DHXT1, a Virulence Factor of Dactylellina haptotyla, Regulates Pathogenicity by Participating in Trap Formation and Metabolite Synthesis.

The capsule-associated protein 10 gene (CAP10) is indispensable due to its involvement in pod formation and virulence maintenance in Cryptococcus neoformans. The function of the CAP10 gene in nematode-predatory fungi remains unreported. As a typical nematode-trapping fungus, Dactylellina haptotyla efficiently captures nematodes using adhesive knobs, which has potential applications in the biological control of plant-parasitic nematodes. In this study, we investigated the function of DHXT1 (a CAP10 homologous protein) in D. haptotyla-nematode interactions based on the disruption and overexpression of DHXT1, phenotypic analysis and metabolomic analysis. As a result, it was shown that the disruption of the DHXT1 gene causes a marked decrease in the number of adhesive knobs, and on the contrary, the overexpression of the DHXT1 gene causes a substantial increase in the number of adhesive knobs. Interestingly, the variety of metabolites increased with the disruption of the DHXT1 and decreased with the overexpression of the DHXT1 gene. The results suggest that DHXT1 effects pathogenicity through its involvement in adhesive knobs' formation and metabolite synthesis and serves as a key virulence factor in D. haptotyla.

Short-term OS as a surrogate endpoint for 5-year OS in nasopharyngeal carcinoma in non-endemic area.

PURPOSE: To address this evidence gap and validate short-term OS at less than 5 years as a reliable surrogate endpoint for 5-year OS. METHODS: We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database, focusing on non-metastatic NPC patients diagnosed between 2010 and 2015. Patients were categorized into radiotherapy and chemoradiotherapy groups. RESULTS: This retrospective study examined 2,047 non-metastatic NPC patients. Among them, 217 received radiotherapy, and 1,830 received chemoradiotherapy. Our analysis results indicated that the 4-year OS may serve as a reliable surrogate endpoint for patients with AJCC clinical stage I (80 vs. 78%, P = 0.250), regardless of the treatment received. Specifically, in the radiotherapy group, patients with stage I, T0-T1, and N0 NPC showed similar OS rates at 4 and 5 years (83 vs. 82%, P = 1.000; 78 vs. 76%, P = 0.250; 78 vs. 77%, P = 0.500, respectively). Similarly, patients with stage II-IV, T2-T4, and N1-3 NPC showed no significant difference in OS rates between 3 and 5 years (57 vs. 51%, P = 0.063; 52 vs. 46%, P = 0.250; 54 vs. 46%, P = 0.125, respectively) in the radiotherapy group. In the chemoradiotherapy group, only the 3-year OS rate did not significantly differ from that at 5 years in stage I patients (79vs. 72%, P = 0.063). CONCLUSIONS: Our study suggests that short-term surrogate endpoints may be valuable for evaluating 5-year OS outcomes in NPC patients in non-endemic areas.

The alleviatory effects of koumine on MSU-induced gouty arthritis via the TLR4/NF-κB/NLRP3 pathway.

The aim of this study was to validate the preventive effects of koumine (KM), a monoterpene indole alkaloid, on gouty arthritis (GA) and to explore its possible mechanisms. C57BL/6 mice were intraperitoneally administered KM (0.8, 2.4 or 7.2 mg/kg), colchicine (3.0 mg/kg) or sterile saline. One hour later, a monosodium urate (MSU) suspension was injected into the right hind paws of the mice to establish an acute gout model. Inflammation symptoms were evaluated at 0, 3, 6, 12 and 24 h, and the mechanical withdrawal threshold was evaluated at 0, 6 and 24 h. After 24 h, the mice were euthanized, and the joint tissue, kidney and blood were collected for subsequent experiments. Histological examination and antioxidant enzyme, kidney index and serum uric acid (UA) measurements were taken. The expression levels of the signalling pathway components were determined. KM effectively alleviated the symptoms of redness, swelling and pain; counteracted inflammatory cell infiltration; and increased antioxidant enzyme levels, reduced kidney index and serum UA levels through regulating UA excretion in MSU-induced mice. The expression of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB)/nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) signalling pathway proteins and mRNA were reduced in the KM group. These results suggest that KM may be effective in alleviating GA through the TLR4/NF-κB/NLRP3 pathway.

GT-CAM: Game Theory based Class Activation Map for GCN.

Graph Convolutional Networks (GCN) have shown outstanding performance in skeleton-based behavior recognition. However, their opacity hampers further development. Researches on the explainability of deep learning have provided solutions to this issue, with Class Activation Map (CAM) algorithms being a class of explainable methods. However, existing CAM algorithms applies to GCN often independently compute the contribution of individual nodes, overlooking the interactions between nodes in the skeleton. Therefore, we propose a game theory based class activation map for GCN (GT-CAM). Firstly, GT-CAM integrates Shapley values with gradient weights to calculate node importance, producing an activation map that highlights the critical role of nodes in decision-making. It also reveals the cooperative dynamics between nodes or local subgraphs for a more comprehensive explanation. Secondly, to reduce the computational burden of Shapley values, we propose a method for calculating Shapley values of node coalitions. Lastly, to evaluate the rationality of coalition partitioning, we propose a rationality evaluation method based on bipartite game interaction and cooperative game theory. Additionally, we introduce an efficient calculation method for the coalition rationality coefficient based on the Monte Carlo method. Experimental results demonstrate that GT-CAM outperforms other competitive interpretation methods in visualization and quantitative analysis.

Computer-aided molecular design and optimization of potent inhibitors disrupting APC‒Asef interaction.

Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide. At initial diagnosis, approximately 20% of patients are diagnosed with metastatic CRC (mCRC). Although the APC‒Asef interaction is a well-established target for mCRC therapy, the discovery and development of effective and safe drugs for mCRC patients remains an urgent and challenging endeavor. In this study, we identified a novel structural scaffold based on MAI inhibitors, the first-in-class APC‒Asef inhibitors we reported previously. ONIOM model-driven optimizations of the N-terminal cap and experimental evaluations of inhibitory activity were performed, and 24-fold greater potency was obtained with the best inhibitor compared to the parental compound. In addition, the cocrystal structure validated that the two-layer π‒π stacking interactions were essential for inhibitor stabilization in the bound state. Furthermore, in vitro and in vivo studies have demonstrated that novel inhibitors suppressed lung metastasis in CRC by disrupting the APC‒Asef interaction. These results provide an intrinsic structural basis to further explore drug-like molecules for APC‒Asef-mediated CRC therapy.

Development of a diagnostic algorithm to ascertain malignant pleural effusion utilizing clinical indicators and serum metal concentrations.

Background: Malignant pleural effusion (MPE) is prevalent among cancer patients, indicating pleural metastasis and predicting poor prognosis. However, accurately identifying MPE in clinical settings is challenging. The aim of this study was to establish an innovative nomogram-derived model based on clinical indicators and serum metal ion levels to identify MPE. Methods: From July 2020 to May 2022, 428 patients diagnosed with pleural effusion (PE) were consecutively recruited. Comprehensive demographic details, clinical symptoms, imaging data, pathological information, and laboratory results, including serum metal ion levels, were systematically collected. The nomogram was created by incorporating the most significant predictors identified through LASSO and multivariate logistic regression analysis. The predictors were assigned weighted points based on their respective regression coefficients, allowing for the calculation of a total score that corresponds to the probability of MPE. Internal validation using bootstrapping techniques assessed the nomogram's performance, including calibration, discrimination, and clinical applicability. Results: Seven key variables were identified using LASSO regression and multiple regression analysis, including dyspnea, fever, X-ray/CT compatible with malignancy, pleural carcinoembryonic antigen(pCEA), serum neuron-specific enolase(sNSE), serum carcinoembryonic antigen(sCEA), and pleural lactate dehydrogenase(pLDH). Internal validation underscored the superior performance of our model (AUC=0.940). Decision curve analysis (DCA) analysis demonstrated substantial net benefit across a probability threshold range > 1%. Additionally, serum calcium and copper levels were significantly higher, while serum zinc levels were significantly lower in MPE patients compared to benign pleural effusion (BPE) patients. Conclusion: This study effectively developed a user-friendly and reliable MPE identification model incorporating seven markers, aiding in the classification of PE subtypes in clinical settings. Furthermore, our study highlights the clinical value of serum metal ions in distinguishing malignant pleural effusion from BPE. This significant advancement provides essential tools for physicians to accurately diagnose and treat patients with MPE.

Heterogeneous metabolic changes of brown and white adipose tissues are associated with metabolic adaptations in periparturient mice.

Pregnancy requires metabolic adaptations in order to meet support fetal growth with nutrient availability. In this study, the influence of pregnancy on metabolically active organs (adipose tissues in particular) was investigated. Our results showed that maternal weight and adipose mass presented dynamic remodeling in the periparturient mice. Meanwhile, pregnancy mice displayed obvious glucose intolerance and insulin resistance in late pregnancy as compared to non-pregnancy, which were partially reversed at parturition. Further analysis revealed that different fat depots exhibited site-specific adaptions of morphology and functionality as pregnancy advanced. Brown and inguinal white adipose tissue (BAT and IngWAT) exhibited obviously decreased thermogenic activity; by contrast, gonadal white adipose tissue (GonWAT) displayed remarkably increased lipid mobilization. Notably, we found that mammary gland differentiation was enhanced in IngWAT, followed by BAT, but not in GonWAT. These result indicated that brown and white adipose tissues might synergistically play a crucial role in maintaining the maxicum of energy supply for mother and fetus, which facilitates the mammary duct luminal epithelium development as well as the growth and development of fetus. Accompanied with adipose adaptation, however, our results revealed that the liver and pancreas also displayed significant metabolic adaptability, which together tended to trigger the risk of maternal metabolic diseases. Importantly, pregnancy-dependent obesity in our mice model resembled the disturbed metabolic phenotypes of pregnant women such as hyperglyceridemia and hypercholesterolemia. Our findings in this study could provide valuable clues for better understanding the underlying mechanisms of metabolic maladaptation, and facilitate the development of the prevention and treatment of metabolic diseases.

Efficient Sorting of Semiconducting Single-Walled Carbon Nanotubes in Bio-Renewable Solvents Through Main-Chain Engineering of Conjugated Polymers.

Conjugated polymer sorting is recognized as an efficient and scalable method for the selective extraction of semiconducting single-walled carbon nanotubes (s-SWCNTs). However, this process typically requires the use of nonpolar and aromatic solvents as the dispersion medium, which are petroleum-based and carry significant production hazards. Moreover, there is still potential for improving the efficiency of batch purification. Here, this study presents fluorene-based conjugated polymer that integrates diamines containing ethylene glycol chains (ODA) as linkers within the main chain, to effectively extract s-SWCNTs in bio-renewable solvents. The introduction of ODA segments enhances the solubility in bio-renewable solvents, facilitating effective wrapping of s-SWCNTs in polar environments. Additionally, the ODA within the main chain enhances affinity to s-SWCNTs, thereby contributing to increased yields and purity. The polymer achieves a high sorting yield of 55% and a purity of 99.6% in dispersion of s-SWCNTs in 2-Methyltetrahydrofuran. Thin-film transistor arrays fabricated with sorted s-SWCNTs solution through slot-die coating exhibit average charge carrier mobilities of 20-23 cm2 V⁻¹ s⁻¹ and high on/off current ratios exceeding 105 together with high spatial uniformity. This study highlights the viability of bio-renewable solvents in the sorting process, paving the way for the eco-friendly approach to the purification of SWCNTs.

Association of metals with early postnatal gut microbiota among infants admitted to the neonatal intensive care unit.

The gut microbiota is closely related to infant health. However, the impact of environmental factors on the gut microbiota has not been widely investigated, particularly in vulnerable populations such as infants admitted to the neonatal intensive care unit (NICU). This study investigated the association between exposure to 12 metals and the composition of the gut microbiota in infants admitted to the NICU. Metal concentrations were determined in serum samples obtained from 107 infants admitted to the NICU at Hunan Children's hospital, China. Gut microbiota data were derived from 16S rRNA sequencing using stool samples. Generalized linear regression (GLR) models and Bayesian kernel machine regression (BKMR) analyses were used to estimate the associations between metals and both alpha-diversity indices and bacterial taxa. The GLR models showed that tin correlated negatively with the Shannon index (ß = -0.55, 95% conficence interval [CI]: -0.79, -0.30, PFDR< 0.001) and positively with the Simpson index (ß = 0.26, 95% CI: 0.13, 0.39, PFDR< 0.001). The BKMR analysis yielded similar results, showing that tin had the largest posterior inclusion probability for both the Shannon (0.986) and the Simpson (0.796) indices. Tin, cadmium, mercury, lead, and thallium were associated with changes in one or more taxa at the genus level. The BKMR analysis also revealed a negative correlation between metal mixtures and Clostridium_sensu_stricto, and tin contibuted mostly to the negative correlation. Early postnatal exposure to metals were associated with differences in the microbiome among infants admitted to the NICU. However, as the study was cross-sectional, these relationships must be confirmed in further studies.

Laser-assisted manipulation of Volta potential pattern on the TC4 surface for improved hBMSCs osteogenesis.

The Ti6Al4V (TC4) alloy, a prevalent biomedical material in orthopedics, still faces limitation of the insufficient osseointegration. To improve the bioactivity of TC4, introducing the electric environment onto the TC4 surface may be an effective way in the view of the necessity of endogenous electric microenvironment in bone regeneration. Herein, a Volta potential pattern was engendered on the TC4 surface via parallel laser patterning, so as to promote the osteogenic differentiation of cells. A 15 W laser successfully transformed the original α + ß dual phase towards radially distributed lath-like martensite phase in the laser treated region. The atomic lattice distortion between the heterogeneous microstructures of the laser treated and untreated regions leads to a significant Volta potential fluctuation on the TC4 surface. The Volta potential pattern as well as the laser-engraved microgrooves respectively induced mutually orthogonal cell alignments. The hBMSCs osteogenic differentiation was significantly enhanced on the laser treated TC4 surfaces in comparison to the surface without the laser treatment. Moreover, a drastic Volta potential gradient on the TC4 surface (treated with 15 W power and 400 µm interval) resulted in the most pronounced osteogenic differentiation tendency compared to other groups. Modulating the electric environment on the TC4 surface by manipulating the phase transformation may provide an effective way in evoking favorable cell response of bone regeneration, thereby improving the bioactivity of TC4 implant.

T1-Weighted Imaging-Based Hippocampal Radiomics in the Diagnosis of Alzheimer's Disease.

RATIONALE AND OBJECTIVES: To investigate the potential of T1-weighted imaging (T1WI)-based hippocampal radiomics as imaging markers for the diagnosis of Alzheimer's disease (AD) and their efficacy in discriminating between mild cognitive impairment (MCI) and dementia in AD. METHODS: A total of 126 AD patients underwent T1WI-based magnetic resonance imaging (MRI) examinations, along with 108 age-sex-matched healthy controls (HC). This was a retrospective, single-center study conducted from November 2021 to February 2023. AD patients were categorized into two groups based on disease progression and cognitive function: AD-MCI and dementia (AD-D). T1WI-based radiomics features of the bilateral hippocampi were extracted. To diagnose AD and differentiate between AD-MCI and AD-D, predictive models were developed using random forest (RF), logistic regression (LR), and support vector machine (SVM). We compared radiomics features between the AD and HC groups, as well as within the subgroups of AD-MCI and AD-D. Area under the curve (AUC), accuracy, sensitivity, and specificity were all used to assess model performance. Furthermore, correlations between radiomics features and Mini-Mental State Examination (MMSE) scores, tau protein phosphorylated at threonine 181 (P-tau-181), and amyloid ß peptide1-42 (Aß1-42) were analyzed. RESULTS: The RF model demonstrated superior performance in distinguishing AD from HC (AUC=0.961, accuracy=90.8%, sensitivity=90.7%, specificity=90.9%) and in identifying AD-MCI and AD-D (AUC=0.875, accuracy=80.7%, sensitivity=87.2%, specificity=73.2%) compared to the other models. Additionally, radiomics features were correlated with MMSE scores, P-tau-181, and Aß1-42 levels in AD. CONCLUSION: T1WI-based hippocampal radiomics features are valuable for diagnosing AD and identifying AD-MCI and AD-D.

Diagnostic potential of TSH to HDL cholesterol ratio in vulnerable carotid plaque identification.

Objective: This study aimed to investigate the predictive value of the thyroid-stimulating hormone to high-density lipoprotein cholesterol ratio (THR) in identifying specific vulnerable carotid artery plaques. Methods: In this retrospective analysis, we included 76 patients with carotid plaques who met the criteria for admission to Zhejiang Hospital from July 2019 to June 2021. High-resolution magnetic resonance imaging (HRMRI) and the MRI-PlaqueView vascular plaque imaging diagnostic system were utilized to analyze carotid artery images for the identification of specific plaque components, including the lipid core (LC), fibrous cap (FC), and intraplaque hemorrhage (IPH), and recording of the area percentage of LC and IPH, as well as the thickness of FC. Patients were categorized into stable plaque and vulnerable plaque groups based on diagnostic criteria for vulnerable plaques derived from imaging. Plaques were categorized based on meeting one of the following consensus criteria for vulnerability: lipid core area over 40% of total plaque area, fibrous cap thickness less than 65 um, or the presence of intraplaque hemorrhage. Plaques meeting the above criteria were designated as the LC-associated vulnerable plaque group, the IPH-associated group, and the FC-associated group. Multivariate logistic regression was employed to analyze the factors influencing carotid vulnerable plaques and specific vulnerable plaque components. Receiver operating characteristic (ROC) curves were used to assess the predictive value of serological indices for vulnerable carotid plaques. Results: We found that THR (OR = 1.976; 95% CI = 1.094-3.570; p = 0.024) and TSH (OR = 1.939, 95% CI = 1.122-3.350, p = 0.018) contributed to the formation of vulnerable carotid plaques. THR exhibited an area under the curve (AUC) of 0.704 (95% CI = 0.588-0.803) (p = 0.003), and the AUC for TSH was 0.681 (95% CI = 0.564-0.783) (p = 0.008). THR was identified as an independent predictor of LC-associated vulnerable plaques (OR = 2.117, 95% CI = 1.064-4.212, p = 0.033), yielding an AUC of 0.815. THR also demonstrated diagnostic efficacy for LC-associated vulnerable plaques. Conclusion: This study substantiated that THR and TSH have predictive value for identifying vulnerable carotid plaques, with THR proving to be a more effective diagnostic indicator than TSH. THR also exhibited predictive value and specificity in the context of LC-associated vulnerable plaques. These findings suggest that THR may be a promising clinical indicator, outperforming TSH in detecting specific vulnerable carotid plaques.

Interfacial Super-Assembly of Vacancy Engineered Ultrathin-Nanosheets Toward Nanochannels for Smart Ion Transport and Salinity Gradient Power Conversion.

Ion-selective nanochannel membranes assembled from two-dimensional (2D) nanosheets hold immense promise for power conversion using salinity gradient. However, they face challenges stemming from insufficient surface charge density, which impairs both permselectivity and durability. Herein, we present a novel vacancy-engineered, oxygen-deficient NiCo layered double hydroxide (NiCoLDH)/cellulose nanofibers-wrapped carbon nanotubes (VOLDH/CNF-CNT) composite membrane. This membrane, featuring abundant angstrom-scale, cation-selective nanochannels, is designed and fabricated through a synergistic combination of vacancy engineering and interfacial super-assembly. The composite membrane shows interlayer free-spacing of ~3.62 Å, which validates the membrane size exclusion selectivity. This strategy, validated by DFT calculations and experimental data, improves hydrophilicity and surface charge density, leading to the strong interaction with K+ ions to benefit the low ion transport resistance and exceptional charge selectivity. When employed in an artificial river water|seawater salinity gradient power generator, it delivers a high-power density of 5.35 W/m2 with long-term durability (20,000s), which is almost 400 % higher than that of the pristine NiCoLDH membrane. Furthermore, it displays both pH- and temperature-sensitive ion transport behavior, offering additional opportunities for optimization. This work establishes a basis for high-performance salinity gradient power conversion and underscores the potential of vacancy engineering and super-assembly in customizing 2D nanomaterials for diverse advanced nanofluidic energy devices.

Haplotype-resolved genome of Prunus zhengheensis provides insight into its evolution and low temperature adaptation in apricot.

Prunus zhengheensis, an extremely rare population of apricots, originated in warm South-East China and is an excellent material for genetic breeding. However, most apricots and two related species (P. sibirica, P. mandshurica) are found in the cold northern regions in China and the mechanism of their distribution is still unclear. In addition, the classification status of P. zhengheensis is controversial. Thus, we generated a high-quality haplotype-resolved genome for P. zhengheensis, exploring key genetic variations in its adaptation and the causes of phylogenetic incongruence. We found extensive phylogenetic discordances between the nuclear and organelle phylogenies of P. zhengheensis, which could be explained by incomplete lineage sorting. A 242.22-Mb pan-genome of the Armeniaca section was developed with 13 chromosomal genomes. Importantly, we identified a 566-bp insertion in the promoter of the HSFA1d gene in apricot and showed that the activity of the HSFA1d promoter increased under low temperatures. In addition, HSFA1d overexpression in Arabidopsis thaliana indicated that HSFA1d positively regulated plant growth under chilling. Therefore, we hypothesized that the insertion in the promoter of HSFA1d in apricot improved its low-temperature adaptation, allowing it to thrive in relatively cold locations. The findings help explain the weather adaptability of Armeniaca plants.

A novel multidisciplinary machine learning approach based on clinical, imaging, colonoscopy, and pathology features for distinguishing intestinal tuberculosis from Crohn's disease.

OBJECTIVES: Differentiating intestinal tuberculosis (ITB) from Crohn's disease (CD) remains a diagnostic dilemma. Misdiagnosis carries potential grave implications. We aim to establish a multidisciplinary-based model using machine learning approach for distinguishing ITB from CD. METHODS: Eighty-two patients including 25 patients with ITB and 57 patients with CD were retrospectively recruited (54 in training cohort and 28 in testing cohort). The region of interest (ROI) for the lesion was delineated on magnetic resonance enterography (MRE) and colonoscopy images. Radiomic features were extracted by least absolute shrinkage and selection operator regression. Pathological feature was extracted automatically by deep-learning method. Clinical features were filtered by logistic regression analysis. Diagnostic performance was evaluated by receiver operating characteristic (ROC) curve and decision curve analysis (DCA). Delong's test was applied to compare the efficiency between the multidisciplinary-based model and the other four single-disciplinary-based models. RESULTS: The radiomics model based on MRE features yielded an AUC of 0.87 (95% confidence interval [CI] 0.68-0.96) on the test data set, which was similar to the clinical model (AUC, 0.90 [95% CI 0.71-0.98]) and higher than the colonoscopy radiomics model (AUC, 0.68 [95% CI 0.48-0.84]) and pathology deep-learning model (AUC, 0.70 [95% CI 0.49-0.85]). Multidisciplinary model, integrating 3 clinical, 21 MRE radiomic, 5 colonoscopy radiomic, and 4 pathology deep-learning features, could significantly improve the diagnostic performance (AUC of 0.94, 95% CI 0.78-1.00) on the bases of single-disciplinary-based models. DCA confirmed the clinical utility. CONCLUSIONS: Multidisciplinary-based model integrating clinical, MRE, colonoscopy, and pathology features was useful in distinguishing ITB from CD.

Exosome-loaded hydrogels for craniofacial bone tissue regeneration.

It is common for maladies and trauma to cause significant bone deterioration in the craniofacial bone, which can cause patients to experience complications with their appearance and their ability to function. Regarding grafting procedures' complications and disadvantages, the newly emerging field of tissue regeneration has shown promise. Tissue -engineered technologies and their applications in the craniofacial region are increasingly gaining prominence with limited postoperative risk and cost. MSCs-derived exosomes are widely applied in bone tissue engineering (BTE) to provide cell-free therapies since they not only do not cause immunological rejection in the same way that cells do, but they can also perform a cell-like role. Additionally, the hydrogel system is a family of multipurpose platforms made of cross-linked polymers with considerable water content, outstanding biocompatibility, and tunable physiochemical properties for the efficient delivery of commodities. Therefore, the promising exosome-loaded hydrogels can be designed for craniofacial bone regeneration. This review lists the packaging techniques for exosomes and hydrogel and discusses the development of a biocompatible hydrogel system and its potential for exosome continuous delivery for craniofacial bone healing.

Allele-Specific Suppression of Variant MHC With High-Precision RNA Nuclease CRISPR-Cas13d Prevents Hypertrophic Cardiomyopathy.

BACKGROUND: Familial hypertrophic cardiomyopathy has severe clinical complications of heart failure, arrhythmia, and sudden cardiac death. Heterozygous single nucleotide variants (SNVs) of sarcomere genes such as MYH7 are the leading cause of this type of disease. CRISPR-Cas13 (clustered regularly interspaced short palindromic repeats and their associated protein 13) is an emerging gene therapy approach for treating genetic disorders, but its therapeutic potential in genetic cardiomyopathy remains unexplored. METHODS: We developed a sensitive allelic point mutation reporter system to screen the mutagenic variants of Cas13d. On the basis of Cas13d homology structure, we rationally designed a series of Cas13d variants and obtained a high-precision Cas13d variant (hpCas13d) that specifically cleaves the MYH7 variant RNAs containing 1 allelic SNV. We validated the high precision and low collateral cleavage activity of hpCas13d through various in vitro assays. We generated 2 HCM mouse models bearing distinct MYH7 SNVs and used adenovirus-associated virus serotype 9 to deliver hpCas13d specifically to the cardiomyocytes. We performed a large-scale library screening to assess the potency of hpCas13d in resolving 45 human MYH7 allelic pathogenic SNVs. RESULTS: Wild-type Cas13d cannot distinguish and specifically cleave the heterozygous MYH7 allele with SNV. hpCas13d, with 3 amino acid substitutions, had minimized collateral RNase activity and was able to resolve various human MYH7 pathological sequence variations that cause hypertrophic cardiomyopathy. In vivo application of hpCas13d to 2 hypertrophic cardiomyopathy models caused by distinct human MYH7 analogous sequence variations specifically suppressed the altered allele and prevented cardiac hypertrophy. CONCLUSIONS: Our study unveils the great potential of CRISPR-Cas nucleases with high precision in treating inheritable cardiomyopathy and opens a new avenue for therapeutic management of inherited cardiac diseases.