BACKGROUND: Knee osteoarthritis (KOA) is a chronic musculoskeletal disorder characterized by pain and functional impairment. Blood flow restriction (BFR) with low-load resistance training (LLRT) demonstrates a similar improvement in clinical outcomes to high-load resistance training (HLRT) in treating KOA. It has not been established whether intermittent blood flow restriction (iBFR) with LLRT can lead to clinical outcomes that are comparable to those produced by continuous blood flow restriction (cBFR) with LLRT and HLRT. The aim of the proposed study is to evaluate the efficacy of iBFR with LLRT on pain, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), muscle strength, muscle mass, physical function, perceptions of discomfort and effort, and adherence in KOA patients. METHODS: This is a three-arm, non-inferiority, randomized controlled trial utilizing blinded assessors. Two hundred thirteen participants will be randomly allocated to one of the following three groups: iBFR group-receiving 4 months of LLRT with iBFR, twice weekly (n = 71); cBFR group-receiving 4 months of LLRT with cBFR, twice weekly (n = 71); or HLRT group-receiving 4 months of HLRT without BFR, twice weekly (n = 71). The primary outcome is pain. The secondary outcomes include the WOMAC, muscle strength, muscle mass, physical function, perceptions of discomfort and effort, and adherence. Pain and WOMAC will be measured at the baseline and 4 and 12 months after randomizations. Muscle strength, muscle mass, and physical function will be measured at the baseline and 4 months after randomizations. The perceptions of discomfort and effort will be measured during the first and final sessions. DISCUSSION: BFR with LLRT has a similar improvement in clinical outcomes as HLRT. However, cBFR may cause elevated ratings of perceived exertion and local discomfort, compromising patient tolerability and treatment adherence. If iBFR with LLRT could produce improvement in clinical outcomes analogous to those of HLRT and iBFR with LLRT, it could be considered an alternative approach for treating patients with KOA. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2300072820. Registered on June 26, 2023.
Blood Flow Restriction Therapy , Muscle Strength , Osteoarthritis, Knee , Resistance Training , Humans , Resistance Training/methods , Osteoarthritis, Knee/physiopathology , Osteoarthritis, Knee/therapy , Aged , Treatment Outcome , Blood Flow Restriction Therapy/methods , Female , Male , Middle Aged , Equivalence Trials as Topic , Pain Measurement , Regional Blood Flow , Randomized Controlled Trials as Topic , Recovery of Function , Time Factors , Knee Joint/physiopathology
Stretchable strain sensors have gained increasing popularity as wearable devices to convert mechanical deformation of the human body into electrical signals. Two-dimensional transition metal carbides (Ti3C2Tx MXene) are promising candidates to achieve excellent sensitivity. However, MXene films have been limited in operating strain ranges due to rapid crack propagation during stretching. In this regard, this study reports MXene/carbon nanotube bilayer films with tunable sensitivity and working ranges. The device is fabricated using a scalable process involving spray deposition of well-dispersed nanomaterial inks. The bilayer sensor's high sensitivity is attributed to the cracks that form in the MXene film, while the compliant carbon nanotube layer extends the working range by maintaining conductive pathways. Moreover, the response of the sensor is easily controlled by tuning the MXene loading, achieving a gauge factor of 9039 within 15% strain at 1.92 mg/cm2 and a gauge factor of 1443 within 108% strain at 0.55 mg/cm2. These tailored properties can precisely match the operation requirements during the wearable application, providing accurate monitoring of various body movements and physiological activities. Additionally, a smart glove with multiple integrated strain sensors is demonstrated as a human-machine interface for the real-time recognition of hand gestures based on a machine-learning algorithm. The design strategy presented here provides a convenient avenue to modulate strain sensors for targeted applications.
Permeability is a significant characteristic of porous media and a crucial parameter for shale gas development. This study focuses on deep marine and marine-continental transitional shale in the southeastern Sichuan area using the gas pulse decay testing method to systematically analyze the gas permeability, stress sensitivity, and gas transport mechanisms of shale under different pressure conditions and directions. The results show that the porosity and gas permeability of the deep marine shale are greater compared to those of the marine-continental transitional shale. The elevated fluid pressure in the deep marine shale offers superior conditions for the preservation of nanopores, while the high quartz content provides advantageous conditions for fluid transport in nanopore channels. The permeability and stress sensitivity of the deep marine shale are greater than those of the marine-continental transitional shale, and the stress sensitivity is greater in the perpendicular bedding direction than in the parallel bedding direction, possibly related to the mineral composition of shale and the compaction it has undergone. The flow mechanism of the deep marine shale is transition flow and Knudsen flow, while that of the marine-continental transitional shale is transition flow. The deep marine shale possesses smaller nanopore sizes and a higher quantity of micropores, which create advantageous conditions for gas transport within nanopores. During the process of extracting shale gas, the extraction of gas causes a decrease in pore pressure and an increase in effective stress, resulting in a reduction in permeability. However, when the pore pressure reaches a specific value, the enhanced slippage effect leads to an increase in permeability, which is advantageous for gas extraction. In the later stage of shale gas well production, intermittent production plans can be developed considering the strength of the slippage effect, leading to a significant improvement in production efficiency.
MOTIVATION: There are many clustered transcriptionally active regions in the human genome, in which the transcription complex can not immediately terminate transcription at the upstream gene termination site, but instead continues to transcribe intergenic regions and downstream genes, resulting in read-through transcripts. Several studies have demonstrated the regulatory roles of read-through transcripts in tumorigenesis and development. However, limited by the read length of next-generation sequencing, discovery of read-through transcripts has been slow. For long but also erroneous third-generation sequencing data, this study developed a novel minimizer sketch algorithm to accurately and quickly identify read-through transcripts. RESULTS: Readon initially splits the reference sequence into distinct active regions. It employs a sliding window approach within each region, calculates minimizers, and constructs the specialized structured arrays for query indexing. Following initial alignment anchor screening of candidate read-through transcripts, further confirmation steps are executed. Comparative assessments against existing software reveal Readon's superior performance on both simulated and validated real data. Additionally, two downstream tools are provided: one for predicting whether a read-through transcript is likely to undergo nonsense-mediated decay or encodes a protein, and another for visualizing splicing patterns. AVAILABILITY: Readon is freely available on GitHub (https://github.com/Bulabula45/Readon). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
As it is central to sustainable urban development, urban mobility has primarily been scrutinised for its scaling and hierarchical properties. However, traditional analyses frequently overlook spatial directionality, a critical factor in city centre congestion and suburban development. Here, we apply vector computation to unravel the spatial directionality of urban mobility, introducing a two-dimensional anisotropy-centripetality metric. Utilising travel data from 90 million mobile users across 60 Chinese cities, we effectively quantify mobility patterns through this metric, distinguishing between strong monocentric, weak monocentric, and polycentric patterns. Our findings highlight a notable difference: residents in monocentric cities face increasing commuting distances as cities expand, in contrast to the consistent commuting patterns observed in polycentric cities. Notably, mobility anisotropy intensifies in the outskirts of monocentric cities, whereas it remains uniform in polycentric settings. Additionally, centripetality wanes as one moves from the urban core, with a steeper decline observed in polycentric cities. Finally, we reveal that employment attraction strength and commuting distance scaling are key to explaining these divergent urban mobility patterns. These insights are important for shaping effective policies aimed at alleviating congestion and guiding suburban housing development.
The enantioselective environmental behavior of difenoconazole, a widely utilized triazole fungicide commonly detected in agricultural soils, has yet to be comprehensively explored within the earthworm-soil system. To address this research gap, we investigated the bioaccumulation and elimination kinetics, degradation pathways, biotransformation mechanisms, spatial distribution, and toxicity of chiral difenoconazole. The four stereoisomers of difenoconazole were baseline separated and analyzed using SFC-MS/MS. Pronounced enantioselectivity was observed during the uptake phase, with earthworms exhibiting a preference for (2R,4R)-difenoconazole and (2R,4S)-difenoconazole. A total of five transformation products (TPs) were detected and identified using UHPLC-QTOF/MS in the earthworm-soil system. Four of the TPs were detected in both earthworm and soil, and one TP was produced only in eaerthwroms. Hydrolysis and hydroxylation were the primary transformation pathways of difenoconazole in both earthworms and soil. Furthermore, a chiral TP, 3-chloro, 4-hydroxy difenoconazole, was generated with significant enantioselectivity, and molecular docking results indicate the greater catalytic bioactivity of (2R,4R)- and (2R,4S)-difenoconazole, leading to the preferential formation of their corresponding hydroxylated TPs. Furthermore, Mass Spectrometry Imaging (MSI) was applied for the first time to explore the spatial distribution of difenoconazole and the TPs in earthworms, and the "secretory zone" was found to be the dominant region to uptake and biodegrade difenoconazole. ECOSAR predictions highlighted the potentially hazardous impact of most difenoconazole TPs on aquatic ecosystems. These findings are important for understanding the environmental fate of difenoconazole, evaluating environmental risks, and offering valuable insights for guiding scientific bioremediation efforts.
The incidence and mortality of pancreatic ductal adenocarcinoma (PDAC) have increased. Exosomes, as a regulatory mode of intercellular communication, contain lncRNAs. SOX21-AS1 has been studied in other cancers, and its expression is elevated in PDAC, but its role in PDAC remains unclear. First, we analyzed the expression of lncRNAs in PDAC tissues and nontumor tissues through the TCGA database. Next, the results of the RT-qPCR experiment confirmed the prediction that the expression of SOX21-AS1 was elevated in PDAC tissues. In vivo and in vitro cell function assays confirmed that the degree of malignancy of PDAC was proportional to the expression of SOX21-AS1. In addition, through exosome isolation and uptake experiments, we first found that PDAC could secrete exosomal SOX21-AS1 and play an angiogenic role in HUVECs. Subsequently, the relationship between SOX21-AS1, miR-451a and epiregulin (EREG) was verified through database prediction and analysis and RIP assays. Finally, functional recovery assays in vivo and in vitro verified that SOX21-AS1 regulates the expression of EREG through combination with miR-451a and thus promotes the malignancy of PDAC. SOX21-AS1 was upregulated in PDAC. The upregulation of SOX21-AS1 can stimulate the proliferation, migration, invasion, stemness and epithelial-mesenchymal transition (EMT) progression of PDAC cells. Furthermore, PDAC cells secrete exosomal SOX21-AS1, which is absorbed by HUVECs and promotes angiogenesis. Our study first identified that SOX21-AS1 promotes the malignancy of PDAC through the SOX21-AS1/miR-451a/EREG axis, and also that exosomal SOX21-AS1 promotes angiogenesis in PDAC.
Introduction: Primary ciliary dyskinesia (PCD) is a rare heterogeneous disease caused by abnormalities in motile cilia. In this case report, we first analyzed the clinical and genetic data of a proband who was suspected of having PCD on the basis of her clinical and radiological findings. Methods: Whole-exome sequencing was performed, and a variant in the RSPH4A gene was identified in the proband. Sanger sequencing was used for validation of RSPH4A variants in the proband, her sister, her daughter and her parents. Finally, the phenotypic features of the patient were analyzed, and the current literature was reviewed to better understand the gene variants in PCD related to hearing loss and the clinical manifestations of the RSPH4A variant in PCD. Results: The chief clinical symptoms of this proband included gradual mixed hearing loss, otitis media, anosmia, sinusitis, recurrent cough and infertility. Her DNA sequencing revealed a novel homozygous T to C transition at position 1321 within exon 3 of RSPH4A according to genetic testing results. This variant had never been reported before. The homozygous variant resulted in an amino acid substitution of tryptophan by arginine at position 441 (p.Trp441Arg). The same variant was also found in the proband's sister, and a heterozygous pathogenic variant was identified among immediate family members, including the proband's daughter and parents. Discussion: A literature review showed that 16 pathogenic variants in RSPH4A have been reported. Hearing loss had only been observed in patients with the RSPH4A (c.921+3_6delAAGT) splice site mutation, and the specific type of hearing loss was not described.
Objective and rationale: To investigate if the 2-h creatinine clearance (Ccr2) provides a more precise and timely assessment of renal function in critically ill patients compared to the Cockcroft-Gault formula (CrC-G). Materials and methods: This cohort study incorporated 74 patients who were hospitalized for more than 48 h in the Intensive Care Unit over 6 months. A 24-h urine collection protocol was observed, and concurrently, 316 2-h urine specimens were obtained. Then calculated and analyzed the correlation and consistency between Ccr2, CrC-G, and 24-h creatinine clearance (Ccr24) values. The rates of change in Ccr2(ΔCcr2) and CrC-G(ΔCrC-G) were compared over two consecutive samples. Results: The R-values of Ccr2 and Ccr24 in the early, middle and late 24 h were 0.640, 0.886 and 0.854 (P < 0.001), with biases of -2.1, 1.7, and 6.3 ml/min/1.73 m2, respectively. Meanwhile, the R-values for CrC-G and Ccr24 at these time points were 0.618, 0.822, and 0.828(P < 0.001), with biases of -14.0, -5.2, and -1.8 ml/min/1.73 m2, respectively. For patients with Ccr24≥60 ml/min/1.73 m2, the R-value of Ccr2 and Ccr24 during the middle 2 h was 0.852(P < 0.001), while the R-values for CrC-G and Ccr24 were 0.763(P < 0.001), with biases of -2.3 ml/min/1.73 m2 and -14.2 ml/min/1.73 m2 respectively. For the group with Ccr24 ≥ 120 ml/min/1.73 m2 (n = 72), both Ccr2 and Ccr24 displayed a statistically significant elevation compared to CrC-G (P < 0.001), yet no significant difference was observed between Ccr2 and Ccr24 (P = 0.289). Out of 50 patients, 46(92 %) experienced a ΔCcr2≥20 % at least once, compared to 20(40 %) with a ΔCrC-G≥20 %(P < 0.001). 25(50 %) with a ΔCcr2≥50 %, compared to 3(6 %) with a ΔCrC-G≥50 %(P < 0.001). Conclusion: Ccr2 demonstrates a more accurate and more timely indicator of renal function in critically ill patients than CrC-G.
Aortic aneurysms (AA) and aorta dissection (AD) are life-threatening conditions with a rising incidence and high mortality rate. Recent research has linked non-coding RNAs to the regulation of AA and AD progression. In this study, we performed circRNA sequencing, microRNA (miRNA) sequencing, and messenger RNA (mRNA) sequencing on plasma samples from AA and AD patients to identify the key circRNA-miRNA-mRNA axis involved in the transition from AA to AD. Our results showed elevated levels of circ_0000006 and circ_0000160, along with decreased levels of hsa-let-7e-5p in AD samples compared to AA samples. Predictive analysis suggested that circ_0000006 and circ_0000160 potentially target hsa-let-7e-5p, which in turn may bind to the mRNA of Ubiquilin 4 (UBQLN4). In an AD cell model using vascular smooth muscle cells (VSMCs), silencing circ_0000006 and circ_0000160 attenuated the effects of platelet-derived growth factor (PDGF)-induced phenotypic changes, proliferation, and migration. This effect was partially reversed by inhibiting hsa-let-7e-5p. Furthermore, we found that overexpression of UBQLN4 counteracted the effects of hsa-let-7e-5p, suggesting UBQLN4 as a downstream mediator of hsa-let-7e-5p. In an animal model of AD, knockdown of circ_0000006 and circ_0000160 also showed protective effects against aortic septation. Overall, our findings indicate that the upregulation of circ_0000006 and circ_0000160 contributes to the progression from AA to AD by influencing abnormal phenotypic changes, migration, and proliferation of VSMCs. The Hsa-let-7e-5p/UBQLN4 axis may play a critical role in AD development. Targeting circ_0000006 and circ_0000160 could be a potential therapeutic strategy for preventing the progression of AD.
Aortic Dissection , MicroRNAs , RNA, Circular , Humans , RNA, Circular/genetics , RNA, Circular/metabolism , Aortic Dissection/genetics , Aortic Dissection/metabolism , Aortic Dissection/pathology , MicroRNAs/genetics , MicroRNAs/metabolism , Animals , Male , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Cell Proliferation , Disease Progression , Myocytes, Smooth Muscle/metabolism , Middle Aged , Mice , Cell Movement , Female , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Aortic Aneurysm/genetics , Aortic Aneurysm/metabolism , Aortic Aneurysm/pathology
Objective: To evaluate the impact of sequential (first- to third-generation) epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment on top-corrected QT interval (top-QTc) in non-small cell lung cancer (NSCLC) patients. Methods: We retrospectively reviewed the medical records of NSCLC patients undergoing sequential EGFR-TKI treatment at Shanghai Chest Hospital between October 2016 and August 2021. The heart rate (HR), top-QT interval, and top-QTc of their ECGs were extracted from the institutional database and analyzed. Logistic regression was performed to identify predictors for top-QTc prolongation. Results: Overall, 228 patients were enrolled. Compared with baseline (median, 368 ms, same below), both first-generation (376 ms vs. 368 ms, p < 0.001) and sequential third-generation EGFR-TKIs (376 ms vs. 368 ms, p = 0.002) prolonged top-QT interval to a similar extent (p = 0.635). Top-QTc (438 ms vs. 423 ms, p < 0.001) and HR (81 bpm vs.79 bpm, p = 0.008) increased after first-generation EGFR-TKI treatment. Further top-QTc prolongation (453 ms vs. 438 ms, p < 0.001) and HR increase (88 bpm vs. 81 bpm, p < 0.001) occurred after treatment advanced. Notably, as HR elevated during treatment, top-QT interval paradoxically increased rather than decreased, and the top-QTc increased rather than slightly fluctuated. Moreover, such phenomena were more significant after treatment advanced. After adjusting for confounding factors, pericardial effusion and lower serum potassium levels were independent predictors of additional QTc prolongation during sequential third-generation EGFR-TKI treatment. Conclusion: First-generation EGFR-TKI could prolong top-QTc, and sequential third-generation EGFR-TKI induced further prolongation. Top-QT interval paradoxically increased and top-QTc significantly increased as HR elevated, which was more significant after sequential EGFR-TKI treatment. Pericardial effusion and lower serum potassium levels were independent predictors of additional QTc prolongation after sequential EGFR-TKI treatment.
Bidirectional trans-kingdom RNA silencing, a pivotal factor in plant-pathogen interactions, remains less explored in plant host-parasite dynamics. Here, using small RNA sequencing in melon root systems, we investigated microRNA (miRNA) expression variation in resistant and susceptible cultivars pre-and post-infection by the parasitic plant, broomrape. This approach revealed 979 known miRNAs and 110 novel miRNAs across 110 families. When comparing susceptible (F0) and resistant (R0) melon lines with broomrape infection (F25 and R25), 39 significantly differentially expressed miRNAs were observed in F25 vs. F0, 35 in R25 vs. R0, and 5 in R25 vs. F25. Notably, two miRNAs consistently exhibited differential expression across all comparisons, targeting genes linked to plant disease resistance. This suggests their pivotal role in melon's defense against broomrape. The target genes of these miRNAs were confirmed via degradome sequencing and validated by qRT-PCR, ensuring reliable sequencing outcomes. GO and KEGG analyses shed light on the molecular functions and pathways of these differential miRNAs. Furthermore, our study unveiled four trans-kingdom miRNAs, forming a foundation for exploring melon's resistance to broomrape.
Electrocatalysis is considered promising in renewable energy conversion and storage, yet numerous efforts rely on catalyst design to advance catalytic activity. Herein, a hydrodynamic single-particle electrocatalysis methodology is developed by integrating collision electrochemistry and microfluidics to improve the activity of an electrocatalysis system. As a proof-of-concept, hydrogen evolution reaction (HER) is electrocatalyzed by individual palladium nanoparticles (Pd NPs), with the development of microchannel-based ultramicroelectrodes. The controlled laminar flow enables the precise delivery of Pd NPs to the electrode-electrolyte interface one by one. Compared to the diffusion condition, hydrodynamic collision improves the number of active sites on a given electrode by 2 orders of magnitude. Furthermore, forced convection enables the enhancement of proton mass transport, thereby increasing the electrocatalytic activity of each single Pd NP. It turns out that the improvement in mass transport increases the reaction rate of HER at individual Pd NPs, thus a phase transition without requiring a high overpotential. This study provides new avenues for enhancing electrocatalytic activity by altering operating conditions, beyond material design limitations.
In floodplains, phytoplankton communities are mainly shaped by environmental heterogeneity, hydrological connectivity, and habitat diversity. However, it remains unclear how hydrological connectivity drives phytoplankton biodiversity in floodplain lakes. This study was carried out in the Dongting Lake connected to the Yangtze River to ascertain the response mechanisms of phytoplankton communities to different hydrological connectivity gradients. We quantified the hydrological connectivity between lake and river habitats using in-lake water turnover time, and identified its relationship with phytoplankton community structure. Changes in hydrological connectivity can lead to different hydrodynamic and environmental conditions, which have a direct or indirect impact on phytoplankton community structure in water environments. The results showed that spatiotemporal changes in the hydrological connectivity and water environment led to distinct spatial variation in phytoplankton community structure across the study area. α and ß diversity showed a consistent change law with the change of turnover time, and the diversity index gradually increased with the decrease of hydrological connectivity, reaching the maximum value at the moderate hydrological connectivity, and then gradually decreasing. The peak of ß diversity occurs earlier than the peak of α diversity during the decline of hydrological connectivity. This study demonstrates that in-lake water turnover time has a non-negligible impact on phytoplankton community distribution in river-connected lakes. Phytoplankton can maintain the highest α diversity and possibly ß diversity under moderate hydrological connectivity, which is crucial for maintaining aquatic biodiversity in floodplain lakes.
The dried root of Bupleurum marginatum var. stenophyllum (H. Wolff) R.H. Shan & Y. Li (BM), which has been used as a Bupleuri radix in Guizhou Province and is listed in the 2003 edition of the Guizhou Quality Standard for Traditional Chinese Medicines and Ethnic Materia Medica, is effective at dispersing the liver and relieving depression and often used in the form of raw or vinegar-processed product (VBM). However, the potential depression-relieving components of BM are unclear. The aim of this study was to determine the potential antidepressant constituents of BM and investigate the effect of vinegar processing on these components. The antidepressant effect and mechanism of BM and VBM were investigated in depressed mice and BV2 cells, respectively. The pharmacodynamic constituents were screened through serum pharmacochemistry, which combined the results of metabolomics analysis of BM and VBM, high-performance liquid chromatography (HPLC) content determination, and verification of the antidepressant effect and mechanism of differential components of SSb2 to clarify the connotation of vinegar processing. Our results demonstrated that BM can exert a significant antidepressant effect by inhibiting microglia polarization and that this effect was enhanced after vinegar processing. Thirty-eight components were identified in the BM, 13 of which were blood-absorbable, mainly saponins, and defined as potential antidepressant components of the BM. The contents of 17 components-6 of which were absorbed into the blood-changed considerably after processing. It was finally determined that vinegar processing can enhance the antidepressant effect of BM by increasing the contents of SSb1 and SSb2. SSb2 exerts this effect via the samemechanism as BM. In conclusion, in this study we clarified the antidepressant effects and potential active components of BM and examined the mechanism of vinegar processing. These findings lay a foundation for the future research on the antidepressant effects of BM as well as for the complete development and application of BM's ethnomedicinal resources.
Consumers respond differently to external nutrient changes than producers, resulting in a mismatch in elemental composition between them and potentially having a significant impact on their interactions. To explore the responses of herbivores and omnivores to changes in elemental composition in producers, we develop a novel stoichiometric model with an intraguild predation structure. The model is validated using experimental data, and the results show that our model can well capture the growth dynamics of these three species. Theoretical and numerical analyses reveal that the model exhibits complex dynamics, including chaotic-like oscillations and multiple types of bifurcations, and undergoes long transients and regime shifts. Under moderate light intensity and phosphate concentration, these three species can coexist. However, when the light intensity is high or the phosphate concentration is low, the energy enrichment paradox occurs, leading to the extinction of ciliate and Daphnia. Furthermore, if phosphate is sufficient, the competitive effect of ciliate and Daphnia on algae will be dominant, leading to competitive exclusion. Notably, when the phosphorus-to-carbon ratio of ciliate is in a suitable range, the energy enrichment paradox can be avoided, thus promoting the coexistence of species. These findings contribute to a deeper understanding of species coexistence and biodiversity.
Ciliophora , Daphnia , Food Chain , Mathematical Concepts , Models, Biological , Predatory Behavior , Animals , Daphnia/physiology , Ciliophora/physiology , Phosphates/metabolism , Computer Simulation , Population Dynamics , Biodiversity , Phosphorus/metabolism
BACKGROUND AIMS: Circulating tumor cells (CTCs) are precursors of cancer metastasis. However, how CTCs evade immunosurveillance during hematogenous dissemination remains unclear. APPROACH RESULTS: We identified CTC-platelet adhesions by single-cell RNA sequencing and multiplex immunofluorescence of blood samples from multiple cancer types. Clinically, CTC-platelet aggregates were associated with significantly shorter progression-free survival and overall survival in hepatocellular carcinoma patients. In vitro, ex vivo, and in vivo assays demonstrated direct platelet adhesions gifted cancer cells with an evasive ability from natural killer (NK) cell killing by upregulating inhibitory checkpoint CD155, therefore facilitating distant metastasis. Mechanistically, CD155 was transcriptionally regulated by the FAK/JNK/c-Jun cascade in a platelet contact-dependent manner. Further competition assays and cytotoxicity experiments revealed that CD155 on CTCs inhibited NK cell cytotoxicity only by engaging with immune receptor TIGIT, but not CD96 and DNAM1, another two receptors for CD155. Interrupting the CD155-TIGIT interactions with a TIGIT antibody restored NK cell immunosurveillance on CTCs and markedly attenuated tumor metastasis. CONCLUSIONS: Our results demonstrated CTC evasion from NK cell-mediated innate immunosurveillance mainly via immune checkpoint CD155-TIGIT, potentially offering an immunotherapeutic strategy for eradicating CTCs.
Background: Chinese nurses working with immense stress may have issues with burnout during COVID-19 regular prevention and control. There were a few studies investigating status of burnout and associated factors among Chinese nurses. However, the relationships remained unclear. Objectives: To investigate status and associated factors of nurses' burnout during COVID-19 regular prevention and control. Methods: 784 nurses completed questionnaires including demographics, Generalized Anxiety Disorder-7, Patient Health Questionnaire-9, Insomnia Severity Index, Impact of Event Scale-revised, Perceived Social Support Scale, Connor-Davidson Resilience Scale, General Self-efficacy Scale and Maslach Burnout Inventory. Results: 310 (39.5%), 393 (50.1%) and 576 (73.5%) of respondents were at high risk of emotional exhaustion (EE), depersonalization (DP) and reduced personal accomplishment (PA). The risk of EE, DP and reduced PA were moderate, high and high. Nurses with intermediate and senior professional rank and title and worked >40 h every week had lower scores in EE. Those worked in low-risk department reported lower scores in PA. Anxiety, post-traumatic stress disorder (PTSD), self-efficacy and social support were influencing factors of EE and DP, while social support and resilience were associated factors of PA. Conclusion: Chinese nurses' burnout during COVID-19 regular prevention and control was serious. Professional rank and title, working unit, weekly working hours, anxiety, PTSD, self-efficacy, social support and resilience were associated factors of burnout.
