Structural Maturation Research Articles

Mature tertiary lymphoid structures are key niches of tumour-specific immune responses in pancreatic ductal adenocarcinomas

ObjectiveTo better understand the immune microenvironment of pancreatic ductal adenocarcinomas (PDACs), here we explored the relevance of T and B cell compartmentalisation into tertiary lymphoid structures (TLSs) for the generation...

Developing a more complete understanding of tropical montane forest disturbance ecology through landslide research

Landslides are a central component of tropical montane forest disturbance regimes, including in the tropical Andes biodiversity hotspot, one of the most biodiverse ecosystems in the world. Technological developments in remote sensing have made landscape-scale landslide studies possible, unlocking new avenues for understanding montane biodiversity, ecosystem functioning, and the future effects of climate change. Here, we outline three axes of inquiry for future landslide ecology research in Andean tropical montane forest. We focus exclusively on the Andes due to the vast floral diversity and high endemicity of the tropical Andes biodiversity hotspot, and its importance for global biodiversity and regional ecosystem service provisioning; the broad elevational, latitudinal, and topographic gradients across which landslide dynamics play out; and the existence of long-term plot networks that provide the necessary baseline data on mature forest structure, composition, and functioning to contextualize disturbance impacts. The three lines of study we outline, which draw heavily on remote sensing data and techniques, will deepen scientific understanding of tropical montane forest biodiversity and ecosystem functioning, and the potential impacts of climate change on both. They are: (1) tracking landslide biodiversity dynamics across time and space with high spatial and temporal resolution satellite and unoccupied aerial vehicle imagery; (2) assessing the ecological influence of landslides through the lens of plant functional diversity with imaging spectroscopy; and (3) understanding current and predicting future landslide regimes at scale by building a living landslide inventory spanning the tropical Andes. The research findings from these three axes of inquiry will shed light on the role of landslides and the process of forest recovery from them in both the Andes and worldwide.

Literature Review: Mediation Effects of Debt Maturity on Good Corporate Governance in Enhancing Financial Performance

This study proposes a research model to investigate the mediating effect of debt maturity on the relationship between good corporate governance (GCG) and financial performance. The qualitative approach employed is a systematic literature review (SLR) technique, analyzing 11 articles selected from 142 related ones found on the Google Scholar database within the 2010-2021 research range based on inclusion and exclusion criteria. Debt maturity was found to play a crucial role in shaping the effectiveness of GCG mechanisms in managing financial risks and improving financial performance. The proposed research model has implications for researchers and practitioners, providing a basis for future empirical studies exploring the interplay between GCG, debt maturity, and financial performance. For practitioners, it offers a theoretical framework for developing policies and practices promoting effective GCG and optimal debt maturity structures to enhance financial performance. The findings inform the development of policies and procedures that promote good corporate governance and optimal debt maturity structures, leading to improved financial performance. Additionally, the proposed research model may be applied to other contexts, contributing to a better understanding of the role of debt maturity in the relationship between GCG and financial performance.

In vivo evaluation of skin of children with LC-OCT: An objective assessment.

Several non-invasive skin imaging methods have been developed in recent years. Line-field confocal optical coherence tomography (LC-OCT) is one of them, leading to the best compromise in terms of resolution and penetration depth. Skin biopsies are an essential technique in paediatric dermatology, but they are a major stressful event for the child and their parents. Current LC-OCT studies have not been dedicated to a paediatric population. If, however, LC-OCT proves to be helpful in children, it may help guide and decrease a certain number of skin biopsies. (1) To evaluate the feasibility of using LC-OCT in paediatric patients, and (2) to assess the maturation of skin structures in children over time with this method. In vivo LC-OCT images were collected on six specific body regions (forehead, forearm, chest, back, dorsum of the hand and palmar surface) and in six age groups (between the ages of 0 and 16 years). In all body areas and age groups assessed, 9 of 10 images were rated as good-to-excellent, the only exception were the images acquired on the palmar surface. LC-OCT allowed visualizing very well the skin structures up to a penetration of 500 μm. We observed that the body regions located on the upper extremities of the body (forearm, dorsum of the hand and palmar surface) showed both a maturation on their structure and differences in thickness with respect to the other regions evaluated. LC-OCT can easily be used for non-invasive imaging of children's skin and allows to document progressive skin changes in the different age groups. It may be a useful asset for imaging and diagnosing superficial skin disorders and as such reducing the number of invasive procedures while increasing the speed of diagnosis in the paediatric population.

Application maturity evaluation of building steel structure welding robotic technology based on multi-level gray theory

PurposeThe purpose of this paper is to establish a maturity evaluation model for the application of construction steel structure welding robotics suitable for the actual situation and specific characteristics of engineering projects in China and then to assess the maturity level of the technology in the application of domestic engineering projects more scientifically.Design/methodology/approachThe research follows a qualitative and quantitative analysis method. In the first stage, the structure of the maturity model is constructed and the evaluation index system is designed by using the ideas of the capability maturity model and WSR methodology for reference. In the second stage, the design of the evaluation process and the selection of evaluation methods (analytic hierarchy process method, multi-level gray comprehensive evaluation method). In the third stage, the data are collected and organized (preparation of questionnaires, distribution of questionnaires, questionnaire collection). In the fourth stage, the established maturity evaluation model is used to analyze the data.FindingsThe evaluation model established by using multi-level gray theory can effectively transform various complex indicators into an intuitive maturity level or score status. The conclusion shows that the application maturity of building steel structure welding robot technology in this project is at the development level as a whole. The maturity levels of “WuLi – ShiLi – RenLi” are respectively: development level, development level, between starting level and development level. Comparison of maturity evaluation values of five important factors (from high to low): environmental factors, technical factors, management factors, benefit factors, personnel and group factors.Originality/valueIn this paper, based on the existing research related to construction steel structure welding robot technology, a quantitative and holistic evaluation of the application of construction steel structure welding robot technology in domestic engineering projects is conducted for the first time from a project perspective by designing a maturity evaluation index system and establishing a maturity evaluation model. This research will help the project team to evaluate the application level (maturity) of the welding robot in the actual project, identify the shortcomings and defects of the application of this technology, then improve the weak links pertinently, and finally realize the gradual improvement of the overall application level of welding robot technology for building steel structure.

Visual alertness and brain diffusion tensor imaging at term age predict neurocognitive development at preschool age in extremely preterm-born children.

Cognitive development is characterized by the structural and functional maturation of the brain. Diffusion-weighted magnetic resonance imaging (dMRI) provides methods of investigating the brain structure and connectivity and their correlations with the neurocognitive outcome. Our aim was to examine the relationship between early visual abilities, brain white matter structures, and the later neurocognitive outcome. This study included 20 infants who were born before 28 gestational weeks and followed until the age of 6.5 years. At term age, visual alertness was evaluated and dMRI was used to investigate the brain white matter structure using fractional anisotropy (FA) in tract-based spatial statistics analysis. The JHU DTI white matter atlas was used to locate the findings. The neuropsychological assessment was used to assess neurocognitive performance at 6.5 years. Optimal visual alertness at term age was significantly associated with better visuospatial processing (p<.05), sensorimotor functioning (p<.05), and social perception (p<.05) at 6.5 years of age. Optimal visual alertness related to higher FA values, and further, the FA values positively correlated with the neurocognitive outcome. The tract-based spatial differences in FA values were detected between children with optimal and nonoptimal visual alertness according to performance at 6.5 years. We provide neurobiological evidence for the global and tract-based spatial differences in the white matter maturation between extremely preterm children with optimal and nonoptimal visual alertness at term age and a link between white matter maturation, visual alertness and the neurocognitive outcome at 6.5 years proposing that early visual function is a building block for the later neurocognitive development.

The Tripartite Pattern of Sharing Bicycles in China: Future Development of Hello bike

Sharing economy is an emerging economic situation in China. After years of development and the failure experience of enterprises testing the water, it has finally formed a more mature three-way structure with shared bikes as the primary form of Hellobike, Qingju, and Meituan. This paper makes a comparison between Hello Bike and its competitors by case analysis, analyzes the competitive strategy and competitive advantage of Hellobike with Porter’s five forces model, and explores the competitive strategy and competitive advantage of the typical blue, orange bike with 4P strategy to study the future competitive strategy of HelloBike. And put forward some suggestions for its future competition in domestic sharing economy enterprises to help Hello Bike avoid being monopolized and gain more competitiveness in the market.

3D bioprinting strategy for engineering vascularized tissue models.

Leveraging three-dimensional (3D) bioprinting in the fields of tissue engineering and regenerative medicine has rapidly accelerated progress toward the development of living tissue constructs and biomedical devices. Ongoing vigorous research has pursued the development of 3D in vitro tissue models to replicate the key aspects of human physiology by incorporating relevant cell populations and adequate environmental cues. Given their advantages of being able to intimately mimic the heterogeneity and complexity of their native counterparts, 3D in vitro models hold promise as alternatives to conventional cell cultures or animal models for translational application to model human physiology/pathology and drug screening. Research has highlighted the importance of in vitro models, and a sophisticated biomanufacturing strategy is vitally required. In particular, vascularization is critical for the prolonged survival and functional maturation of the engineered tissues, which has remained one of the major challenges in the establishment of physiologically relevant 3D in vitro models. To this end, 3D bioprinting can efficiently generate solid and reproducible vascularized tissue models with high architectural and compositional similarity to the native tissues, leading to improve the structural maturation and tissue-specific functionality. Multiple bioprinting strategies have been developed to vascularize in vitro tissues by spatially controlled patterning of vascular precursors or generating readily perfusable vascular structures. This review presents an overview of the advanced 3D bioprinting strategies for vascularized tissue model development. We present the key elements for rebuilding functional vasculature in 3D-bioprinted tissue models and discuss the recent achievements in the engineering of 3D vascularized in vitro models using 3D bioprinting. Finally, we delineate the current challenges and future outlooks of 3D bioprinting-based vascularized tissue models.

Wool cortisol concentrations trends in the lamb from birth to slaughter

Over time, cortisol has drawn more and more attention in the research on how the body reacts to stress. Furthermore, it has a catabolic role, in energy mobilisation, and in the immune response, in the activation of processes to defend the organism. This hormone is present in wool, which, differently from other biological samples, allows for an easily sampling procedure and provides a reliable retrospective matrix unaffected by acute stress. The two major goals of this study were to assess cortisol as an index of the activity of the hypothalamic-pituitary-adrenal axis in lambs prior birth to the time of slaughtering by wool in four European sheep breeds and to investigate if an increased HPA axis activity may impact the average daily weight gain in lambs. A total of 97 lambs were involved in the study. Wool samples were collected from the left shoulder of the lambs included in the study in different sampling times (ST): at birth (ST1) and then at 30-day intervals from the same area of skin for a period of up to 120 days of age as re-shaved wool (ST2, ST3, ST4 and ST5). All animals were weighed at birth and the day before slaughter. The wool cortisol was evaluated by the AlphaLISA immunoassay method after having extracted steroids from the samples. The wool cortisol concentrations were affected both by breed (P < 0.01) and ST (P < 0.01). All the breeds considered showed a reduction of the wool cortisol during the experimental period, but with different trends. The wool cortisol at the ST1 and the live weight at birth was negatively correlated (r = −0.574; P < 0.01) as well as the average wool cortisol concentrations without the values recorded at ST1 and the average daily gain (r = −0.542; P < 0.01). The higher concentrations recorded in the sample collected at birth could origin from the progressive rise in foetal plasma cortisol concentrations that have an important role in structural maturation and in the neonatal adaptation to the extrauterine life. The trends of wool cortisol decreasing after birth till four months of age suggest that each breed could have an its own HPA axis setting. Our findings may be related to the idea of animal robustness and the various metabolic tactics used by various breeds to adapt to their environments during evolution. In conclusion, this study underlined a time-specific and a breed-characteristic wool cortisol concentration. Moreover, from the analyses emerged that the wool cortisol at birth and the live weight at birth was negatively correlated as well as the average of the wool cortisol concentrations recorded postnatally and the average daily gain.

Experimental study on the sandstone abrasiveness via mineral composition and microstructure analysis

Rock abrasiveness is an important factor affecting the tool's lifetime and efficiency in breaking a rock. Characterizing rock abrasiveness helps in the design, optimization, and mean-life prediction of tools. X-ray diffraction, cast thin section analysis, and CERCHAR abrasiveness tests were performed on 18 different sandstones to characterize rock abrasiveness and explore new methods for characterization. The relationship between the mineral composition and microstructure of sandstone and abrasiveness was investigated. The results show that different structural maturities have varying effects on abrasiveness. In addition, the higher the structural maturity, the more the abrasiveness. Furthermore, in sandstones of the same structural maturity, the abrasiveness increases with equivalent quartz content (EQC). The texture coefficient (TC) and CERCHAR abrasiveness index (CAI) of sandstones with the same structural maturity showed a good linear relationship. Moreover, the correlation coefficients considering the combined parameters are above 0.85. Therefore, obtaining the microstructure and mineral composition of sandstone can effectively characterize rock abrasiveness. It also provides a new method for predicting the abrasiveness of the rock in the well.

The Firm Life Cycle and Debt Maturity Structure: Evidence from ASEAN Countries

This study aims to examine the firm’s debt maturity structure policy across the firm life cycle stage in five ASEAN countries, namely Indonesia, Malaysia, Singapore, Thailand and Vietnam. The Firm life cycle stages are classified based on its cashflow pattern into four stages, namely introduction, growth, mature, and decline. The study was conducted using 2769 samples of non-financial listed companies in these five ASEAN countries in the period 2007-2020. The data analysis method used is a panel data model with a fixed effect. The results of the study from the research conducted show that the company's life cycle in the introduction and growth stages chooses to use long-term debt compared to companies in the mature and decline stages. It’s possible that during introduction and growth stages, firms are overloaded with many investment opportunities that they want to invest. Internal funds might not be enough for them and they opt to acquire external debt such as long-term debt. DOI: 10.26905/jkdp.v27i2.9958

Effective risk management in the shadow of COVID-19 pandemic: The evidence of Indonesian listed corporations

The study uses COVID-19 to identify the treatment group as the difference in change of non-financial corporations (NFCs) risk management ratios over time to investigate the causal effect of the NFCs' effective risk management (ERM) practices on operational efficiency (OE). ERM was measured by solvency and liquidity ratios, while the risk management theory was developed to refine the scope of the study. The data were collected from the central bank of Indonesia to map the empirical analysis, and the difference in difference (DID) technique was used to illustrate how NFCs react to mitigate the negative impact of COVID-19 and generate OE. Specifically, a quasi-natural experiment was used to size the effect of ERM practices on corporate OE during the COVID-19 pandemic. The descriptive analysis revealed that the COVID-19 pandemic effect has been unequal across different industrial sectors. Moreover, the empirical findings showed that corporate risk management during COVID-19 is the source of structural change, which affects its existence and operational efficiency. While debt amount and age may affect corporate credit score, ERM practices led the indebted corporation to the flexibility of debt refinancing or/and restructuring, which offers them the ability to prevent bankruptcy and adapt to the changes while operating efficiently. The finding revealed evidence of the important role of long-term debt in offering protection to NFCs during the credit supply shock brought in by the COVID-19 pandemic. Furthermore, the findings show that long-term debt is negatively associated with corporate OE. This was expected given that corporations use long-term debt financing for long-term investment, while short-term debt funds the working capital. Thus, to assess the effect of debts on corporate OE, managers should consider their maturity structure, among other factors.

Adolescent alcohol exposure changes RNA modifications in adult brain by mass spectrometry-based comprehensive profiling analysis

Alcohol consumption is one of the leading causes of death worldwide. Adolescence is a critical period of structural and functional maturation of the brain. Adolescent alcohol use can alter epigenetic modifications. However, little is known on the long-term effects of alcohol consumption during adolescence on RNA epigenetic modifications in brain. Herein, we systematically explored the long-term effects of alcohol exposure during adolescence on small RNA modifications in adult rat brain tissues by comprehensive liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) analysis. We totally detected 26 modifications in small RNA of brain tissues. Notably, we observed most of these modifications were decreased in brain tissues. These results suggest that alcohol exposure during adolescence may impose a long-lasting impact on RNA modifications in brain tissues. This is the first report that alcohol use during adolescence can alter RNA modifications in adult brain. Collectively, this study suggests a long-term adverse effects of alcohol consumption on brain from RNA epigenetics angle by comprehensive mass spectrometry analysis.

Prefrontal microglia deficiency during adolescence disrupts adult cognitive functions and synaptic structures: A follow-up study in female mice

The prefrontal cortex (PFC) provides executive top-down control of a variety of cognitive processes. A distinctive feature of the PFC is its protracted structural and functional maturation throughout adolescence to early adulthood, which is necessary for acquiring mature cognitive abilities. Using a mouse model of cell-specific, transient and local depletion of microglia, which is based on intracerebral injection of clodronate disodium salt (CDS) into the PFC of adolescent male mice, we recently demonstrated that microglia contribute to the functional and structural maturation of the PFC in males. Because microglia biology and cortical maturation are partly sexually dimorphic, the main objective of the present study was to examine whether microglia similarly regulate this maturational process in female mice as well. Here, we show that a single, bilateral intra-PFC injection of CDS in adolescent (6-week-old) female mice induces a local and transient depletion (70 to 80% decrease from controls) of prefrontal microglia during a restricted window of adolescence without affecting neuronal or astrocytic cell populations. This transient microglia deficiency was sufficient to disrupt PFC-associated cognitive functions and synaptic structures at adult age. Inducing transient prefrontal microglia depletion in adult female mice did not cause these deficits, demonstrating that the adult PFC, unlike the adolescent PFC, is resilient to transient microglia deficiency in terms of lasting cognitive and synaptic maladaptations. Together with our previous findings in males, the present findings suggest that microglia contribute to the maturation of the female PFC in a similar way as to the prefrontal maturation occurring in males.

Deciphering the maturation of tertiary lymphoid structures in cancer and inflammatory diseases of the digestive tract using imaging mass cytometry.

Persistent inflammation can promote the development of tertiary lymphoid structures (TLS) within tissues resembling secondary lymphoid organs (SLO) such as lymph nodes (LN). The composition of TLS across different organs and diseases could be of pathophysiological and medical interest. In this work, we compared TLS to SLO in cancers of the digestive tract and in inflammatory bowel diseases. Colorectal and gastric tissues with different inflammatory diseases and cancers from the department of pathology of CHU Brest were analyzed based on 39 markers using imaging mass cytometry (IMC). Unsupervised and supervised clustering analyses of IMC images were used to compare SLO and TLS. Unsupervised analyses tended to group TLS per patient but not per disease. Supervised analyses of IMC images revealed that LN had a more organized structure than TLS and non-encapsulated SLO Peyer's patches. TLS followed a maturation spectrum with close correlations between germinal center (GC) markers' evolution. The correlations between organizational and functional markers made relevant the previously proposed TLS division into three stages: lymphoid-aggregates (LA) (CD20+CD21-CD23-) had neither organization nor GC functionality, non-GC TLS (CD20+CD21+CD23-) were organized but lacked GC's functionality and GC-like TLS (CD20+CD21+CD23+) had GC's organization and functionality. This architectural and functional maturation grading of TLS pointed to differences across diseases. TLS architectural and functional maturation grading is accessible with few markers allowing future diagnostic, prognostic, and predictive studies on the value of TLS grading, quantification and location within pathological tissues in cancers and inflammatory diseases.

Overexpression of KCNJ2 enhances maturation of human-induced pluripotent stem cell-derived cardiomyocytes

BackgroundAlthough human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are a promising cell resource for cardiovascular research, these cells exhibit an immature phenotype that hampers their potential applications. The inwardly rectifying potassium channel Kir2.1, encoded by the KCNJ2 gene, has been thought as an important target for promoting electrical maturation of iPSC-CMs. However, a comprehensive characterization of morphological and functional changes in iPSC-CMs overexpressing KCNJ2 (KCNJ2 OE) is still lacking.MethodsiPSC-CMs were generated using a 2D in vitro monolayer differentiation protocol. Human KCNJ2 construct with green fluorescent protein (GFP) tag was created and overexpressed in iPSC-CMs via lentiviral transduction. The mixture of iPSC-CMs and mesenchymal cells was cocultured with decellularized natural heart matrix for generation of 3D human engineered heart tissues (EHTs).ResultsWe showed that mRNA expression level of KCNJ2 in iPSC-CMs was dramatically lower than that in human left ventricular tissues. KCNJ2 OE iPSC-CMs yielded significantly increased protein expression of Kir2.1 and current density of Kir2.1-encoded IK1. The larger IK1 linked to a quiescent phenotype that required pacing to elicit action potentials in KCNJ2 OE iPSC-CMs, which can be reversed by IK1 blocker BaCl2. KCNJ2 OE also led to significantly hyperpolarized maximal diastolic potential (MDP), shortened action potential duration (APD) and increased maximal upstroke velocity. The enhanced electrophysiological maturation in KCNJ2 OE iPSC-CMs was accompanied by improvements in Ca2+ signaling, mitochondrial energy metabolism and transcriptomic profile. Notably, KCNJ2 OE iPSC-CMs exhibited enlarged cell size and more elongated and stretched shape, indicating a morphological phenotype toward structural maturation. Drug testing using hERG blocker E-4031 revealed that a more stable MDP in KCNJ2 OE iPSC-CMs allowed for obtaining significant drug response of APD prolongation in a concentration-dependent manner. Moreover, KCNJ2 OE iPSC-CMs formed more mature human EHTs with better tissue structure and cell junction.ConclusionsOverexpression of KCNJ2 can robustly enhance maturation of iPSC-CMs in electrophysiology, Ca2+ signaling, metabolism, transcriptomic profile, cardiomyocyte structure and tissue engineering, thus providing more accurate cellular model for elucidating cellular and molecular mechanisms of cardiovascular diseases, screening drug-induced cardiotoxicity, and developing personalized and precision cardiovascular medicine.

Does Enhanced Structural Maturity of hiPSC-Cardiomyocytes Better for the Detection of Drug-Induced Cardiotoxicity?

Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are currently used following the Comprehensive in vitro Proarrhythmic Assay (CiPA) initiative and subsequent recommendations in the International Council for Harmonization (ICH) guidelines S7B and E14 Q&A, to detect drug-induced cardiotoxicity. Monocultures of hiPSC-CMs are immature compared to adult ventricular cardiomyocytes and might lack the native heterogeneous nature. We investigated whether hiPSC-CMs, treated to enhance structural maturity, are superior in detecting drug-induced changes in electrophysiology and contraction. This was achieved by comparing hiPSC-CMs cultured in 2D monolayers on the current standard (fibronectin matrix, FM), to monolayers on a coating known to promote structural maturity (CELLvo™ Matrix Plus, MM). Functional assessment of electrophysiology and contractility was made using a high-throughput screening approach involving the use of both voltage-sensitive fluorescent dyes for electrophysiology and video technology for contractility. Using 11 reference drugs, the response of the monolayer of hiPSC-CMs was comparable in the two experimental settings (FM and MM). The data showed no functionally relevant differences in electrophysiology between hiPSC-CMs in standard FM and MM, while contractility read-outs indicated an altered amplitude of contraction but not changes in time course. RNA profiling for cardiac proteins shows similarity of the RNA expression across the two forms of 2D culture, suggesting that cell-to-matrix adhesion differences may explain account for differences in contraction amplitude. The results support the view that hiPSC-CMs in both 2D monolayer FM and MM that promote structural maturity are equally effective in detecting drug-induced electrophysiological effects in functional safety studies.

An Assessment of Clinical Mentorship for Quality Improvement: The African Health Professions Regional Collaborative for Nurses and Midwives.

The African Regional Collaborative for nurses and midwives funded quality improvement projects in five countries to enhance clinical mentorship programs supporting HIV service delivery for women, infants, and children. Each country team implemented specific interventions focused on the application of nurse-initiated and managed antiretroviral therapy guidelines and competencies. A site-level tool, the nursing practice framework, measured structural maturation in clinical mentorship programs across five stages at eight facilities. Clinical competencies that aligned with the framework were evaluated through a provider-level knowledge assessment to identify on-going needs for mentees before and after the implementation period. Key trends observed in the assessment include positive program progression for all facilities; competencies were higher for pregnant and breastfeeding women and lower for HIV-exposed infants; there was an increase in posttest participation for all facilities. The nursing practice framework provides a rapid assessment of structural changes and exploration of context to identify quality improvement needs.

TEAD1 trapping by the Q353R-Lamin A/C causes dilated cardiomyopathy.

Mutations in the LMNA gene encoding Lamin A and C (Lamin A/C), major components of the nuclear lamina, cause laminopathies including dilated cardiomyopathy (DCM), but the underlying molecular mechanisms have not been fully elucidated. Here, by leveraging single-cell RNA sequencing (RNA-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), protein array, and electron microscopy analysis, we show that insufficient structural maturation of cardiomyocytes owing to trapping of transcription factor TEA domain transcription factor 1 (TEAD1) by mutant Lamin A/C at the nuclear membrane underlies the pathogenesis of Q353R-LMNA-related DCM. Inhibition of the Hippo pathway rescued the dysregulation of cardiac developmental genes by TEAD1 in LMNA mutant cardiomyocytes. Single-cell RNA-seq of cardiac tissues from patients with DCM with the LMNA mutation confirmed the dysregulated expression of TEAD1 target genes. Our results propose an intervention for transcriptional dysregulation as a potential treatment of LMNA-related DCM.

PDGF Receptors and Signaling Are Required for 3D-Structure Formation and Differentiation of Human iPSC-Derived Hepatic Spheroids.

Human iPSC-derived liver organoids (LO) or hepatic spheroids (HS) have attracted widespread interest, and the numerous studies on them have recently provided various production protocols. However, the mechanism by which the 3D structures of LO and HS are formed from the 2D-cultured cells and the mechanism of the LO and HS maturation remain largely unknown. In this study, we demonstrate that PDGFRA is specifically induced in the cells that are suitable for HS formation and that PDGF receptors and signaling are required for HS formation and maturation. Additionally, in vivo, we show that the localization of PDGFRα is in complete agreement with mouse E9.5 hepatoblasts, which begin to form the 3D-structural liver bud from the single layer. Our results present that PDGFRA play important roles for 3D structure formation and maturation of hepatocytes in vitro and in vivo and provide a clue to elucidate the hepatocyte differentiation mechanism.