Benzoic Acid: Electrode-Regenerated Molecular Catalyst to Boost Cycloolefin Epoxidation.

Stoichiometric oxidants are always consumed in organic oxidation reactions. For example, olefins react with peroxy acids to be converted to epoxy, while the oxidant, peroxy acid, is downgraded to carboxylic acid. In this paper, we aim to regenerate carboxylic acid into peroxy acid through electric water splitting at the anode, in order to construct an electrochemical catalytic cycle to accomplish the cycloolefin epoxidation reaction. Benzoic acid, which can be strongly adsorbed onto the anode and rapidly converted to peroxy acid, was selected to catalyze the cycloolefin epoxidation. Furthermore, the peroxybenzoic acid will be further activated on the electrode to fulfill the epoxidation and release the benzoic acid to complete the catalytic cycle. In this designed reaction cycle, benzoic acid acts as a molecular catalyst with the assistance of the electrode-generated reactive oxygen species (ROS). This method can successfully reform the consumable oxidants to molecular catalysts, which can be generalized to other green organic syntheses.

Stable Lithium-Sulfur Batteries Ensured by GeS2 and α-S8 Lattice Matching During the Charge Process.

The charge process of lithium-sulfur batteries (LSBs) is a process in which molecular polarity decreases and the volume shrinks gradually, which is the process most likely to cause lithium polysulfides (LiPSs) loss and interfacial collapse. In this work, GeS2 is utilized, whose (111) lattice plane exactly matches with the (113) lattice of α-S8 , to solve these problems. GeS2 can regulate the interconversion-deposition behavior of S-species during the charge process. Soluble LiPSs can be spontaneously adsorbed on the GeS2 surface, then obtain electrons and eventually convert to α-S8 molecules. More importantly, the α-S8 molecules will crystallize uniformly along the (111) lattice plane of GeS2 to maintain a stable cathode-electrolyte interface. Therefore, outstanding charge/discharge LSBs are successfully accomplished.

Self-assembly of fullerene C60-based amphiphiles in solutions.

Fullerene C60 is an all-carbon cage molecule with rich physicochemical properties. It is highly symmetric and hydrophobic, which can be used as a building block for the preparation of amphiphiles that self-assemble into diverse supramolecular structures in aqueous solutions. Meanwhile, C60 is also lipophobic, which is different from the alkyl chains in traditional surfactants. By attaching alkyl chains to the C60 sphere, a new type of lipophobic-lipophilic amphiphiles can be constructed which undergo self-assembly in n-alkanes. When inorganic clusters such as polyoxometalate are linked to the C60 sphere, organic-inorganic hybrids will be obtained which can self-assemble in polar organic solvents. Pristine C60 has also been modified by polar groups such as hydroxy and carboxy, which are linked to hydrophobic moieties and form a new class of amphiphiles. In this review, the self-assembly of C60-based amphiphiles in aqueous and nonaqueous solutions will be summarized. The characteristics exhibited by C60-based amphiphiles during the self-assembly will be discussed with close comparison to traditional surfactants, and the influences of the aggregate formation on the physicochemical properties of the C60 sphere will be described. Finally, a brief summary will be given together with a promising perspective in near future.

Water-Soluble, Alanine-Modified Fullerene C60 Promotes the Proliferation and Neuronal Differentiation of Neural Stem Cells.

As carbon-based nanomaterials, water-soluble C60 derivatives have potential applications in various fields of biomedicine. In this study, a water-soluble fullerene C60 derivative bearing alanine residues (Ala-C60) was synthesized. The effects of Ala-C60 on neural stem cells (NSCs) as seed cells were explored. Ala-C60 can promote the proliferation of NSCs, induce NSCs to differentiate into neurons, and inhibit the migration of NSCs. Most importantly, the Ala-C60 can significantly increase the cell viability of NSCs treated with hydrogen peroxide (H2O2). The glutathioneperoxidase (GSH-Px) and superoxide dismutase (SOD) activities and glutathione (GSH) content increased significantly in NSCs treated even by 20 µM Ala-C60. These findings strongly indicate that Ala-C60 has high potential to be applied as a scaffold with NSCs for regeneration in nerve tissue engineering for diseases related to the nervous system.

Fluorescent Immunoassay with a Copper Polymer as the Signal Label for Catalytic Oxidation of O-Phenylenediamine.

This work suggested that Cu2+ ion coordinated by the peptide with a histidine (His or H) residue in the first position from the free N-terminal reveals oxidase-mimicking activity. A biotinylated polymer was prepared by modifying His residues on the side chain amino groups of lysine residues (denoted as KH) to chelate multiple Cu2+ ions. The resulting biotin-poly-(KH-Cu)20 polymer with multiple catalytic sites was employed as the signal label for immunoassay. Prostate specific antigen (PSA) was determined as the model target. The captured biotin-poly-(KH-Cu)20 polymer could catalyze the oxidation of o-phenylenediamine (OPD) to produce fluorescent 2,3-diaminophenazine (OPDox). The signal was proportional to PSA concentration from 0.01 to 2 ng/mL, and the detection limit was found to be eight pg/mL. The high sensitivity of the method enabled the assays of PSA in real serum samples. The work should be valuable for the design of novel biosensors for clinical diagnosis.

Penne-Like MoS2 /Carbon Nanocomposite as Anode for Sodium-Ion-Based Dual-Ion Battery.

The dual-ion battery (DIB) system has attracted great attention owing to its merits of low cost, high energy, and environmental friendliness. However, the DIBs based on sodium-ion electrolytes are seldom reported due to the lack of appropriate anode materials for reversible Na+ insertion/extraction. Herein, a new sodium-ion based DIB named as MoS2 /C-G DIB using penne-like MoS2 /C nanotube as anode and expanded graphite as cathode is constructed and optimized for the first time. The hierarchical MoS2 /C nanotube provides expanded (002) interlayer spacing of 2H-MoS2 , which facilitates fast Na+ insertion/extraction reaction kinetics, thus contributing to improved DIB performance. The MoS2 /C-G DIB delivers a reversible capacity of 65 mA h g-1 at 2 C in the voltage window of 1.0-4.0 V, with good cycling performance for 200 cycles and 85% capacity retention, indicating the feasibility of potential applications for sodium-ion based DIBs.

Comparative genomic evidence for duplication of TLR1 subfamily and miiuy croaker TLR1 perceives LPS stimulation via MyD88 and TIRAP.

Being indispensable pattern recognition receptors in innate immune responses in host protection, Toll-like receptors (TLRs) play an important role in pathogen recognition. Fish TLRs exhibit high variety and distinct features, although little is known about their function on ligand recognition and signaling pathway in fish. This paper reports the evolutionary spectrum of the TLR1 subfamily (referred to as TLR1, TLR6, and TLR10) as determined using the comparative genomic approach. We hypothesized that the TLR1 subfamily underwent two rounds of gene duplication events; the first duplication occurred prior to the divergence of amphibians, and the second one occurred prior to the divergence of eutherians. To further study the function of fish TLR1, we identified miiuy croaker (Miichthys miiuy) TLR1 (mmiTLR1) and determined its potential ability to perceive Vibrio anguillarum and lipopolysaccharide stimulation. Data further suggested that mmiTLR1 is dependent on TIRAP and MyD88 for signal transmission. In addition, immunocytochemistry showed the speculative interaction between MyD88 and mmiTLR1 TIR domain. Overall, we systematically and comprehensively analyzed evolution of TLR1 subfamily and the function of mmiTLR1, which will provide the basis for future scientific research on fish TLRs.

Comparative genomic and evolution of vertebrate NOD1 and NOD2 genes and their immune response in miiuy croaker.

The nucleotide-binding oligomerization domain proteins NOD1 and NOD2 are important cytoplasmic pathogen recognition receptors which sense microbial infections molecules to induce innate immune response. In this study, the sequence analysis showed that NOD1 and NOD2 genes in miiuy croaker (miichthys miiuy, mmiNOD1 and mmiNOD2) share some highly conserved motifs that crucial for recognizing the bacterial and viral components. Quantitative expression analysis revealed mmiNOD1 and mmiNOD2 had the highest level of expression in liver. Induction experiments with Vibrio anguillarum indicated the different expression levels of mmiNOD1 and mmiNOD2 in liver, spleen and kidney. The expressions of mmiNOD1 and mmiNOD2 increased more significantly after Poly(I:C) stimulation, meanwhile, we carried out the expression analysis at the transcriptome level and the regulation of microRNAs. In addition, the evolutionary analysis showed that the ancestral lineages of NOD1 in bony fish detected one positively selected site, however, both the current lineages of NOD1 and NOD2 genes in bony fish underwent purifying selection indicating that NOD1 gene in the ancestor of bony fish experienced positive selection. To further understand the evolutionary pattern of NOD1 and NOD2 in vertebrates, we were the first to conduct comparative genomic analysis by comparing the number and synteny of NOD1 and NOD2. Combining the duplication of NOD1, the lost of NOD2 and the more conserved synteny of NOD2 than NOD1, we proposed that the hypothetical evolutionary pattern is different between NOD1 and NOD2.

Characterization of NLR-A subfamily members in miiuy croaker and comparative genomics revealed NLRX1 underwent duplication and lose in actinopterygii.

The NOD-like receptors (NLRs, nucleotide-binding domain and leucine-rich repeat containing receptors) are a recently identified family of intracellular pathogen recognition receptors in vertebrates. Several subfamilies of NLRs have been characterized in mammals and implicated in immunity and apoptosis, but studies of NLRs in teleost species have been lacking. Here we analyzed three NLR-A subfamily members from miiuy croaker: NLRC3, NLRC5, and NLRX1. Structural analysis showed that miiuy croaker NLR-A subfamily members own the feature of 5'UTR intron which may influence their role in enhancing translation level. Comparative analysis revealed NLRX1 duplicated into NLRX1a and NLRX1b, then NLRX1a was lost in actinopterygii and NLRX1b formed NLRX1 that now we called. Simultaneously, molecular evolutionary analysis indicated that the ancestral lineages of NLRX1 in tetrapod and actinopterygii under positive selection pressure. The positively sites in actinopterygii are mainly located in NACHT domain which was the critical region for signal transduction, suggesting that the evolution of NLRX1 gene in the ancestor of actinopterygii is beneficial in immune response. Pathogens challenge demonstrated that the expressions of NLRC3 and NLRC5 in miiuy croaker were induced not only by Vibrio anguillarum but also by poly (I:C), whereas NLRX1 exhibited more sensitive response to bacteria than virus.

Pregabalin-induced rhabdomyolysis: a case series and literature analysis.

Pregabalin is a prescription medicine that has recently been approved for individuals who suffer from fibromyalgia, neuropathic pain, anxiety disorder, or epilepsy. Pregabalin has the side effects of dizziness, sleepiness, and angioedema. Pregabalin-induced rhabdomyolysis has been rarely reported, with only four reports to date. We report two cases of rhabdomyolysis after pregabalin treatment. A man aged older than 90 years presented with exhaustion, muscle aches, and a high serum creatine kinase concentration after taking 75 mg of pregabalin on the first day of treatment. A woman in her 90s with long-term use of pregabalin presented with considerably elevated serum creatine kinase concentrations. Both patients had a long history of taking statins. Pregabalin therapy was stopped, high-volume intravenous fluids were administered, and serum electrolytes were frequently checked. Alkalinisation was performed with excellent outcomes. The Naranjo Adverse Drug Reaction scale and previous research suggest an association between pregabalin and rhabdomyolysis. Clinicians should be alert to the possibility of rhabdomyolysis occurring with the use of pregabalin, especially when taking statins.

Detection and Identification of Tassel States at Different Maize Tasseling Stages Using UAV Imagery and Deep Learning.

The tassel state in maize hybridization fields not only reflects the growth stage of the maize but also reflects the performance of the detasseling operation. Existing tassel detection models are primarily used to identify mature tassels with obvious features, making it difficult to accurately identify small tassels or detasseled plants. This study presents a novel approach that utilizes unmanned aerial vehicles (UAVs) and deep learning techniques to accurately identify and assess tassel states, before and after manually detasseling in maize hybridization fields. The proposed method suggests that a specific tassel annotation and data augmentation strategy is valuable for substantial enhancing the quality of the tassel training data. This study also evaluates mainstream object detection models and proposes a series of highly accurate tassel detection models based on tassel categories with strong data adaptability. In addition, a strategy for blocking large UAV images, as well as improving tassel detection accuracy, is proposed to balance UAV image acquisition and computational cost. The experimental results demonstrate that the proposed method can accurately identify and classify tassels at various stages of detasseling. The tassel detection model optimized with the enhanced data achieves an average precision of 94.5% across all categories. An optimal model combination that uses blocking strategies for different development stages can improve the tassel detection accuracy to 98%. This could be useful in addressing the issue of missed tassel detections in maize hybridization fields. The data annotation strategy and image blocking strategy may also have broad applications in object detection and recognition in other agricultural scenarios.

Ultra-strong and tough cellulose-based conductive hydrogels via orientation inspired by noodles pre-stretching.

Due to the unsatisfactory mechanical properties of natural polymer-based conductive hydrogels, their applications are limited. Shaanxi Biangbiang noodles can be toughened by applying external mechanical forces through stretching and beating movements; this process provides inspiration for the preparation of high-strength hydrogels. In this paper, we propose a strategy for the preparation of ultrastrong and ultratough conductive hydrogels by directional prestretching and solvent exchange. Neatly arranged fiber bundles containing many intermolecular hydrogen bonds and metal ion coordination bonds are successfully constructed inside the prepared hydrogels. The hydrogel has exceptional mechanical properties, with a fracture stress exceeding 50 MPa, fracture strain approaching 105 %, fracture toughness exceeding 30 MJ m-3, and high conductivity reaching 11.738 ± 0.06 mS m-1. Impressively, the hydrogel can maintain its high mechanical properties after being frozen at an ultralow temperature of -80 °C for 7 days. Compared with other tough hydrogels, natural tendons and synthetic rubbers, the hydrogel exhibits excellent mechanical properties. The cellulose-based conductive hydrogel prepared in this study can be applied to robotic soft tissues (such as the Achilles tendon) that require high strength and are operated in extreme environments.

Toward robust lithium-sulfur batteries via advancing Li2S deposition.

Lithium-sulfur batteries (LSBs) with two typical platforms during discharge are prone to the formation of soluble lithium polysulfides (LiPS), leading to a decrease in the cycling life of the battery. Under practical working conditions, the transformation of S8 into Li2S is cross-executed rather than a stepwise reaction, where the liquid LiPS to solid Li2S conversion can occur at a high state of charge (SOC) to maintain the current requirement. Therefore, advancing Li2S deposition can effectively reduce the accumulation of LiPSs and ultimately improve the reaction kinetics. Herein, a "butterfly material" GeS2-MoS2/rGO is used as a sulfur host. Rich catalytic heterointerfaces can be obtained via the abundant S-S bonds formed between GeS2 and MoS2. MoS2 (left wing) can enhance LiPS adsorption, while the lattice-matching nature of Fdd2 GeS2 (right wing) and Fm3̄m Li2S can induce multiple nucleation and regulate the 3D growth of Li2S. Li2S deposition can be advanced to occur at 80% SOC, thereby effectively inhibiting the accumulation of soluble LiPSs. Attributed to the synergistic effect of catalytic and lattice-matching properties, robust coin and pouch LSBs can be achieved.

Correction: Toward robust lithium-sulfur batteries via advancing Li2S deposition.

[This corrects the article DOI: 10.1039/D4SC02420F.].

Heme Oxygenase-1 Gene (GT)n Polymorphism Linked to Deep White Matter Hyperintensities, Not Periventricular Hyperintensities.

BACKGROUND: Oxidative stress plays a principal role in the pathogenesis of white matter hyperintensities (WMHs). The induction of heme oxygenase-1 (HO-1) gene in the brain represents 1 of the pivotal mechanisms to counteract the noxious effects of reactive oxygen species, and the transcriptional modulation of HO-1 induction depends on the length of a GT-repeat (GT)n in the promoter region. We investigated whether the HO-1 gene (GT)n polymorphism is associated with the risk of WMHs. METHODS AND RESULTS: A total of 849 subjects from the memory clinic were consecutively enrolled, and the HO-1 (GT)n genotype was determined. WMHs were assessed with the Fazekas scale and further divided into periventricular WMHs and deep WMHs (DWMHs). Allelic HO-1 (GT)n polymorphisms were classified as short (≤24 (GT)n), median (25≤[GT]n<31), or long (31≤[GT]n). Multivariate logistic regression analysis was used to evaluate the effect of the HO-1 (GT)n variants on WMHs. The number of repetitions of the HO-1 gene (GT)n ranged from 15 to 39 with a bimodal distribution at lengths 23 and 30. The proportion of S/S genotypes was higher for moderate/severe DWMHs than none/mild DWMHs (22.22% versus 12.44%; P=0.001), but the association for periventricular WMHs was not statistically significant. Logistic regression suggested that the S/S genotype was significantly associated with moderate/severe DWMHs (S/S versus non-S/S: odds ratio, 2.001 [95% CI, 1.323-3.027]; P<0.001). The HO-1 gene (GT)n S/S genotype and aging synergistically contributed to the progression of DWMHs (relative excess risk attributable to interaction, 6.032 [95% CI, 0.149-11.915]). CONCLUSIONS: Short (GT)n variants in the HO-1 gene may confer susceptibility to rather than protection from DWMHs, but not periventricular WMHs. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR2100045869.

Textured Potassium Sodium Niobate Lead-Free Ceramics with High d33 and Qm for Meeting High-Power Applications.

Potassium sodium niobate (KNN) lead-free piezoceramics have garnered significant attention for their environmentally friendly attributes, desired piezoelectric activity (d33), and high Curie temperature (Tc). However, the limited applicability of most KNN systems in high-power apparatus, including ultrasonic motors, transformers, and resonators, persists due to the inherent low mechanical quality factor (Qm). Herein, we proposed an innovative strategy for achieving high Qm accompanied by desirable d33 via synergistic chemical doping and texturing in KNN piezoceramics. Comprehensive electrical measurements along with quantitative structural characterization at multilength scales reveal that the excellent electromechanical properties (kp = 0.58, d33 ∼ 134 pC·N-1, Qm = 582, and Tc ∼ 415 °C) originate from the high <001> texturing degree, nanodomain, as well as acceptor hardening. Our findings provide an insight and guidance for achieving high-power performance in lead-free KNN-based piezoceramics, which were expected to be used in advanced transducer technology.

Stereoselective Synthesis of Less Accessible α-Tertiary Amino Ketimines via Electrophilic Amination of α-Branched N-tert-Butanesulfinyl Ketimines.

A stereocontrolled electrophilic amination of α-branched N-tert-butanesulfinyl ketimines was developed to construct α-aminoketone derivatives containing less accessible α-tetrasubstituted stereocenters. Stereospecific α-deprotonation of ketimines with potassium tert-butoxide gave stereodefined metalloenamine intermediates that could act as nucleophiles to attack azodicarboxylic derivatives, affording α-aminated products in high yields with excellent stereoselectivities.

Prominent Vessel Signs After Endovascular Thrombectomy Corelates with Unexplained Neurological Deterioration and is a More Reliable Imaging Predictor of Prognosis in Anterior Large Vessel Occlusion Stroke.

OBJECTIVE: Fifty percent of patients who undergo endovascular thrombectomy (EVT) for large-vessel occlusion exhibit unfavorable outcomes. The primary factor is attributed to persistent brain impairment even after successful EVT. The prominent vessel sign (PVS) on magnetic resonance susceptibility-weighted imaging reflects the territory of dysmetabolism and may facilitate an expeditious assessment for prognostication. We aimed to examine the relationship between PVS after EVT and the occurrence of early neurological deterioration (END) and 3-month outcomes. METHODS: Patients who underwent EVT and multimodal magnetic resonance imaging were included. END was defined as an increase of ≥2 in the National Institutes of Health Stroke Scale within 72 hours after EVT. Symptomatic intracranial hemorrhage, malignant edema, and surgical complications were defined as definite END, whereas the other symptoms were categorized as unexplained END (ux-END). The PVS-Alberta Stroke Program Early CT Score (ASPECTS) score was used to evaluate the asymmetric cerebral venous signal on the susceptibility-weighted imaging sequences semiquantitatively. RESULTS: A total of 116 eligible patients were included, 18 (15.5%) of whom presented with ux-END. The 72 hour National Institutes of Health Stroke Scale was strongly correlated with diffusion-weighted imaging infarct volume and PVS-ASPECTS and was significantly higher in the ux-END group (16 ± 6 vs. 5 ± 4, P = 0.001). The PVS-ASPECTS score was significantly associated with poor outcomes (odds ratio 2.551, 95% confidence interval (CI) 1.722-3.780, P＜0.001), and PVS-ASPECTS (area under the curve 0.884, 95% CI 0.815-0.953, P < 0.001) was superior to diffusion-weighted imaging infarct volume (area under the cure 0.720, 95% CI 0.620-0.820, P = 0.001) in predicting 3-month poor outcome. At the optimal cut-off of 2, the PVS-ASPECT predicted poor outcomes with a sensitivity of 89.7% and a specificity of 78.2%. CONCLUSIONS: PVS 72 hours after EVT correlated with ux-END. The PVS-ASPECTS is a more reliable predictor of stroke prognosis and provides valuable information regarding post-EVT management.

A Non-Linear Role of Hyperlipidemia on Progression of Intracranial Atherosclerotic Plaques and Acute Downstream Ischemic Events.

AIM: Intracranial atherosclerotic stenosis (ICAS) is the leading cause of ischemic stroke worldwide. Hyperlipidemia is a major contributor to atherosclerosis. However, the effect of hyperlipidemia on the evolution of intracranial atherosclerotic plaques and downstream ischemic episodes remains unclear. In this study, we aimed to assess the radiological features of ICAS plaques and to explore the relationship between hyperlipidemia and plaque progression. METHODS: We included people with ICAS (≥50% stenosis) undergoing high-resolution magnetic resonance imaging. The culprit plaque was defined as the sole, or in case of multiple stenosis, the narrowest plaque on the intracranial artery responsible for acute ischemic stroke. Demographic, clinical data, plaque features on MRI, and lipid parameters were compared between culprit and non-culprit plaques. Plaque enhancement was graded as Grade 0, 1 and 2 by comparing to the adjacent normal vessel wall and pituitary funnel after contrast enhancement on T1-weighted sequences. RESULTS: 162 patients were included (mean age 57.7±12.1 years, male 61.6%), 110 of whom were identified as culprit plaque with an ipsilateral acute stroke. High-grade enhancement was the most prominent MRI feature of the culpable plaque (Grade-2: OR 6.539, 95%CI 1.706-23.707, p=0.006). LDL cholesterol was significantly associated with overall acute ischemic stroke caused by culprit plaque. After stratification by enhancement grading LDL was independently associated with ischemic events in Grade-1 enhancement plaques (OR 6.778, 95%CI 2.122-21.649, p=0.001). In patients with Grade-2 enhancement plaques, however, LDL was not associated with ischemic event; in contrast, Neutrophil/Lymphocyte ratio was independently associated with ischemic events caused by Grade-2 enhancement plaques (OR 2.188, 95%CI 1.209-3.961, p=0.010). CONCLUSIONS: LDL was related with ischemia events in intermediate stage of intracranial atherosclerotic plaque progression, an excellent period for intensive lipid-lowering treatment. In advanced stage, inflammatory agents maybe the main contributor to ischemic events.

Nucleosome assembly protein 1 like 1 (NAP1L1) promotes cardiac fibrosis by inhibiting YAP1 ubiquitination and degradation.

Myocardial fibrosis post myocardial infarction (MI) is characterized by abnormal extracellular matrix (ECM) deposition and cardiac dysfunction could finally develop into serious heart disease, like heart failure. Lots of regulating factors involved in this pathological process have been reported while the specific mediators and underlying mechanisms remain to need to be further investigated. As part of the NAP1 family, Nucleosome assembly protein 1 like 1 (NAP1L1) is expressed in a wide variety of tissues. Here, we report that NAP1L1 is a significant regulator of cardiac fibrosis and is upregulated in ischemic cardiomyopathy patient hearts. Enhanced expression of NAP1L1 can promote cardiac fibroblasts (CFs) proliferation, migration, and differentiation into myofibroblasts. In contrast, loss of NAP1L1 decreased fibrosis-related mRNA and protein levels, inhibited the trans-differentiation, and blunted migration and proliferation of CFs after Transforming Growth Factorß1（TGF-ß1）stimulation. In vivo, NAP1L1 knockout mice enhanced cardiac function and reduced fibrosis area in response to MI stimuli. Mechanically, NAP1L1 binding to Yes-associated protein 1 (YAP1) protein influences its stability, and silencing NAP1L1 can inhibit YAP1 expression by promoting its ubiquitination and degradation in CFs. Collectively, NAP1L1 could potentially be a new therapeutic target for various cardiac disorders, including myocardial fibrosis.