Circular RNAs (circRNAs) have been indicated as potentially critical mediators in various types of tumor progression, generally acting as microRNA (miRNA) sponges to regulate downstream gene ...expression. However, the aberrant expression profile and dysfunction of circRNAs in human clear cell renal cell carcinoma (ccRCC) need to be further investigated. This study mined key prognostic circRNAs and elucidates the potential role and molecular mechanism of circRNAs in regulating the proliferation and metastasis of ccRCC.
circCHST15 (hsa_circ_0020303) was identified by mining two circRNA microarrays from the Gene Expression Omnibus database and comparing matched tumor versus adjacent normal epithelial tissue pairs or matched primary versus metastatic tumor tissue pairs. These results were validated by quantitative real-time polymerase chain reaction and agarose gel electrophoresis. We demonstrated the biological effect of circCHST15 in ccRCC both in vitro and in vivo. To test the interaction between circCHST15 and miRNAs, we conducted a number of experiments, including RNA pull down assay, dual-luciferase reporter assay and fluorescence in situ hybridization.
The expression of circCHST15 was higher in ccRCC tissues compared to healthy adjacent kidney tissue and higher in RCC cell lines compared to normal kidney cell lines. The level of circCHST15 was positively correlated with aggressive clinicopathological characteristics, and circCHST15 served as an independent prognostic indicator for overall survival and progression-free survival in patients with ccRCC after surgical resection. Our in vivo and in vitro data indicate that circCHST15 promotes the proliferation, migration, and invasion of ccRCC cells. Mechanistically, we found that circCHST15 directly interacts with miR-125a-5p and acts as a microRNA sponge to regulate EIF4EBP1 expression.
We found that sponging of miR-125a-5p to promote EIF4EBP1 expression is the underlying mechanism of hsa_circ_0020303-induced ccRCC progression. This prompts further investigation of circCHST15 as a potential prognostic biomarker and therapeutic target for ccRCC.
Abstract
Background
N6-methyladenosine (m6A) related long noncoding RNAs (lncRNAs) may have prognostic value in bladder cancer for their key role in tumorigenesis and innate immunity.
Methods
Bladder ...cancer transcriptome data and the corresponding clinical data were acquired from the Cancer Genome Atlas (TCGA) database. The m6A-immune-related lncRNAs were identified using univariate Cox regression analysis and Pearson correlation analysis. A risk model was established using least absolute shrinkage and selection operator (LASSO) Cox regression analyses, and analyzed using nomogram, time-dependent receiver operating characteristics (ROC) and Kaplan–Meier survival analysis. The differences in infiltration scores, clinical features, and sensitivity to Talazoparib of various immune cells between low- and high-risk groups were investigated.
Results
Totally 618 m6A-immune-related lncRNAs and 490 immune-related lncRNAs were identified from TCGA, and 47 lncRNAs of their intersection demonstrated prognostic values. A risk model with 11 lncRNAs was established by Lasso Cox regression, and can predict the prognosis of bladder cancer patients as demonstrated by time-dependent ROC and Kaplan–Meier analysis. Significant correlations were determined between risk score and tumor malignancy or immune cell infiltration. Meanwhile, significant differences were observed in tumor mutation burden and stemness-score between the low-risk group and high-risk group. Moreover, high-risk group patients were more responsive to Talazoparib.
Conclusions
An m6A-immune-related lncRNA risk model was established in this study, which can be applied to predict prognosis, immune landscape and chemotherapeutic response in bladder cancer.
In this paper, a dual-ligand design strategy is demonstrated to modulate the performance of the electronically conductive metalorganic frameworks (EC-MOFs) thin film with a spray layer-by-layer ...assembly method. The thin film not only can be precisely prepared in nanometer scale (20–70 nm), but also shows the pin-hole-free smooth surface. The high quality nano-film of 2,3,6,7,10,11-hexaiminotriphenylene (HITP) doped Cu-HHTP enables the precise modulation of the chemiresistive sensitivity and selectivity. Selectivity improvement over 220% were realized for benzene vs. NH
3
, as well as enhanced response and recovery properties. In addition, the selectivity of the EC-MOF thin film sensors toward other gases (e.g. triethylamine, methane, ethylbenzene, hydrogen, butanone, and acetone) vs. NH
3
at room temperature is also discussed.
The deep sea remains the largest unknown territory on Earth because it is so difficult to explore
. Owing to the extremely high pressure in the deep sea, rigid vessels
and pressure-compensation ...systems
are typically required to protect mechatronic systems. However, deep-sea creatures that lack bulky or heavy pressure-tolerant systems can thrive at extreme depths
. Here, inspired by the structure of a deep-sea snailfish
, we develop an untethered soft robot for deep-sea exploration, with onboard power, control and actuation protected from pressure by integrating electronics in a silicone matrix. This self-powered robot eliminates the requirement for any rigid vessel. To reduce shear stress at the interfaces between electronic components, we decentralize the electronics by increasing the distance between components or separating them from the printed circuit board. Careful design of the dielectric elastomer material used for the robot's flapping fins allowed the robot to be actuated successfully in a field test in the Mariana Trench down to a depth of 10,900 metres and to swim freely in the South China Sea at a depth of 3,224 metres. We validate the pressure resilience of the electronic components and soft actuators through systematic experiments and theoretical analyses. Our work highlights the potential of designing soft, lightweight devices for use in extreme conditions.
Artificial intelligence robots predicted in sci‐fi movies have attracted increasing attention in recent years, and much effort has been devoted to improving the sensing and manipulation performance ...of robots. The development of robotic skins capable of handling complex external pressure environments is highly desired for intelligent robots. However, this remains a major challenge due to the lack of pressure sensing materials that can combine extremely low detection limits and wide detection ranges. Inspired by the synergistic strategy of dual mechanoreceptors in human skin, here, the design and 3D printing of laminated graphene pressure sensing materials consisting of both ultrathin‐ and thick‐walled cellular microstructures are demonstrated. Based on such laminated graphene, the piezoresistive pressure sensor achieves a low detection limit of 1 Pa, a wide detection range (1 Pa–400 kPa), and high sensitivities of 3.1 and 0.22 kPa−1 in the pressure regions of 1 Pa–13 kPa and 13−400 kPa, respectively, and the laminated graphene‐based skin enables quantitative pressure/weight detection. This laminated graphene can be easily integrated into flexible pressure sensing arrays that enable mapping the spatial distribution of pressure, showing great potential for applications such as electronic skin, physiological signal monitoring, and human–machine interfaces.
Inspired by the synergistic strategy of dual mechanoreceptors in human skin, laminated graphene pressure‐sensing materials consisting of ultrathin‐ and thick‐walled cellular microstructures are printed via a direct‐ink‐writing 3D printing process. The synergy of the different piezoresistive properties of different layers enables the flexible pressure sensing devices to achieve both ultralow detection limits and ultrawide detection ranges.
Two porous coordination polymers (PCPs) with different topologies (NTU‐19: sql and NTU‐20: dia) underwent finely controlled, stepwise crystal conversions to yield a common water‐stable, flexible 2D ...framework (NTU‐22: kgm). The crystal conversions occurred directly at higher temperature via the 3D intermediate (NTU‐21: nbo), which could be observed at lower temperature. The successful isolation of the intermediate product of NTU‐21, characterization with in situ PXRD and UV/Vis spectra were combined with DFT calculations to allow an understanding of the dynamic processes at the atomic level. Remarkably, breakthrough experiments demonstrate NTU‐22 with integral structural properties allowed significant CO2/CH4 mixture separation.
Crystal to crystal: Two porous coordination polymers (PCPs) with different topologies (sql and dia) underwent crystal conversion to yield the first water‐stable, two‐dimensional and flexible kgm PCP, via or not via a 3D nbo intermediate. Plausible mechanisms for crystal conversions were elucidated at the atomic level both experimentally and theoretically (see figure).
Human brain function undergoes complex transformations across the lifespan. We employed resting-state functional MRI and graph-theory approaches to systematically chart the lifespan trajectory of the ...topological organization of human whole-brain functional networks in 126 healthy individuals ranging in age from 7 to 85 years. Brain networks were constructed by computing Pearson's correlations in blood-oxygenation-level-dependent temporal fluctuations among 1024 parcellation units followed by graph-based network analyses. We observed that the human brain functional connectome exhibited highly preserved non-random modular and rich club organization over the entire age range studied. Further quantitative analyses revealed linear decreases in modularity and inverted-U shaped trajectories of local efficiency and rich club architecture. Regionally heterogeneous age effects were mainly located in several hubs (e.g., default network, dorsal attention regions). Finally, we observed inverse trajectories of long- and short-distance functional connections, indicating that the reorganization of connectivity concentrates and distributes the brain's functional networks. Our results demonstrate topological changes in the whole-brain functional connectome across nearly the entire human lifespan, providing insights into the neural substrates underlying individual variations in behavior and cognition. These results have important implications for disease connectomics because they provide a baseline for evaluating network impairments in age-related neuropsychiatric disorders.
Background
The prognostic significance of hyperperfusion after reperfusion therapy in patients with acute ischemic stroke (AIS) remains controversial.
Purpose
To investigate the clinical factors ...associated with hyperperfusion, and the 90‐day prognostic value of hyperperfusion after mechanical thrombectomy in AIS patients.
Study Type
Retrospective.
Population/Subjects
Fifty‐four AIS patients who underwent mechanical thrombectomy.
Field Strength/Sequence
Time‐of‐flight MR angiography, pulsed arterial spin labeling (ASL), diffusion‐weighted imaging (DWI), and susceptibility‐weighted imaging were performed at 3.0T within 1 week after thrombectomy.
Assessment
Clinical factors including demographics, risk factors, stroke and treatment characteristics were collected and assessed. Hyperperfusion on ASL was defined as a focal increased cerebral blood flow on the affected side ≥130% of its mirror counterpart. Good clinical outcome at 90 days was defined as modified Rankin Scale score of 0–2.
Statistical Tests
The interrater agreement was assessed using Cohen's kappa or the intraclass correlation coefficient. The relationship between hyperperfusion and clinical factors were analyzed by appropriate univariate statistics. Predictors of 90‐day functional outcome were assessed by univariate analyses followed by multivariate logistic regression analysis and receiver‐operating‐characteristic curves.
Results
Thirty‐six (66.7%) patients developed hyperperfusion on ASL after thrombectomy. Hyperperfusion was significantly correlated with successful recanalization (P < 0.05) and improvement of National Institutes of Health Stroke Scale scores at 24 hours (NIHSS24h) (P < 0.05). A higher incidence of hemorrhage transformation was observed in patients with hyperperfusion than those without (63.9% vs. 50.0%), but no significant difference was found (P = 0.327). NIHSS24h (odds ratio OR, 0.75, 95% confidence interval CI 0.62–0.91, P < 0.05), lesion volume on diffusion‐weighted imaging (OR, 0.97, 95% CI 0.95–1.00, P < 0.05), and hyperperfusion on ASL (OR, 9.8, 95% CI 1.7–55.3, P < 0.05) were independent variables for predicting good functional outcomes.
Data Conclusion
Hyperperfusion on ASL correlated with successful recanalization and may be an independent prognostic marker for good neurological outcomes at 90 days in AIS patients after mechanical thrombectomy.
Level of Evidence
4
Technical Efficacy Stage
2
Background
Only a proportion of patients with bladder cancer may benefit from durable response to immune checkpoint inhibitor (ICI) therapy. More precise indicators of response to immunotherapy are ...warranted. Our study aimed to construct a more precise classifier for predicting the benefit of immune checkpoint inhibitor therapy.
Methods
This multi-cohort study examined the top 20 frequently mutated genes in five cohorts of patients with bladder cancer and developed the
TP53
/
PIK3CA
/
ATM
mutation classifier based on the MSKCC ICI cohort. The classifier was then validated in a validation set consisting of IMvigor210 cohort and Broad/Dana-Farber cohort. The molecular profile and immune infiltration characteristics in each subgroup as defined by this classifier were explored.
Results
Among all 881 patients with bladder cancer, the mutation frequency of
TP53
,
PIK3CA
, and
ATM
ranked in the top 20 mutated genes. The
TP53
/
PIK3CA
/
ATM
mutation classifier was constructed based on the Memorial Sloan Kettering Cancer Center (MSKCC) ICI cohort and only showed predictive value for patients with bladder cancer who received ICI therapy (median overall survival: low-risk group, not reached; moderate-risk group, 13.0 months; high-risk group, 8.0 months; P<0.0001). Similar results were found in subgroups of MSKCC ICI cohort defined by tumor mutation burden. Multivariate Cox analysis revealed that the risk group defined by the classifier served as an independent prognostic factor for overall survival in patients with bladder cancer. Efficacy of the classifier was verified in a validation set consisting of IMvigor210 cohort and Broad/Dana-Farber cohort. Lower expression of PD-1/PD-L1 and less tumor immune infiltration were observed in the high-risk group than the other two groups of the TCGA cohort and the IMvigor210 cohort.
Conclusion
Our study constructed a
TP53
/
PIK3CA
/
ATM
mutation classifier to predict the benefit of immune checkpoint inhibitor therapy for patients with bladder cancer. This classifier can potentially complement the tumor mutation burden and guide clinical ICI treatment decisions according to distinct risk levels.
Aberrant lipid metabolism is reported to be closely related to the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). Selenium (Se) and folate are two ideal and safe ...nutritional supplements, whose biological effects include regulating redox and homocysteine (Hcy) homeostasis in vivo. Here, to achieve effective multitarget therapy for AD, we combined Se and folic acid in a co-supplementation regimen (Se-FA) to study the therapeutic potential and exact mechanism in two transgenic mouse models of AD (APP/Tau/PSEN and APP/PS1). In addition to a reduction in Aβ generation and tau hyperphosphorylation, a restoration of synaptic plasticity and cognitive ability was observed in AD mice upon Se-FA administration. Importantly, by using untargeted metabolomics, we found that these improvements were dependent on the modulation of brain lipid metabolism, which may be associated with an antioxidant effect and the promotion of Hcy metabolism. Thus, from mechanism to effects, this study systematically investigated Se-FA as an intervention for AD, providing important mechanistic insights to inform its potential use in clinical trials.
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