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Abstract Background Elderly patients suffering from osteoporotic fractures are more susceptible to delayed union or nonunion, and their bodies then are in a state of low-grade chronic inflammation with decreased antioxidant capacity. Tanshinone IIA is widely used in treating cardiovascular and cerebrovascular diseases in China and has anti-inflammatory and antioxidant effects. We aimed to observe the antioxidant effects of Tanshinone IIA on mesenchymal stem cells (MSCs), which play important roles in bone repair, and the effects of local application of Tanshinone IIA using an injectable biodegradable hydrogel on osteoporotic fracture healing. Methods MSCs were pretreated with or without different concentrations of Tanshinone IIA followed by H2O2 treatment. Ovariectomized (OVX) C57BL/6 mice received a mid-shaft transverse osteotomy fracture on the left tibia, and Tanshinone IIA was applied to the fracture site using an injectable hydrogel. Results Tanshinone IIA pretreatment promoted the expression of nuclear factor erythroid 2-related factor 2 and antioxidant enzymes, and inhibited H2O2-induced reactive oxygen species accumulation in MSCs. Furthermore, Tanshinone IIA reversed H2O2-induced apoptosis and decrease in osteogenic differentiation in MSCs. After 4 weeks of treatment with Tanshinone IIA in OVX mice, the bone mineral density of the callus was significantly increased and the biomechanical properties of the healed tibias were improved. Cell apoptosis was decreased and Nrf2 expression was increased in the early stage of callus formation. Conclusions Taken together, these results indicate that Tanshinone IIA can activate antioxidant enzymes to protect MSCs from H2O2-induced cell apoptosis and osteogenic differentiation inhibition. Local application of Tanshinone IIA accelerates fracture healing in ovariectomized mice.

Point clouds are highly regarded in the field of 3D object detection for their superior geometric properties and versatility. However, object occlusion and defects in scanning equipment frequently result in sparse and missing data within point clouds, adversely affecting the final prediction. Recognizing the synergistic potential between the rich semantic information present in images and the geometric data in point clouds for scene representation, we introduce a two-stage fusion framework (TSFF) for 3D object detection. To address the issue of corrupted geometric information in point clouds caused by object occlusion, we augment point features with image features, thereby enhancing the reference factor of the point cloud during the voting bias phase. Furthermore, we implement a constrained fusion module to selectively sample voting points using a 2D bounding box, integrating valuable image features while reducing the impact of background points in sparse scenes. Our methodology was evaluated on the SUNRGB-D dataset, where it achieved a 3.6 mean average percent (mAP) improvement in the mAP@0.25 evaluation criterion over the baseline. In comparison to other great 3D object detection methods, our method had excellent performance in the detection of some objects.

Remote islands, comprising over one-sixth of the Earth's surface area and home to approximately 9% of the global population, face formidable challenges in securing affordable, sustainable, and reliable energy. This paper presents a pioneering investigation into Mornington Island's transition from diesel reliance to renewable energy predominance over the next four decades. By demonstrating the tangible benefits of renewable energy implementation on Mornington Island, this research provides compelling simulated evidence that blending traditional and renewable energy sources can revolutionize energy provision for small island communities. Employing hybrid Wind-Solar renewable energy systems bolstered by an effective battery storage system (ESS), this innovative approach ensures a seamless shift to renewable energy, resilient against seasonal variations and extreme weather events such as cyclones. Our analysis, conducted through a tech-economic model simulating each 5% increment of renewable energy penetration, reveals that renewable energy outperforms traditional diesel generation in terms of affordability over a 40-year operational span. Specifically, a 95% renewable energy penetration yields the lowest levelized energy cost ($162.2/MWh), resulting in a remarkable $8.54 million reduction in diesel costs. A 5% diesel component secures annual energy supply, bridging the gap during periods of seasonal renewable energy variability and extreme cyclonic weather. While achieving 100% renewable energy generation is financially feasible, challenges arise in scaling battery capacity to stabilize energy supply during cyclone seasons. Moreover, our carbon accounting model indicates that although the construction of renewable energy infrastructure entails some indirect (Scope 3) carbon emissions, a 95% renewable penetration mitigates emissions by 90% compared to traditional diesel generation, amounting to a reduction of 39.17 kilotons over the 40-year period. This comprehensive study provides policymakers with invaluable insights, fostering a holistic understanding of the financial, technical, environmental, and political dimensions inherent in island energy transitions.

Abstract Gut bacteriome dysbiosis is known to be implicated in the pathogenesis of inflammatory bowel disease (IBD). Crohn’s disease (CD) is an IBD subtype with extensive mucosal inflammation, yet the mucosal virome, an empirical modulator of the bacteriome and mucosal immunity, remains largely unclear regarding its composition and role. Here, we exploited trans-cohort CD patients and healthy individuals to compositionally and functionally investigate the small bowel (terminal ileum) virome and bacteriome. The CD ileal virome was characterised by an under-representation of both lytic and temperate bacteriophages (especially those targeting bacterial pathogens), particularly in patients with flare-up. Meanwhile, the virome-bacteriome ecology in CD ileal mucosa was featured by a lack of Bifidobacterium- and Lachnospiraceae-led mutualistic interactions between bacteria and bacteriophages; surprisingly it was more pronounced in CD remission than flare-up, underlining the refractory and recurrent nature of mucosal inflammation in CD. Lastly, we substantiated that ileal virions from CD patients causally exacerbated intestinal inflammation in IBD mouse models, by reshaping a gut virome-bacteriome ecology preceding intestinal inflammation (microbial trigger) and augmenting microbial sensing/defence pathways in the intestine cells (host response). Altogether, our results highlight the significance of mucosal virome in CD pathogenesis and importance of mucosal virome restoration in CD therapeutics.

Abstract Large constellations of small satellites will significantly increase the number of objects orbiting the Earth. Satellites burn up at the end of service life during reentry, generating aluminum oxides as the main byproduct. These are known catalysts for chlorine activation that depletes ozone in the stratosphere. We present the first atomic‐scale molecular dynamics simulation study to resolve the oxidation process of the satellite's aluminum structure during mesospheric reentry, and investigate the ozone depletion potential from aluminum oxides. We find that the demise of a typical 250‐kg satellite can generate around 30 kg of aluminum oxide nanoparticles, which may endure for decades in the atmosphere. Aluminum oxide compounds generated by the entire population of satellites reentering the atmosphere in 2022 are estimated at around 17 metric tons. Reentry scenarios involving mega‐constellations point to over 360 metric tons of aluminum oxide compounds per year, which can lead to significant ozone depletion.

Objective: To explore the potential targets for melatonin in the treatment of periodontitis through network pharmacologic analysis and experimental validation via in vivo animal models and in vitro cellular experiments. Materials and methods: In this study, we first screened melatonin targets from Pharm Mapper for putative targets, Drug Bank, and TCMSP databases for known targets. Then, disease database was searched and screened for differential expressed genes associated with periodontitis. The intersection of disease and melatonin-related genes yielded potential target genes of melatonin treatment for periodontitis. These target genes were further investigated by protein-protein interaction network and GO/KEGG enrichment analysis. In addition, the interactions between melatonin and key target genes were interrogated by molecular docking simulations. Then, we performed animal studies to validate the therapeutic effect of melatonin by injecting melatonin into the peritoneal cavity of ligation-induced periodontitis (LIP) mice. The effects of melatonin on the predicted target proteins were also analyzed using Western blot and immunofluorescence techniques. Finally, we constructed an in vitro cellular model and validated the direct effect of melatonin on the predicted targets by using qPCR. Results: We identified 8 potential target genes by network pharmacology analysis. Enrichment analysis suggests that melatonin may treat periodontitis by inhibiting the expression of three potential targets (MPO, MMP8, and MMP9). Molecular docking results showed that melatonin could effectively bind to MMP8 and MMP9. Subsequently, melatonin was further validated in a mouse LIP model to inhibit the expression of MPO, MMP8, and MMP9 in the periodontal tissue. Finally, we verified the direct effect of melatonin on the mRNA expression of MPO, MMP8, and MMP9 in an in vitro cellular model. Conclusions: Through a combination of network pharmacology and experimental validation, this study provides a more comprehensive understanding of the mechanism of melatonin to treat periodontitis. Our study suggests that MPO, MMP8, and MMP9 as key target genes of melatonin to treat periodontitis. These findings present a more comprehensive basis for further investigation into the mechanisms of pharmacological treatment of periodontitis by melatonin.

Smoking disrupts bone homeostasis and serves as an independent risk factor for the development and progression of osteoporosis. Tobacco toxins inhibit the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), promote BMSCs aging and exhaustion, but the specific mechanisms are not yet fully understood. Herein, we successfully established a smoking-related osteoporosis (SROP) model in rats and mice through intraperitoneal injection of cigarette smoke extract (CSE), which significantly reduced bone density and induced aging and inhibited osteogenic differentiation of BMSCs both in vivo and in vitro. Bioinformatics analysis and in vitro experiments confirmed that CSE disrupts mitochondrial homeostasis through oxidative stress and inhibition of mitophagy. Furthermore, we discovered that CSE induced BMSCs aging by upregulating phosphorylated AKT, which in turn inhibited the expression of FOXO3a and the Pink1/Parkin pathway, leading to the suppression of mitophagy and the accumulation of damaged mitochondria. MitoQ, a mitochondrial-targeted antioxidant and mitophagy agonist, was effective in reducing CSE-induced mitochondrial oxidative stress, promoting mitophagy, significantly downregulating the expression of aging markers in BMSCs, restoring osteogenic differentiation, and alleviating bone loss and autophagy levels in CSE-exposed mice. In summary, our results suggest that BMSCs aging caused by the inhibition of mitophagy through the AKT/FOXO3a/Pink1/Parkin axis is a key mechanism in smoking-related osteoporosis.

Abstract Background The liver is a common site for metastatic disease for a variety of cancers, including colorectal cancer. Both primary and secondary liver tumors are supplied through the hepatic artery while the healthy liver is supplied by the portal vein. Transarterial radioembolization (TARE) using yttrium-90 glass or resin microspheres have shown promising results with reduced side-effects but have similar survival benefits as chemoembolization in patients with hepatocellular carcinoma (HCC). This highlights the need for new novel agents against HCC. Targeted alpha therapy (TAT) is highly potent treatment due to the short range (sparing adjacent normal tissue), and densely ionizing track (high linear energy transfer) of the emitted α-particles. The incorporation of α-particle-emitting radioisotopes into treatment of HCC has been extremely limited, with our recent publication pioneering the field of α-particle-emitting TARE (αTARE). This study focuses on an in-depth evaluation of the αTARE-agent [225Ac]Ac-DOTA-TDA-Lipiodol® as an effective therapeutic agent against HCC regarding pharmacokinetics, dosimetry, stability, and therapeutic efficacy. Results [225Ac]Ac-DOTA-TDA was shown to be a highly stable with bench-top stability at ≥ 95% radiochemical purity (RCP) over a 3-day period and serum stability was ≥ 90% RCP over 5-days. The pharmacokinetic data showed retention in the tumor of [225Ac]Ac-DOTA-TDA-Lipiodol® and clearance through the normal organs. In addition, the tumor and liver acted as suppliers of the free daughters, which accumulated in the kidneys supplied via the blood. The dose limiting organ was the liver, and the estimated maximum tolerable activity based on the rodents whole-body weight: 728–3641 Bq/g (male rat), 396–1982 Bq/g (male mouse), and 453–2263 Bq/g (female mouse), depending on an RBE-value (range 1–5). Furthermore, [225Ac]Ac-DOTA-TDA-Lipiodol® showed significant improvement in survival for both the male and female mice (median survival 47-days) compared with controls (26-days untreated, and 33–35-days Lipiodol® alone). Conclusions This study shows that [225Ac]Ac-DOTA-TDA-Lipiodol® is a stable compound allowing for centralized manufacturing and distribution world-wide. Furthermore, the result of this study support the continue development of evaluation of the αTARE-agent [225Ac]Ac-DOTA-TDA-Lipiodol® as a potential treatment option for treating hepatic tumors.

Three-dimensional reconstruction from point clouds is an important research topic in computer vision and computer graphics. However, the discrete nature, sparsity, and noise of the original point cloud contribute to the results of 3D surface generation based on global features often appearing jagged and lacking details, making it difficult to describe shape details accurately. We address the challenge of generating smooth and detailed 3D surfaces from point clouds. We propose an adaptive octree partitioning method to divide the global shape into local regions of different scales. An iterative loop method based on GRU is then used to extract features from local voxels and learn local smoothness and global shape priors. Finally, a moving least-squares approach is employed to generate the 3D surface. Experiments demonstrate that our method outperforms existing methods on benchmark datasets (ShapeNet dataset, ABC dataset, and Famous dataset). Ablation studies confirm the effectiveness of the adaptive octree partitioning and GRU modules.

In this article, we propose a joint waveform based on universal filtered multicarrier (UFMC) chirp for radar jamming and communication joint systems. Modulation of radar jamming chirp signals and communication signals on different subcarrier groups in the UFMC sub-band is used to achieve the waveform design. The jamming signal in the waveform contains a frequency shift coefficient that depends on the delay time, which can effectively improve the anti-frequency hopping ability and enhance the overall jamming efficiency. Simultaneously jamming signals can provide assistance in channel estimation and equalization of communication, improving the information transmission quality of communication subsystems. We concluded through reasonable trade-off analysis that the combined weight of radar jamming and communication is closely related to the overall performance of the waveform. The simulation results show that the proposed UFMC chirp synthesized waveform has good jamming and communication performance. Software defined radio (SDR) simulation experiments demonstrated the effectiveness of this method in practical environments.

Micropillars have emerged as promising tools for a wide range of biological applications, while the influence of magnetic fields on cell behavior regulation has been increasingly recognized. However, the combined effect of micropillars and magnetic fields on cell behaviors remains poorly understood. In this study, we investigated the responses of H9c2 cells to ultramicromagnetic micropillar arrays using NdFeB as the tuned magnetic particles. We conducted a comparative analysis between PDMS micropillars and NdFeB/PDMS micropillars to assess their impact on cell function. Our results revealed that H9c2 cells exhibited significantly enhanced proliferation and notable cytoskeletal rearrangements on the ultramicromagnetic micropillars, surpassing the effects observed with pure PDMS micropillars. Immunostaining further indicated that cells cultured on ultramicromagnetic micropillars displayed heightened contractility compared to those on PDMS micropillars. Remarkably, the ultramicromagnetic micropillars also demonstrated the ability to decrease reactive oxygen species (ROS) levels, thereby preventing F-actin degeneration. Consequently, this study introduces ultramicromagnetic micropillars as a novel tool for the regulation and detection of cell behaviors, thus paving the way for advanced investigations in tissue engineering, single-cell analysis, and the development of flexible sensors for cellular-level studies.

ABSTRACTThe world is witnessing a global increase in the urban population, particularly in developing Asian and African countries. Concomitantly, the global burden of non-communicable diseases (NCDs) is rising, markedly associated with the changing landscape of lifestyle and environment during urbanization. Accumulating studies have revealed the role of the gut microbiome in regulating the immune and metabolic homeostasis of the host, which potentially bridges external factors to the host (patho-)physiology. In this review, we discuss the rising incidences of NCDs during urbanization and their links to the compositional and functional dysbiosis of the gut microbiome. In particular, we elucidate the effects of urbanization-associated factors (hygiene/pollution, urbanized diet, lifestyles, the use of antibiotics, and early life exposure) on the gut microbiome underlying the pathogenesis of NCDs. We also discuss the potential and feasibility of microbiome-inspired and microbiome-targeted approaches as novel avenues to counteract NCDs, including fecal microbiota transplantation, diet modulation, probiotics, postbiotics, synbiotics, celobiotics, and precision antibiotics.

Abstract Background Multiple primary melanoma (MPM) is known to be associated with familial melanoma. However, the association between MPM and other personal and familial cancers is not well documented. The objective of this study was to evaluate the association between MPM and personal history of other cancers or cancer history among first‐degree relatives (FDRs). Methods We performed a retrospective case–control study including cases with gender‐matched MPM and single primary melanoma (SPM) at a 1:2 ratio from the University of Pittsburgh Cancer Institute Melanoma Center Biological Sample and Nevus Bank. The associations between MPM and other cancers were evaluated using univariable and multivariable logistic regression models. Results In total, 378 patients (44.2% men; median age 52 years) were enrolled, including 252 with SPM and 126 with MPM. In comparison to patients with SPM, patients with MPM were more likely to have squamous cell carcinoma (odds ratio [OR] 1.95, 95% confidence interval [CI] 1.001–3.79, p = 0.047) and prostate cancer (OR 2.72, 95% CI 1.07–7.01, p = 0.034). FDRs of patients with MPM had higher prevalence of melanoma (OR 2.37, 95% CI 1.31–4.28, p = 0.004) and prostate cancer (OR 2.92, 95% CI 1.47–6.14, p = 0.002) but not other cancers. In multivariable analysis, the association remained significant between MPM and squamous cell carcinoma (OR 2.18, 95% CI 1.08–4.39, p = 0.028), prostate cancer (OR 2.85, 95% CI 1.09–7.54, p = 0.032), FDR history of melanoma (OR 2.37, 95% CI 1.31–4.29, p = 0.004), and FDR history of prostate cancer (OR 3.26, 95% CI 1.59–6.83, p = 0.001). Conclusions Patients with MPM have a higher prevalence of personal and FDR histories of nonmelanoma skin cancers and prostate cancer.

Despite recent advances in cancer therapy, ovarian cancer remains the most lethal gynecological cancer worldwide, making it crucial and of the utmost importance to establish novel therapeutic strategies. Adjuvant radiotherapy has been assessed historically, but its use was limited by intestinal toxicity. We recently established the role of Limosilactobacillus reuteri in releasing IL-22 (LR-IL-22) as an effective radiation mitigator, and we have now assessed its effect in an ovarian cancer mouse model. We hypothesized that an LR-IL-22 gavage would enable intestinal radioprotection by modifying the tumor microenvironment and, subsequently, improving overall survival in female C57BL/6MUC-1 mice with widespread abdominal syngeneic 2F8cis ovarian cancer. Herein, we report that the LR-IL-22 gavage not only improved overall survival in mice when combined with a PD-L1 inhibitor by inducing differential gene expression in irradiated stem cells but also induced PD-L1 protein expression in ovarian cancer cells and mobilized CD8+ T cells in whole abdomen irradiated mice. The addition of LR-IL-22 to a combined treatment modality with fractionated whole abdomen radiation (WAI) and systemic chemotherapy and immunotherapy regimens can facilitate a safe and effective protocol to reduce tumor burden, increase survival, and improve the quality of life of a locally advanced ovarian cancer patient.

Abstract Background and aims The human gut is home to a largely underexplored microbiome component, the archaeome. Little is known of the impact of geography, urbanization, ethnicity, and diet on the gut archaeome in association with host health. We aim to delineate the variation of the human gut archaeome in healthy individuals and its association with environmental factors and host homeostasis. Methods Using metagenomic sequencing, we characterized the fecal archaeomes of 792 healthy adult subjects from 5 regions in China, spanning 6 ethnicities (Han, Zang, Miao, Bai, Dai, and Hani), consisting of both urban and rural residents for each ethnicity. In addition, we sampled 119 host variables (including lifestyle, diet, and blood parameters) and interrogated the influences of those factors, individually and combined, on gut archaeome variations. Results Population geography had the strongest impact on the gut archaeome composition, followed by urbanization, dietary habit, and ethnicity. Overall, the metadata had a cumulative effect size of 11.0% on gut archaeome variation. Urbanization decreased both the α-diversity (intrinsic microbial diversity) and the β-diversity (inter-individual dissimilarities) of the gut archaeome, and the archaea-to-bacteria ratios in feces, whereas rural residents were enriched for Methanobrevibacter smithii in feces. Consumption of buttered milk tea (a characteristic diet of the rural Zang population) was associated with increased abundance of M. smithii. M. smithii was at the central hub of archaeal-bacterial interactions in the gut microecology, where it was positively correlated with the abundances of a multitude of short chain fatty acid (SCFA)-producing bacteria (including Roseburia faecis, Collinsella aerofaciens, and Prevotella copri). Moreover, a decreased abundance of M. smithii was associated with increased human blood levels of cholinesterase in the urban population, coinciding with the increasing prevalence of noncommunicable diseases (such as dementia) during urbanization. Conclusions Our data highlight marked contributions of environmental and host factors (geography, urbanization, ethnicity, and habitual diets) to gut archaeome variations across healthy individuals, and underscore the impact of urbanization on the gut archaeome in association with host health in modern society. Video Abstract

BackgroundPre-clinical studies have shown that metformin reduces intratumoral hypoxia, improves T-cell function, and increases sensitivity to PD-1 blockade, and metformin exposure has been associated with improved clinical outcomes in various types of cancer. However, the impact of this drug in diabetic melanoma patients has not yet been fully elucidated.MethodsWe reviewed 4,790 diabetic patients with stage I-IV cutaneous melanoma treated at the UPMC-Hillman Cancer Center and Memorial Sloan Kettering Cancer Center between 1996-2020. The primary endpoints included recurrence rates, progression free survival (PFS), and overall survival (OS) with and without metformin exposure. Tabulated variables included BRAF mutational status, immunotherapy (IMT) by type, and incidence of brain metastases.ResultsThe five-year incidence of recurrence in stage I/II patients was significantly reduced with metformin exposure (32.3% vs 47.7%, p=0.012). The five-year recurrence rate for stage III patients was also significantly reduced (58.3% vs 77.3%, p=0.013) in the metformin cohort. OS was numerically increased in nearly all stages exposed to metformin, though this did not reach statistical significance. The incidence of brain metastases was significantly lower in the metformin cohort (8.9% vs 14.6%, p=0.039).ConclusionThis is the first study to demonstrate significantly improved clinical outcomes in diabetic melanoma patients exposed to metformin. Overall, these results provide further rationale for ongoing clinical trials studying the potential augmentation of checkpoint blockade with metformin in advanced melanoma.

Manipulation of micro-objects have been playing an essential role in biochemical analysis or clinical diagnostics. Among the diverse technologies for micromanipulation, acoustic methods show the advantages of good biocompatibility, wide tunability, a label-free and contactless manner. Thus, acoustic micromanipulations have been widely exploited in micro-analysis systems. In this article, we reviewed the acoustic micromanipulation systems that were actuated by sub-MHz acoustic waves. In contrast to the high-frequency range, the acoustic microsystems operating at sub-MHz acoustic frequency are more accessible, whose acoustic sources are at low cost and even available from daily acoustic devices (e.g. buzzers, speakers, piezoelectric plates). The broad availability, with the addition of the advantages of acoustic micromanipulation, make sub-MHz microsystems promising for a variety of biomedical applications. Here, we review recent progresses in sub-MHz acoustic micromanipulation technologies, focusing on their applications in biomedical fields. These technologies are based on the basic acoustic phenomenon, such as cavitation, acoustic radiation force, and acoustic streaming. And categorized by their applications, we introduce these systems for mixing, pumping and droplet generation, separation and enrichment, patterning, rotation, propulsion and actuation. The diverse applications of these systems hold great promise for a wide range of enhancements in biomedicines and attract increasing interest for further investigation.

Cancer cellular immunotherapy has made inspiring therapeutic effects in clinical practices, which brings new hope for the cure of cervical cancer. CD8+T cells are the effective cytotoxic effector cells against cancer in antitumor immunity, and T cells-based immunotherapy plays a crucial role in cellular immunotherapy. Tumor infiltrated Lymphocytes (TIL), the natural T cells, is approved for cervical cancer immunotherapy, and Engineered T cells therapy also has impressive progress. T cells with natural or engineered tumor antigen binding sites (CAR-T, TCR-T) are expanded in vitro, and re-infused back into the patients to eradicate tumor cells. This review summarizes the preclinical research and clinical applications of T cell-based immunotherapy for cervical cancer, and the challenges for cervical cancer immunotherapy.

Abstract Background Chimeric antigen receptor T-cell (CART) therapy is a form of cellular immunotherapy used to treat hematologic malignancies. Major adverse cardiovascular events have been seen in CART patients who have high grade CRS, higher baseline creatinine, and troponin elevation. However, the incidence and factors associated with orthostatic hypotension after CART therapy have not previously been reported in the literature. Methods We looked at patients who underwent CD-19 directed CART therapy at UPMC Shadyside hospital from April 1st 2018 to December 1st 2020. Patients were classified as having orthostatic hypotension if they had recorded orthostatic vital signs that were positive or provider notes indicated that vitals had been taken and were positive in the time period from discharge to 3 months post-CART. Data was analyzed with univariate and multivariate analysis using logistic regression. Results 79% of patients had orthostatic hypotension after discharge from their CART hospitalization and 64% of those patients were symptomatic. Older age, lower BMI, lower ambulatory diastolic blood pressure and grade 2 CRS were associated with orthostatic hypotension in the univariate analysis. Older age and lower ambulatory systolic blood pressure were associated with orthostatic hypotension in the multivariate analysis. Symptomatic orthostatic hypotension was associated with a history of hypertension in both the univariate and multivariate analysis. Patients with symptoms also had a higher pre-CART ejection fraction but this association was not seen in the regression model. Conclusion There is a high incidence of orthostatic hypotension after CART therapy even after discharge. Therefore, orthostatic vitals signs and associated symptoms should be assessed in both the inpatient and outpatient setting. Older patients and patients with lower BMIs, lower ambulatory blood pressures, grade 2 CRS, or a history of hypertension may need closer monitoring.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, the responses to ICI treatment are highly variable in different individuals and the underlying mechanisms remain poorly understood. Here, we employed a mouse squamous cell carcinoma (SCC) model where tumor-bearing recipients diverged into responders (R) versus non-responders (NR) upon anti-PD-L1 treatment. We performed in-depth TCRβ sequencing with immunoSEQ platform to delineate the differences in CD8 tumor-infiltrating lymphocytes (TILs). We found that R and NR CD8 TILs both exhibited evidence of clonal expansion, suggesting activation regardless of response status. We detected no differences in clonal expansion or clonal diversity indexes between R vs. NR. However, the top expanded (>1%) TCRβ clonotypes appeared to be mutually exclusive between R and NR CD8 TILs, showing a preferential expansion of distinct TCRβ clonotypes in response to the same SCC tumor in R vs. NR. Notably, the mutual exclusivity of TCR clonotypes in R vs. NR was only observed when top TCRβ clonotypes were counted, because such top-expanded clonotypes are present in the opposite outcome group at a much lower frequency. Many TCRβ sequences were detected in only one recipient at a high frequency, implicating highly individualized anti-tumor immune responses. We conclude that differences in the clonal frequency of top TCR clonotypes between R and NR CD8 TILs may be one of the factors underlying differential anti-PD-L1 responses. This notion may offer a novel explanation for variable ICI responses in different individuals, which may substantially impact the development of new strategies for personalized cancer immunotherapy.

Liquid phase exfoliation (LPE) has emerged as a promising method for the industrial-scale production of graphene. However, one of its critical steps, namely sonication, has faced challenges due to high power consumption and low efficiency, leading to limited applicability in industrial settings. This study introduces a novel, cost-effective microfluidic sonication device designed to significantly reduce power consumption while efficiently assisting the LPE process for graphene production. By coupling a capillary with a buzzer and applying an appropriate electric signal, simulation and particle tracing experiments reveal the generation of robust shear forces resulting from acoustic streaming and cavitation when the capillary end is immersed in the liquid. For the first time, the capillary-based sonication device was effectively utilized for graphene exfoliation in a DMF (N,N-Dimethylformamide) + NaOH liquid phase system. The SEM (Scanning Electron Microscope) and Raman characterization results corroborate the successful exfoliation of 100 nm with thicknesses below 10 nm graphene sheets from graphite flakes using this pioneering device. The values of I2D/IG increase after processing, which suggests the exfoliation of graphite flakes into thinner graphene sheets. The vibration-based acoustofluidic effector represents a versatile and scalable miniature device, capable of being employed individually for small-batch production, thereby optimizing the utilization of raw 2D materials, particularly in experimental scenarios. Alternatively, it holds the potential for large-scale manufacturing through extensive parallelization, offering distinct advantages in terms of cost-efficiency and minimal power consumption.

Abstract Instability and excessive use of the knee joint can cause osteoarthritis (OA). Reasonable exercise can enhance the stability of the knee joint and prevent and relieve the occurrence and development of OA. As a key switch for inflammation, P2X purinoceptor 7 (P2X7) has attracted much attention in studies of OA. Exercise can regulate P2X7 expression and activation. However, the role of P2X7 in exercise-based prevention and treatment of OA is unknown. We previously showed that moderate-intensity exercise can significantly alleviate OA symptoms. Accordingly, in this study, we evaluated the effects of exercise on P2X7 expression and activation in chondrocytes. Micro-computed tomography, hematoxylin, and eosin staining, Toluidine Blue O staining, immunohistochemistry, and terminal deoxynucleotidyl transferase dUTP nick-end labeling experiments showed that P2X7 expression was lower in the moderate-intensity exercise group than in the inflammation and low- and high-intensity exercise groups. Additionally, chondrocyte death, cartilage destruction, and the degree and severity of pyroptosis were significantly reduced, whereas autophagy levels were significantly increased in the moderate-intensity exercise group. Cell Counting Kit-8 assay, lactate dehydrogenase release, flow cytometry, enzyme-linked immunosorbent assay, cell fluorescence, western blot, reverse transcription-quantitative polymerase chain reaction, and transmission electron microscopy experiments showed that moderate activation of P2X7 promoted autophagy through the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway and promoted autolysosome targeting for degradation of the inflammasome component NLRP3, thereby inhibiting pyroptosis. Additionally, the use of AMPK and mTOR activators and inhibitors indicated that the AMPK-mTOR signaling pathway, as the downstream of P2X7, played a key role in delaying the occurrence and development of OA. We propose that moderate-intensity exercise promoted chondrocyte autophagy through the P2X7/AMPK/mTOR signal axis to alleviate pyroptosis. Our findings provide novel insights into the positive and preventative effects of exercise on OA.

Proallergic type 2 helper T (Th2A) cells are a subset of memory Th2 cells confined to atopic individuals, and they include all the allergen-specific Th2 cells. Recently, many studies have shown that Th2A cells characterized by CD3+ CD4+ HPGDS+ CRTH2+ CD161high ST2high CD49dhigh CD27low play a crucial role in allergic diseases, such as atopic dermatitis (AD), food allergy (FA), allergic rhinitis (AR), asthma, and eosinophilic esophagitis (EoE). In this review, we summarize the discovery, biomarkers, and biological properties of Th2A cells to gain new insights into the pathogenesis of allergic diseases.

Irradiation can be an effective treatment for ovarian cancer, but its use is limited by intestinal toxicity. Thus, strategies to mitigate toxicity are important and can revitalize the current standard of care. We previously established that LR-IL-22 protects the intestine from WAI. We now hypothesize that LR-IFN-β is an effective radiation protector and mitigator and is rapidly cleared from the digestive tract, making it an option for intestinal radioprotection. We report that the gavage of LR-IFN-β during WAI provides improved intestinal barrier integrity and significantly preserves the numbers of Lgr5+GFP+ intestinal stem cells, improving survival. The rapid clearance of the genetically engineered probiotic from the digestive tract renders it a safe and feasible radiation mitigator. Therefore, the above genetically engineered probiotic is both a feasible and effective radiation mitigator that could potentially revolutionize the management of OC patients. Furthermore, the subsequent addition of platinum/taxane-based chemotherapy to the combination of WAI and LR-IFN-β should reduce tumor volume while protecting the intestine and should improve the overall survival in OC patients.

The reliable monitoring of the depth of anesthesia (DoA) is essential to control the anesthesia procedure. Electroencephalography (EEG) has been widely used to estimate DoA since EEG could reflect the effect of anesthetic drugs on the central nervous system (CNS). In this study, we propose that a deep learning model consisting mainly of a deep residual shrinkage network (DRSN) and a 1 × 1 convolution network could estimate DoA in terms of patient state index (PSI) values. First, we preprocessed the four raw channels of EEG signals to remove electrical noise and other physiological signals. The proposed model then takes the preprocessed EEG signals as inputs to predict PSI values. Then we extracted 14 features from the preprocessed EEG signals and implemented three conventional feature-based models as comparisons. A dataset of 18 patients was used to evaluate the models’ performances. The results of the five-fold cross-validation show that there is a relatively high similarity between the ground-truth PSI values and the predicted PSI values of our proposed model, which outperforms the conventional models, and further, that the Spearman’s rank correlation coefficient is 0.9344. In addition, an ablation experiment was conducted to demonstrate the effectiveness of the soft-thresholding module for EEG-signal processing, and a cross-subject validation was implemented to illustrate the robustness of the proposed method. In summary, the procedure is not merely feasible for estimating DoA by mimicking PSI values but also inspired us to develop a precise DoA-estimation system with more convincing assessments of anesthetization levels.

In premature infants, necrotizing enterocolitis (NEC) is one of the most prevalent diseases among premature infants and has a high mortality rate. Previous studies have shown that human milk oligosaccharides (HMOs) could effectively decrease the incidence of NEC. However, it is not known whether the efficacy of oligosaccharides is related to their structure. We found that among the HMOs, 3′-sialyllactose (3′-SL) and 6′-sialyllactose (6′-SL) significantly restored proliferation, reduced apoptosis, and relieved inflammation of the intestinal cells of neonatal mice under hypoxia. In addition, our findings indicated that 3′-SL and 6′-SL provide protection against NEC-induced intestinal damage by inhibiting the activation of the TLR4/NF-κB pathway. In sum, 3′-SL and 6′-SL, which are formed when Sia monosaccharide is linked to lactose, are HMO components that can effectively alleviate hypoxia-induced damage in NEC and should be considered as a potential nutritional supplement that can be added to infant formula.

Osteoarthritis (OA) is a common chronic disease and a significant health concern that needs to be urgently solved. OA affects the cartilage and entire joint tissues, including the subchondral bone, synovium, and infrapatellar fat pads. The physiological and pathological changes in these tissues affect the occurrence and development of OA. Understanding complex crosstalk among different joint tissues and their roles in OA initiation and progression is critical in elucidating the pathogenic mechanism of OA. In this review, we begin with an overview of the role of chondrocytes, synovial cells (synovial fibroblasts and macrophages), mast cells, osteoblasts, osteoclasts, various stem cells, and engineered cells (induced pluripotent stem cells) in OA pathogenesis. Then, we discuss the various mechanisms by which these cells communicate, including paracrine signaling, local microenvironment, co-culture, extracellular vesicles (exosomes), and cell tissue engineering. We particularly focus on the therapeutic potential and clinical applications of stem cell-derived extracellular vesicles, which serve as modulators of cell-to-cell communication, in the field of regenerative medicine, such as cartilage repair. Finally, the challenges and limitations related to exosome-based treatment for OA are discussed. This article provides a comprehensive summary of key cells that might be targets of future therapies for OA.

Moderate-intensity exercise can help delay the development of osteoarthritis (OA). Previous studies have shown that the purinergic receptor P2X ligand gated ion channel 7 (P2X7) is involved in OA development and progression. To investigate the effect of exercise on P2X7 activation and downstream signaling in OA, we used the anterior cruciate ligament transection (ACLT)-induced OA rat model and primary chondrocyte culture system. Our in vivo experiments confirmed that treadmill exercise increased P2X7 expression and that this effect was more pronounced at the later time points. Furthermore, P2X7 activation induced endoplasmic reticulum (ER) stress and increased the expression levels of ER stress markers, such as 78 kDa glucose-regulated protein (GRP78), protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme-1 (IRE1), and activating transcription factor 6 (ATF6). At the early time points, IRE1 and PERK were activated, and mTOR was inhibited. At the later time points, mTOR was activated, mediating PERK to promote ER stress-apoptosis, whereas IRE1 and autophagy were inhibited. To confirm our observations in vitro, we treated primary chondrocytes with the P2X7 agonist benzoylbenzoyl-ATP (Bz-ATP). Our results confirmed that P2X7-mediated Ca2+ influx activated IRE1-mediated autophagic flux and induced PERK-mediated ER stress-apoptosis. To further investigate the role of P2X7 in OA, we injected mTOR antagonist rapamycin or P2X7 antagonist A740003 into the knee joints of ACLT rats. Our results demonstrated that mTOR inhibition induced autophagy, decreased apoptosis, and reduced cartilage loss. However, injection of mTOR agonist MHY1485 or Bz-ATP had the opposite effect. In summary, our results indicated that during the early stages of moderate-intensity exercise, P2X7 was activated and autophagic flux was increased, delaying OA development. At the later stages, P2X7 became over-activated, and the number of apoptotic cells increased, promoting OA development. We propose that the IRE1-mTOR-PERK signaling axis was involved in the regulation of autophagy inhibition and the induction of apoptosis. Our findings provide novel insights into the positive and preventative effects of exercise on OA, suggesting that the intensity and duration of exercise play a critical role. We also demonstrated that on a molecular level, P2X7 and its downstream pathways could be potential therapeutic targets for OA.

Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) is a difficult enzyme to work with. Here, the authors covalently immobilized it in a microfluidic reactor to enhance its storage/thermal stabilities and reusability, which enabled the continuous artificial synthesis of glucose precursor.

Abstract Precipitation is a key hydrometeorological variable for understanding surface energy partitioning and water budget over the Tibetan Plateau (TP). A substantial proportion of summer precipitation falls as rain. The effects of different land surface models (LSMs) on the TP’s precipitation and their inner mechanisms remain unclear. Therefore, the assessments of different LSMs coupled with the Weather Research and Forecasting model in precipitation simulation were investigated over the TP during June 28–29 of 2008. The simulated results were evaluated with the merged Climate Prediction Center (CPC) MORPHing technique (CMORPH) precipitation data set developed by the China Meteorological Administration. The assessment demonstrated that precipitation simulated by the Community Land Model Version 4 (CLM4), Noah‐Multiparameterization (Noah‐MP), and Pleim‐Xiu LSM schemes was wider and stronger compared with the merged CMORPH over the central and western TP but was underestimated over the eastern and southern regions. Generally, both CLM4 and Noah‐MP schemes exhibited higher forecasting quality and accuracy in simulating precipitation over the TP. The optimal precipitation simulation was achieved by applying the Noah‐MP scheme, with a lowest root mean square error of 9.53 mm/day, mainly attributed to its corrections of overforecasting for precipitation that did not occur. Further mechanism analysis indicated that soil moisture‐energy flux‐precipitation feedback play an important role in different LSM schemes.

Osteoarthritis (OA) is the most common joint disease. With the increasing aging population, the associated socio-economic costs are also increasing. Analgesia and surgery are the primary treatment options in late-stage OA, with drug treatment only possible in early prevention to improve patients’ quality of life. The most important structural component of the joint is cartilage, consisting solely of chondrocytes. Instability in chondrocyte balance results in phenotypic changes and cell death. Therefore, cartilage degradation is a direct consequence of chondrocyte imbalance, resulting in the degradation of the extracellular matrix and the release of pro-inflammatory factors. These factors affect the occurrence and development of OA. The P2X7 receptor (P2X7R) belongs to the purinergic receptor family and is a non-selective cation channel gated by adenosine triphosphate. It mediates Na+, Ca2+ influx, and K+ efflux, participates in several inflammatory reactions, and plays an important role in the different mechanisms of cell death. However, the relationship between P2X7R-mediated cell death and the progression of OA requires investigation. In this review, we correlate potential links between P2X7R, cartilage degradation, and inflammatory factor release in OA. We specifically focus on inflammation, apoptosis, pyroptosis, and autophagy. Lastly, we discuss the therapeutic potential of P2X7R as a potential drug target for OA.

In this work, micro-modified polyvinylidene fluoride (PVDF) and its copolymer poly(vinylidene-trifluoroethylene) (P(VDF-TrFE)) with salient enhancement in current output are demonstrated. The influence of surface-modified structure characteristics on electrical properties of energy harvester is systematically analyzed based on the finite element method. For vertical load mode, eight structures consisting of banded and disjunctive groups are compared to evaluate the voltage performance. The cylinder is proved to be the best structure of 3.25 V, compared to the pristine structure of 0.99 V (P(VDF-TrFE)). The relevant experiment has been done to verify the simulation. The relationship between radius, height, force and distance to the voltage output of the cylinder allocation is discussed. For periodical changing load mode, the cylinder modified structure shows a conspicuous enhancement in current output. The suitable resistance, current–voltage and frequency, the relationship between loading speed and current, and the ductility of current loading are studied. For 30 kHz, the peak current is 20 times larger than the flat plate structure. Tip shape mode and fusiform shape mode are found, which show the different shapes of the peak current-frequency curves. Four electrical loading circuit properties are also discussed: the suitable resistance of the system, synchronism of current and voltage, time delay nature of energy harvester and current-loading relationship. The simulation results can provide some theoretical basis for designing the energy harvester and piezoelectric nanogenerator (PENG).

Topological optimization can realize the optimization of the mass distribution in the whole objective domain. Compared with morphology and size optimization, it has a higher degree of freedom. In this work, the three-dimensional topological optimization based on piezoelectric materials was discussed. Using the Optimality Criteria, topology optimization was applied to the cantilever piezoelectric transducer. The structure optimization was realized with the voltage and stiffness as the multi-objective function. The corresponding codes are given to show the process of optimization. With 70% of the origin volume, the bi-objective optimization increases the global stiffness by 50.9% and the voltage by 30%. As the iteration process shows, the results of bi-objective optimization prove the value of additive mass at the bottom of the cantilever. This lays the foundation for future piezoelectric transducer structural optimization. Using only stiffness as the objective, the final objective increases inconspicuously. Bi-objective optimization shows its superiority. There are quite a few papers that research the combination of stiffness and voltage, and research which studies three-dimensionality is a point of innovation. Furthermore, this is also the first time a piezoelectric topology code has been shared.

Calculation of actual evapotranspiration (AET) is of vital importance for the study of climate change, ecosystem carbon cycling, flooding, drought, and agricultural water demand. It is one of the more important components in the hydrological cycle and surface energy balance (SEB). How to accurately estimate AET especially for the Tibetan Plateau (TP) with complex terrain remains a challenge for the scientific community. Using multi-sensor remote sensing data, meteorological forcing data, and field observations, AET was derived for the Nagqu river basin of the Northern Tibetan Plateau from a surface energy balance system (SEBS) model. As inputs for SEBS, improved algorithms and datasets for land surface albedo and a cloud-free normalized difference vegetation index (NDVI) were also constructed. The model-estimated AET were compared with results by using the combinatory method (CM). The validation indicated that the model estimates of AET agreed well with the correlation coefficient, the root mean square error, and the mean percentage error of 0.972, 0.052 mm/h, and −10.4%, respectively. The comparison between SEBS estimation and CM results also proved the feasibility of parameterization schemes for land surface parameters and AET.