognitive impairment. One of the most significant pathological features of AD is the accumulation of ß­amyloid (Aß) peptide in the brain. Resveratrol (Res) is a polyphenol derived from peanuts, red grapes and other plants, which has received increasing attention due to its neuroprotective features. Tg6799 mice are transgenic mice with five familial AD (FAD) mutations that are also known as 5XFAD mice. The present study aimed to investigate the effects of Res on Tg6799 mice. The transgenic mice were randomly divided into the Res treatment group and the vehicle control group, and were treated with 0.5% Res solution (60 mg/kg) or volume­matched normal saline, respectively. Treatment was administered by oral gavage daily for 60 consecutive days. Res reduced amyloid plaque formation and the levels of Aß42, and ß­secretase 1 levels were also significantly decreased. Furthermore, Res was able to reduce the expression of amyloid precursor protein and its cleavage products. The administration of Res to Tg6799 mice also improved their spatial working memory, as measured by the Y­maze test, and rescued spatial memory deficits, as measured using the Morris water maze test; however, Res did not affect their motor function. In conclusion, this study suggested that Res may reduce Aß­induced neuronal damage, thus preventing memory loss.

Wide-field auroral imager onboard the Fengyun satellite.

The newly launched Fengyun-3D (FY-3D) satellite carried a wide-field auroral imager (WAI) that was developed by Changchun Institute of Optics, Fine Mechanics and Physics, Chinese Academy of Sciences (CIOMP), which will provide a large field of view (FOV), high spatial resolution, and broadband ultraviolet images of the aurora and the ionosphere by imaging the N2 LBH bands of emissions. The WAI consists of two identical cameras, each with an FOV of 68° in the along-track direction and 10° in the cross-track direction. The two cameras are tilted relative to each other to cover a fan-shaped field of size 130° × 10°. Each camera consists of an unobstructed four-mirror anastigmatic optical system, a BaF2 filter, and a photon-counting imaging detector. The spatial resolution of WAI is ~10 km at the nadir point at a reference height of 110 km above the Earth's surface. The sensitivity is >0.01 counts s-1 Rayleigh-1 pixel-1 (140-180 nm) for both cameras, which is sufficient for mapping the boundaries and the fine structures of the auroral oval during storms/substorms. Based on the tests and calibrations that were conducted prior to launch, the data processing algorithm includes photon signal decoding, geometric distortion correction, photometric correction, flat-field correction, line-of-sight projection and correction, and normalization between the two cameras. Preliminarily processed images are compared with DMSP SSUSI images. The agreement between the images that were captured by two instruments demonstrates that the WAI and the data processing algorithm operate normally and can provide high-quality scientific data for future studies on auroral dynamics.

Effects of Aptamer to U87-EGFRvIII Cells on the Proliferation, Radiosensitivity, and Radiotherapy of Glioblastoma Cells.

Glioblastoma multiforme (GBM) is the most prevalent and lethal malignant intracranial tumor in the brain, with very poor prognosis and survival. The epidermal growth factor receptor variant III (EGFRvIII) contributes to increased oncogenicity that does not occur through binding EGFR ligands and instead occurs through constitutive activation, which enhances glioma tumorigenicity and resistance to targeted therapy. Aptamers are nucleic acids with high affinity and specificity to targets selected by systematic evolution of ligands by exponential enrichment (SELEX), and are usually developed as antagonists of disease-associated factors. Herein, we generated a DNA aptamer U2, targeting U87-EGFRvIII cells, and demonstrated that U2 alters the U87-EGFRvIII cell growth, radiosensitivity, and radiotherapy of glioblastoma cells. We detected U2 and U87-EGFRvIII cells by flow cytometry and confocal microscopy to explore the binding ability of U2 to U87-EGFRvIII cells. Then, we found that aptamer U2 inhibits the proliferation, migration, invasion, and downstream signaling of U87-EGFRvIII cells. Moreover, the U2 aptamer can increase the radiosensitivity of U87-EGFRvIII in vitro and has a better antitumor effect on 188Re-U2 in vivo. Therefore, the results revealed the promising potential of the U2 aptamer to be a new type of drug candidate and aptamer-targeted drug delivery system for glioblastoma therapy.

UVA Irradiation Enhances Brusatol-Mediated Inhibition of Melanoma Growth by Downregulation of the Nrf2-Mediated Antioxidant Response.

Brusatol (BR) is a potent inhibitor of Nrf2, a transcription factor that is highly expressed in cancer tissues and confers chemoresistance. UVA-generated reactive oxygen species (ROS) can damage both normal and cancer cells and may be of potential use in phototherapy. In order to provide an alternative method to treat the aggressive melanoma, we sought to investigate whether low-dose UVA with BR is more effective in eliminating melanoma cells than the respective single treatments. We found that BR combined with UVA led to inhibition of A375 melanoma cell proliferation by cell cycle arrest in the G1 phase and triggers cell apoptosis. Furthermore, inhibition of Nrf2 expression attenuated colony formation and tumor development from A375 cells in heterotopic mouse models. In addition, cotreatment of UVA and BR partially suppressed Nrf2 and its downstream target genes such as HO-1 along with the PI3K/AKT pathway. We propose that cotreatment increased ROS-induced cell cycle arrest and cellular apoptosis and inhibits melanoma growth by regulating the AKT-Nrf2 pathway in A375 cells which offers a possible therapeutic intervention strategy for the treatment of human melanoma.