Tumor-derived exosomal PD-L1: a new perspective in PD-1/PD-L1 therapy for lung cancer.

Exosomes play a crucial role in facilitating intercellular communication within organisms. Emerging evidence indicates that a distinct variant of programmed cell death ligand-1 (PD-L1), found on the surface of exosomes, may be responsible for orchestrating systemic immunosuppression that counteracts the efficacy of anti-programmed death-1 (PD-1) checkpoint therapy. Specifically, the presence of PD-L1 on exosomes enables them to selectively target PD-1 on the surface of CD8+ T cells, leading to T cell apoptosis and impeding T cell activation or proliferation. This mechanism allows tumor cells to evade immune pressure during the effector stage. Furthermore, the quantification of exosomal PD-L1 has the potential to serve as an indicator of the dynamic interplay between tumors and immune cells, thereby suggesting the promising utility of exosomes as biomarkers for both cancer diagnosis and PD-1/PD-L1 inhibitor therapy. The emergence of exosomal PD-L1 inhibitors as a viable approach for anti-tumor treatment has garnered significant attention. Depleting exosomal PD-L1 may serve as an effective adjunct therapy to mitigate systemic immunosuppression. This review aims to elucidate recent insights into the role of exosomal PD-L1 in the field of immune oncology, emphasizing its potential as a diagnostic, prognostic, and therapeutic tool in lung cancer.

Elucidating the enhanced role of carbonate radical in propranolol degradation by UV/peroxymonosulfate system.

Carbonate radical (CO3•-) has been proved to be an important secondary radical in advanced oxidation processes due to various radical reactions involved HCO3-/CO32-. However, the roles and contributions of CO3•- in organic micropollutant degradation have not been explored systematically. Here, we quantified the impact of CO3•- on the degradation kinetics of propranolol, a representative pollutant in the UV/peroxymonosulfate (PMS) system, by constructing a steady-state radical model. Substantially, the measured values were coincident with the predictive values, and the contributions of CO3•- on propranolol degradation were the water matrix-dependent. Propranolol degradation increased by 130% in UV/PMS system containing 10 mM HCO3-, and the contribution of CO3•- was as high as 58%. Relatively high pH values are beneficial for propranolol degradation in pure water containing HCO3-, and the contributions of CO3•- also enhanced, while an inverse phenomenon was shown for the effects of propranolol concentrations. Dissolved organic matter exhibited significant scavenging effects on HO•, SO4•-, and CO3•-, substantially retarding the elimination process. The developed model successfully predicted oxidation degradation kinetics of propranolol in actual sewage, and CO3•- contribution was up to 93%, which in indicative of the important role of CO3•- in organic micropollutant removal via AOPs treatment.

Replenishment of mitochondrial Na+ and H+ by ionophores potentiates cutaneous wound healing in diabetes.

Diabetic foot ulcer (DFU) is a highly morbid complication in patients with diabetes mellitus, necessitating the development of innovative pharmaceuticals to address unmet medical needs. Sodium ion (Na+) is a well-established mediator for membrane potential and osmotic equilibrium. Recently, Na+ transporters have been identified as a functional regulator of regeneration. However, the role of Na+ in the intricate healing process of mammalian wounds remains elusive. Here, we found that the skin wounds in hyponatremic mice display a hard-to-heal phenotype. Na+ ionophores that were employed to increase intracellular Na+ content could facilitate keratinocyte proliferation and migration, and promote angiogenesis, exhibiting diverse biological activities. Among of them, monensin A emerges as a promising agent for accelerating the healing dynamics of skin wounds in diabetes. Mechanistically, the elevated mitochondrial Na+ decelerates inner mitochondrial membrane fluidity, instigating the production of reactive oxygen species (ROS), which is identified as a critical effector on the monensin A-induced improvement of wound healing. Concurrently, Na+ ionophores replenish H+ to the mitochondrial matrix, causing an enhancement of mitochondrial energy metabolism to support productive wound healing programs. Our study unfolds a new role of Na+, which is a pivotal determinant in wound healing. Furthermore, it directs a roadmap for developing Na+ ionophores as innovative pharmaceuticals for treating chronic dermal wounds in diabetic patients.

Intranational synergies and trade-offs reveal common and differentiated priorities of sustainable development goals in China.

Accelerating efforts for the Sustainable Development Goals requires understanding their synergies and trade-offs at the national and sub-national levels, which will help identify the key hurdles and opportunities to prioritize them in an indivisible manner for a country. Here, we present the importance of the 17 goals through synergy and trade-off networks. Our results reveal that 19 provinces show the highest trade-offs in SDG13 (Combating Climate Change) or SDG5 (Gender Equality) consistent with the national level, with other 12 provinces varying. 24 provinces show the highest synergies in SDG1 (No Poverty) or SDG6 (Clean Water and Sanitation) consistent with the national level, with the remaining 7 provinces varying. These common but differentiated SDG priorities reflect that to ensure a coordinated national response, China should pay more attention to the provincial situation, so that provincial governments can formulate more targeted policies in line with their own priorities towards accelerating sustainable development.

The oncogene MYBL2 promotes the malignant phenotype and suppresses apoptosis through hedgehog signaling pathway in clear cell renal cell carcinoma.

Multiple cancers have been associated with MYB-related protein B (MYBL2), its involvement in clear cell renal cell carcinoma (ccRCC) has yet to be demonstrated. Our study revealed a significant upregulation of MYBL2 in ccRCC tissues, correlating with clinicopathological features and patient prognosis. Increased MYBL2 expression promoted cell proliferation and suppressed apoptosis. RNA-seq analysis unveiled a reduction in smoothened (SMO) expression upon MYBL2 silencing. However, luciferase and chromatin immunoprecipitation (ChIP) assays demonstrated MYBL2's positive regulation of SMO expression by directly targeting the SMO promoter. Reintroduction of SMO expression in MYBL2-knocked down cells partially restored cell proliferation and mitigated apoptosis inhibition. Overall, these results indicate that MYBL2 facilitates ccRCC progression by enhancing SMO expression, suggesting its potential as an intriguing drug target for ccRCC therapy.

Deciphering Recursive Polyploidization in Lamiales and Reconstructing Their Chromosome Evolutionary Trajectories.

Lamiales is an order of core eudicots with abundant diversity, and many Lamiales plants have important medicinal and ornamental values. Here, we comparatively reanalyzed 11 Lamiales species with well-assembled genome sequences and found evidence that Lamiales plants, in addition to a hexaploidization or whole-genome triplication (WGT) shared by core eudicots, experienced further polyploidization events, establishing new groups in the order. Notably, we identified a whole-genome duplication (WGD) occurred just before the split of Scrophulariaceae from the other Lamiales families, such as Acanthaceae, Bignoniaceae, and Lamiaceae, suggesting its likely being the causal reason for the establishment and fast divergence of these families. We also found that a WGT occurred ∼68-78 Mya, near the split of Oleaceae from the other Lamiales families, implying that it may have caused their fast divergence and the establishment of the Oleaceae family. Then, by exploring and distinguishing intra- and inter-genomic chromosomal homology due to recursive polyploidization and speciation, respectively, we inferred that the Lamiales ancestral cell karyotype had 11 proto-chromosomes. We reconstructed the evolutionary trajectories from these proto-chromosomes to form the extant chromosomes in each Lamiales plant under study. We must note that most of the inferred 11 proto-chromosomes, duplicated during a WGD thereafter, have been well preserved in Jacaranda (Jacaranda mimosifolia) genome, showing the credibility of the present inference implementing a telomere-centric chromosome repatterning model. These efforts are important to understand genome repatterning after recursive polyploidization, especially shedding light on the origin of new plant groups and angiosperm cell karyotype evolution.

Characteristics of typical intermediate and semi volatile organic compounds in Shanghai during China International Import Expo event.

To ensure good air quality during the China International Import Expo (CIIE) event, stringent emission-reduction measures were implemented in Shanghai. To assess the efficacy of these measures, this study measured typical categories of intermediate/semi volatile organic compounds (I/SVOCs), including alkanes (C10-C26 n-alkanes and pristane), EPA-priority polycyclic aromatic hydrocarbons (PAHs), alkylnaphthalenes, benzothiazole (BTH) and chlorobenzenes (CBs), at an urban site of Shanghai before and during two CIIE events (2019 and 2020; non-CIIE versus CIIE). The average concentrations of alkanes and PAHs during both 2019 and 2020 CIIE events decreased by approximately 41% and 17%, respectively, compared to non-CIIE periods. However, the decline in BTH and CBs was only observed during CIIE-2019. Secondary organic aerosol (SOA) formation from alkanes, PAHs and BTH was evaluated under atmospheric conditions, revealing considerable SOA contributions from dimethylnaphthalenes and BTH. Positive matrix factorization (PMF) analysis further revealed that life-related sources, such as cooking and residential emissions, make a noticeable contribution (21.6%) in addition to the commonly concerned gasoline-vehicle sources (31.5%), diesel-related emissions (20.8%), industrial emissions (18.6%) and ship emissions (7.5%). These findings provide valuable insights into the efficacy of the implemented measures in reducing atmospheric I/SVOCs levels. Moreover, our results highlight the significance of exploring additional individual species of I/SVOCs and life-related sources for further research and policy development.

Improved adaptive regularization for simulated annealing inversion of transient electromagnetic.

Geophysical inversion usually involves ill-posed problem. Regularization is the most commonly used method to mitigate this problem. There are many regularization parameter selection methods, among which the adaptive regularization method can automatically update parameters during iteration, reducing the difficulty of parameter selection. Therefore, it is widely used in linear inversion. However, there are very few studies on the use of adaptive regularization methods in stochastic optimization algorithms. The biggest difficulty is that in stochastic optimization algorithms, the search direction of any iteration is completely random. Data fitting term and stabilizing term vary in a wide range, making it difficult for traditional methods to work. In this paper, we consider the contributions of the data fitting term and the stabilizing term in the objective function and give an improved adaptive regularization method for very fast simulated annealing (VFSA) inversion for transient electromagnetic (TEM) data. The optimized method adjusts the two terms dynamically to make them in balance. We have designed several numerical experiments, and the experimental results demonstrate that the method in this paper not only accelerates the convergence, but also the inversion results are very little affected by the initial regularization parameter. Finally, we apply this method to field data, and the inversion results show very good agreements with nearby borehole data.

CRISPR/Cas gene editing and delivery systems for cancer therapy.

CRISPR/Cas systems stand out because of simplicity, efficiency, and other superiorities, thus becoming attractive and brilliant gene-editing tools in biomedical field including cancer therapy. CRISPR/Cas systems bring promises for cancer therapy through manipulating and engineering on tumor cells or immune cells. However, there have been concerns about how to overcome the numerous physiological barriers and deliver CRISPR components to target cells efficiently and accurately. In this review, we introduced the mechanisms of CRISPR/Cas systems, summarized the current delivery strategies of CRISPR/Cas systems by physical methods, viral vectors, and nonviral vectors, and presented the current application of CRISPR/Cas systems in cancer clinical treatment. Furthermore, we discussed prospects related to delivery approaches of CRISPR/Cas systems. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Recent Developments in CaCO3 Nano-Drug Delivery Systems: Advancing Biomedicine in Tumor Diagnosis and Treatment.

Calcium carbonate (CaCO3), a natural common inorganic material with good biocompatibility, low toxicity, pH sensitivity, and low cost, has a widespread use in the pharmaceutical and chemical industries. In recent years, an increasing number of CaCO3-based nano-drug delivery systems have been developed. CaCO3 as a drug carrier and the utilization of CaCO3 as an efficient Ca2+ and CO2 donor have played a critical role in tumor diagnosis and treatment and have been explored in increasing depth and breadth. Starting from the CaCO3-based nano-drug delivery system, this paper systematically reviews the preparation of CaCO3 nanoparticles and the mechanisms of CaCO3-based therapeutic effects in the internal and external tumor environments and summarizes the latest advances in the application of CaCO3-based nano-drug delivery systems in tumor therapy. In view of the good biocompatibility and in vivo therapeutic mechanisms, they are expected to become an advancing biomedicine in the field of tumor diagnosis and treatment.

Dynamic Neural Patterns of Human Emotions in Virtual Reality: Insights from EEG Microstate Analysis.

Emotions play a crucial role in human life and affect mental health. Understanding the neural patterns associated with emotions is essential. Previous studies carried out some exploration of the neural features of emotions, but most have designed experiments in two-dimensional (2D) environments, which differs from real-life scenarios. To create a more real environment, this study investigated emotion-related brain activity using electroencephalography (EEG) microstate analysis in a virtual reality (VR) environment. We recruited 42 healthy volunteers to participate in our study. We explored the dynamic features of different emotions, and four characteristic microstates were analyzed. In the alpha band, microstate A exhibited a higher occurrence in both negative and positive emotions than in neutral emotions. Microstate C exhibited a prolonged duration of negative emotions compared to positive emotions, and a higher occurrence was observed in both microstates C and D during positive emotions. Notably, a unique transition pair was observed between microstates B and C during positive emotions, whereas a unique transition pair was observed between microstates A and D during negative emotions. This study emphasizes the potential of integrating virtual reality (VR) and EEG to facilitate experimental design. Furthermore, this study enhances our comprehension of neural activities during various emotional states.

Reversing cancer immunoediting phases with a tumor-activated and optically reinforced immunoscaffold.

In situ vaccine (ISV) is a promising immunotherapeutic tactic due to its complete tumoral antigenic repertoire. However, its efficiency is limited by extrinsic inevitable immunosuppression and intrinsic immunogenicity scarcity. To break this plight, a tumor-activated and optically reinforced immunoscaffold (TURN) is exploited to trigger cancer immunoediting phases regression, thus levering potent systemic antitumor immune responses. Upon response to tumoral reactive oxygen species, TURN will first release RGX-104 to attenuate excessive immunosuppressive cells and cytokines, and thus immunosuppression falls and immunogenicity rises. Subsequently, intermittent laser irradiation-activated photothermal agents (PL) trigger abundant tumor antigens exposure, which causes immunogenicity springs and preliminary infiltration of T cells. Finally, CD137 agonists from TURN further promotes the proliferation, function, and survival of T cells for durable antitumor effects. Therefore, cancer immunoediting phases reverse and systemic antitumor immune responses occur. TURN achieves over 90 % tumor growth inhibition in both primary and secondary tumor lesions, induces potent systemic immune responses, and triggers superior long-term immune memory in vivo. Taken together, TURN provides a prospective sight for ISV from the perspective of immunoediting phases.

In Vivo Evaluation of Corneal Biomechanics Following Cross-Linking Surgeries Using Optical Coherence Elastography in a Rabbit Model of Keratoconus.

Purpose: Validation of the feasibility of novel acoustic radiation force optical coherence elastography (ARF-OCE) for the evaluation of biomechanical enhancement of the in vivo model of keratoconus by clinical cross-linking (CXL) surgery. Methods: Twelve in vivo rabbit corneas were randomly divided into two groups. Both groups were treated with collagenase type II, and a keratoconus model was obtained. Then, the two groups were treated with CXL procedures with different irradiation energy of 15 J and 30 J (CXL-15 J and CXL-30 J, respectively). An ARF-OCE probe with an ultrasmall ultrasound transducer was used to detect the biomechanical properties of cornea. An antisymmetric Lamb wave model was combined with the frequency dispersion relationship to achieve depth-resolved elastography. Results: Compared with the phase velocity of the Lamb wave in healthy corneas (approximately 3.96 ± 0.27 m/s), the phase velocity of the Lamb wave was lower in the keratoconus region (P < 0.05), with an average value of 3.12 ± 0.12 m/s. Moreover, the corneal stiffness increased after CXL treatment (P < 0.05), and the average phase velocity of the Lamb wave was 4.3 ± 0.19 m/s and 4.54 ± 0.13 m/s after CXL-15 J and CXL-30 J treatment. Conclusions: The Young's moduli of the keratoconus regions were significantly lower than the healthy corneas. Moreover, the Young's modulus of the keratoconus regions was significantly higher after CXL-30 J treatment than after CXL-15 J treatment. We demonstrated that the ARF-OCE technique has great potential in screening keratoconus and guiding clinical CXL treatment. Translational Relevance: This work accelerates the clinical translation of OCE systems using ultrasmall ultrasound transducers and is used to guide CXL procedures.

Total Neoadjuvant Therapy With PD-1 Blockade for High-Risk Proficient Mismatch Repair Rectal Cancer.

Importance: Total neoadjuvant therapy (TNT) is the standard treatment for locally advanced rectal cancer, especially for patients with high-risk factors. However, the efficacy of TNT combined with immunotherapy for patients with proficient mismatch repair (pMMR) rectal cancer is unknown. Objectives: To evaluate the safety and efficacy of TNT with induction chemoimmunotherapy followed by long-course chemoradiation in patients with high-risk, pMMR rectal cancer and to identify potential molecular biomarkers associated with treatment efficacy. Design, Setting, and Participants: This cohort study was a single-arm phase 2 trial conducted at Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, from June 2020 to October 2021. Biopsies and plasma were collected before treatment for whole-exome sequencing and cell-free DNA sequencing, respectively. Data were analyzed from May 2022 to September 2022. Interventions: Participants received 3 cycles of induction oxaliplatin and capecitabine combined with camrelizumab and radiotherapy (50.6 Gy in 22 fractions) with concurrent capecitabine. Patients without disease progression received 2 cycles of consolidation oxaliplatin/capecitabine. Main Outcomes and Measures: The primary end point was pathologic complete response rate. Results: Of 25 patients enrolled (19 men [76%]; 6 women [24%]; median [IQR] age, 58 [48-64] years), 22 patients (88%) completed the TNT schedule. The pathologic complete response rate was 33.3% (7/21). Twelve patients (48%) achieved clinical complete response, and 4 patients (16%) chose to watch and wait. R0 resection was achieved in 21 of 21 patients, and the major pathologic response rate was 38.1% (8/21). The most common adverse event was nausea (80%, 20/25); grade 3 toxic effects occurred in 9 of 25 patients (36%). Patients with tumor shrinkage of 50% or greater after induction oxaliplatin/capecitabine and camrelizumab or clinical complete response had higher percentages of LRP1B mutation. Mutation of LRP1B was associated with high tumor mutation burden and tumor neoantigen burden. Patients with high tumor mutation burden all benefited from therapy. Conclusions and Relevance: This study found that TNT with induction chemoimmunotherapy followed by long-course chemoradiation was safe and effective for patients with high-risk rectal cancer with pMMR status. Longer follow-up and larger clinical studies are needed to validate this innovative regimen. There is also an urgent need to further validate the predictive value of LRP1B and discover other novel biomarkers with potential predictive value for rectal cancer.

A self-powered and self-sensing knee negative energy harvester.

Wearable devices realize health monitoring, information transmission, etc. In this study, the human-friendliness, adaptability, reliability, and economy (HARE) principle for designing human energy harvesters is first proposed and then a biomechanical energy harvester (BMEH) is proposed to recover the knee negative energy to generate electricity. The proposed BMEH is mounted on the waist of the human body and connected to the ankles by ropes for driving. Double-rotor mechanism and half-wave rectification mechanism design effectively improves energy conversion efficiency with higher power output density for more stable power output. The experimental results demonstrate that the double-rotor mechanism increases the output power of the BMEH by 70% compared to the single magnet-rotor mechanism. And the output power density of BMEH reaches 0.07 W/kg at a speed of 7 km/h. Furthermore, the BMEH demonstrates the excitation mode detection accuracy of 99.8% based on the Gate Recurrent Unit deep learning model with optimal parameters.

Low-cost and efficient strategy for brown algal hydrolysis: Combination of alginate lyase and cellulase.

Brown algae are rich in biostimulants that not only stimulate the overall development and growth of plants but also have great beneficial effects on the whole soil-plant system. However, alginate, the major component of brown algae, is comparatively difficult to degrade. The cost of preparing alginate oligosaccharides (AOSs) is still too high to produce seaweed fertilizer. In this work, the marine bacterium Vibrio sp. B1Z05 is found to be capable of efficient alginate depolymerization and harbors an extended pathway for alginate metabolism. The B1Z05 extracellular cell-free supernatant exhibited great potential for AOS production at low cost, which, together with cellulase, can efficiently hydrolyze seaweed. The brown algal hydrolysis rates were significantly greater than those of the commercial alginate lyase product CE201, and the obtained seaweed extracts were rich in phytohormones. This work provides a low-cost but efficient strategy for the sustainable production of desirable AOSs and seaweed fertilizer.

The effects of resonance acoustic mixing modulation on the structural and emulsifying properties of pea protein isolate.

The effects of resonant acoustic mixing (RAM) with different treatment times (0, 5, 10, 15, 20 and 30 min) on the structural and emulsifying properties of pea protein isolate (PPI) were investigated for the first time. Increasing the RAM treatment time from 0 to 20 min decreased the α-helix/ß-sheet ratio and particle size of the PPI samples by 37.84 % and 46.44 %, respectively, accompanied by an increase in solubility from 54.79 % to 71.80 % (P < 0.05). Consequently, the emulsifying activity index of PPI (from 10.45 m2/g to 14.2 m2/g) and the physical stability of RAM-PPI emulsions were effectively enhanced, which was confirmed by the small and uniformly distributed oil droplets in the micrographs of the emulsions. However, excessive RAM treatment (30 min) diminished the effectiveness of the aforementioned improvements. Therefore, obviously enhanced solubility and emulsifying properties of PPI can be attained through proper RAM treatment (15-20 min).

Effect of oxide impurities on the dissolution behavior of Th4+, Be2+ and U4+ in fluoride salts.

Oxides are one of the most important impurities in the fuel salt of molten salt reactors (MSRs), and excessive oxide impurities pose a risk to the safe operation of MSRs. This study focused on investigating the precipitation behavior between Th4+, U4+, and Be2+ with O2- in the 2LiF-BeF2 (FLiBe) eutectic salt system. The results showed that the solubility of UO2 was 5.52 × 10-3 mol kg-1, and the solubility product (Ksp) of UO2 was 6.14 × 10-7 mol3 kg-3 in FLiBe salt at 650 °C. It was also found that the O2- ion would firstly react with U4+ to form UO2, and then the excessive O2- would react with Be2+ to generate BeO in the FLiBe system. Despite conducting the solubility experiment of ThO2 and titration experiment of FLiBe-ThF4, the system failed to achieve the solubility and the Ksp of ThO2. The main reason for this was that O2- preferentially reacted with Be2+ over Th4+ to form precipitates, in other words, Be2+ exerted a protective effect against Th4+. Above all, this work experimentally demonstrated that in the FLiBe system, O2- preferentially combines with U4+ to form a precipitate, followed by Be2+, while Th4+ is relatively inert.

Hierarchical-unlocking virus-esque NanoCRISPR precisely disrupts autocrine and paracrine pathway of VEGF for tumor inhibition and antiangiogenesis.

Vascular endothelial growth factor (VEGF) not only serves as an autocrine survival factor for tumor cells themselves, but also stimulates angiogenesis by paracrine pathway. Strategies targeting VEGF holds tremendous potential for tumor therapy, however, agents targeting VEGF are limited by intolerable side effects, together with incomplete and temporary blocking of VEGF, resulting in unsatisfactory and unsustained therapeutic outcomes. Herein, hierarchical-unlocking virus-esque NanoCRISPR (HUNGER) is constructed for complete, permanent and efficient intracellular disruption of autocrine and paracrine pathway of VEGF, thereby eliciting notable tumor inhibition and antiangiogenesis. After intravenous administration, HUNGER exhibits prolonged blood circulation and hyaluronic acid-CD44 mediated tumor-targeting capability. Subsequently, when matrix metalloproteinase-2 is overexpressed in the tumor microenvironment, the PEG layer will be removed. The cell-penetrating peptide R8 endows HUNGER deep tumor penetration and specific cellular uptake. Upon cellular internalization, HUNGER undergoes hyaluronidase-triggered deshielding in lysosome, lysosomal escape is realized swiftly, and then the loaded CRISPR/Cas9 plasmid (>8 kb) is transported to nucleus efficiently. Consequentially, complete, permanent and efficient intracellular disruption of autocrine and paracrine pathway of VEGF ensures inhibition of angiogenesis and tumor growth with inappreciable toxicity. Overall, this work opens a brand-new avenue for anti-VEGF therapy and presents a feasible strategy for in vivo delivery of CRISPR/Cas9 system.