An artificial intelligence powered study of enlarged facial pore prevalence on one million Chinese from different age groups and its correlation with environmental factors.

BACKGROUND: Enlarged pores are amidst one of the top cosmetic concerns, especially among Chinese. Many small-group studies have been conducted in understanding their prevalence and beauty relevance. Nonetheless, population-level investigations are still lacking because of gaps in data collection and processing of large-scale studies. Owing to the recent technological advancement enabled by artificial intelligence, databases on the scale of millions can be processed and analyzed readily. MATERIALS AND METHODS: Powered by big data capabilities, revealed a number of novel trends on pore conditions among over-a-million Chinese participants recruited via the "You Look Great Today" mobile application. A scoring model was constructed, which demonstrated high consistency with conventional grading method from dermatologists. Environmental data (weather, air pollution, light at night satellite) were applied to correlate with pore severity. RESULTS: Intraclass correlations between the two scoring systems were strong, with coefficients ranging from 0.79 to 0.92 for different facial areas. Statistical differences in pore severity among all four facial areas (cheek, forehead, nose, and overall) were observed, with the cheek exhibiting the most severe pore condition. Interestingly, Chinese men suffer from more severe pore condition than females. Multiple environmental factors exhibited strong correlations with cheek pore severity and were statistically fitted into linear regressions. Specifically, incremental risk with Each Low Temperature, Low Humidity, And High Solar Exposure correlate to worse cheek pore conditions. Although the Pearson correlation was low between cheek pore severity and light at night, comparison between representative cities demonstrated that in geologically similar cities, higher light at night corresponds to more severe cheek pore conditions. CONCLUSION: Our study is showcasing a robust and reliable AI model in facial pore evaluation. More importantly, insights uncovered using this facile approach also bear significant cosmetic ramifications in treatment of pore enlargement.

A chemoenzymatic method for simultaneous profiling N- and O-glycans on glycoproteins using one-pot format.

Glycosylation is generally characterized and controlled as a critical quality attribute for therapeutic glycoproteins because glycans can impact protein drug-product efficacy, half-life, stability, and safety. Analytical procedures to characterize N-glycans are relatively well established, but the characterization of O-glycans is challenging due to the complex workflows and lack of enzymatic tools. Here, we present a simplified chemoenzymatic method to simultaneously profile N- and O-glycans from the same sample using a one-pot format by mass spectrometry (MS). N-glycans were first released by PNGase F, followed by O-glycopeptide generation by proteinase K, selective N-glycan reduction, and O-glycan release by ß-elimination during permethylation of both N- and O-glycans. Glycan structural assignments and determination of N- to O-glycan ratio was obtained from the one-pot mass spectra. The streamlined, one-pot method is a reliable approach that will facilitate advanced characterizations for quality assessments of therapeutic glycoproteins.

The role and mechanism of thrombospondin-4 in pulmonary arterial hypertension associated with congenital heart disease.

BACKGROUND: Due to a special hemodynamic feature, pulmonary vascular disease in pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) has two stages: reversible and irreversible. So far, the mechanism involved in the transition from reversible to irreversible stage is elusive. Moreover, no recognized and reliable assessments to distinguish these two stages are available. Furthermore, we found that compared with control and reversible PAH, thrombospondin-4 (THBS4) was significantly upregulated in irreversible group by bioinformatic analysis. Hence, we further verify and investigate the expression and role of THBS4 in PAH-CHD. METHODS: We established the monocrotaline plus aorto-cava shunt-induced (MCT-AV) rat model. We measured the expression of THBS4 in lung tissues from MCT-AV rats. Double immunofluorescence staining of lung tissue for THBS4 and α-SMA (biomarker of smooth muscle cells) or vWF (biomarker of endothelial cells) to identify the location of THBS4 in the pulmonary artery. Primary pulmonary artery smooth muscle cells (PASMCs) were cultivated, identified, and used in this study. THBS4 was inhibited and overexpressed by siRNA and plasmid, respectively, to explore the effect of THBS4 on phenotype transformation, proliferation, apoptosis, and migration of PASMCs. The effect of THBS4 on pulmonary vascular remodeling was evaluated in vivo by adeno-associated virus which suppressed THBS4 expression. Circulating level of THBS4 in patients with PAH-CHD was measured by ELISA. RESULTS: THBS4 was upregulated in the lung tissues of MCT-AV rats, and was further upregulated in severe pulmonary vascular lesions. And THBS4 was expressed mainly in PASMCs. When THBS4 was inhibited, contractile markers α-SMA and MYH11 were upregulated, while the proliferative marker PCNA was decreased, the endothelial-mensenchymal transition marker N-cad was downregulated, proapototic marker BAX was increased. Additionally, proliferation and migration of PASMCs was inhibited and apoptosis was increased. Conversely, THBS4 overexpression resulted in opposite effects. And the impact of THBS4 on PASMCs was probably achieved through the regulation of the PI3K/AKT pathway. THBS4 suppression attenuated pulmonary vascular remodeling. Furthermore, compared with patients with simple congenital heart disease and mild PAH-CHD, the circulating level of THBS4 was higher in patients with severe PAH-CHD. CONCLUSIONS: THBS4 is a promising biomarker to distinguish reversible from irreversible PAH-CHD before repairing the shunt. THBS4 is a potential treatment target in PAH-CHD, especially in irreversible stage.

The discovery of in situ thrombus attached to the patent foramen ovale channel in myocardial infarction with normal coronary arteries.

OBJECTIVE: Paradoxical embolism caused by a patent foramen ovale (PFO) is a rare cause of myocardial infarction (MI) in individuals presenting with normal coronary arteries on angiography; however, the deduction is often made due to the inability to identify the exact thrombus that penetrates the atrial septum. Previous studies using optical coherence tomography (OCT) have reported in situ thrombi attached to PFO tunnel in patients with cryptogenic stroke. However, the presence of such thrombi in patients with cryptogenic MI (without a definite cause) remains uncertain. METHOD: We retrospectively analyzed OCT data collected from February to July 2023 on PFO tunnels in MI adults with normal coronary arteries on angiography. RESULTS: Three patients diagnosed with cryptogenic MI and a PFO underwent OCT examination. These patients exhibited varying OCT findings. White thrombi and endocardial abnormalities in the channel were observed in two patients with MI. No thrombus or anomalous morphology on the endocardial surface was noted in the third patient. PFO closure was performed on all patients, and follow-up was completed by October 1, 2023. None of the patients reported recurrence of chest pain. CONCLUSION: In situ thrombus was identified within the PFO channel in patients with cryptogenic MI, potentially serving as a novel etiological factor for coronary thrombosis.

The protective role of cardiovascular health against kidney stones: A study based on LE8 score.

Objectives: The American Heart Association recently released an updated algorithm for evaluating cardiovascular health (CVH)-Life's Essential 8 (LE8) score. Our objective was to investigate the correlation between levels of CVH, as determined by the LE8 score, and the risk of kidney stones among a representative sample of adults in the United States. Methods: We included data from the National Health and Nutrition Examination Survey (NHANES) covering the years 2007-2016 for further analysis. The LE8 score, a comprehensive measurement ranging from 0 to 100, was used to evaluate overall CVH and classified into three categories: low (0-49), moderate (50-79), and high (80-100) CVH. Logistic regression was employed to assess the association between the LE8 score and kidney stones. Furthermore, sensitivity analysis was conducted to validate the findings, and the presence of a non-linear relationship was examined using restricted cubic spline (RCS) regression methods. Results: A total of 19,988 participants were included in this study (weighted mean age, 47.99 years; 95 % confidence interval [CI]: 47.46-48.53 years), with 10,319 being female (weighted percentage, 51.98 %; 95 % CI: 51.26-52.71 %) and 1923 identified as having kidney stones (weighted percentage, 9.95 %; 95 % CI: 9.41-10.53 %). In the fully-adjusted multivariable model, higher LE8 scores were associated with prevalence of self-reported kidney stones (odds ratio [OR] for a 10-unit increase in score, 0.86; 95 % CI: 0.82-0.91), presenting a linear dose-response relationship. Compared to the low CVH group, participants in the moderate and high CVH groups exhibited a lower prevalence of kidney stones (OR = 0.80; 95 % CI: 0.69-0.92; OR = 0.54; 95 % CI: 0.43-0.69, respectively). Similar trends were observed when assessing the association between health behavior scores and kidney stones. Moreover, the negative correlation between the LE8 score and the prevalence of kidney stones was markedly more pronounced in various stratified analyses. Conclusion: Our study suggests that a higher level of CVH, as assessed by the LE8 metrics, is independently associated with a lower prevalence of self-reported kidney stones in a linear relationship. Further research, particularly through longitudinal or intervention studies, is required to establish whether actively promoting optimal CVH levels can effectively reduce the incidence of kidney stones.

Inventorization and ecological risk assessment of tetrabromobisphenol A and hexabromocyclododecane in sediments from Guangdong coastal area of South China Sea.

Brominated flame retardants (BFRs) exhibit excellent flame retardant properties and are widely used in various industries. Among the common BFRs, tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCDs) pose substantial ecological and human health risks due to their extensive application and long-range transport. This study established 131 sample collection sites along the coast of the South China Sea (SCS) in Guangdong Province to assess the concentration, distribution, inventory, and ecological risk of TBBPA and HBCDs in surface sediments. The concentrations of TBBPA in SCS sediments ranged from < limit of detection (LOD) to 80 µg/kg dry weight (dw), and those of HBCDs from < LOD to 18 µg/kg dw. The diastereoisomers of HBCDs (α-, ß-, and γ-HBCD) in the sediment samples accounted for 36 %, 13 %, and 51 %, respectively. Human activities, particularly those associated with nearby electronic waste disassembly and textile and garment industries, considerably influenced the dispersion of TBBPA and HBCDs. The inventories of TBBPA and HBCDs in Guangdong Province's SCS were estimated to be 3.2 × 105 kg and 7.2 × 104 kg, respectively. The average risk quotient values ranged from <0.01 to 0.016, indicating a low to negligible environmental risk. This study provides deeper insights into the distribution and scientific significance of HBCDs and TBBPA in SCS sediment samples, elucidates the current state of BFR contamination, and offers recommendations for future research on environmental safety and human health in the region.

A novel lateral myelotomy approach for the treatment of lateral or ventrolateral spinal gliomas.

OBJECTIVE: To describe a novel surgical approach in which myelotomy was performed lateral to the dorsal root entry zone (LDREZ), for the treatment of lateral or ventrolateral spinal intramedullary glioma. METHODS: This study reviewed six patients with lateral or ventrolateral spinal intramedullary glioma who received surgical treatments by using myelotomy technique of LDREZ approach. The patient's clinical characteristics, magnetic resonance imaging (MRI) results, and follow-up outcomes were analyzed. The neurological function of patients before and after operation was assessed based on the Frankel scale system. The anatomical feasibility, surgical techniques, advantages and disadvantages of LDREZ approach were analyzed. RESULTS: Myelotomy technique of LDREZ approach was employed in all 6 patients. Gross total resections were achieved in 4 patients, and 2 patients with astrocytoma (case 2, 6) underwent partial removal. The perioperative recovery was all smooth and all the patients were discharged on schedule. All the patients who suffered from neuropathic pain were relieved. After surgery, neurological function remained unchanged in 3 patients. 2 patients improved from Frankel grade B to C, and 1 patient deteriorated from Frankel grade D to C immediately after surgery and returned to Frankel grade D at 3 months follow-up. Regarding to the poor prognosis of high-grade glioma, the two cases with WHO IV glioma didn't achieve long survival. CONCLUSION: LDREZ approach is feasible and safe for the surgical removal of lateral or ventrolateral spinal gliomas. This approach can provide a direct pathway to lateral or ventrolateral spinal gliomas with minimal damage to normal spinal cord.

C1q enables influenza hemagglutinin stem binding antibodies to block viral attachment and broadens the antibody escape repertoire.

Antigenic drift, the gradual accumulation of amino acid substitutions in the influenza virus hemagglutinin (HA) receptor protein, enables viral immune evasion. Antibodies (Abs) specific for the drift-resistant HA stem region are a promising universal influenza vaccine target. Although anti-stem Abs are not believed to block viral attachment, here we show that complement component 1q (C1q), a 460-kilodalton protein with six Ab Fc-binding domains, confers attachment inhibition to anti-stem Abs and enhances their fusion and neuraminidase inhibition. As a result, virus neutralization activity in vitro is boosted up to 30-fold, and in vivo protection from influenza PR8 infection in mice is enhanced. These effects reflect increased steric hindrance and not increased Ab avidity. C1q greatly expands the anti-stem Ab viral escape repertoire to include residues throughout the HA, some of which cause antigenic alterations in the globular region or modulate HA receptor avidity. We also show that C1q enhances the neutralization activity of non-receptor binding domain anti-SARS-CoV-2 spike Abs, an effect dependent on spike density on the virion surface. These findings demonstrate that C1q can greatly expand Ab function and thereby contribute to viral evolution and immune escape.

Angular Position Sensor Based on Anisotropic Magnetoresistive and Anomalous Nernst Effect.

Magnetic position sensors have extensive applications in various industrial sectors and consumer products. However, measuring angles in the full range of 0-360° in a wide field range using a single magnetic sensor remains a challenge. Here, we propose a magnetic position sensor based on a single Wheatstone bridge structure made from a single ferromagnetic layer. By measuring the anisotropic magnetoresistance (AMR) signals from the bridge and two sets of anomalous Nernst effect (ANE) signals from the transverse ports on two perpendicular Wheatstone bridge arms concurrently, we show that it is possible to achieve 0-360° angle detection using a single bridge sensor. The combined use of AMR and ANE signals allows a mean angle error in the range of 0.51-1.05° within a field range of 100 Oe-10,000 Oe to be achieved.

MAIVeSS: streamlined selection of antigenically matched, high-yield viruses for seasonal influenza vaccine production.

Vaccines are the main pharmaceutical intervention used against the global public health threat posed by influenza viruses. Timely selection of optimal seed viruses with matched antigenicity between vaccine antigen and circulating viruses and with high yield underscore vaccine efficacy and supply, respectively. Current methods for selecting influenza seed vaccines are labor intensive and time-consuming. Here, we report the Machine-learning Assisted Influenza VaccinE Strain Selection framework, MAIVeSS, that enables streamlined selection of naturally circulating, antigenically matched, and high-yield influenza vaccine strains directly from clinical samples by using molecular signatures of antigenicity and yield to support optimal candidate vaccine virus selection. We apply our framework on publicly available sequences to select A(H1N1)pdm09 vaccine candidates and experimentally confirm that these candidates have optimal antigenicity and growth in cells and eggs. Our framework can potentially reduce the optimal vaccine candidate selection time from months to days and thus facilitate timely supply of seasonal vaccines.

Structure-based development of potent and selective type-II kinase inhibitors of RIPK1.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

Structure-based design of potent FABP4 inhibitors with high selectivity against FABP3.

Fatty-acid binding protein 4 (FABP4) presents an attractive target for therapeutic intervention in metabolic and inflammatory diseases in recent years. However, highly similar three-dimensional structures and fatty acid binding ability of multiple FABP family members pose a significant challenge in design of FABP4-selective inhibitors. Particularly, inhibition of FABP3 raises safety concerns such as cardiac dysfunction and exercise intolerance. Here, we reported the discovery of new FABP4 inhibitors with high selectivity over FABP3 by exploiting the little structural difference in the ligand binding pockets of FABP4 and FABP3. On the basis of our previously reported FABP4 inhibitors with nanomolar potency, different substituents were further introduced to perfectly occupy two sub-pockets of FABP4 that are distinct from those of FABP3. Remarkably, a single methyl group introduction leads to the discovery of compound C3 that impressively exhibits a 601-fold selectivity over FABP3 when maintained nanomolar binding affinity for FABP4. Moreover, C3 also shows good metabolic stability and potent cellular anti-inflammatory activity, making it a promising inhibitor for further development. Therefore, the present study highlights the utility of the structure-based rational design strategy for seeking highly selective and potent inhibitors of FABP4 and the importance of identifying the appropriate subsite as well as substituent for gaining the desired selectivity.

Yang-Lee Zeros, Semicircle Theorem, and Nonunitary Criticality in Bardeen-Cooper-Schrieffer Superconductivity.

Yang and Lee investigated phase transitions in terms of zeros of partition functions, namely, Yang-Lee zeros [Phys. Rev. 87, 404 (1952)PHRVAO0031-899X10.1103/PhysRev.87.404; Phys. Rev. 87, 410 (1952)PHRVAO0031-899X10.1103/PhysRev.87.410]. We show that the essential singularity in the superconducting gap is directly related to the number of roots of the partition function of a BCS superconductor. Those zeros are found to be distributed on a semicircle in the complex plane of the interaction strength due to the Fermi-surface instability. A renormalization-group analysis shows that the semicircle theorem holds for a generic quantum many-body system with a marginal coupling, in sharp contrast with the Lee-Yang circle theorem for the Ising spin system. This indicates that the geometry of Yang-Lee zeros is directly connected to the Fermi-surface instability. Furthermore, we unveil the nonunitary criticality in BCS superconductivity that emerges at each individual Yang-Lee zero due to exceptional points and presents a universality class distinct from that of the conventional Yang-Lee edge singularity.

Monoclonal Antibodies as SARS-CoV-2 Serology Standards: Experimental Validation and Broader Implications for Correlates of Protection.

COVID-19 has highlighted challenges in the measurement quality and comparability of serological binding and neutralization assays. Due to many different assay formats and reagents, these measurements are known to be highly variable with large uncertainties. The development of the WHO international standard (WHO IS) and other pool standards have facilitated assay comparability through normalization to a common material but does not provide assay harmonization nor uncertainty quantification. In this paper, we present the results from an interlaboratory study that led to the development of (1) a novel hierarchy of data analyses based on the thermodynamics of antibody binding and (2) a modeling framework that quantifies the probability of neutralization potential for a given binding measurement. Importantly, we introduced a precise, mathematical definition of harmonization that separates the sources of quantitative uncertainties, some of which can be corrected to enable, for the first time, assay comparability. Both the theory and experimental data confirmed that mAbs and WHO IS performed identically as a primary standard for establishing traceability and bridging across different assay platforms. The metrological anchoring of complex serological binding and neuralization assays and fast turn-around production of an mAb reference control can enable the unprecedented comparability and traceability of serological binding assay results for new variants of SARS-CoV-2 and immune responses to other viruses.

Efficient Noncollinear Antiferromagnetic State Switching Induced by the Orbital Hall Effect in Chromium.

Recently, orbital Hall current has attracted attention as an alternative method to switch the magnetization of ferromagnets. Here we present our findings on electrical switching of the antiferromagnetic state in Mn3Sn/Cr, where despite the much smaller spin Hall angle of Cr, the switching current density is comparable to heavy metal-based heterostructures. However, the inverse process, i.e., spin-to-charge conversion in Cr-based heterostructures, is much less efficient than the Pt-based equivalents, as manifested in the 1 order of magnitude smaller terahertz emission intensity and spin current-induced magnetoresistance. These results in combination with the slow decay of terahertz emission against Cr thickness (diffusion length of ∼11 nm) suggest that the observed magnetic switching can be attributed to orbital current generation in Cr, followed by efficient conversion to spin current. Our work demonstrates the potential of light metals like Cr as efficient orbital/spin current sources for antiferromagnetic spintronics.

Metal-Free Hydrazinium Halide Perovskitoid Single Crystals for X-ray Detection.

Metal-free perovskitoids (MFPs) with N2H5+ as B-site component possess higher crystal density and hydrogen bonding networks and have been recently expanded into X-ray detection. However, research on this material is in its infancy and lacks an understanding of the function of halide components on physical properties and device performance. Here, N2H5-based MFP single crystals (SCs) with different halides are fabricated, and the influence of halides on the crystal structure, band nature, charge transport characteristics, and final device performance is actively explored. Based on theory and experiments, the tolerance factor and octahedral factor jointly determine the octahedral composition. Further, halides with different electronegativities and ionic radii also affect octahedral distortion and energy band bending, further influencing carrier transport and device performance. Finally, a sensitivity of 1284 µC Gyair-1 cm-2 and low detection limits (LoD) of 5.62 µGyair s-1 were obtained by the Br-based device due to its superior physical properties.

Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir.

The persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants accentuates the great demand for developing effective therapeutic agents. Here, we report the development of an orally bioavailable SARS-CoV-2 3C-like protease (3CLpro) inhibitor, namely simnotrelvir, and its preclinical evaluation, which lay the foundation for clinical trials studies as well as the conditional approval of simnotrelvir in combination with ritonavir for the treatment of COVID-19. The structure-based optimization of boceprevir, an approved HCV protease inhibitor, leads to identification of simnotrelvir that covalently inhibits SARS-CoV-2 3CLpro with an enthalpy-driven thermodynamic binding signature. Multiple enzymatic assays reveal that simnotrelvir is a potent pan-CoV 3CLpro inhibitor but has high selectivity. It effectively blocks replications of SARS-CoV-2 variants in cell-based assays and exhibits good pharmacokinetic and safety profiles in male and female rats and monkeys, leading to robust oral efficacy in a male mouse model of SARS-CoV-2 Delta infection in which it not only significantly reduces lung viral loads but also eliminates the virus from brains. The discovery of simnotrelvir thereby highlights the utility of structure-based development of marked protease inhibitors for providing a small molecule therapeutic effectively combatting human coronaviruses.

Tuning Intrinsic Spin Hall Effect in Platinum/Ferrimagnetic Insulator Heterostructure in Moderately Dirty Regime.

Studying the mechanisms of the spin Hall effect (SHE) is essential for the fundamental understanding of spintronic physics. By now, despite the intensive studies of SHE on heavy metal (HM)/metallic magnet heterostructures, the SHE on HM/ferrimagnetic insulator (FMI) heterostructures still remains elusive. Here, we study the mechanism of SHE in the Pt/Tm3Fe5O12 (TmIG) heterostructure. We first tune the crystallinity and resistivity of Pt by an annealing method, and then study the spin-orbit torque (SOT) in the tuned-Pt/TmIG devices. The SOT generation efficiency per unit electric field and spin Hall angle were obtained, which are insensitive to the annealing temperature. We further demonstrate that the intrinsic contribution in the moderately dirty regime is responsible for the SHE in our Pt/TmIG bilayer. Our study provides an important piece of information for the SHE in FMI-based spintronic physics.

Host heparan sulfate promotes ACE2 super-cluster assembly and enhances SARS-CoV-2-associated syncytium formation.

SARS-CoV-2 infection causes spike-dependent fusion of infected cells with ACE2 positive neighboring cells, generating multi-nuclear syncytia that are often associated with severe COVID. To better elucidate the mechanism of spike-induced syncytium formation, we combine chemical genetics with 4D confocal imaging to establish the cell surface heparan sulfate (HS) as a critical stimulator for spike-induced cell-cell fusion. We show that HS binds spike and promotes spike-induced ACE2 clustering, forming synapse-like cell-cell contacts that facilitate fusion pore formation between ACE2-expresing and spike-transfected human cells. Chemical or genetic inhibition of HS mitigates ACE2 clustering, and thus, syncytium formation, whereas in a cell-free system comprising purified HS and lipid-anchored ACE2, HS stimulates ACE2 clustering directly in the presence of spike. Furthermore, HS-stimulated syncytium formation and receptor clustering require a conserved ACE2 linker distal from the spike-binding site. Importantly, the cell fusion-boosting function of HS can be targeted by an investigational HS-binding drug, which reduces syncytium formation in vitro and viral infection in mice. Thus, HS, as a host factor exploited by SARS-CoV-2 to facilitate receptor clustering and a stimulator of infection-associated syncytium formation, may be a promising therapeutic target for severe COVID.

DNMT1-induced miR-133b suppression via methylation promotes myocardial fibrosis after myocardial infarction.

Myocardial fibrosis is an underlying cause of many cardiovascular diseases. Novel insights into the epigenetic control of myocardial fibrosis are now emerging. The current work is focused on investigating the biological role of DNA methyltransferase 1 (DNMT1) in myocardial fibrosis as well as the underlying mechanism. Our findings revealed that DNMT1 expression levels were upregulated, whereas miR-133b expression levels were decreased in a rat model of myocardial fibrosis following myocardial infarction. In vitro, the expression levels of DNMT1 increased and those of miR-133b decreased after Ang-II treatment in cardiac fibroblasts. DNMT1 knockdown inhibited Ang-II-induced cardiac myofibroblast activation, and DNMT1 overexpression increased the proliferation and collagen generation of cardiac myofibroblasts. Furthermore, DNMT1 expression levels decreased, while miR-133b expression levels increased after treatment with 5-Aza (5-Azacytidine, a known inhibitor of DNA methylation) in Ang-II-induced cardiac fibroblasts. BSP (Bisulfite sequencing PCR) results showed a marked decrease in methylation levels in the miR-133b promoter region upon overexpression of DNMT1, whereas knockdown of DNMT1 blocked increased methylation levels in the miR-133b promoter region in Ang-II-induced cardiac fibroblasts. Finally, 5-Aza treatment reduced the progression of myocardial fibrosis after myocardial infarction in rats in vivo. Collectively, our results suggest that DNMT1 mediates CTGF expression in cardiac fibroblast activation by regulating the methylation of miR-133b. The present work reveals the unique role of the DNMT1/miR-133b/CTGF axis in myocardial fibrosis, thus suggesting its great therapeutic potential in the treatment of cardiac diseases.