Acidity-Actuated Polymer/Calcium Phosphate Hybrid Nanomotor (PCaPmotor) for Penetrating Drug Delivery and Synergistic Anticancer Immunotherapy.

Tumor acidity-driven nanomotors may offer robust propulsion for tumor-specific penetrating drug delivery. Herein, an acidity-actuated poly(amino acid) calcium phosphate (CaP) hybrid nanomotor (PCaPmotor) was designed, using a mPEG-PAsp-PPhe@THZ531 micelle (Poly@THZ) for CaP mineralization accompanied by αPD-L1 antibody encapsulation. Dissolution of the CaP layer in an acidic tumor environment gave off heat energy to propel the nanomotor to augment the cellular uptake and penetration into deeply seated cancer cells while facilitating αPD-L1 release. THZ531 delivered by the PCaPmotor inhibited CDK12 and its down-streamed phosphorylation of RNAP-II to increase the cancer immunogenicity events such as the DNA damage, cell apoptosis, immunogenic cell death, lysosomal function disturbance, and MHC-I upregulation. THZ531 and αPD-L1 cosupplied by PCaPmotor significantly increased the frequency of DCs maturation and intratumoral infiltration of CTLs, but the two free drugs did not. Consequently, the PCaP@THZ/αPD-L1 nanomotor resulted in synergistic anticancer immunotherapy in mice. This acid-actuated PCaPmotor represented a new paradigm for penetrating drug delivery.

An 18-gene signature of recurrence-associated endothelial cells predicts tumor progression and castration resistance in prostate cancer.

BACKGROUND: The prognostic and therapeutic implications of endothelial cells (ECs) heterogeneity in prostate cancer (PCa) are poorly understood. METHODS: We investigated associations of EC heterogeneity with PCa recurrence and castration resistance in 8 bulk transcriptomic and 4 single-cell RNA-seq cohorts. A recurrence-associated EC (RAEC) signature was constructed by comparing 11 machine learning algorithms through nested cross-validation. Functional relevances of RAEC-specific genes were also tested. RESULTS: A subset of ECs was significantly associated with recurrence in primary PCa and named RAECs. RAECs were characteristic of tip and immature cells and were enriched in migration, angiogenesis, and collagen-related pathways. We then developed an 18-gene RAEC signature (RAECsig) representative of RAECs. Higher RAECsig scores independently predicted tumor recurrence and performed better or comparably compared to clinicopathological factors and commercial gene signatures in multiple PCa cohorts. Of the 18 RAECsig genes, FSCN1 was upregulated in ECs from PCa with higher Gleason scores; and the silencing of FSCN1, TMEME255B, or GABRD in ECs either attenuated tube formation or inhibited PCa cell proliferation. Finally, higher RAECsig scores predicted castration resistance in both primary and castration-resistant PCa. CONCLUSION: This study establishes an endothelial signature that links a subset of ECs to prostate cancer recurrence and castration resistance.

Paclitaxel Overload Supramolecular Oxidative Stress Nanoamplifier with a CDK12 Inhibitor for Enhanced Cancer Therapy.

Combination therapy has emerged as a promising approach for treating tumors, although there is room for improvement. This study introduced a novel strategy that combined the enhancement of apoptosis, ferroptosis, and DNA damage to improve therapeutic outcomes for prostate cancer. Specifically, we have developed a supramolecular oxidative stress nanoamplifier, which was comprised of ß-cyclodextrin, paclitaxel, and ferrocene-poly(ethylene glycol). Paclitaxel within the system disrupted microtubule dynamics, inducing G2/M phase arrest and apoptosis. Concurrently, ferrocene utilized hydrogen peroxide to generate toxic hydroxyl radicals in cells through the Fenton reaction, triggering a cascade of reactive oxygen species expansion, reduction of glutathione levels, lipid peroxidation, and ferroptosis. The increased number of hydroxyl radicals and the inhibitory effect of THZ531 on DNA repair mechanisms exacerbated DNA damage within tumor cells. As expected, the supramolecular nanoparticles demonstrated excellent drug delivery ability to tumor cells or tissues, exhibited favorable biological safety in vivo, and enhanced the killing effect on prostate cancer.

Photoswitchable Metal-Organic Framework as a Smart Nanoreactor for Ultraviolet Light-Enhanced Confined Catalysis.

Confined catalysis, where a chemical reaction is accommodated within a nanoscale host, provides an effective approach to control the pathways and outcomes of catalytic transformations. However, the confinement effect is typically limited to a fixed rate and/or selectivity once the nanohost is chosen. Herein, we developed a photoresponsive metal-organic framework (MOF) as a "smart" nanohost to realize ultraviolet (UV) light-enhanced confined catalysis of Knoevenagel condensation. Photoresponsive MOF of Zn-ADA was thus prepared by solvothermal strategy where azobenzene-4,4'-dicarboxylic acid (ADA) was used as the photoactive linker to coordinate with zinc nitrate. Characterization results suggested that UV light could decrease the pore size of Zn-ADA due to suppressed bending of the azobenzene-containing ADA linker in Zn-ADA. It enforced the proximity between substrates and catalytic groups within the confined space, and thus enhanced the confinement effect on Knoevenagel condensation. The UV light-enhanced confined catalysis enabled the translation of light stimulus into chemical signal, which may open up new control on the basis of the specific reaction field.

Promoting the Achievement of Carbon Neutrality Targets: Systematic Review of Research Dimensions and Measure Methods on Carbon Equity in China.

Carbon equity is the balance between carbon reduction responsibilities and development rights. The review of carbon equity in China can help it achieve carbon neutrality targets and provide valuable insights to other emerging countries. This study aimed to systematically sort, classify, compare, and prospect the research dimensions and measure methods for carbon equity. The research dimensions were first classified into intergenerational, regional, trade, and income carbon equity by literature analysis. Intergenerational carbon equity explores the balance of carbon emission rights among generations using integrated assessment models (IAM). Regional carbon equity analyzes the socioeconomic effect of regional carbon emission rights allocation by IAM or regional differences under a specific allocation assumption by the Theil index. Trade carbon equity studies the relationship between carbon emissions and economic benefit transfer embodied in inter-regional trade, which is more suitable for calculating by methods with comparable results, such as the optimized regional environmental inequality index. Income carbon equity investigates the carbon footprint heterogeneity among income groups by the carbon Gini coefficient. This paper further discusses potential research directions for each dimension. Notably, all research dimensions did not consider promoted strategies for carbon equity, which should be a priority for future studies.

The role of the paraspinal muscles in the development of adolescent idiopathic scoliosis based on surface electromyography and radiographic analysis.

BACKGROUND: Patients with idiopathic scoliosis commonly present with an imbalance of the paraspinal muscles. However, it is unclear whether this muscle imbalance is an underlying cause or a result of idiopathic scoliosis. This study aimed to investigate the role of paraspinal muscles in the development of idiopathic scoliosis based on surface electromyography (sEMG) and radiographic analyses. METHODS: This was a single-center prospective study of 27 patients with single-curve idiopathic scoliosis. Posteroanterior whole-spine radiographs and sEMG activity of the erector spinae muscles were obtained for all patients in the habitual standing position (HSP), relaxed prone position (RPP), and prone extension position (PEP). The Cobb angle, symmetrical index (SI) of the sEMG activity (convex/concave), and correlation between the two factors were analyzed. RESULTS: In the total cohort, the mean Cobb angle in the HSP was significantly greater than the mean Cobb angle in the RPP (RPP-Cobb) (p < 0.001), whereas the mean Cobb angle in the PEP (PEP-Cobb) did not differ from the RPP-Cobb. Thirteen patients had a PEP-Cobb that was significantly smaller than their RPP-Cobb (p = 0.007), while 14 patients had a PEP-Cobb that was significantly larger than their RPP-Cobb (p < 0.001). In the total cohort and two subgroups, the SI of sEMG activity at the apex vertebra (AVSI) in the PEP was significantly greater than 1, revealing significant asymmetry, and was also significantly larger than the AVSI in the RPP. In the RPP, the AVSI was close to 1 in the total cohort and two subgroups, revealing no significant asymmetry. CONCLUSION: The coronal Cobb angle and the SI of paraspinal muscle activity in AIS patients vary with posture changes. Asymmetrical sEMG activity of the paraspinal muscles may be not an inherent feature of AIS patients, but is evident in the challenging tasks. The potential significance of asymmetric paraspinal muscle activity need to be explored in further research.

Efficacy and safety of transurethral resection of bladder tumour combined with chemotherapy and immunotherapy in bladder-sparing therapy in patients with T1 high-grade or T2 bladder cancer: a protocol for a randomized controlled trial.

BACKGROUND: Bladder cancer is the tenth most common cancer worldwide. For patients with T1 high-grade or T2 bladder cancer, radical cystectomy is recommended. However, radical cystectomy is associated with various complications and has a detrimental impact on the quality of life. Bladder-sparing therapy has been widely explored in patients with muscle-invasive bladder cancer, and whether a combination of transurethral resection of bladder tumour (TURBT) with chemotherapy and immunotherapy shows definite superiority over TURBT plus chemotherapy is still a matter of debate. The aim of this study is to investigate the efficacy and safety of TURBT combined with chemotherapy and immunotherapy in bladder-sparing therapy in patients with T1 high-grade or T2 bladder cancer who are unwilling or unsuitable to undergo radical cystectomy. METHODS: An open-label, multi-institutional, two-armed randomized controlled study will be performed with 86 patients with T1 high-grade or T2 bladder cancer meeting the eligibility criteria. Participants in the experimental group (n = 43) will receive TURBT combined with chemotherapy (GC: gemcitabine 1000 mg/m2 on the 1st day and the 8th day, cisplatin 70 mg/m2 on the 2nd day, repeated every 21 days) and immunotherapy (toripalimab 240 mg on the 5th day, repeated every 21 days), and those in the control group (n = 43) will receive TURBT plus chemotherapy (GC). The primary outcome is pathological response, and the secondary outcomes include progression-free survival, overall survival, toxicities, and quality of life. DISCUSSION: To the best of our knowledge, this is the first study to evaluate the efficacy and safety of TURBT combined with GC regimen and toripalimab in bladder-sparing therapy in patients with T1 high-grade or T2 bladder cancer. The expected benefit is that the combination of TURBT with chemotherapy and immunotherapy would be more effective than TURBT plus chemotherapy without compromising the quality of life and increasing the toxicity. TRIAL REGISTRATION: ChiCTR2200060546, chictr.org.cn, registered on June 14, 2022.

Development of a high-performance label-free electrochemical immunosensor for early cancer diagnosis using anti-CEA/Ag-MOF/GO/GCE nanocomposite.

In order to detect carcinoembryonic antigen (CEA) as a tumor marker in lung cancer for early cancer diagnosis, this study aimed to develop a label-free electrochemical immunosensor based on the immobilization of an Anti-CEA antibody on a metal-organic framework (MOF)-graphene oxide nanocomposite modified glassy carbon electrode (Anti-CEA/Ag-MOF/GO/GCE). Ag-MOF/GO nanocomposite was prepared on the GCE surface using the ultrasonic irradiation method, and Anti-CEA antibody was subsequently immobilized on the surface. Analysis of the crystal structure and morphology of the modified electrode using FE-SEM and XRD revealed that the correct combination of GO nanosheets and Ag-MOF nanoparticles produced a high surface area to trap the antibodies. Electrochemical tests utilizing the CV and DPV methods revealed that the immunosensor's sensitivity, stability, and selectivity were improved by Anti-CEA/Ag-MOF/GO/GCE. Results showed that, with a detection limit of 0.005 ng/mL, the change in the reduction peak current was inversely correlated with the logarithm concentration of CEA in the range of 10-3 to 5000 ng/mL. The suggested CEA immunosensor's applicability in a human serum sample was investigated, and findings of analytical studies via standard addition technique for both ELISA and DPV assays revealed that significant agreement existed between the outcomes of the two assays. Additionally, the recoveries ranged from 99.00% to 99.25%, and all relative standard deviations (RSDs) for the sample detections were below 5.01%, indicating satisfactory accuracy in results measured with the proposed CEA immunosensor, indicating that the prepared CEA immunosensor in this study can be used in clinical applications and human fluids.

Association of cigarette smoking habits with the risk of prostate cancer: a systematic review and meta-analysis.

BACKGROUND: Association of cigarette smoking habits with the risk of prostate cancer is still a matter of debate. This systematic review and meta-analysis aimed to assess the association between cigarette smoking and prostate cancer risk. METHODS: We conducted a systematic search on PubMed, Embase, Cochrane Library, and Web of Science without language or time restrictions on June 11, 2022. Literature search and study screening were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Prospective cohort studies that assessed the association between cigarette smoking habits and the risk of prostate cancer were included. Quality assessment was conducted using the Newcastle-Ottawa Scale. We used random-effects models to obtain pooled estimates and the corresponding 95% confidence intervals. RESULTS: A total of 7296 publications were screened, of which 44 cohort studies were identified for qualitative analysis; 39 articles comprising 3 296 398 participants and 130 924 cases were selected for further meta-analysis. Current smoking had a significantly reduced risk of prostate cancer (RR, 0.74; 95% CI, 0.68-0.80; P < 0.001), especially in studies completed in the prostate-specific antigen screening era. Compared to former smokers, current smokers had a significant lower risk of PCa (RR, 0.70; 95% CI, 0.65-0.75; P < 0.001). Ever smoking showed no association with prostate cancer risk in overall analyses (RR, 0.96; 95% CI, 0.93-1.00; P = 0.074), but an increased risk of prostate cancer in the pre-prostate-specific antigen screening era (RR, 1.05; 95% CI, 1.00-1.10; P = 0.046) and a lower risk of prostate cancer in the prostate-specific antigen screening era (RR, 0.95; 95% CI, 0.91-0.99; P = 0.011) were observed. Former smoking did not show any association with the risk of prostate cancer. CONCLUSIONS: The findings suggest that the lower risk of prostate cancer in smokers can probably be attributed to their poor adherence to cancer screening and the occurrence of deadly smoking-related diseases, and we should take measures to help smokers to be more compliant with early cancer screening and to quit smoking. TRIAL REGISTRATION: This study was registered on PROSPERO (CRD42022326464).

A systematic review and network meta-analysis of virtual reality, audiovisuals and music interventions for reducing dental anxiety related to tooth extraction.

BACKGROUND: Tooth extraction is a common procedure performed by oral and maxillofacial surgeons or dentists, often resulting in dental fear and anxiety. The use of relaxing music, audiovisuals, and virtual reality (VR) technologies has been employed to reduce dental anxiety. This network meta-analysis (NMA) aimed to assess the comparative effectiveness of relaxing music, audiovisuals, and VR in reducing dental anxiety associated with tooth extraction. METHODS: Four electronic databases were searched up to March 8, 2023, to identify randomized controlled trials (RCTs) evaluating different multimedia interventions, including the application of using relaxing music, audiovisuals, and VR technologies for dental anxiety. Studies utilizing various anxiety scales for tooth extraction were considered eligible. The pooled standard mean difference (SMD) and 95% confidence interval (CI) of anxiety scale scores were analyzed using Bayesian NMA. RESULTS: A total of 11 RCTs were included in this NMA. The Bayesian NMA results demonstrated that relaxing music (SMD = -0.64, 95% CI: -1.04, -0.25) and VR (SMD = -0.54, 95% CI: -1.08, -0.02) were associated with a reduction in dental anxiety, while audiovisuals (SMD = -0.34, 95% CI: -0.97, 0.33) required further consideration. Ranking probabilities indicated that relaxing music might be the most acceptable method for individuals with dental anxiety. The frequentist NMA yielded consistent rankings in a sensitivity analysis. CONCLUSIONS: Relaxing music shows the greatest potential for reducing dental anxiety related to tooth extraction when compared to other multimedia interventions.

[An attention-guided network for bilateral ventricular segmentation in pediatric echocardiography].

Accurate segmentation of pediatric echocardiograms is a challenging task, because significant heart-size changes with age and faster heart rate lead to more blurred boundaries on cardiac ultrasound images compared with adults. To address these problems, a dual decoder network model combining channel attention and scale attention is proposed in this paper. Firstly, an attention-guided decoder with deep supervision strategy is used to obtain attention maps for the ventricular regions. Then, the generated ventricular attention is fed back to multiple layers of the network through skip connections to adjust the feature weights generated by the encoder and highlight the left and right ventricular areas. Finally, a scale attention module and a channel attention module are utilized to enhance the edge features of the left and right ventricles. The experimental results demonstrate that the proposed method in this paper achieves an average Dice coefficient of 90.63% in acquired bilateral ventricular segmentation dataset, which is better than some conventional and state-of-the-art methods in the field of medical image segmentation. More importantly, the method has a more accurate effect in segmenting the edge of the ventricle. The results of this paper can provide a new solution for pediatric echocardiographic bilateral ventricular segmentation and subsequent auxiliary diagnosis of congenital heart disease.

CABEAN: a software for the control of asynchronous Boolean networks.

SUMMARY: Direct cell reprogramming, also called transdifferentiation, has great potential for tissue engineering and regenerative medicine. Boolean networks, a popular modelling framework for gene regulatory networks, make it possible to identify intervention targets for direct cell reprogramming with computational methods. In this work, we present our software, CABEAN, for the control of asynchronous Boolean networks. CABEAN identifies efficacious nodes, whose perturbations can drive the dynamics of a network from a source attractor (the initial cell type) to a target attractor (the desired cell type). CABEAN provides several control methods integrating practical constraints. Thus, it has the ability to provide a rich set of control sets, such that biologists can select suitable ones for validation based on specific experimental settings. AVAILABILITY AND IMPLEMENTATION: The executable binary and the user guide of the software are publicly available at https://satoss.uni.lu/software/CABEAN/.

Overexpression of PFKFB3 promotes cell glycolysis and proliferation in renal cell carcinoma.

BACKGROUND: Cancer cells prefer utilizing aerobic glycolysis in order to exacerbate tumor mass and maintain un-regulated proliferative rates. As a key glycolytic activator, phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) has been implicated in multiple tumor type progression. However, the specific function and clinical significance of PFKFB3 in renal cell carcinoma (RCC) are yet not clarified. This investigation assessed PFKFB3 roles in RCC. METHODS: PFKFB3 expression levels were analyzed in clear cell renal cell carcinoma (ccRCC) tissues, together with its relationship with clinical characteristics of ccRCC. Real-time PCR and Western blot assays were employed for determining PFKFB3 expression in different RCC cell lines. Furthermore, we determined the glycolytic activity by glucose uptake, lactate secretion assay and ECAR analysis. CCK-8 assay, clone formation, flow cytometry and EdU assessments were performed for monitoring tumor proliferative capacity and cell-cycle distribution. Furthermore, a murine xenograft model was employed for investigating the effect of PFKFB3 on tumor growth in vivo. RESULTS: PFKFB3 was significantly up-regulated in RCC specimens and cell lines in comparison to normal control. Overexpression of PFKFB3 was directly correlated to later TNM stages, thus becoming a robust prognostic biomarker for ccRCC cases. Furthermore, PFKFB3 knockdown suppressed cell glycolysis, proliferative rate and cell-cycle G1/S conversion in RCC cells. Importantly, in vivo experiments confirmed that PFKFB3 knockdown delayed tumor growth derived from the ACHN cell line. CONCLUSIONS: Such results suggest that PFKFB3 is a key molecular player in RCC progression via mediating glycolysis / proliferation and provides a potential therapeutic target against RCC.

Efficacy and safety of Androgen Deprivation Therapy (ADT) combined with modified docetaxel chemotherapy versus ADT combined with standard docetaxel chemotherapy in patients with metastatic castration-resistant prostate cancer: study protocol for a multicentre prospective randomized controlled trial.

BACKGROUND: Androgen deprivation therapy (ADT) combined with docetaxel chemotherapy is the standard treatment for metastatic castration-resistant prostate cancer (mCRPC) patients. However, mCRPC patients are mainly frail elderly men, constantly accompanied by comorbidities and showing poor tolerance to standard docetaxel chemotherapy. Some exploratory studies administering modified chemotherapy regimens have reported noninferior oncologic outcomes with fewer adverse events, yet most are retrospective or small studies, and prospective randomized controlled trials have rarely been conducted. Therefore, we designed this modified docetaxel chemotherapy regimen in patients with mCRPC, aiming to evaluate its efficacy and safety compared with the standard docetaxel chemotherapy regimen. METHODS: This is an open-label, multi-institutional, prospective, randomized non-inferiority trial. A total of 128 patients with mCRPC will be randomized to receive ADT combined with modified docetaxel chemotherapy (experimental group, n=64) or ADT combined with standard docetaxel chemotherapy (control group, n=64). Patients in the experimental group will receive a modified regimen with docetaxel 40 mg/m2 on the 1st day and 35 mg/m2 on the 8th day, repeated every 21 days. The primary endpoint is progression-free survival at 2 years. Secondary endpoints include overall survival, prostate-specific antigen response rate, pain response rate, toxicity and quality of life. DISCUSSION: The expected benefit for the patient in the experimental arm is noninferior efficacy with decreased toxicity and improved quality of life compared with that in the control arm. To the best of our knowledge, this will be the first multicentre prospective randomized study to assess the efficacy and safety of modified docetaxel chemotherapy in patients with mCRPC in China. The results of this trial may provide benefit to mCRPC patients, especially those with poor performance. TRIAL REGISTRATION: chictr.org.cn Identifier: ChiCTR2100046636 (May 24, 2021). Ongoing study.

Pirfenidone ameliorates silica-induced lung inflammation and fibrosis in mice by inhibiting the secretion of interleukin-17A.

Silicosis is a global occupational disease characterized by lung dysfunction, pulmonary inflammation, and fibrosis, for which there is a lack of effective drugs. Pirfenidone has been shown to exert anti-inflammatory and anti-fibrotic properties in the lung. However, whether and how pirfenidone is effective against silicosis remains unknown. Here, we evaluated the efficacy of pirfenidone in the treatment of early and advanced silicosis in an experimental mouse model and explored its potential pharmacological mechanisms. We found that pirfenidone alleviated silica-induced lung dysfunction, secretion of inflammatory cytokines (TNF-α, IL-1ß, IL-6) and deposition of fibrotic proteins (collagen I and fibronectin) in both early and advanced silicosis models. Moreover, we observed that both 100 and 200 mg/kg pirfenidone can effectively treat early-stage silicosis, while 400 mg/kg was recommended for advanced silicosis. Mechanistically, antibody array and bioinformatic analysis showed that the pathways related to IL-17 secretion, including JAK-STAT pathway, Th17 differentiation, and IL-17 pathway, might be involved in the treatment of silicosis by pirfenidone. Further in vivo experiments confirmed that pirfenidone reduced the production of IL-17A induced by silica exposure via inhibiting STAT3 phosphorylation. Neutralizing IL-17A by anti-IL-17A antibody improved lung function and reduced pulmonary inflammation and fibrosis in silicosis animals. Collectively, our study has demonstrated that pirfenidone effectively ameliorated silica-induced lung dysfunction, pulmonary inflammation and fibrosis in mouse models by inhibiting the secretion of IL-17A.

Carrageenophyte Kappaphycus malesianus Inhibits Microglia-Mediated Neuroinflammation via Suppression of AKT/NF-κB and ERK Signaling Pathways.

Neuroinflammation is an inflammatory response in any part of the central nervous system triggered by the activation of microglia and astrocytes to produce proinflammatory cytokines in the brain. However, overproduction of proinflammatory cytokines further contributes to the development of neurodegenerative disorders. Red seaweed, Kappaphycus malesianus, is a predominant carrageenophyte commercially cultivated in Semporna, Sabah, Malaysia. It is an important source of raw material for kappa-carrageenan productions in the food, pharmaceutical and cosmetics industries. However, no studies have been conducted focusing on the antineuroinflammatory effects of K. malesianus. The aim of the present study was to investigate the effect of the antineuroinflammatory activity of K. malesianus extracts (ethyl acetate, ethanol and methanol) on lipopolysaccharide-stimulated BV2 microglia and the underlying mechanisms involved in the regulation of neuroinflammatory pathways. Extract with the most promising antineuroinflammatory activity was analyzed using liquid chromatography-mass spectrometry (LC-MS). Our results show that methanol extract has a convincing antineuroinflammatory effect by suppressing both AKT/NF-κB and ERK signaling pathways to inhibit the expression of all proinflammatory cytokines without causing a cytotoxicity effect. LC-MS analysis of methanol extract revealed two compounds: prosopinine and eplerenone. Our findings indicated that metabolites of K. malesianus are potent antineuroinflammatory agents with respect to prevention of neurological disorders.

[Expression and role of the TRPC family in TGF-ß1-induced calcium influx in podocytes].

The TRPC family consists of multiple important cationic channels in mammals that participate in a variety of physiological and pathological processes. Our previous studies have shown that transforming growth factor-ß1 (TGF-ß1) increases the expression of TRPC6 in podocytes, but the roles of other members of the TRPC family in podocytes require further investigation. In this study, we investigated the effect of TGF-ß1 on the expression of the TRPC family and the role of the TRPC family in the changes of the intracellular Ca2+ concentration ([Ca2+]i) in podocytes induced by TGF-ß1. The model of podocyte injury was established by treatment with TGF-ß1 in immortalized glomerular podocytes (MPC5) in vitro. qRT-PCR and Western blot were used to detect the effect of TGF-ß1 on the mRNA and protein expression of each TRPC family member. After the expression of each TRPC family member was knocked down by a siRNA-based approach and blocked by SKF96365, respectively, free cytosolic Ca2+ was measured using the fluorescent Ca2+ indicator Fluo-3/AM, and the dynamic change of [Ca2+]i in podocytes was detected by a dynamic high-speed calcium imaging system. The results showed that TGF-ß1 increased the protein expression of TRPC1/3/6 in podocytes, but had no effects on the protein expression of TRPC4. The protein expression levels of TRPC5/7 were only affected by 4 ng/mL and 8 ng/mL TGF-ß1, respectively. TGF-ß1 increased TRPC1/3/6 mRNA levels in podocytes, however had no effects on TRPC4/5/7 mRNA. TGF-ß1 significantly increased [Ca2+]i in podocytes. Knockdown of TRPC1/4/5/7 in podocytes had no significant effect on the [Ca2+]i induced by TGF-ß1, but TRPC3/6 knockdown significantly decreased the [Ca2+]i. There was no significant difference in the [Ca2+]i between the TRPC6 siRNA-treated group and SKF96365-treated group, but the [Ca2+]i of the TRPC3 siRNA-treated group was significantly higher than that of SKF96365-treated group. These results demonstrate that TGF-ß1 increases the expression of the TRPC1/3/6 in podocytes. TGF-ß1 increases [Ca2+]i in podocytes, which is dependent on the TRPC3/6 expression. Our results also suggest that the effect of TRPC6 on [Ca2+]i in podocytes may be greater than that of TRPC3.

Exploring Spillover Effects for COVID-19 Cascade Prediction.

An information outbreak occurs on social media along with the COVID-19 pandemic and leads to an infodemic. Predicting the popularity of online content, known as cascade prediction, allows for not only catching in advance information that deserves attention, but also identifying false information that will widely spread and require quick response to mitigate its negative impact. Among the various information diffusion patterns leveraged in previous works, the spillover effect of the information exposed to users on their decisions to participate in diffusing certain information has not been studied. In this paper, we focus on the diffusion of information related to COVID-19 preventive measures due to its special role in consolidating public efforts to slow down the spread of the virus. Through our collected Twitter dataset, we validate the existence of the spillover effects. Building on this finding, we propose extensions to three cascade prediction methods based on Graph Neural Networks (GNNs). Experiments conducted on our dataset demonstrated that the use of the identified spillover effects significantly improves the state-of-the-art GNN methods in predicting the popularity of not only preventive measure messages, but also other COVID-19 messages.

The Role of Surface Electromyography in Data Fusion with Inertial Sensors to Enhance Locomotion Recognition and Prediction.

Locomotion recognition and prediction is essential for real-time human-machine interactive control. The integration of electromyography (EMG) with mechanical sensors could improve the performance of locomotion recognition. However, the potential of EMG in motion prediction is rarely discussed. This paper firstly investigated the effect of surface EMG on the prediction of locomotion while integrated with inertial data. We collected EMG signals of lower limb muscle groups and linear acceleration data of lower limb segments from ten healthy participants in seven locomotion activities. Classification models were built based on four machine learning methods-support vector machine (SVM), k-nearest neighbor (KNN), artificial neural network (ANN), and linear discriminant analysis (LDA)-where a major vote strategy and a content constraint rule were utilized for improving the online performance of the classification decision. We compared four classifiers and further investigated the effect of data fusion on the online locomotion classification. The results showed that the SVM model with a sliding window size of 80 ms achieved the best recognition performance. The fusion of EMG signals does not only improve the recognition accuracy of steady-state locomotion activity from 90% (using acceleration data only) to 98% (using data fusion) but also enables the prediction of the next steady locomotion (∼370 ms). The study demonstrates that the employment of EMG in locomotion recognition could enhance online prediction performance.

Controlling large Boolean networks with single-step perturbations.

MOTIVATION: The control of Boolean networks has traditionally focussed on strategies where the perturbations are applied to the nodes of the network for an extended period of time. In this work, we study if and how a Boolean network can be controlled by perturbing a minimal set of nodes for a single-step and letting the system evolve afterwards according to its original dynamics. More precisely, given a Boolean network (BN), we compute a minimal subset Cmin of the nodes such that BN can be driven from any initial state in an attractor to another 'desired' attractor by perturbing some or all of the nodes of Cmin for a single-step. Such kind of control is attractive for biological systems because they are less time consuming than the traditional strategies for control while also being financially more viable. However, due to the phenomenon of state-space explosion, computing such a minimal subset is computationally inefficient and an approach that deals with the entire network in one-go, does not scale well for large networks. RESULTS: We develop a 'divide-and-conquer' approach by decomposing the network into smaller partitions, computing the minimal control on the projection of the attractors to these partitions and then composing the results to obtain Cmin for the whole network. We implement our method and test it on various real-life biological networks to demonstrate its applicability and efficiency. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.