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Abstract To improve the prognosis of bladder and prostate cancer, highly specific and sensitive biomarkers are needed for early detection, prognosis prediction, and therapeutic stratification. Extracellular vesicles (EV) from plasma could fill this gap due to their potential to serve as cancer biomarkers. However, the enrichment of EV is a major challenge, because the highly abundant plasma proteins are interfering with analytical downstream applications like mass spectrometry (MS). Therefore, the purity requirements of the EV samples must be carefully considered when selecting or developing a suitable EV enrichment method. The aim of this study was to compare a self-designed EV enrichment method based on density cushion centrifugation (DCC) combined with size exclusion chromatography (SEC) and concentration (method 1) with the exoRNeasy midi kit from Qiagen (method 2) and with unprocessed plasma. Furthermore, the single steps of method 1 were evaluated for their effectiveness to enrich EV from plasma. The results showed that the EV samples enriched with method 1 contained the highest levels of EV and exosome markers with simultaneously low levels of highly abundant plasma proteins. In summary, the combination of DCC, SEC and concentration proved to be a promising approach to discover EV-based biomarkers from plasma of cancer patients.

Abstract Linking clinical multi-omics with mechanistic studies may improve the understanding of rare cancers. We leverage two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective therapies. All tumors exhibit outlier ALK expression, partly accompanied by intragenic deletions and aberrant splicing resulting in ALK variants that are oncogenic and sensitive to ALK inhibitors. Additionally, recurrent CKDN2A/MTAP co-deletions provide a rationale for PRMT5-targeted therapies. Functional studies show that FUS-TFCP2 blocks myogenic differentiation, induces transcription of ALK and truncated TERT, and inhibits DNA repair. Unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibit genomic instability and signs of defective homologous recombination. DNA methylation profiling demonstrates a close relationship with undifferentiated sarcomas. In two patients, sarcoma was preceded by benign lesions carrying FUS-TFCP2, indicating stepwise sarcomagenesis. This study illustrates the potential of linking precision oncology with preclinical research to gain insight into the classification, pathogenesis, and therapeutic vulnerabilities of rare cancers.

Abstract Recent advances in the genomics of glioblastoma (GBM) led to the introduction of molecular neuropathology but failed to translate into treatment improvement. This is largely attributed to the genetic and phenotypic heterogeneity of GBM, which are considered the major obstacle to GBM therapy. Here, we use advanced human GBM-like organoid (LEGO: Laboratory Engineered Glioblastoma-like Organoid) models and provide an unprecedented comprehensive characterization of LEGO models using single-cell transcriptome, DNA methylome, metabolome, lipidome, proteome, and phospho-proteome analysis. We discovered that genetic heterogeneity dictates functional heterogeneity across molecular layers and demonstrates that NF1 mutation drives mesenchymal signature. Most importantly, we found that glycerol lipid reprogramming is a hallmark of GBM, and several targets and drugs were discovered along this line. We also provide a genotype-based drug reference map using LEGO-based drug screen. This study provides new human GBM models and a research path toward effective GBM therapy.

Abstract Background Despite multiple therapeutic modalities, the overall survival of patients with gastric adenocarcinoma remains poor, especially for advanced tumor stages. Although the tyrosine kinase MerTK has shown therapeutic relevance in several tumor entities, its potential effects in gastric adenocarcinoma have not yet been sufficiently characterized. Methods MerTK expression and its influence on patient survival were evaluated by immunohistochemistry in a cohort of 140 patients with gastric adenocarcinoma. CRISPR/Cas9 knockout and siRNA knockdown of MerTK in the gastric cancer cell lines SNU1, SNU5, and MKN45 was used to analyze protein expression, growth, migration, and invasion properties in vitro and in a murine xenograft model. MerTK was pharmacologically targeted with the small molecule inhibitor UNC2025 in vitro and in vivo. Results In patients, high MerTK expression was associated with decreased overall survival (OS) and lymph node metastasis especially in patients without neoadjuvant therapy (p

Abstract Epithelial membrane protein 3 (EMP3) is an N-glycosylated tetraspanin with a putative trafficking function. It is highly expressed in isocitrate dehydrogenase-wild-type glioblastoma (IDH-wt GBM), and its high expression correlates with poor survival. However, the exact trafficking role of EMP3 and how it promotes oncogenic signaling in GBM remain unclear. Here, we show that EMP3 promotes EGFR/CDK2 signaling by regulating the trafficking and enhancing the stability of EGFR. BioID2-based proximity labeling revealed that EMP3 interacts with endocytic proteins involved in the vesicular transport of EGFR. EMP3 knockout (KO) enhances epidermal growth factor (EGF)-induced shuttling of EGFR into RAB7 + late endosomes, thereby promoting EGFR degradation. Increased EGFR degradation is rescued by the RAB7 negative regulator and novel EMP3 interactor TBC1D5. Phosphoproteomic and transcriptomic analyses further showed that EMP3 KO converges into the inhibition of the cyclin-dependent kinase CDK2 and the repression of EGFR-dependent and cell cycle transcriptional programs. Phenotypically, EMP3 KO cells exhibit reduced proliferation rates, blunted mitogenic response to EGF, and increased sensitivity to the pan-kinase inhibitor staurosporine and the EGFR inhibitor osimertinib. Furthermore, EGFR-dependent patient-derived glioblastoma stem cells display a transcriptomic signature consistent with reduced CDK2 activity, as well as increased susceptibility to CDK2 inhibition upon EMP3 knockdown. Lastly, using TCGA data, we showed that GBM tumors with high EMP3 expression have increased total and phosphorylated EGFR levels. Collectively, our findings demonstrate a novel EMP3-dependent mechanism by which EGFR/CDK2 activity is sustained in GBM. Consequently, EMP3’s stabilizing effect provides an additional layer of tumor cell resistance against targeted kinase inhibition.

Abstract Background Colorectal cancer ranks second in terms of cancer associated deaths worldwide, whereas miRNA play a pivotal role in the etiology of cancer and its metastases. Aims Studying the expression and cellular function of miR‐18a in metastatic colorectal cancer and association to progression‐free survival. Methods and Results Colorectal liver metastases (N = 123) and primary colorectal cancer (N = 27) where analyzed by RT‐PCR and correlated with clinical follow up data. Invasion and migration assays were performed with the liver metastatic cell line LIM2099 after miR‐18a knockdown. Cell viability under FOLFOX treatment and knockdown was measured. We found that the expression of miR‐18a was increased 4.38‐fold in liver metastases and 3.86‐fold in colorectal tumor tissue compared to healthy liver tissue and colorectal mucosa, respectively (p ≤ .001). Patients with a high miR‐18a expression in liver metastases had a progression‐free survival (PFS) of 13.6 months versus 8.9 months in patients with low expression (N = 123; p = .024). In vitro migration of LIM2099 cells was reduced after miR‐18a knockdown and cell viability was significantly increased after miR‐18a knockdown and treatment with folinic acid or oxaliplatin. Subgroup analysis of PFS revealed significant benefits for patients with high miR‐18a expression receiving 5‐FU, folinic acid or oxaliplatin. Conclusions High expression of miR‐18a in colorectal liver metastases might have a protective effect after resection of metastases and FOLFOX treatment regarding PFS.

Abstract Background Physical activity and BMI have been individually associated with cancer survivorship but have not yet been studied in combinations in colorectal cancer patients. Here, we investigate individual and combined associations of physical activity and BMI groups with colorectal cancer survival outcomes. Methods Self-reported physical activity levels (MET hrs/wk) were assessed using an adapted version of the International Physical Activity Questionnaire (IPAQ) at baseline in 931 patients with stage I-III colorectal cancer and classified into ‘highly active’ and’not-highly active’(≥ /

To cope with the megatrends electrification, automated driving, and connectivity, new functionalities and electric and/or electronic systems must be developed, which require a safe power supply. This leads to increased functional safety requirements for the power supply system, particularly regarding availability. Fault tolerance measures can be implemented to comply with a safety goal (SG) specifying a safety-related availability requirement. To verify an architecture concerning the residual risk of an SG violation, several quantitative target values are provided in ISO 26262. This technical elaboration presents a systematic and holistic approach how to gain benefit in the quantitative evaluation from cyclic safety mechanisms (SMs)– in a fault tolerant item– which have a fault handling time interval (FHTI) longer than the fault tolerant time interval. Modelling cyclic SMs only based on conventional AND-gates is not sufficient. Instead, the fault sequence is differentiated to enable ISO 26262-compliance. Within this paper, an innovative approach including its mathematical background is presented how cyclic SMs can be modelled in a fault tree analysis– with focus on multiple-point faults. The results are verified by a Monte-Carlo-Simulation. Besides the scalability of the approach regarding the number of considered cyclic SMs, the relevant FHTI of each cyclic SM can be considered in a traceable and comprehensible manner.

For textile-based electronic systems with multiple contacts distributed over a large area, it is very complex to create reliable electrical and mechanical interconnections. In this work, we report for the first time on the use of rotating ultrasonic polymer welding for the continuous integration and interconnection of highly conductive ribbons with textile-integrated conductive tracks. For this purpose, the conductive ribbons are prelaminated on the bottom side with a thermoplastic film, which serves as an adhesion agent to the textile carrier, and another thermoplastic film is laminated on the top side, which serves as an electrical insulation layer. Experimental tests are used to investigate the optimum welding process parameters for each material combination. The interconnects are initially electrically measured and then tested by thermal cycling, moisture aging, buckling and washing tests, followed by electrical and optical analyses. The interconnects obtained are very low ohmic across the materials tested, with resulting contact resistances between 1 and 5 mOhm. Material-dependent results were observed in the reliability tests, with climatic and mechanical tests performing better than the wash tests for all materials. In addition, the development of a heated functional prototype demonstrates a first industrial application.

Existing optogenetic silencing methods affect membrane potential, biochemistry or protein integrity. Here, the authors demonstrate an approach for silencing synaptic transmission that combines fast activation and reversibility, by using nondisruptive, reversible, light-evoked clustering of synaptic vesicles, which they validate in Caenorhabditis elegans, zebrafish, and murine cell culture.

Summary: Diffuse large B cell lymphoma (DLBCL) is one of the most common types of aggressive lymphoid malignancies. Here, we explore the contribution of RNA editing to DLBCL pathogenesis. We observed that DNA mutations and RNA editing events are often mutually exclusive, suggesting that tumors can modulate pathway outcomes by altering sequences at either the genomic or the transcriptomic level. RNA editing targets transcripts within known disease-driving pathways such as apoptosis, p53 and NF-κB signaling, as well as the RIG-I-like pathway. In this context, we show that ADAR1-mediated editing within MAVS transcript positively correlates with MAVS protein expression levels, associating with increased interferon/NF-κB signaling and T cell exhaustion. Finally, using targeted RNA base editing tools to restore editing within MAVS 3′UTR in ADAR1-deficient cells, we demonstrate that editing is likely to be causal to an increase in downstream signaling in the absence of activation by canonical nucleic acid receptor sensing.

mTORC1 blocks lysosomal nutrient generation. Here, the authors show that mTORC1 inactivation triggers V-ATPase assembly, which rapidly initiates lysosomal acidification and degradation of protein contents throughout the lysosomal population.

Here the authors show that antibody-dependent phagocytosis of ring-stage P. falciparum parasites is mediated by merozoite antigens and is a strong predictor of protection following challenge in a controlled human malaria infection study in semi-immune Kenyan adults.

Minimizing and quantifying the uncertainty of wind simulations are essential for the wind energy industry during the planning phase of wind farm projects and for financial considerations. Measurements at 118 sites onshore and offshore in Germany are analyzed and used for the verification of wind simulations with the mesoscale model WRF. In order to minimize the difference between simulations and observations a correction of the annual cycle is applied and a remodeling approach is developed which allows for a correction of the simulated wind speed time series. The remodeling methodology is based on a linear regression analysis of simulated and observed wind speed time series accounting for sub‑grid variations of orography and roughness. Averaging the regression parameter for 26 measurement sites results in an overall global parameter set which is applied to the wind atlas data. While the “raw” data (without optimization) before any correction showed differences of up to 30 % with respect to the annual mean wind speed the remodeling process reduced the bias to below 5 % for the majority of measurements. When being compared with data from the NEWA wind atlas and the EMD‑WRF Europe+ data set an overall bias between 0.6 m/s and 0.8 m/s is found for the NEWA, EMD‑WRF Europe+ and anemos “raw” data. This bias is reduced to zero with a small standard deviation when the remodeling process and the site-specific adaptation are applied.

Abstract Background MicroRNAs (miRNAs) and isomiRs play important roles in tumorigenesis as essential regulators of gene expression. 5’isomiRs exhibit a shifted seed sequence compared to the canonical miRNA, resulting in different target spectra and thereby extending the phenotypic impact of the respective common pre-miRNA. However, for most miRNAs, expression and function of 5’isomiRs have not been studied in detail yet. Therefore, this study aims to investigate the functions of miRNAs and their 5’isomiRs. Methods The expression of 5’isomiRs was assessed in The Cancer Genome Atlas (TCGA) breast cancer patient dataset. Phenotypic effects of miR-183 overexpression in triple-negative breast cancer (TNBC) cell lines were investigated in vitro and in vivo by quantifying migration, proliferation, tumor growth and metastasis. Direct targeting of E2F1 by miR-183-5p|+2 was validated with a 3’UTR luciferase assay and linked to the phenotypes of isomiR overexpression. Results TCGA breast cancer patient data indicated that three variants of miR-183-5p are highly expressed and upregulated, namely miR-183-5p|0, miR-183-5p|+1 and miR-183-5p|+2. However, TNBC cell lines displayed reduced proliferation and invasion upon overexpression of pre-miR-183. While invasion was reduced individually by all three isomiRs, proliferation and cell cycle progression were specifically inhibited by overexpression of miR-183-5p|+2. Proteomic analysis revealed reduced expression of E2F target genes upon overexpression of this isomiR, which could be attributed to direct targeting of E2F1, specifically by miR-183-5p|+2. Knockdown of E2F1 partially phenocopied the effect of miR-183-5p|+2 overexpression on cell proliferation and cell cycle. Gene set enrichment analysis of TCGA and METABRIC patient data indicated that the activity of E2F strongly correlated with the expression of miR-183-5p, suggesting transcriptional regulation of the miRNA by a factor of the E2F family. Indeed, in vitro, expression of miR-183-5p was regulated by E2F1. Hence, miR-183-5p|+2 directly targeting E2F1 appears to be part of a negative feedback loop potentially fine-tuning its activity. Conclusions This study demonstrates that 5’isomiRs originating from the same arm of the same pre-miRNA (i.e. pre-miR-183-5p) may exhibit different functions and thereby collectively contribute to the same phenotype. Here, one of three isomiRs was shown to counteract expression of the pre-miRNA by negatively regulating a transcriptional activator (i.e. E2F1). We speculate that this might be part of a regulatory mechanism to prevent uncontrolled cell proliferation, which is disabled during cancer progression. Graphical Abstract

Background Liver metastases severely reduce the long term survival of colorectal cancer patients. Long non-coding RNAs (lncRNAs) CCAT1 and CCAT2 have previously been found to be associated with impaired patient outcomes in primary colorectal cancer. We aimed to elucidate the role of CCAT1 and CCAT2 in colorectal liver metastases. Methods Total RNA was isolated from 97 human tissue samples of colorectal liver metastases and adjacent normal liver tissue. Gene expression analysis was performed by RT-qPCR and Multiplex ELISA and correlated with patient characteristics and survival. Gene expression, cancer cell migration, invasion, and proliferation were studied after siRNA-mediated knockdown of CCAT1, CCAT2, and MYC in metastatic colorectal cancer cell lines Colo205 and HROC277Met2. Results Elevated expression levels of lncRNAs CCAT1 and CCAT2, and their common target MYC in colorectal liver metastases were associated with prolonged progression-free survival after liver resection. High expression of CCAT1 was likewise associated with prolonged overall survival. Knockdown of CCAT1, CCAT2, and MYC resulted in increased migratory and invasive potential in metastatic colorectal cancer cell lines. Gene expression analysis revealed alterations in constituents of Wnt signaling following knockdown. Conclusion Our findings demonstrate tumor-suppressive functions of lncRNAs CCAT1 and CCAT2 in colorectal liver metastases. They suppress Wnt signaling directly and indirectly through target gene MYC and might prevent further metastatic spread from colorectal liver metastases.

Purpose The overarching goal of the FOCUS (biomarkers related to folate-dependent one-carbon metabolism in colorectal cancer (CRC) recurrence and survival) Consortium is to unravel the effect of folate and folate-mediated one-carbon metabolism (FOCM) biomarkers on CRC prognosis to provide clinically relevant advice on folate intake to cancer patients and define future tertiary prevention strategies.Participants The FOCUS Consortium is an international, prospective cohort of 2401 women and men above 18 years of age who were diagnosed with a primary invasive non-metastatic (stages I–III) CRC. The consortium comprises patients from Austria, two sites from the Netherlands, Germany and two sites from the USA. Patients are recruited after CRC diagnosis and followed at 6 and 12 months after enrolment. At each time point, sociodemographic data, data on health behaviour and clinical data are collected, blood samples are drawn.Findings to date An increased risk of cancer recurrences was observed among patients with higher compared with lower circulating folic acid concentrations. Furthermore, specific folate species within the FOCM pathway were associated with both inflammation and angiogenesis pathways among patients with CRC. In addition, higher vitamin B6 status was associated with better quality of life at 6 months post-treatment.Future plans Better insights into the research on associations between folate and FOCM biomarkers and clinical outcomes in patients with CRC will facilitate the development of guidelines regarding folate intake in order to provide clinically relevant advice to patients with cancer, health professionals involved in patient care, and ultimately further tertiary prevention strategies in the future. The FOCUS Consortium offers an excellent infrastructure for short-term and long-term research projects and for combining additional biomarkers and data resulting from the individual cohorts within the next years, for example, microbiome data, omics and multiomics data or CT-quantified body composition data.

Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD). HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) control cellular adaptation to hypoxia and are considered promising therapeutic targets in IBD. However, their relevance in the pathogenesis of CAC remains elusive. We induced CAC in Phd1–/–, Phd2+/–, Phd3–/–, and WT mice with azoxymethane (AOM) and dextran sodium sulfate (DSS). Phd1–/– mice were protected against chronic colitis and displayed diminished CAC growth compared with WT mice. In Phd3–/– mice, colitis activity and CAC growth remained unaltered. In Phd2+/– mice, colitis activity was unaffected, but CAC growth was aggravated. Mechanistically, Phd2 deficiency (i) increased the number of tumor-associated macrophages in AOM/DSS-induced tumors, (ii) promoted the expression of EGFR ligand epiregulin in macrophages, and (iii) augmented the signal transducer and activator of transcription 3 and extracellular signal–regulated kinase 1/2 signaling, which at least in part contributed to aggravated tumor cell proliferation in colitis-associated tumors. Consistently, Phd2 deficiency in hematopoietic (Vav:Cre-Phd2fl/fl) but not in intestinal epithelial cells (Villin:Cre-Phd2fl/fl) increased CAC growth. In conclusion, the 3 different PHD isoenzymes have distinct and nonredundant effects, promoting (PHD1), diminishing (PHD2), or neutral (PHD3), on CAC growth.

Cu-Cu direct interconnects are highly desirable for the microelectronic industry as they allow for significant reductions in the size and spacing of microcontacts. The main challenge associated with using Cu is its tendency to rapidly oxidize in air. This research paper describes a method of Cu passivation using a self-assembled monolayer (SAM) to protect the surface against oxidation. However, this approach faces two main challenges: the degradation of the SAM at room temperature in the ambient atmosphere and the monolayer desorption technique prior to Cu-Cu bonding. In this paper, the systematic investigation of these challenges and their possible solutions are presented. The methods used in this study include thermocompression (TC) bonding, X-ray photoelectron spectroscopy (XPS), shear strength testing, scanning electron microscopy (SEM), and energy dispersive X-ray spectroscopy (EDX). The results indicate nearly no Cu oxidation (4 at.%) for samples with SAM passivation in contrast to the bare Cu surface (27 at.%) after the storage at −18 °C in a conventional freezer for three weeks. Significant improvement was observed in the TC bonding with SAM after storage. The mean shear strength of the passivated samples reached 65.5 MPa without storage. The average shear strength values before and after the storage tests were 43% greater for samples with SAM than for the bare Cu surface. In conclusion, this study shows that Cu-Cu bonding technology can be improved by using SAM as an oxidation inhibitor, leading to a higher interconnect quality.

BackgroundImpairment of bowel, urogenital and fertility-related function in patients treated for rectal cancer is common. While the rate of rectal cancer in the young (

ObjectivesIn this in-vitro study, teeth were imaged using photoacoustic tomography (PAT), cone-beam computed tomography (CBCT), and micro-computed tomography (μ-CT). The study had aim: to identify the best wavelength for PAT images to determine the accuracy of the three imaging methods, and to determine whether PAT images of teeth can achieve acceptable reconstruction quality.MethodsNineteen human mandibular single-rooted incisors were extracted from patients with trauma or periodontitis. To determine the best wavelength for acquiring photoacoustic images, all 19 teeth were scanned in vitro with PAT, using different laser wavelengths between 680 and 960 nm. The images were analyzed using image analysis software. To assess the accuracy of PAT and compare it with the accuracy of CBCT, each tooth was also scanned in vitro using CBCT and the reference standard technique of μ-CT. Subsequently, three different three-dimensional models, one for each imaging technique, were created for each tooth. Finally, the three different three-dimensional models acquired for the same tooth were matched and analyzed regarding volume and surface.ResultsThe highest quality tooth images were achieved using the 680 nm wavelength, which showed the best contrast ratio. The full geometry of the dental root (μ-CT compared with PAT) could be visualized with relative standard deviations of 0.12 mm for the surface and -7.33 mm3 for the volume (n = 19). The full geometry of the dental root (μ-CT compared with CBCT) could be visualized with relative standard deviations of 0.06 mm for the surface and -14.56 mm3 for the volume (n = 19). The difference between the PAT-μ-CT group and CBCT-μ-CT group regarding the total average of the root surface area was not significant (p>0.06).ConclusionImages, which were acquired using PAT at 680nm showed the best contrast ration, enabling the identification of dentin, cementum and the dental pulp. No significant differences were found between the PAT-μ-CT group and CBCT-μ-CT group regarding the total average of the RSA and the total volume. Thus, three-dimensional reconstructions based on in-vitro PAT are already of acceptable reconstruction quality.

Digital federated platforms and data cooperatives for secure, trusted and sovereign data exchange will play a central role in the construction industry of the future. With the help of platforms, cooperatives and their novel value creation, the digital transformation and the degree of organization of the construction value chain can be taken to a new level of collaboration. The goal of this research project was to develop an experimental prototype for a federated innovation data platform along with a suitable exemplary use case. The prototype is to serve the construction industry as a demonstrator for further developments and form the basis for an innovation platform. It exemplifies how an overall concept is concretely implemented along one or more use cases that address high-priority industry pain points. This concept will create a blueprint and a framework for further developments, which will then be further established in the market. The research project illuminates the perspective of various governance innovations to increase industry collaboration, productivity and capital project performance and transparency as well as the overall potential of possible platform business models. However, a comprehensive expert survey revealed that there are considerable obstacles to trust-based data exchange between the key stakeholders in the industry value network. The obstacles to cooperation are predominantly not of a technical nature but rather of a competitive, predominantly trust-related nature. To overcome these obstacles and create a pre-competitive space of trust, the authors therefore propose the governance structure of a data cooperative model, which is discussed in detail in this paper.

Adverse effects of drug combinations and their underlying mechanisms are highly relevant for safety evaluation, but often not fully studied. Hydroxychloroquine (HCQ) and azithromycin (AZM) were used as a combination therapy in the treatment of COVID-19 patients at the beginning of the pandemic, leading to higher complication rates in comparison to respective monotherapies. Here, we used human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to systematically investigate the effects of HCQ, AZM, and their combination on the structure and functionality of cardiomyocytes, and to better understand the underlying mechanisms. Our results demonstrate synergistic adverse effects of AZM and HCQ on electrophysiological and contractile function of iPSC-CMs. HCQ-induced prolongation of field potential duration (FPDc) was gradually increased during 7-day treatment period and was strongly enhanced by combination with AZM, although AZM alone slightly shortened FPDc in iPSC-CMs. Combined treatment with AZM and HCQ leads to higher cardiotoxicity, more severe structural disarrangement, more pronounced contractile dysfunctions, and more elevated conduction velocity, compared to respective monotreatments. Mechanistic insights underlying the synergistic effects of AZM and HCQ on iPSC-CM functionality are provided based on increased cellular accumulation of HCQ and AZM as well as increased Cx43- and Nav1.5-protein levels.

Safety is a crucial issue in hydrogen energy applications due to the unique properties of hydrogen. Accordingly, a suitable hydrogen sensor for leakage detection must have at least high sensitivity and selectivity, rapid response/recovery, low power consumption and stable functionality, which requires further improvements on the available hydrogen sensors. In recent years, the mature development of nanomaterials engineering technologies, which facilitate the synthesis and modification of various materials, has opened up many possibilities for improving hydrogen sensing performance. Current research of hydrogen detection sensors based on both conservational and innovative materials are introduced in this review. This work mainly focuses on three material categories, i.e., transition metals, metal oxide semiconductors, and graphene and its derivatives. Different hydrogen sensing mechanisms, such as resistive, capacitive, optical and surface acoustic wave-based sensors, are also presented, and their sensing performances and influence based on different nanostructures and material combinations are compared and discussed, respectively. This review is concluded with a brief outlook and future development trends.