Passive imaging through inhomogeneous scattering media.

According to the atmospheric scattering model (ASM), the object signal's attenuation diminishes exponentially as the imaging distance increases. This imposes limitations on ASM-based methods in situations where the scattering medium one wish to look through is inhomogeneous. Here, we extend ASM by taking into account the spatial variation of the medium density, and propose a two-step method for imaging through inhomogeneous scattering media. In the first step, the proposed method eliminates the direct current component of the scattered pattern by subscribing to the estimated global distribution (background). In the second step, it eliminates the randomized components of the scattered light by using threshold truncation, followed by the histogram equalization to further enhance the contrast. Outdoor experiments were carried out to demonstrate the proposed method.

Elastic-Plastic Fully π-Conjugated Polymer with Excellent Energy Dissipation Capacity for Ultra-Deep-Blue Flexible Polymer Light-Emitting Diodes with CIEy = 0.04.

Emerging intrinsically flexible fully π-conjugated polymers (FπCPs) are a promising functional material for flexible optoelectronics, attributed to their potential interchain interpenetration and entanglement. However, the challenge remains in obtaining elastic-plastic FπCPs with intrinsic robust optoelectronic property and excellent long-term and cycling deformation stability simultaneously for applications in deep-blue flexible polymer light-emitting diodes (PLEDs). This study, demonstrates a series of elastic-plastic FπCPs (P1-P4) with an excellent energy dissipation capacity via side-chain internal plasticization for the ultra-deep-blue flexible PLEDs. First, the freestanding P1 film exhibited a maximum fracture strain of 34.6%. More interestingly, the elastic behavior is observed with a low strain (≤10%), and the stretched film with a high deformation (>10%) attributed to plastic processing revealed the robust capacity to realize energy absorption and release. The elastic-plastic P1 film exhibits outstanding ultra-deep-blue emission, with an efficiency of 56.38%. Subsequently, efficient PLEDs are fabricated with an ultra-deep-blue emission of CIE (0.16, 0.04) and a maximum external quantum efficiency of 1.73%. Finally, stable and efficient ultra-deep-blue electroluminescence are obtained from PLEDs based on stretchable films with different strains and cycling deformations, suggesting excellent elastic-plastic behavior and deformation stability for flexible electronics.

Three-stage Dynamic Brain-cognitive Model of Understanding Action Intention Displayed by Human Body Movements.

The ability to comprehend the intention conveyed through human body movements is crucial for effective interpersonal interactions. If people can't understand the intention behind other individuals' isolated or interactive actions, their actions will become meaningless. Psychologists have investigated the cognitive processes and neural representations involved in understanding action intention, yet a cohesive theoretical explanation remains elusive. Hence, we mainly review existing literature related to neural correlates of action intention, and primarily propose a putative Three-stage Dynamic Brain-cognitive Model of understanding action intention, which involves body perception, action identification and intention understanding. Specifically, at the first stage, body parts/shapes are processed by those brain regions such as extrastriate and fusiform body areas; During the second stage, differentiating observed actions relies on configuring relationships between body parts, facilitated by the activation of the Mirror Neuron System; The last stage involves identifying various intention categories, utilizing the Mentalizing System for recruitment, and different activation patterns concerning the nature of the intentions participants dealing with. Finally, we delves into the clinical practice, like intervention training based on a theoretical model for individuals with autism spectrum disorders who encounter difficulties in interpersonal communication.

Environmental BaP/BPDE suppressed trophoblast cell invasion/migration and induced miscarriage by down-regulating lnc-HZ01/MEST/VIM axis.

Environmental benzo(a)pyrene (BaP) and itsmetabolite benzo(a)pyrene-7, 8-dihydrodiol-9, 10-epoxide (BPDE), classic endocrine disrupting chemical and persistent organic pollutant, could cause miscarriage. However, the detailed mechanisms are still largely unclear and should be further explored. In this study, we discovered that exposure of trophoblast cells with BPDE could suppressed cell invasion/migration by inhibiting MEST/VIM (Vimentin) pathway. Moreover, BPDE exposure also increased lnc-HZ01 expression level, which further inhibited MEST/VIM pathway and then suppressed invasion/migration. Knockdown of lnc-HZ01 or overexpression of MEST could efficiently rescue invasion/migration of BPDE-exposed Swan 71 cells. Furthermore, lnc-HZ01 was highly expressed and MEST/VIM were lowly expressed in recurrent miscarriage (RM) villous tissues compared with healthy control (HC) group. Finally, we also found that BaP exposure inhibited murine Mest/Vim pathway in placental tissues and induced miscarriage in BaP-exposed mice. Therefore, the regulatory mechanisms were similar in BPDE-exposed human trophoblast cells, RM villous tissues, and placental tissues of BaP-exposed mice with miscarriage, building a bridge to connect BaP/BPDE exposure, invasion/migration, and miscarriage. This study provided novel insights in the toxicological effects and molecular mechanisms of BaP/BPDE-induced miscarriage, which is helpful for better elucidating the toxicological risks of BaP/BPDE on female reproduction.

Softening the tumor matrix through cholesterol depletion breaks the physical barrier for enhanced antitumor therapy.

The tumor develops defense tactics, including conversing the mechanical characteristics of tumor cells and their surrounding environment. A recent study reported that cholesterol depletion stiffens tumor cells, which could enhance adaptive T-cell immunotherapy. However, it remains unclear whether reducing the cholesterol in tumor cells contributes to re-educating the stiff tumor matrix, which serves as a physical barrier against drug penetration. Herein, we found that depleting cholesterol from tumor cells can demolish the intratumor physical barrier by disrupting the mechanical signal transduction between tumor cells and the extracellular matrix through the destruction of lipid rafts. This disruption allows nanoparticles (H/S@hNP) to penetrate deeply, resulting in improved photodynamic treatment. Our research also indicates that cholesterol depletion can inhibit the epithelial-mesenchymal transition and repolarize tumor-associated macrophages from M2 to M1, demonstrating the essential role of cholesterol in tumor progression. Overall, this study reveals that a cholesterol-depleted, softened tumor matrix reduces the difficulty of drug penetration, leading to enhanced antitumor therapeutics.

BaP/BPDE suppresses human trophoblast cell migration/invasion and induces unexplained miscarriage by up-regulating a novel lnc-HZ11 in extracellular vesicles: An intercellular study.

Extracellular vesicles (EVs) mediate the intercellular crosstalk by transferring functional cargoes. Recently, we have discovered that BaP/BPDE exposure suppresses trophoblast cell migration/invasion and induces miscarriage, which are also regulate by lncRNAs at intracelluar levels. However, the EVs-mediated intercellular regulatory mechanisms are completely unexplored. Specifically, whether EVs might transfer BPDE-induced toxic lncRNA to fresh recipient trophoblast cells and suppress their migration/invasion to further induce miscarriage is completely unknown. In this study, we find that BPDE exposure up-regulates a novel lnc-HZ11, which suppresses EGR1/NF-κB/CXCL12 pathway and migration/invasion of trophoblast cells. Intercellular studies show that EV-HZ11 (lnc-HZ11 in EVs), which is highly expressed in BPDE-exposed donor cells, suppresses EGR1/NF-κB/CXCL12 pathway and migration/invasion in recipient cells by transferring lnc-HZ11 through EVs. Analysis of villous tissues collected from UM (unexplained miscarriage) patients and HC (healthy control) group shows that the levels of BPDE-DNA adducts, lnc-HZ11 or EV-lnc-HZ11, and EGR1/NF-κB/CXCL12 pathway are all associated with miscarriage. Mouse assays show that BaP exposure up-regulates the levels of lnc-Hz11 or EV-Hz11, suppresses Egr1/Nf-κb/Cxcl12 pathway, and eventually induces miscarriage. Knockdown of lnc-Hz11 by injecting EV-AS-Hz11 could effectively alleviate miscarriage in BaP-exposed mice. Furthermore, EV-HZ11 in serum samples could well predict the risk of miscarriage. Collectively, this study not only discovers EVs-HZ11-mediated intercellular mechanisms that BaP/BPDE suppresses trophoblast cell migration/invasion and induces miscarriage but also provides new approach for treatment against unexplained miscarriage through EV-HZ11.

Environmental copper exposure, placental cuproptosis, and miscarriage.

Copper pollution has become global environmental concern. Widespread Cu pollution results in excessive Cu exposure in human. Epidemiological studies and animal experiments revealed that Cu exposure might have reproductive toxicity. Cuproptosis is a newly reported Cu-dependent and programmed cell death formTsvetkov et al., 2022. However, whether copper exposure at real environmental exposure dose might cause placental cuproptosis and induce miscarriage was completely unexplored. In this study, we found that Cu exposure during pregnancy induced miscarriage or complete pregnancy loss by inducing placenta cuproptosis in CuCl2-exposed pregnant mice. Notably, Cu exposure at 1.3 mg/kg/d (a real environmental exposure dose) was enough to cause placenta cuproptosis. CuCl2 exposure disrupts the TCA cycle, causes proteotoxic stress, increases Cu2+ ion import/decreases Cu2+ export, and results in the loss of Fe-S cluster proteins in mouse placenta, which induces placenta cuproptosis. Moreover, we also identified that Cu exposure down-regulates the expression levels of mmu-miR-3473b, which interacts with Dlst or Rtel1 mRNA and simultaneously positively regulates Dlst or Rtel1 expression, thereby disrupting the TCA cycle and resulting in the loss of Fe-S cluster proteins, and thus epigenetically regulates placental cuproptosis. Treatment with TTM (a cuproptosis inhibitor) suppressed placental cuproptosis and alleviated miscarriage in CuCl2-exposed mice. This work provides novel reproductive toxicity of Cu exposure in miscarriage or complete pregnancy loss by causing placental cuproptosis. This study also provides new ways for further studies on other toxicological effects of Cu and proposes a new approach for protection against Cu-induced reproductive diseases.

Tyrosinase-Modified UHMW SELP Polymers as Wet and Underwater Adhesives to Achieve Multi-interface Adhesion.

The presence of a hydration layer in humid and underwater environments challenges adhesive-substrate interactions and prevents effective bonding, which has become a significant obstacle to the development of adhesives in the industrial and biomedical fields. In this study, ultrahigh-molecular-weight (UHMW) silk-elastin-like proteins (SELP) with 3,4-dihydroxyphenylalanine (DOPA) converted from tyrosine residues by tyrosinase exhibited excellent adhesive properties on different interfaces, such as glass, aluminum, wood, polypropylene sheets, and pigskin, under both dry and wet conditions. Additionally, by incorporating trace amounts of cross-linking agents like Fe3+, NaIO4, and tris(hydroxymethyl) phosphine (THP), the mussel-inspired adhesives maintained a stable and excellent adhesion, broadening the conditions of application. Notably, the UHMW SELP adhesive exhibited remarkable underwater adhesion properties with a shear strength of 0.83 ± 0.17 MPa on glass. It also demonstrated good adhesion to biological tissues including the kidney, liver, heart, and lungs. In vitro cytocompatibility testing using L929 cells showed minimal toxicity, highlighting its potential application in the biomedical field. The sustainable, cytocompatible, cost-effective, and highly efficient adhesive provides valuable insights for the design and development of a new protein-based underwater adhesive for medical application.

Triphenylamine Spirofunctionalized Light-Emitting Conjugated Polymer with an Ultradeep-Blue Narrowband Emission for Large-Area Printed Display.

Emerging printed large-area polymer light-emitting diodes (PLEDs) are essential for manufacturing flat-panel displays and solid lighting devices. However, it is challenging to obtain large-area and stable ultradeep-blue PLEDs because of the lack of light-emitting conjugated polymers (LCPs) with robust deep-blue emissions, excellent morphological stabilities, and high charging abilities. Here, a novel unsymmetrically substituted polydiarylfluorene (POPSAF) is obtained with stable narrowband emission for large-area printed displays via triphenylamine (TPA) spirofunctionalization of LCPs. POPSAF films show narrowband and stable ultradeep-blue emission with a full width at half maximum (FWHM) of 36 nm, associated with their intrachain excitonic behavior without obvious polaron formation. Compared to controlled poly[4-(octyloxy)-9,9-diphenylfluoren-2,7-diyl]-co-[5-(octyloxy)-9,9-diphenylfluoren-2,7-diyl] (PODPF), excellent charge transport is observed in the POPSAF films because of the intrinsic hole transport ability of the TPA units. Large-area PLEDs are fabricated via blade-coating with an emission area of 9 cm2, which exhibit uniform ultradeep-blue emission with an FWHM of 36 nm and corresponding Commission internationale de l'éclairage (CIE) coordinates of (0.155, 0.072). These findings are attributed to the synergistic effects of robust emission, stable morphology, and printing capacity. Finally, preliminary printed passive matrix (PM) PLED displays with 20 × 20 pixels monochromes are fabricated, confirmed the effectiveness of spirofunctionalization in optoelectronics.

Hypoxia causes trophoblast cell ferroptosis to induce miscarriage through lnc-HZ06/HIF1α-SUMO/NCOA4 axis.

Defects of human trophoblast cells may induce miscarriage (abnormal early embryo loss), which is generally regulated by lncRNAs. Ferroptosis is a newly identified iron-dependent programmed cell death. Hypoxia is an important and unavoidable feature in mammalian cells. However, whether hypoxia might induce trophoblast cell ferroptosis and then induce miscarriage, as well as regulated by a lncRNA, was completely unknown. In this work, we discovered at the first time that hypoxia could result in ferroptosis of human trophoblast cells and then induce miscarriage. We also identified a novel lncRNA (lnc-HZ06) that simultaneously regulated hypoxia (indicated by HIF1α protein), ferroptosis, and miscarriage. In mechanism, HIF1α-SUMO, instead of HIF1α itself, primarily acted as a transcription factor to promote the transcription of NCOA4 (ferroptosis indicator) in hypoxic trophoblast cells. Lnc-HZ06 promoted the SUMOylation of HIF1α by suppressing SENP1-mediated deSUMOylation. HIF1α-SUMO also acted as a transcription factor to promote lnc-HZ06 transcription. Thus, both lnc-HZ06 and HIF1α-SUMO formed a positive auto-regulatory feedback loop. This loop was up-regulated in hypoxic trophoblast cells, in RM villous tissues, and in placental tissues of hypoxia-treated mice, which further induced ferroptosis and miscarriage by up-regulating HIF1α-SUMO-mediated NCOA4 transcription. Furthermore, knockdown of either murine lnc-hz06 or Ncoa4 could efficiently suppress ferroptosis and alleviate miscarriage in hypoxic mouse model. Taken together, this study provided new insights in understanding the regulatory roles of lnc-HZ06/HIF1α-SUMO/NCOA4 axis among hypoxia, ferroptosis, and miscarriage, and also offered an effective approach for treatment against miscarriage.

A Holistic Review of C = C Crosslinkable Conjugated Molecules in Solution-Processed Organic Electronics: Insights into Stability, Processibility, and Mechanical Properties.

Solution-processable organic conjugated molecules (OCMs) consist of a series of aromatic units linked by σ-bonds, which present a relatively freedom intramolecular motion and intermolecular re-arrangement under external stimulation. The cross-linked strategy provides an effective platform to obtain OCMs network, which allows for outstanding optoelectronic, excellent physicochemical properties, and substantial improvement in device fabrication. An unsaturated double carbon-carbon bond (C = C) is universal segment to construct crosslinkable OCMs. In this review, the authors will set C = C cross-linkable units as an example to summarize the development of cross-linkable OCMs for solution-processable optoelectronic applications. First, this review provides a comprehensive overview of the distinctive chemical, physical, and optoelectronic properties arising from the cross-linking strategies employed in OCMs. Second, the methods for probing the C = C cross-linking reaction are also emphasized based on the perturbations of chemical structure and physicochemical property. Third, a series of model C = C cross-linkable units, including styrene, trifluoroethylene, and unsaturated acid ester, are further discussed to design and prepare novel OCMs. Furthermore, a concise overview of the optoelectronic applications associated with this approach is presented, including light-emitting diodes (LEDs), solar cells (SCs), and field-effect transistors (FETs). Lastly, the authors offer a concluding perspective and outlook for the improvement of OCMs and their optoelectronic application via the cross-linking strategy.

Defective Homologous Recombination Repair By Up-Regulating Lnc-HZ10/Ahr Loop in Human Trophoblast Cells Induced Miscarriage.

Human trophoblast cells are crucial for healthy pregnancy. However, whether the defective homologous recombination (HR) repair of dsDNA break (DSB) in trophoblast cells may induce miscarriage is completely unknown. Moreover, the abundance of BRCA1 (a crucial protein for HR repair), its recruitment to DSB foci, and its epigenetic regulatory mechanisms, are also fully unexplored. In this work, it is identified that a novel lnc-HZ10, which is highly experssed in villous tissues of recurrent miscarriage (RM) vs their healthy control group, suppresses HR repair of DSB in trophoblast cell. Lnc-HZ10 and AhR (aryl hydrocarbon receptor) form a positive feedback loop. AhR acts as a transcription factor to promote lnc-HZ10 transcription. Meanwhile, lnc-HZ10 also increases AhR levels by suppressing its CUL4B-mediated ubiquitination degradation. Subsequently, AhR suppresses BRCA1 transcription; and lnc-HZ10 (mainly 1-447 nt) interacts with γ-H2AX; and thus, impairs its interactions with BRCA1. BPDE exposure may trigger this loop to suppress HR repair in trophoblast cells, possibly inducing miscarriage. Knockdown of murine Ahr efficiently recovers HR repair in placental tissues and alleviates miscarriage in a mouse miscarriage model. Therefore, it is suggested that AhR/lnc-HZ10/BRCA1 axis may be a promising target for alleviation of unexplained miscarriage.

STK19 is a DNA/RNA-binding protein critical for DNA damage repair and cell proliferation.

STK19 was originally identified as a manganese-dependent serine/threonine-specific protein kinase, but its function has been highly debated. Here, the crystal structure of STK19 revealed that it does not contain a kinase domain, but three intimately packed winged helix (WH) domains. The third WH domain mediated homodimerization and double-stranded DNA binding, both being important for its nuclear localization. STK19 participated in the nucleotide excision repair (NER) and mismatch repair (MMR) pathways by recruiting damage repair factors such as RPA2 and PCNA. STK19 also bound double-stranded RNA through the DNA-binding interface and regulated the expression levels of many mRNAs. Furthermore, STK19 knockdown cells exhibited very slow cell proliferation, which cannot be rescued by dimerization or DNA-binding mutants. Therefore, this work concludes that STK19 is highly unlikely to be a kinase but a DNA/RNA-binding protein critical for DNA damage repair (DDR) and cell proliferation. To prevent further confusions, we renamed this protein as TWH19 (Tandem Winged Helix protein formerly known as STK19).

Polystyrene Nanoplastics Activate Autophagy and Suppress Trophoblast Cell Migration/Invasion and Migrasome Formation to Induce Miscarriage.

Nanoplastics (NPs), as emerging pollutants, have attracted global attention. Nevertheless, the adverse effects of NPs on female reproductive health, especially unexplained miscarriage, are poorly understood. Defects of trophoblast cell migration and invasion are associated with miscarriage. Migrasomes were identified as cellular organelles with largely unidentified functions. Whether NPs might affect migration, invasion, and migrasome formation and induce miscarriage has been completely unexplored. In this study, we selected polystyrene nanoplastics (PS-NPs, 50 nm) as a model of plastic particles and treated human trophoblast cells and pregnant mice with PS-NPs at doses near the actual environmental exposure doses of plastic particles in humans. We found that exposure to PS-NPs induced a pregnant mouse miscarriage. PS-NPs suppressed ROCK1-mediated migration/invasion and migrasome formation. SOX2 was identified as the transcription factor of ROCK1. PS-NPs activated autophagy and promoted the autophagy degradation of SOX2, thus suppressing SOX2-mediated ROCK1 transcription. Supplementing with murine SOX2 or ROCK1 could efficiently rescue migration/invasion and migrasome formation and alleviate miscarriage. Analysis of the protein levels of SOX2, ROCK1, TSPAN4, NDST1, P62, and LC-3BII/I in PS-NP-exposed trophoblast cells, villous tissues of unexplained miscarriage patients, and placental tissues of PS-NP-exposed mice gave consistent results. Collectively, this study revealed the reproductive toxicity of nanoplastics and their potential regulatory mechanism, indicating that NP exposure is a risk factor for female reproductive health.

Mitochondrial-Targeting Nanotrapper Captured Copper Ions to Alleviate Tumor Hypoxia for Amplified Photoimmunotherapy in Breast Cancer.

Hypoxia is a pervasive feature of solid tumors, which significantly limits the therapeutic effect of photodynamic therapy (PDT) and further influences the immunotherapy efficiency in breast cancer. However, the transient alleviation of tumor hypoxia fails to address the underlying issue of increased oxygen consumption, resulting from the rapid proliferation of tumor cells. At present, studies have found that the reduction of the oxygen consumption rate (OCR) by cytochrome C oxidase (COX) inhibition that induced oxidative phosphorylation (OXHPOS) suppression was able to solve the proposed problem. Herein, we developed a specific mitochondrial-targeting nanotrapper (I@MSN-Im-PEG), which exhibited good copper chelating ability to inhibit COX for reducing the OCR. The results proved that the nanotrapper significantly alleviated the hypoxic tumor microenvironment by copper chelation in mitochondria and enhanced the PDT effect in vitro and in vivo. Meanwhile, the nanotrapper improved photoimmunotherapy through both enhancing PDT-induced immunogenetic cell death (ICD) effects and reversing Treg-mediated immune suppression on 4T1 tumor-bearing mice. The mitochondrial-targeting nanotrapper provided a novel and efficacious strategy to enhance the PDT effect and amplify photoimmunotherapy in breast cancer.

A potential bilayer skin substitute based on electrospun silk-elastin-like protein nanofiber membrane covered with bacterial cellulose.

Skin substitutes are designed to promote wound healing by replacing extracellular matrix. Silk-elastin-like protein is a renewable extracellular matrix-like material that integrated the advantages of silk and elastin-like protein. In this study, electrospun silk-elastin-like protein (SELP) nanofiber membrane covered with bacterial cellulose (BC) was created as a potential skin substitute to mimic gradient structure of epidermis and dermis of skin. The two layers were glued together using adhesive SELP containing 3,4-dihydroxyphenylalanine (DOPA) converted from tyrosine by tyrosinase. Skin topical drugs commonly used in clinical practice can penetrate through the SELP/BC barrier, and the rate of penetration is proportional to drug concentration. BC with dense fibrous structure can act as a barrier to preserve the inner SELP layer and prevent bacterial invasion, with a blocking permeation efficiency over 99% against four species of bacteria. Cell experiments demonstrated that the reticular fibers of SELP could provide an appropriate growth environment for skin cells proliferation and adhesion, which is considered to promote tissue repair and regeneration. The promising results support this strategy to fabricate a silk-elastin-like protein-based biomaterial for skin substitutes in the clinical treatment of full skin injuries and ulcers.

Biodegradable and Efficient Charge-Migrated Z-Scheme Heterojunction Amplifies Cancer Ferroptosis by Blocking Defensive Redox System.

Ferroptosis is an emerging non-apoptotic death process, mainly involving lipid peroxidation (LPO) caused by iron accumulation, which is potentially lethal to the intrinsically apoptotic-resistant malignant tumor. However, it is still restricted by the inherent antioxidant systems of tumor cells and the poor efficacy of traditional iron-based ferroptosis initiators. Herein, the study develops a novel ferroptosis-inducing agent based on PEGylated Cu+/Cu2+-doped black phosphorus@polypyrrole heterojunction (BP@CPP), which is constructed by utilizing the phosphate on the surface of BP to chelate Cu ions and initiating subsequent in situ polymerization of pyrrole. As a novel Z-scheme heterojunction, BP@CPP possesses an excellent photocatalytic activity in which the separated electron-hole pairs under laser irradiation endow it with powerful oxidizing and reducing capacities, which synergy with Cu+/Cu2+ self-cycling catalyzing Fenton-like reaction to further strengthen reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, and glutathione peroxidase 4 (GPX4) inactivation, ultimately leading to efficient ferroptosis. Systematic in vitro and in vivo evaluations demonstrate that BP@CPP effectively inhibit tumor growth by inducing desired ferroptosis while maintaining a favorable biosafety in the body. Therefore, the developed BP@CPP-based ferroptosis initiator provides a promising strategy for ferroptosis-like cancer therapy.

Discovery of a Hidden Pocket beneath the NES Groove by Novel Noncovalent CRM1 Inhibitors.

Protein localization is frequently manipulated to favor tumor initiation and progression. In cancer cells, the nuclear export factor CRM1 is often overexpressed and aberrantly localizes many tumor suppressors via protein-protein interactions. Although targeting protein-protein interactions is usually challenging, covalent inhibitors, including the FDA-approved drug KPT-330 (selinexor), were successfully developed. The development of noncovalent CRM1 inhibitors remains scarce. Here, by shifting the side chain of two methionine residues and virtually screening against a large compound library, we successfully identified a series of noncovalent CRM1 inhibitors with a stable scaffold. Crystal structures of inhibitor-protein complexes revealed that one of the compounds, B28, utilized a deeply hidden protein interior cavity for binding. SAR analysis guided the development of several B28 derivatives with enhanced inhibition on nuclear export and growth of multiple cancer cell lines. This work may benefit the development of new CRM1-targeted therapies.

Temporal and spatial dynamics of immune cells in spontaneous liver transplant tolerance.

The liver has long been deemed a tolerogenic organ. We employed high-dimensional mass cytometry and immunohistochemistry to depict the temporal and spatial dynamics of immune cells in the spleen and liver in a murine model of spontaneous liver allograft acceptance. We depicted the immune landscape of spontaneous liver tolerance throughout the rejection and acceptance stages after liver transplantation and highlighted several points of importance. Of note, the CD4+/CD8+ T cell ratio remained low, even in the tolerance phase. Furthermore, a PhenoGraph clustering analysis revealed that exhausted CD8+ T cells were the most dominant metacluster in graft-infiltrating lymphocytes (GILs), which highly expressed the costimulatory molecule CD86. The temporal and spatial dynamics of immune cells revealed by high-dimensional analyses enable a fine-grained analysis of GIL subsets, contribute to new insights for the discovery of immunological mechanisms of liver tolerance, and provide potential ways to achieve clinical operational tolerance after liver transplantation.

CD93 overexpresses in liver hepatocellular carcinoma and represents a potential immunotherapy target.

Background: Liver hepatocellular carcinoma (LIHC) is one of the malignant tumors with high incidence as well as high death, which is ranked as the sixth most common tumor and the third highest mortality worldwide. CD93, a transmembrane protein, has been widely reported to play an important role in different types of diseases, including many types of cancer by mainly functioning in extracellular matrix formation and vascular maturation. However, there are few researches focusing on the role and potential function of CD93 in LIHC. Methods: In this study, we comprehensively analyzed the relationship between CD93 and LIHC. We not only discovered transcriptional expression of CD93 in LIHC by using the TIMER, GEPIA and UALCAN database, but also performed WB and IHC to verify the protein expression of CD93 in LIHC. Meantime, Kaplan-Meier Plotter Database Analysis were used to assess the prognosis of CD93 in LIHC. After knowing close correlation between CD93 expression and LIHC, there were STRING, GeneMania and GO and KEGG enrichment analyses to find how CD93 functions in LIHC. We further applied CIBERSORT Algorithm to explore the correlation between CD93 and immune cells and evaluate prognostic value of CD93 based on them in LIHC patients. Results: The transcriptional and protein expression of CD93 were both obviously increased in LIHC by above methods. There was also a significant and close correlation between the expression of CD93 and the prognosis of LIHC patients by using Kaplan-Meier Analysis, which showed that LIHC patients with elevated expression of CD93 were associated with a predicted poor prognosis. We found that the functions of CD93 in different cancers are mainly related to Insulin like growth factor binding protein 7 Gene (IGFBP7)/CD93 pathway via STRING, GeneMania and functional enrichment analyses. Further, our data obtained from CIBERSORT Algorithm suggested CD93 was also associated with the immune response. There is a close positive correlation between CD93 expression and the infiltration levels of all six types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells). Importantly, CD93 can affect the prognosis of patients with LIHC partially due to immune infiltration. Conclusion: Our results demonstrated CD93 may be a candidate predictor of clinical prognosis and immunotherapy response in LIHC.