ABSTRACT
The heart, which is the first organ to develop, is highly dependent on its form to function1,2. However, how diverse cardiac cell types spatially coordinate to create the complex morphological structures that are crucial for heart function remains unclear. Here we integrated single-cell RNA-sequencing with high-resolution multiplexed error-robust fluorescence in situ hybridization to resolve the identity of the cardiac cell types that develop the human heart. This approach also provided a spatial mapping of individual cells that enables illumination of their organization into cellular communities that form distinct cardiac structures. We discovered that many of these cardiac cell types further specified into subpopulations exclusive to specific communities, which support their specialization according to the cellular ecosystem and anatomical region. In particular, ventricular cardiomyocyte subpopulations displayed an unexpected complex laminar organization across the ventricular wall and formed, with other cell subpopulations, several cellular communities. Interrogating cell-cell interactions within these communities using in vivo conditional genetic mouse models and in vitro human pluripotent stem cell systems revealed multicellular signalling pathways that orchestrate the spatial organization of cardiac cell subpopulations during ventricular wall morphogenesis. These detailed findings into the cellular social interactions and specialization of cardiac cell types constructing and remodelling the human heart offer new insights into structural heart diseases and the engineering of complex multicellular tissues for human heart repair.
Subject(s)
Body Patterning , Heart , Myocardium , Animals , Humans , Mice , Heart/anatomy & histology , Heart/embryology , Heart Diseases/metabolism , Heart Diseases/pathology , Heart Ventricles/anatomy & histology , Heart Ventricles/cytology , Heart Ventricles/embryology , In Situ Hybridization, Fluorescence , Models, Animal , Myocardium/cytology , Myocytes, Cardiac/cytology , Myocytes, Cardiac/metabolism , Single-Cell Gene Expression AnalysisABSTRACT
Herein, we present catalyst-regulated switchable site-selective hydrosilylation of enynes, which are suitable for a wide range of alkyl and aryl substituted polar enynes and exhibit excellent functional group compatibility. Under the optimized conditions, silyl groups can be precisely installed at various positions of 1,3-dienes. While α- and γ-silylation products were obtained under platinum-catalytic systems, ß-silylation products were delivered with [Cp*RuCl]4 as catalyst. This process lead to the formation of 1,3-dienoates with diverse substitutions, which would pose challenges with other methodologies.
ABSTRACT
BACKGROUND: The association between the use of angiotensin-converting enzyme inhibitors (ACEIs) and lung cancer risk remains controversial. This study evaluated the association between the use of ACEIs and lung cancer risk. METHODS: Records from five databases were searched from inception to 26 January 2022. Clinical studies involving persons aged ≥18 years with at least one year of follow-up and reporting adverse events, including lung cancer, were recorded with separate outcome reports supplied for the ACEIs and control groups. Data were extracted independently by three authors and pooled using a random-effects model. The primary outcome was lung cancer development. Odds ratios (ORs) with 95% confidence intervals (CIs) and lung cancer-related morbidity were calculated. RESULTS: Of 2400 records screened, 13,061,226 patients were included from seven cohort studies and four case-control studies. Pooled results showed that ACEIs use was linked to increased lung cancer risk (OR 1.19, 95% CI 1.05-1.36; P = 0.008), with high heterogeneity (I2 = 98%). CONCLUSIONS: ACEI usage is a greater risk factor for lung carcinogenesis than angiotensin receptor blocker use, especially in Asian patients. Further randomised controlled trials are needed to confirm the causal association between the use of ACEIs and lung cancer risk.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Lung Neoplasms , Humans , Adolescent , Adult , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Angiotensin Receptor Antagonists , Risk Factors , Lung Neoplasms/epidemiology , Case-Control StudiesABSTRACT
BACKGROUND: Umbilical artery serum-derived exosomes (UEs) serve as messengers for maternal-fetal information exchange and cellular regulation. Intravenous remifentanil could be considered as an effective adjunct to epidural anesthesia in providing a favorable analgesia effect for cesarean section (C-section), but its effects on UEs are currently unknown. METHODS: From 01/12/2021 to 30/06/2022, eligible parturients scheduled for repeated C-section at the First Affiliated Hospital of Wenzhou Medical University were randomized to receive either an intravenous bolus (0.15 µg/kg) followed by a continuous infusion (0.075 µg/kg/min) of remifentanil or normal saline throughout the procedure. The primary outcome was the number of UEs. Secondary outcomes included the size and protein amount of UEs, the vital signs, visceral pain score, sedation score, maternal satisfaction score, Apgar score, the incidence of neonatal asphyxia, umbilical arterial pH, and the presence of complications. RESULTS: Nanoparticle tracking analysis indicated similar size of UEs between the two groups, but the number and protein amount of UEs were increased in the remifentanil group compared to the control group (P < 0.05). In parturients receiving remifentanil, visceral pain scores were decreased, which was accompanied by the increased scores of maternal satisfaction with the anesthetic method (P < 0.05). Other maternal and neonatal outcomes were comparable between the two groups (P > 0.05). CONCLUSION: The intravenous administration of remifentanil increased the number of UEs in parturients undergoing repeated C-section under epidural anesthesia, with improved birth experience and minimal neonatal complications.
Subject(s)
Anesthesia, Epidural , Exosomes , Visceral Pain , Infant, Newborn , Pregnancy , Humans , Female , Remifentanil , Analgesics, Opioid/therapeutic use , Piperidines , Cesarean Section , Umbilical Arteries , Visceral Pain/drug therapy , Anesthesia, Epidural/methods , Infusions, IntravenousABSTRACT
The transcription of interferon-stimulated gene 15 (isg15) is induced by type I interferons. ISG15 can covalently modify target proteins through the sequential action of enzymesE1, E2, and E3, a process known as ISGylation. The ISGylation of host proteins is widely involved in immune responses, such as host antiviral defence. Ubiquitin-specific protease 18 (USP18), as a deubiquitinase (DUB), can remove ISG15 conjugated to target proteins and inhibit host immune responses by suppressing the type I interferon signaling. The dynamic balance between ISGylation and deISGylation mediated by ISG15 or USP18 respectively plays a significant role in the tuberculosis. Furthermore, similar to ISG15, USP18 is extensively involved in virus-host interaction. In this review, we summarize the roles of ISGylation and deISGylation in tuberculosis and other important diseases mediated by ISG15 and USP18 respectively, underlying regulator network. Further studies in this aspect will inspire new host-targeted strategies to control important diseases such as tuberculosis.
Subject(s)
Cytokines , Tuberculosis , Ubiquitin Thiolesterase , Ubiquitins , Humans , Ubiquitin Thiolesterase/metabolism , Ubiquitin Thiolesterase/genetics , Ubiquitins/metabolism , Ubiquitins/genetics , Tuberculosis/metabolism , Tuberculosis/microbiology , Cytokines/metabolism , Animals , Signal TransductionABSTRACT
Stereochemistry in polymers can be used as an effective tool to control the mechanical and physical properties of the resulting materials. Typically, though, in synthetic polymers, differences among polymer stereoisomers leads to incremental property variation, i.e., no changes to the baseline plastic or elastic behavior. Here we show that stereochemical differences in sugar-based monomers yield a family of nonsegmented, alternating polyurethanes that can be either strong amorphous thermoplastic elastomers with properties that exceed most cross-linked rubbers or robust, semicrystalline thermoplastics with properties comparable to commercial plastics. The stereochemical differences in the monomers direct distinct intra- and interchain supramolecular hydrogen-bonding interactions in the bulk materials to define their behavior. The chemical similarity among these isohexide-based polymers enables both statistical copolymerization and blending, which each afford independent control over degradability and mechanical properties. The modular molecular design of the polymers provides an opportunity to create a family of materials with divergent properties that possess inherently built degradability and outstanding mechanical performance.
ABSTRACT
A copper-catalyzed regiodivergent hydrosilylation of a wide range of simple allenes is reported. Linear and branched allylsilanes were formed by judicious choice of solvents. Furthermore, branched allylsilanes were obtained with high enantioselectivity (up to 97% enantiomeric excess) with the aid of a C2-symmetric bisphosphine ligand in the unprecedented asymmetric allene hydrosilylation.
Subject(s)
Alkadienes , Copper , Catalysis , StereoisomerismABSTRACT
The remarkable elasticity and tensile strength found in natural elastomers are challenging to mimic. Synthetic elastomers typically feature covalently cross-linked networks (rubbers), but this hinders their reprocessability. Physical cross-linking via hydrogen bonding or ordered crystallite domains can afford reprocessable elastomers, but often at the cost of performance. Herein, we report the synthesis of ultra-tough, reprocessable elastomers based on linear alternating polymers. The incorporation of a rigid isohexide adjacent to urethane moieties affords elastomers with exceptional strain hardening, strain rate dependent behavior, and high optical clarity. Distinct differences were observed between isomannide and isosorbide-based elastomers where the latter displays superior tensile strength and strain recovery. These phenomena are attributed to the regiochemical irregularities in the polymers arising from their distinct stereochemistry and respective inter-chain hydrogen bonding.
Subject(s)
Elastomers , Isosorbide , Elastomers/chemistry , Hydrogen Bonding , Isosorbide/chemistryABSTRACT
SUMMARY: Genome-wide association studies (GWAS), particularly designed with thousands and thousands of single-nucleotide polymorphisms (SNPs) (big p) genotyped on tens of thousands of subjects (small n), are encountered by a major challenge of p ⪠n. Although the integration of longitudinal information can significantly enhance a GWAS's power to comprehend the genetic architecture of complex traits and diseases, an additional challenge is generated by an autocorrelative process. We have developed several statistical models for addressing these two challenges by implementing dimension reduction methods and longitudinal data analysis. To make these models computationally accessible to applied geneticists, we wrote an R package of computer software, HiGwas, designed to analyze longitudinal GWAS datasets. Functions in the package encompass single SNP analyses, significance-level adjustment, preconditioning and model selection for a high-dimensional set of SNPs. HiGwas provides the estimates of genetic parameters and the confidence intervals of these estimates. We demonstrate the features of HiGwas through real data analysis and vignette document in the package. AVAILABILITY AND IMPLEMENTATION: https://github.com/wzhy2000/higwas. CONTACT: rwu@phs.psu.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Subject(s)
Genome-Wide Association Study , Software , Genotype , Humans , Multifactorial Inheritance , Polymorphism, Single NucleotideABSTRACT
Endometriosis (EMs) is recorded as Zheng Jia in traditional Chinese medicine (TCM) books. Guizhi Fuling Pills (GFPs), a classic prescription for promoting blood circulation and removing blood stasis, is widely used for women's blood stasis diseases represented by Zheng Jia. At present, it has been applied to treat EMs in clinical settings. In this review, we systematically summarized the active ingredients and pharmacological mechanism of five Chinese herbs contained in GFPs and clinical applications of GFPs. The potential pathways of GFPs in the treatment of EMs were explored through network pharmacology. The current researches results indicate that the mechanisms of GFPs in the treatment of EMs mainly include acesodyne, anti-inflammation and improvement of hemodynamics. The main active compounds that are responsible for pharmacological effects in five Chinese herbs are paeonol, pachymic acid, cinnamaldehyde, amygdaloside and Paeoniflorin. This review can lay the foundation and identify the research direction for the development of GFPs as a new drug therapy for the treatment of EMs.
Subject(s)
Drugs, Chinese Herbal/therapeutic use , Endometriosis/drug therapy , Medicine, Chinese Traditional/methods , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Female , Humans , Protein Interaction Mapping , Protein Interaction Maps/drug effectsABSTRACT
Morphogenesis is a phenomenon by which a wide variety of functional organs are formed in biological systems. In plants, morphogenesis is primarily driven by differential growth of tissues. Much effort has been devoted to identifying the role of genetic and biomolecular pathways in regulating cell division and cell expansion and in influencing shape formation in plant organs. However, general principles dictating how differential growth controls the formation of complex 3D shapes in plant leaves and flower petals remain largely unknown. Through quantitative measurements on live plant organs and detailed finite-element simulations, we show how the morphology of a growing leaf is determined by both the maximum value and the spatial distribution of growth strain. With this understanding, we develop a broad scientific framework for a morphological phase diagram that is capable of rationalizing four configurations commonly found in plant organs: twisting, helical twisting, saddle bending, and edge waving. We demonstrate the robustness of these findings and analyses by recourse to synthetic reproduction of all four configurations using controlled polymerization of a hydrogel. Our study points to potential approaches to innovative geometrical design and actuation in such applications as building architecture, soft robotics and flexible electronics.
Subject(s)
Flowers/growth & development , Orchidaceae/growth & development , Plant Development , Plant Leaves/growth & development , Models, BiologicalABSTRACT
Planar, terpyridine-based metal complexes with the Sierpinski triangular motif and alkylated corners undergo a second self-assembly event to give megastructural Sierpinski pyramids; assembly is driven by the facile lipophilic-lipophilic association of the alkyl moieties and complementary perfect fit of the triangular building blocks. Confirmation of the 3D, pyramidal structures was verified and supported by a combination of TEM, AFM, and multiscale simulation techniques.
ABSTRACT
Mineral trioxide aggregate (MTA), as a bioactive material, has a widespread application in clinical practice. To date, the effects of MTA on the proliferation and differentiation of human periodontal ligament stem cells (hPDLSCs) remain unclear. hPDLSCs were isolated from human periodontal ligament tissues and cultured with MTA conditioned media. Cell counting kit-8 (CCK-8) assay was performed to assess the proliferation capacity of MTA-treated hPDLSCs. Immunofluorescence assay, alkaline phosphatase (ALP) activity, alizarin red staining, real-time RT-PCR, and western blot analyses were used to investigate the odonto/osteogenic capacity of hPDLSCs as well as the involvement of NF-κB and MAPK pathways. ALP activity assay revealed that 2 mg/ml was the optimal concentration for the induction of hPDLSCs by MTA. The protein expression of DSP, RUNX2, OCN, OSX, OPN, DMP1, ALP, and COL-I in MTA-treated hPDLSCs was significantly higher than those in control group (p < 0.01). When hPDLSCs were treated with the inhibitors of NF-κB and MAPK pathways (U0126, SP600125, SB203580, and BMS345541), the effects of MTA on the differentiation of hPDLSCs were suppressed. Mechanistically, P65 was detected to transfer from cytoplasm to nuclei, as indicated by western blot and immunofluorescence assay. Moreover, MAPK-related proteins and its downstream transcription factors were also upregulated in MTA-treated hPDLSCs. Together, mineral trioxide aggregate can promote the odonto/osteogenic capacity of hPDLSCs via activating the NF-κB and MAPK pathways.
Subject(s)
Aluminum Compounds/pharmacology , Calcium Compounds/pharmacology , Cell Differentiation/drug effects , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Osteogenesis/drug effects , Oxides/pharmacology , Periodontal Ligament/drug effects , Signal Transduction/drug effects , Silicates/pharmacology , Stem Cells/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Drug Combinations , Gene Expression Regulation , Humans , Periodontal Ligament/enzymology , Stem Cells/enzymology , Time Factors , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
Pulmonary vascular remodeling characterized by concentric wall thickening and intraluminal obliteration is a major contributor to the elevated pulmonary vascular resistance in patients with idiopathic pulmonary arterial hypertension (IPAH). Here we report that increased hypoxia-inducible factor 2α (HIF-2α) in lung vascular endothelial cells (LVECs) under normoxic conditions is involved in the development of pulmonary hypertension (PH) by inducing endothelial-to-mesenchymal transition (EndMT), which subsequently results in vascular remodeling and occlusive lesions. We observed significant EndMT and markedly increased expression of SNAI, an inducer of EndMT, in LVECs from patients with IPAH and animals with experimental PH compared with normal controls. LVECs isolated from IPAH patients had a higher level of HIF-2α than that from normal subjects, whereas HIF-1α was upregulated in pulmonary arterial smooth muscle cells (PASMCs) from IPAH patients. The increased HIF-2α level, due to downregulated prolyl hydroxylase domain protein 2 (PHD2), a prolyl hydroxylase that promotes HIF-2α degradation, was involved in enhanced EndMT and upregulated SNAI1/2 in LVECs from patients with IPAH. Moreover, knockdown of HIF-2α (but not HIF-1α) with siRNA decreases both SNAI1 and SNAI2 expression in IPAH-LVECs. Mice with endothelial cell (EC)-specific knockout (KO) of the PHD2 gene, egln1 (egln1EC-/-), developed severe PH under normoxic conditions, whereas Snai1/2 and EndMT were increased in LVECs of egln1EC-/- mice. EC-specific KO of the HIF-2α gene, hif2a, prevented mice from developing hypoxia-induced PH, whereas EC-specific deletion of the HIF-1α gene, hif1a, or smooth muscle cell (SMC)-specific deletion of hif2a, negligibly affected the development of PH. Also, exposure to hypoxia for 48-72 h increased protein level of HIF-1α in normal human PASMCs and HIF-2α in normal human LVECs. These data indicate that increased HIF-2α in LVECs plays a pathogenic role in the development of severe PH by upregulating SNAI1/2, inducing EndMT, and causing obliterative pulmonary vascular lesions and vascular remodeling.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/physiology , Endothelial Cells/pathology , Epithelial-Mesenchymal Transition , Hypertension, Pulmonary/etiology , Hypoxia-Inducible Factor-Proline Dioxygenases/physiology , Animals , Cells, Cultured , Endothelial Cells/metabolism , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/pathology , Hypoxia/physiopathology , Hypoxia-Inducible Factor 1, alpha Subunit/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Snail Family Transcription Factors/genetics , Snail Family Transcription Factors/metabolism , Vascular RemodelingABSTRACT
Results of the coarse-grained molecular dynamics simulations are used to show that the force balance analysis at the triple-phase contact line formed at an elastic substrate has to include a quartet of forces: three surface tensions (surface free energies) and an elastic force per unit length. In the case of the contact line formed by a droplet on an elastic substrate an elastic force is due to substrate deformation generated by formation of the wetting ridge. The magnitude of this force fel is proportional to the product of the ridge height h and substrate shear modulus G. Similar elastic line force should be included in the force analysis at the triple-phase contact line of a solid particle in contact with an elastic substrate. For this contact problem elastic force obtained from contact angles and surface tensions is a sum of the elastic forces acting from the side of a solid particle and an elastic substrate. By considering only three line forces acting at the triple-phase contact line, one implicitly accounts the bulk stress contribution as a part of the resultant surface stresses. This "contamination" of the surface properties by a bulk contribution could lead to unphysically large values of the surface stresses in soft materials.
ABSTRACT
Dendritic polymers with highly branching structures exhibit many unique properties. In this paper, a computational study using the Wang-Landau sampling technique is carried out to reveal the phase transition behaviours of dendritic homopolymers with various branching structures. Two types of dendritic homopolymers, dendrimers/dendrigrafts (D/D) and hyperbranched (HB) polymers are studied. It is found that with increasing degree of branching in the dendritic polymer, the liquid-solid (LS) transition temperature increases and the coil-globule (CG) transition becomes weak. Additionally, under similar degrees of branching and polymerization, D/D polymers have a higher LS transition temperature than HB polymers. The reason is that the D/D polymers have greater regularity in the radial distribution of the branching units, which facilitates monomer packing during the LS transition. The distinctive internal unit distribution at various temperatures is quantitatively analysed. Our results show the importance of dendritic polymer structure regularity in phase transition behaviours and are valuable in guiding the structural design of dendritic macromolecules for functionalization applications.
ABSTRACT
A deep understanding to the denaturation and renaturation behaviors of DNA in a confined state is fundamentally important to control the self-assembly of DNA in a chamber or channel for various applications. In this report, we study the denaturation and renaturation behaviors of short DNA confined in cylindrical and spherical spaces with the 3-Site-Per-Nucleotide coarse-grained DNA model applying the replica exchange molecular dynamics technology. It is found that as the confinement size decreases, the melting temperature Tm increases and the transition becomes broad. The analysis of the potential of mean force shows that the confinement increases the relative free energy of the denatured state of DNA and decreases the renaturation energy barrier. Besides the denatured and native states, the metastable parallel-stranded structure is also found. The simulation results show that the shapes of the confinement spaces and the short DNA sequences remarkably affect the renaturation behavior. In the cylindrical space, the DNA renaturation changes from random-binding to slithering-binding with the size of the confinement space decreasing. In contrast, the DNA renaturation in the spherical and symmetrical confinement space proceeds through strand binding and rolling. The relationship between the melting temperature and the confinement size, ΔTm/Tm â¼ Rc (-υ), is estimated and the exponential index υ equals about 1.32 and 1.75 in the cylindrical and spherical confinements, respectively. It is further compared with the theoretical result of the rigid rod model and a qualitative agreement with the simulation is achieved.
Subject(s)
DNA/chemistry , Models, Genetic , Molecular Dynamics Simulation , Nucleic Acid Conformation , Nucleic Acid Denaturation , Transition TemperatureABSTRACT
We use coarse-grained molecular dynamics simulations to study deformation of networks and gels of linear and brush strands in both linear and nonlinear deformation regimes under constant pressure conditions. The simulations show that the Poisson ratio of networks and gels could exceed 0.5 in the nonlinear deformation regime. This behavior is due to the ability of the network and gel strands to sustain large reversible deformation, which, in combination with the finite strand extensibility results in strand alignment and monomer density, increases with increasing strand elongation. We developed a nonlinear network and gel deformation model which defines conditions for the Poisson ratio to exceed 0.5. The model predictions are in good agreement with the simulation results.