Iron-Catalyzed Friedel-Crafts-type 3,5-Diacylation of Indoles.

The exploration of remote functionalization of indoles is impeded by the inherently dominant reactivity intrinsic to the pyrrole moiety. Herein, we delineate a novel strategy facilitated by Lewis acid mediation, enabling the remote C-H functionalization, which culminates in the synthesis of an array of selectively functionalized indole derivatives, encompassing 3-trifluoroacetyl and 5-benzoyl motifs, utilizing trifluoroacetic anhydride and various acyl chlorides. Notably, the protocol exhibits versatility, as epitomized by the extension of C5-acylation to alkylation and sulfonation reactions. This methodology is distinguished by its exemplary regio- and chemo-selectivity, extensive substrate scope, commendable tolerance to a diverse array of functional groups, and the employment of comparatively mild reaction conditions.

Selective CO2 Photoreduction into CH4 Triggered by the Synergy between Oxygen Vacancy and Ru Substitution under Near-Infrared Light Irradiation.

Near-infrared (NIR) light powdered CO2 photoreduction reaction is generally restricted to the separation efficiency of photogenerated carriers and the supply of active hydrogen (*H). Herein, the study reports a retrofitting hydrogenated MoO3-x (H-MoO3-x) nanosheet photocatalysts with Ru single atom substitution (Ru@H-MoO3-x) fabricated by one-step solvothermal method. Experiments together with theoretical calculations demonstrate that the synergistic effect of Ru substitution and oxygen vacancy can not only inhibit the recombination of photogenerated carriers, but also facilitate the CO2 adsorption/activation as well as the supply of *H. Compared with H-MoO3-x, the Ru@H-MoO3-x exhibit more favorable formation of *CHO in the process of *CO conversion due to the fast *H generation on electron-rich Ru sites and transfer to *CO intermediates, leading to the preferential photoreduction of CO2 to CH4 with high selectivity. The optimized Ru@H-MoO3-x exhibits a superior CO2 photoreduction activity with CH4 evolution rate of 111.6 and 39.0 µmol gcatalyst -1 under full spectrum and NIR light irradiation, respectively, which is 8.8 and 15.0 times much higher than that of H-MoO3-x. This work provides an in-depth understanding at the atomic level on the design of NIR responsive photocatalyst for achieving the goal of carbon neutrality.

Serum signature of antibodies to Toxoplasma gondii, rubella virus, and cytomegalovirus in females with bipolar disorder: A cross-sectional study.

BACKGROUND AND AIM: Immunity alterations have been observed in bipolar disorder (BD). However, whether serum positivity of antibodies to Toxoplasma gondii (T gondii), rubella, and cytomegalovirus (CMV) shared clinical relevance with BD, remains controversial. This study aimed to investigate this association. METHODS: Antibody seropositivity of IgM and IgG to T gondii, rubella virus, and CMV of females with BD and controls was extracted based on medical records from January 2018 to January 2023. Family history, type of BD, onset age, and psychotic symptom history were also collected. RESULTS: 585 individuals with BD and 800 healthy controls were involved. Individuals with BD revealed a lower positive rate of T gondii IgG in the 10-20 aged group (OR = 0.10), and a higher positive rate of rubella IgG in the 10-20 (OR = 5.44) and 20-30 aged group (OR = 3.15). BD with family history preferred a higher positive rate of T gondii IgG (OR = 24.00). Type-I BD owned a decreased positive rate of rubella IgG (OR = 0.37) and an elevated positive rate of CMV IgG (OR = 2.12) compared to type-II BD, while BD with early onset showed contrast results compared to BD without early onset (Rubella IgG, OR = 2.54; CMV IgG, OR = 0.26). BD with psychotic symptom history displayed a lower positive rate of rubella IgG (OR = 0.50). LIMITATIONS: Absence of male evidence and control of socioeconomic status and environmental exposure. CONCLUSIONS: Differential antibody seropositive rates of T gondii, rubella, and cytomegalovirus in BD were observed.

Enhancing Hi-C contact matrices for loop detection with Capricorn: a multiview diffusion model.

MOTIVATION: High-resolution Hi-C contact matrices reveal the detailed three-dimensional architecture of the genome, but high-coverage experimental Hi-C data are expensive to generate. Simultaneously, chromatin structure analyses struggle with extremely sparse contact matrices. To address this problem, computational methods to enhance low-coverage contact matrices have been developed, but existing methods are largely based on resolution enhancement methods for natural images and hence often employ models that do not distinguish between biologically meaningful contacts, such as loops and other stochastic contacts. RESULTS: We present Capricorn, a machine learning model for Hi-C resolution enhancement that incorporates small-scale chromatin features as additional views of the input Hi-C contact matrix and leverages a diffusion probability model backbone to generate a high-coverage matrix. We show that Capricorn outperforms the state of the art in a cross-cell-line setting, improving on existing methods by 17% in mean squared error and 26% in F1 score for chromatin loop identification from the generated high-coverage data. We also demonstrate that Capricorn performs well in the cross-chromosome setting and cross-chromosome, cross-cell-line setting, improving the downstream loop F1 score by 14% relative to existing methods. We further show that our multiview idea can also be used to improve several existing methods, HiCARN and HiCNN, indicating the wide applicability of this approach. Finally, we use DNA sequence to validate discovered loops and find that the fraction of CTCF-supported loops from Capricorn is similar to those identified from the high-coverage data. Capricorn is a powerful Hi-C resolution enhancement method that enables scientists to find chromatin features that cannot be identified in the low-coverage contact matrix. AVAILABILITY AND IMPLEMENTATION: Implementation of Capricorn and source code for reproducing all figures in this paper are available at https://github.com/CHNFTQ/Capricorn.

Insights into dynamic structural evolution and its sodium storage mechanisms of P2/P3 composite cathode materials for sodium-ion batteries.

Cobalt substitution for manganese sites in Na0.44MnO2 initiates a dynamic structural evolution process, yielding a composite cathode material comprising intergrown P2 and P3 phases. The novel P2/P3 composite cathode exhibits a reversible phase transition process during Na+ extraction/insertion, showcasing its attractive battery performance in sodium-ion batteries.

Construction of a pathway-level model for preeclampsia based on gene expression data.

Preeclampsia (PE) is a heterogeneous disease that seriously affects the health of mothers and fetuses. Lack of detection assays, its diagnosis and intervention are often delayed when the clinical symptoms are atypical. Using personalized pathway-based analysis and machine learning algorithms, we built a PE diagnosis model consisting of nine core pathways using multiple cohorts from the Gene Expression Omnibus database. The model showed an area under the receiver operating characteristic (AUROC) curve of 0.959 with the data from the placental tissue samples in the development cohort. In the two validation cohorts, the AUROCs were 0.898 and 0.876, respectively. The model also performed well with the maternal plasma data in another validation cohort (AUROC: 0.815). Moreover, we identified tyrosine-protein kinase Lck (LCK) as the hub gene in this model and found that LCK and pLCK proteins were downregulated in placentas from PE patients. The pathway-level model for PE can provide a novel direction to develop molecular diagnostic assay and investigate potential mechanisms of PE in future studies.

Human Amniotic Epithelial Stem Cells Alleviate Autoimmune Premature Ovarian Insufficiency in Mice by Targeting Granulosa Cells via AKT/ERK Pathways.

Autoimmune factors play an important role in premature ovarian insufficiency (POI). Human amniotic epithelial stem cells (hAESCs) have recently shown promising treatment effects on chemotherapy-induced POI. However, the therapeutic efficacy and underlying mechanisms of hAESCs in autoimmune POI remain to be investigated. In this study, we showed for the first time that intravenous transplantation of hAESCs could reside in the ovary of zona pellucida 3 peptide (pZP3) induced autoimmune POI mice model for at least 4 weeks. hAESCs could improve ovarian function and fertility, alleviate inflammation and reduce apoptosis of granulosa cells (GCs) in autoimmune POI mice. The transcriptome analysis of mice ovaries and in vitro co-cultivation experiments suggest that activation of the AKT and ERK pathways may be the key mechanism in the therapeutic effect of hAESCs. Our work provides the theoretical and experimental foundation for optimizing the administration of hAESCs, as well as the clinical application of hAESCs in autoimmune POI patients.

A Comprehensive Study on Implant Stability Quotient (ISQ) in View of Resonance Frequency and Spectrum Analysis.

PURPOSE: This experimental study investigated how well implant stability quotient (ISQ) represents resonance frequency. Benchtop experiments on standardized samples, mimicking a premolar section of a mandible, were conducted to correlate an ISQ value and a resonance frequency to synthetic bone density and an incremental insertion torque. A frequency spectrum analysis was performed to check the validity of the resonance frequency analysis (RFA). MATERIALS AND METHODS: Branemark Mk III implants with dimensions ∅4 Å~ 11.5 mm were placed in Sawbones test models of five different densities (40, 30, 40/20, 20, 15 PCF). An incremental insertion torque was recorded during implant placement. To perform stability measurements, the test models were clamped partially in a vise (unclamped volume 10 Å~ 20 Å~ 34 mm). A MultiPeg was attached onto the implants, and a Penguin RFA measured ISQ. Simultaneously, motion of the MultiPeg was monitored via a laser Doppler vibrometer and processed by a spectrum analyzer to obtain the resonance frequency. Tightness of the clamp was adjusted to vary the resonance frequency. A statistical analysis produced a linear correlation coefficient 𝑅 among the measured ISQ, resonance frequency, and incremental insertion torque. RESULTS: The resonance frequency had high correlation to the incremental insertion torque (𝑅 = 0.978), confirming the validity of using RFA for this study. Measured ISQ data were scattered and had low correlation to the resonance frequency (𝑅 = 0.214) as well as the incremental insertion torque (𝑅 = -0.386). The spectrum analysis revealed simultaneous presence of multiple resonance frequencies. CONCLUSIONS: For the designed benchtop tests, resonance frequency does indicate implant stability in view of Sawbones density and incremental insertion torque. ISQ measurements, however, do not correlate well to the resonance frequency, and may not reflect the stability when multiple resonance frequencies are present simultaneously.

Interfacial Spinel Local Interlocking Strategy Toward Structural Integrity in P3 Oxide Cathodes.

P3-layered transition oxide cathodes have garnered considerable attention owing to their high initial capacity, rapid Na+ kinetics, and less energy consumption during the synthesis process. Despite these merits, their practical application is hindered by the substantial capacity degradation resulting from unfavorable structural transformations, Mn dissolution and migration. In this study, we systematically investigated the failure mechanisms of P3 cathodes, encompassing Mn dissolution, migration, and the irreversible P3-O3' phase transition, culminating in severe structural collapse. To address these challenges, we proposed an interfacial spinel local interlocking strategy utilizing P3/spinel intergrowth oxide as a proof-of-concept material. As a result, P3/spinel intergrowth oxide cathodes demonstrated enhanced cycling performance. The effectiveness of suppressing Mn migration and maintaining local structure of interfacial spinel local interlocking strategy was validated through depth-etching X-ray photoelectron spectroscopy, X-ray absorption spectroscopy, and in situ synchrotron-based X-ray diffraction. This interfacial spinel local interlocking engineering strategy presents a promising avenue for the development of advanced cathode materials for sodium-ion batteries.

Spin-Phonon Coupling in Iron-Doped Ultrathin Bismuth Halide Perovskite Derivatives.

Spin in semiconductors facilitates magnetically controlled optoelectronic and spintronic devices. In metal halide perovskites (MHPs), doping magnetic ions is proven to be a simple and efficient approach to introducing a spin magnetic momentum. In this work, we present a facile metal ion doping protocol through the vapor-phase metal halide insertion reaction to the chemical vapor deposition (CVD)-grown ultrathin Cs3BiBr6 perovskites. The Fe-doped bismuth halide (Fe:CBBr) perovskites demonstrate that the iron spins are successfully incorporated into the lattice, as revealed by the spin-phonon coupling below the critical temperature Tc around 50 K observed through temperature-dependent Raman spectroscopy. Furthermore, the phonons exhibit significant softening under an applied magnetic field, possibly originating from magnetostriction and spin exchange interaction. The spin-phonon coupling in Fe:CBBr potentially provides an efficient way to tune the spin and lattice parameters for halide perovskite-based spintronics.

Spatially Resolved Anion Diffusion and Tunable Waveguides in Bismuth Halide Perovskites.

Bismuth halide perovskites are widely regarded as nontoxic alternatives to lead halide perovskites for optoelectronics and solar energy harvesting applications. With a tailorable composition and intriguing optical properties, bismuth halide perovskites are also promising candidates for tunable photonic devices. However, robust control of the anion composition in bismuth halide perovskites remains elusive. Here, we established chemical vapor deposition and anion exchange protocols to synthesize bismuth halide perovskite nanoflakes with controlled dimensions and variable compositions. In particular, we demonstrated the gradient bromide distribution by controlling the anion exchange and diffusion processes, which is spatially resolved by time-of-flight secondary ion mass spectrometry. Moreover, the optical waveguiding properties of bismuth halide perovskites can be modulated by flake thicknesses and anion compositions. With a unique gradient anion distribution and controllable optical properties, bismuth halide perovskites provide new possibilities for applications in optoelectronic devices and integrated photonics.

Iodine-mediated oxidative triple functionalization of indolines with azoles and diazonium salts.

We report an innovative synthetic strategy for the generation of polysubstituted indoles from indolines, aryldiazonium salts, and azoles. The methodology encompasses an electrophilic substitution reaction affording C5-indoline intermediates which undergo an iodine-mediated oxidative transformation coupled with C-H functionalization to yield the indole derivatives.

Developing an abnormal high-Na-content P2-type layered oxide cathode with near-zero-strain for high-performance sodium-ion batteries.

Layered transition metal oxides (NaxTMO2) possess attractive features such as large specific capacity, high ionic conductivity, and a scalable synthesis process, making them a promising cathode candidate for sodium-ion batteries (SIBs). However, NaxTMO2 suffer from multiple phase transitions and Na+/vacancy ordering upon Na+ insertion/extraction, which is detrimental to their electrochemical performance. Herein, we developed a novel cathode material that exhibits an abnormal P2-type structure at a stoichiometric content of Na up to 1. The cathode material delivers a reversible capacity of 108 mA h g-1 at 0.2C and 97 mA h g-1 at 2C, retaining a capacity retention of 76.15% after 200 cycles within 2.0-4.3 V. In situ diffraction studies demonstrated that this material exhibits an absolute solid-solution reaction with a low volume change of 0.8% during cycling. This near-zero-strain characteristic enables a highly stabilized crystal structure for Na+ storage, contributing to a significant improvement in battery performance. Overall, this work presents a simple yet effective approach to realizing high Na content in P2-type layered oxides, offering new opportunities for high-performance SIB cathode materials.

Associations of rumination with suicidal ideation and suicide attempts amongst individuals with major depressive disorder: A 12-month longitudinal study in China.

BACKGROUND: This study aimed to explore the longitudinal associations of rumination with suicidal ideation and suicide attempts in individuals with major depressive disorder (MDD). METHODS: Participants were derived from the Depression Cohort in China study (DCC). Those who completed at least one follow-up visit during the 12 months were included in the analysis. Dimensions of rumination including brooding and reflection were each measured using five items of the Ruminative Responses Scale. Suicidal ideation was assessed using the Beck Scale for Suicide Ideation. Suicide attempts were also assessed and all were analyzed with generalized estimating equations. RESULTS: Our final sample included 532 participants aged 18 to 59 years (mean [SD], 26.91 [6.94] years) consisting of 148 (27.8%) males and 384 (72.2%) females. After adjusting for temporal trend and potential confounders, individuals with higher levels of reflection were more likely to report suicidal ideation (AOR =1.11, 95% CI:1.01-1.22). However, no statistically significant association was found between brooding and suicidal ideation (AOR =1.06, 95% CI:0.96-1.17). Conversely, individuals with higher levels of brooding were more likely to report suicide attempts (AOR =1.13, 95% CI:1.02-1.24), while no statistically significant association was observed between reflection and suicide attempts (AOR =0.91, 95% CI:0.82-1.01). CONCLUSION: Rumination reflects a disturbance in cognitive emotional processing and manifests in different dimensions. Our findings suggest that high levels of reflection and brooding may be associated with a higher likelihood of having suicidal ideation and suicide attempts, respectively. However, it should be interpreted with caution, given that effect sizes are small.

Associations between somatic symptoms and remission of major depressive disorder: A longitudinal study in China.

Previous studies have documented negative associations between somatic symptoms and remission of major depressive disorder (MDD). However, the correlations of specific somatic symptoms with remission remain uncertain. We aimed to explore the associations between specific somatic symptoms and remission focusing on sex differences among patients with MDD. We used data from patients with MDD in the Depression Cohort in China. At baseline, total somatic symptoms were evaluated using the 28-item Somatic Symptoms Inventory and were categorized into pain, autonomic, energy, and central nervous system (CNS) symptoms. To measure remission of MDD, depressive symptoms were evaluated using the Patient Health Questionnaire-9 after 3 months of treatment. We ultimately included 634 patients. Compared with quartile 1 of total somatic symptom scores, the full-adjusted ORs (95% CIs) for remission from quartile 2 to quartile 4 were 0.52 (0.30, 0.90), 0.44 (0.23, 0.83), and 0.36 (0.17, 0.75), respectively (P-value for trend = 0.005). The restricted cubic spline showed no non-linear associations between total somatic symptoms with remission (P-value for non-linear = 0.238). Pain, autonomic, and CNS symptoms showed similar results. Sex-stratified analysis showed that total somatic symptoms, pain symptoms, and autonomic symptoms were negatively correlated with remission in females, whereas CNS symptoms were negatively associated with remission in males. Our findings indicate that specific somatic symptoms exert differential effects on remission of MDD. Therapeutic interventions that target pain, autonomic, and CNS symptoms may increase the probability of remission. Furthermore, interventions for somatic symptoms should be tailored by sex, and females deserve more attention.

Re-evaluating a historic cohort of sinonasal and skull base mucoepidermoid carcinoma: an institutional experience.

AIMS: Primary mucoepidermoid carcinomas (MECs) of the sinonasal tract and nasopharynx are rare entities that represent a diagnostic challenge, especially in biopsy samples. Herein, we present a case series of MECs of the sinonasal and skull base and its mimics to evaluate the clinicopathological and molecular characteristics in order to avoid misdiagnosis. METHODS: We reviewed the pathology records of patients diagnosed from 2014 to 2022. Thirty MECs were consecutively diagnosed during that period. RESULTS: Based on morphological and fluorescence in situ hybridization (FISH) analyses, 30 tumors originally diagnosed as MECs were separated into MAML2 fusion-positive (7 cases) and MAML2 fusion-negative groups (23 cases), in which 14 tumors were positive for the EWSR1::ATF1 fusion; these tumors were reclassified to have hyalinizing clear cell carcinoma (HCCC). The remaining nine MAML2 FISH negative cases were reconfirmed as squamous cell carcinoma (SCC, 3 cases) which showed keratinization and high Ki-67 expression; DEK::AFF2 carcinomas (2 cases), in which DEK gene rearrangement was detected by FISH; and MECs as previously described (4 cases) with typical morphological features. Including 7 MAML2 rearrangements tumors, 11 MEC cases had a male-to-female ratio of 4.5:1, and 6 tumors arose from the nasopharyngeal region, while 5 tumors arose from the sinonasal region. The prognosis of this series of salivary gland-type MECs was favorable. CONCLUSIONS: Our study confirmed that HCCC runs the risk of being misdiagnosed as MEC in the sinonasal tract and nasopharynx, particularly with biopsy specimens. Careful histological evaluation with supporting molecular testing can facilitate pathological diagnoses.

Tuning Local Atomic Structures in MoS2 Based Catalysts for Electrochemical Nitrate Reduction.

In recent years, there has been a substantial surge in the investigation of transition-metal dichalcogenides such as MoS2 as a promising electrochemical catalyst. Inspired by denitrification enzymes such as nitrate reductase and nitrite reductase, the electrochemical nitrate reduction catalyzed by MoS2 with varying local atomic structures is reported. It is demonstrated that the hydrothermally synthesized MoS2 containing sulfur vacancies behaves as promising catalysts for electrochemical denitrification. With copper doping at less than 9% atomic ratio, the selectivity of denitrification to dinitrogen in the products can be effectively improved. X-ray absorption characterizations suggest that two sulfur vacancies are associated with one copper dopant in the MoS2 skeleton. DFT calculation confirms that copper dopants replace three adjacent Mo atoms to form a trigonal defect-enriched region, introducing an exposed Mo reaction center that coordinates with Cu atom to increase N2 selectivity. Apart from the higher activity and selectivity, the Cu-doped MoS2 also demonstrates remarkably improved tolerance toward oxygen poisoning at high oxygen concentration. Finally, Cu-doped MoS2 based catalysts exhibit very low specific energy consumption during the electrochemical denitrification process, paving the way for potential scale-up operations.

Identifying novel proteins for suicide attempt by integrating proteomes from brain and blood with genome-wide association data.

Genome-wide association studies (GWASs) have identified risk loci for suicide attempt (SA), but deciphering how they confer risk for SA remains largely unknown. This study aims to identify the key proteins and gain insights into SA pathogenesis. We integrated data from the brain proteome (N = 376) and blood proteome (N = 35,559) and combined it with the largest SA GWAS summary statistics to date (N = 518,612). A comprehensive set of methods was employed, including Mendelian randomization (MR), Steiger filtering, Bayesian colocalization, proteome­wide association studies (PWAS), transcript-levels, cell-type specificity, correlation, and protein-protein interaction (PPI) network analysis. Validation was performed using other protein datasets and the SA dataset from FinnGen study. We identified ten proteins (GLRX5, GMPPB, B3GALTL, FUCA2, TTLL12, ADCK1, MMAA, HIBADH, ACP1, DOC2A) associated with SA in brain proteomics. GLRX5, GMPPB, and FUCA2 showed strong colocalization evidence and were supported by PWAS and transcript-level analysis, and were predominantly expressed in glutamatergic neuronal cells. In blood proteomics, one significant protein (PEAR1) and three near-significant proteins (NDE1, EVA1C, B4GALT2) were identified, but lacked colocalization evidence. Moreover, despite the limited correlation between the same protein in brain and blood, the PPI network analysis provided new insights into the interaction between brain and blood in SA. Furthermore, GLRX5 was associated with the GSTP1, the target of Clozapine. The comprehensive analysis provides strong evidence supporting a causal association between three genetically determined brain proteins (GLRX5, GMPPB, and FUCA2) with SA. These findings offer valuable insights into SA's underlying mechanisms and potential therapeutic approaches.

Pathogenic Somatic Mutation of DICER1 and Clinicopathological Features in Nasal Chondromesenchymal Hamartomas: A Series of Nine Cases.

Nasal chondromesenchymal hamartoma (NCMH) is a rare benign polypoid mesenchymal tumor arising in the nasal cavity and/or paranasal sinuses. Recognizing these sporadic, rare lesions is crucial, as surgical complete removal of the mass is the common treatment approach. This retrospective study analyzed the demographics, symptoms, and imaging data of 9 patients diagnosed with NCMH between January 2017 and June 2023, possibly representing the largest single-center adult case cohort to date. Diagnostic techniques included nasal endoscopy, CT/MRI scan, immunohistological studies, and morphologic comparisons. Pathologic specimens were subjected to Sanger sequencing of exons 24 and 25 of DICER1. The average age of 9 cases was 24.4 years, and the oldest was 55 years. Four of the patients were children, ranging from 1 year old to 11 years old, with an average of 4.5 years. Nasal congestion is the most common registered symptom. Endoscopic findings showed that most patients had smooth pink neoplasms or polypoid masses in the nasal meatus. Radiologic scanning revealed soft-tissue density masses that occupied the nasal cavity. Histologically, the characteristic structure of NCMHs is immature cellular cartilage nodules and mature cartilage nodules distributed in a loose mucoid matrix. Five of the 9 patients had somatic DICER1 missense mutations. Four of the patients with DICER1-mutated NCMH exhibited a p.E1813 missense hotspot mutation. We also report a case of a rare p.P1836H missense mutation. The detected DICER1 somatic mutations provide compelling evidence of an association with the DICER1 tumor family. We emphasize the importance of pathologic consultation and the need for pathologists to accumulate experience in NCMH diagnosis to avoid misdiagnosis.

FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease. Although HCM has been reported to be associated with many variants of genes involved in sarcomeric protein biomechanics, pathogenic genes have not been identified in patients with partial HCM. FARS2 (the mitochondrial phenylalanyl-tRNA synthetase), a type of mitochondrial aminoacyl-tRNA synthetase, plays a role in the mitochondrial translation machinery. Several variants of FARS2 have been suggested to cause neurological disorders; however, FARS2-associated diseases involving other organs have not been reported. We identified FARS2 as a potential novel pathogenic gene in cardiomyopathy and investigated its effects on mitochondrial homeostasis and the cardiomyopathy phenotype. METHODS: FARS2 variants in patients with HCM were identified using whole-exome sequencing, Sanger sequencing, molecular docking analyses, and cell model investigation. Fars2 conditional mutant (p.R415L) or knockout mice, fars2-knockdown zebrafish, and Fars2-knockdown neonatal rat ventricular myocytes were engineered to construct FARS2 deficiency models both in vivo and in vitro. The effects of FARS2 and its role in mitochondrial homeostasis were subsequently evaluated using RNA sequencing and mitochondrial functional analyses. Myocardial tissues from patients were used for further verification. RESULTS: We identified 7 unreported FARS2 variants in patients with HCM. Heart-specific Fars2-deficient mice presented cardiac hypertrophy, left ventricular dilation, progressive heart failure accompanied by myocardial and mitochondrial dysfunction, and a short life span. Heterozygous cardiac-specific Fars2R415L mice displayed a tendency to cardiac hypertrophy at age 4 weeks, accompanied by myocardial dysfunction. In addition, fars2-knockdown zebrafish presented pericardial edema and heart failure. FARS2 deficiency impaired mitochondrial homeostasis by directly blocking the aminoacylation of mt-tRNAPhe and inhibiting the synthesis of mitochondrial proteins, ultimately contributing to an imbalanced mitochondrial quality control system by accelerating mitochondrial hyperfragmentation and disrupting mitochondrion-related autophagy. Interfering with the mitochondrial quality control system using adeno-associated virus 9 or specific inhibitors mitigated the cardiac and mitochondrial dysfunction triggered by FARS2 deficiency by restoring mitochondrial homeostasis. CONCLUSIONS: Our findings unveil the previously unrecognized role of FARS2 in heart and mitochondrial homeostasis. This study may provide new insights into the molecular diagnosis and prevention of heritable cardiomyopathy as well as therapeutic options for FARS2-associated cardiomyopathy.