Genetic identification of familial hypercholesterolemia within whole genome sequences in 6820 newborns.

Familial hypercholesterolemia (FH) is defined as a monogenic disease, characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels. FH remains underdiagnosed and undertreated in Chinese. We whole-genome sequenced 6820 newborns from Qingdao of China to investigate the FH-related gene (LDLR, APOB, PCSK9) mutation types, carrier ratio and genotype-phenotype correlation. In this study, the prevalence of FH in Qingdao of China was 0.47% (95% CI: 0.32%-0.66%). The plasma lipid levels of FH-related gene mutation carriers begin to increase as early as infant. T-CHO and LDL-C of FH infants was higher by 48.1% (p < 0.001) and 42.9% (p < 0.001) relative to non-FH infants. A total of 22 FH infants and their parent participate in further studies. The results indicated that FH infant parent noncarriers have the normal plasma lipid level, while T-CHO and LDL-C increased in FH infants and FH infant parent carriers, but no difference between the groups. This highlights the importance of genetic factors. In conclusion, the spectrum of FH-causing mutations in the newborns of Qingdao, China was described for the first time. These data can serve as a considerable dataset for next-generation sequencing analysis of the Chinese population with FH and potentially helping reform regional policies for early detection and prevention of FH.

Prediction of coronary artery lesions in children with Kawasaki syndrome based on machine learning.

OBJECTIVE: Kawasaki syndrome (KS) is an acute vasculitis that affects children < 5 years of age and leads to coronary artery lesions (CAL) in about 20-25% of untreated cases. Machine learning (ML) is a branch of artificial intelligence (AI) that integrates complex data sets on a large scale and uses huge data to predict future events. The purpose of the present study was to use ML to present the model for early risk assessment of CAL in children with KS by different algorithms. METHODS: A total of 158 children were enrolled from Women and Children's Hospital, Qingdao University, and divided into 70-30% as the training sets and the test sets for modeling and validation studies. There are several classifiers are constructed for models including the random forest (RF), the logistic regression (LR), and the eXtreme Gradient Boosting (XGBoost). Data preprocessing is analyzed before applying the classifiers to modeling. To avoid the problem of overfitting, the 5-fold cross validation method was used throughout all the data. RESULTS: The area under the curve (AUC) of the RF model was 0.925 according to the validation of the test set. The average accuracy was 0.930 (95% CI, 0.905 to 0.956). The AUC of the LG model was 0.888 and the average accuracy was 0.893 (95% CI, 0,837 to 0.950). The AUC of the XGBoost model was 0.879 and the average accuracy was 0.935 (95% CI, 0.891 to 0.980). CONCLUSION: The RF algorithm was used in the present study to construct a prediction model for CAL effectively, with an accuracy of 0.930 and AUC of 0.925. The novel model established by ML may help guide clinicians in the initial decision to make a more aggressive initial anti-inflammatory therapy. Due to the limitations of external validation and regional population characteristics, additional research is required to initiate a further application in the clinic.

Favorable Loci Identified for Stripe Rust Resistance in Chinese Winter Wheat Accessions via Genome-Wide Association Study.

Stripe rust (or yellow rust), caused by Puccinia striiformis f. sp. tritici (Pst), is one of the most devastating diseases of wheat worldwide. Currently, the utilization of resistant cultivars is the most viable way to reduce yield losses. In this study, a panel of 188 wheat accessions from China was evaluated for stripe rust resistance, and genome-wide association studies were performed using high-quality Diversity Arrays Technology markers. According to the phenotype and genotype data, a total of 26 significant marker-trait associations were identified, representing 18 quantitative trait loci (QTLs) on chromosomes 1B, 2A, 2B, 3A, 3B, 5A, 5B, 6B, 7B, and 7D. Of the 18 QTLs, almost all were associated with adult plant resistance (APR) except QYr.nwsuaf-6B.2, which was associated with all-stage resistance (also known as seedling resistance). Three of the 18 QTLs were mapped far from previously identified Pst resistance genes and QTLs and were considered potentially new loci. The other 15 QTLs were mapped close to known resistance genes and QTLs. Subsequent haplotype analysis for QYr.nwsuaf-2A and QYr.nwsuaf-7B.3 revealed the degrees of resistance of the panel in the APR stage. In summary, the favorable alleles identified in this study may be useful in breeding for disease resistance to stripe rust.

Ribosomal protein L22-like1 promotes prostate cancer progression by activating PI3K/Akt/mTOR signalling pathway.

Prostate cancer (PCa) is one of the most common malignancies in men. Ribosomal protein L22-like1 (RPL22L1), a component of the ribosomal 60 S subunit, is associated with cancer progression, but the role and potential mechanism of RPL22L1 in PCa remain unclear. The aim of this study was to investigate the role of RPL22L1 in PCa progression and the mechanisms involved. Bioinformatics and immunohistochemistry analysis showed that the expression of RPL22L1 was significantly higher in PCa tissues than in normal prostate tissues. The cell function analysis revealed that RPL22L1 significantly promoted the proliferation, migration and invasion of PCa cells. The data of xenograft tumour assay suggested that the low expression of RPL22L1 inhibited the growth and invasion of PCa cells in vivo. Mechanistically, the results of Western blot proved that RPL22L1 activated PI3K/Akt/mTOR pathway in PCa cells. Additionally, LY294002, an inhibitor of PI3K/Akt pathway, was used to block this pathway. The results showed that LY294002 remarkably abrogated the oncogenic effect of RPL22L1 on PCa cell proliferation and invasion. Taken together, our study demonstrated that RPL22L1 is a key gene in PCa progression and promotes PCa cell proliferation and invasion via PI3K/Akt/mTOR pathway, thus potentially providing a new target for PCa therapy.

Author Correction: Genetically encoded tags for direct synthesis of EM-visible gold nanoparticles in cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Genetically encoded tags for direct synthesis of EM-visible gold nanoparticles in cells.

Genetically encoded tags for single-molecule imaging in electron microscopy (EM) are long-awaited. Here, we report an approach for directly synthesizing EM-visible gold nanoparticles (AuNPs) on cysteine-rich tags for single-molecule visualization in cells. We first uncovered an auto-nucleation suppression mechanism that allows specific synthesis of AuNPs on isolated tags. Next, we exploited this mechanism to develop approaches for single-molecule detection of proteins in prokaryotic cells and achieved an unprecedented labeling efficiency. We then expanded it to more complicated eukaryotic cells and successfully detected the proteins targeted to various organelles, including the membranes of endoplasmic reticulum (ER) and nuclear envelope, ER lumen, nuclear pores, spindle pole bodies and mitochondrial matrices. We further implemented cysteine-rich tag-antibody fusion proteins as new immuno-EM probes. Thus, our approaches should allow biologists to address a wide range of biological questions at the single-molecule level in cellular ultrastructural contexts.

Dispersion Turning Attenuation Microfiber for Flowrate Sensing.

We demonstrated a new optical fiber modal interferometer (MI) for airflow sensing; the novelty of the proposed structure is that an MI is fabricated based on a piece of HAF, which makes the sensitive MI itself also a hotwire. The interferometer is made by applying arc-discharge tapering and then flame tapering on a 10 mm length high attenuation fiber (HAF, 2 dB/cm) with both ends spliced to a normal single mode fiber. When the diameter of the fiber in the processing region is reduced to about 2 µm, the near-infrared dispersion turning point (DTP) can be observed in the interferometer's transmission spectrum. Due to the absorption of the HAF, the interferometer will have a large temperature increase under the action of a pump laser. At the same time, the spectrum of the interferometer with a DTP is very sensitive to the change in ambient temperature. Since airflow will significantly affect the temperature around the fiber, this thermosensitive interferometer with an integrated heat source is suitable for airflow sensing. Such an airflow sensor sample with a 31.2 mm length was made and pumped by a 980 nm laser with power up to 200 mW. In the comparative experiment with an electrical anemometer, this sensor exhibits a very high air-flow sensitivity of -2.69 nm/(m/s) at a flowrate of about 1.0 m/s. The sensitivity can be further improved by enlarging the waist length, increasing the pump power, etc. The optical anemometer with an extremely high sensitivity and a compact size has the potential to measure a low flowrate in constrained microfluidic channels.

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OBJECTIVES: To explore the role and potential mechanisms of chitinase-3-like protein 1 (CHI3L1) in coronary artery lesions in a mouse model of Kawasaki disease (KD)-like vasculitis. METHODS: Four-week-old male SPF-grade C57BL/6 mice were randomly divided into a control group and a model group, with 10 mice in each group. The model group mice were intraperitoneally injected with 0.5 mL of lactobacillus casei cell wall extract (LCWE) to establish a mouse model of KD-like vasculitis, while the control group mice were injected with an equal volume of normal saline. The general conditions of the mice were observed on the 3rd, 7th, and 14th day after injection. Changes in coronary artery tissue pathology were observed using hematoxylin-eosin staining. The level of CHI3L1 in mouse serum was measured by enzyme-linked immunosorbent assay. Immunofluorescence staining was used to detect the expression and localization of CHI3L1, von Willebrand factor (vWF), and α-smooth muscle actin (α-SMA) in coronary artery tissue. Western blot analysis was used to detect the expression of CHI3L1, vWF, vascular endothelial cadherin (VE cadherin), Caspase-3, B cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), nuclear factor κB (NF-κB), and phosphorylated NF-κB (p-NF-κB) in coronary artery tissue. RESULTS: The serum level of CHI3L1 in the model group was significantly higher than that in the control group (P<0.05). Compared to the control group, the expression of CHI3L1 in the coronary artery tissue was higher, while the expression of vWF was lower in the model group. The relative expression levels of CHI3L1, Bax, Caspase-3, NF-κB, and p-NF-κB were significantly higher in the model group than in the control group (P<0.05). The relative expression levels of vWF, VE cadherin, and Bcl-2 were lower in the model group than in the control group (P<0.05). CONCLUSIONS: In the LCWE-induced mouse model of KD-like vasculitis, the expression levels of CHI3L1 in serum and coronary arteries increase, and it may play a role in coronary artery lesions through endothelial cell apoptosis mediated by inflammatory reactions.

Liquid Pressure Sensor Based on Fiber Bragg Grating with an Adjustable Structure.

In this paper, a fiber-optic liquid pressure sensor is designed and developed by encapsulating the fiber Bragg grating (FBG) inside the adjustable double-flange cylinder rigid structure with flexible polymer polydimethylsiloxane (PDMS). Within the elastic deformation range of the PDMS, the proposed adjustable FBG-based liquid pressure sensor is proven to change its measuring range while maintaining high measurement sensitivity by simply adjusting the structure, that is, the sensor can achieve high measurement sensitivity in various liquid levels. In addition, the simulation and experimental results show that the sensor sensitivity can be enhanced by the proper changes of the structural parameters, such as the inner diameter, etc. The proposed sensor has shown that it has good linearity and stability, which provides a new opportunity for the monitoring of liquid pressure in oceans, dams and other environments.

Euphorhelipanes A and B, Triglyceride-Lowering Euphorbia Diterpenoids with a Bicyclo[4.3.0]nonane Core from Euphorbia helioscopia.

Euphorhelipanes A (1) and B (2), two Euphorbia diterpenoids with a new 4-(5,5-dimethylheptan-2-yl)-2,7-dimethylbicyclo[4.3.0]nonane skeleton, were isolated from a 95% ethanol extract of the whole plants of Euphorbia helioscopia. Their structures were elucidated by spectroscopic data analysis, quantum chemical calculations, and single-crystal X-ray diffraction data. Compounds 1 and 2 represent the first examples of Euphorbia diterpenoids with a 5/6 fused carbon ring system, and their plausible biosynthetic pathways originating from jatrophanes are proposed. Compounds 1 and 2 showed a triglyceride-lowering effect in oleic-acid-stimulated HuH7 cells at concentrations of 1-50 µM.

Evodialones A and B: Polyprenylated Acylcyclopentanone Racemates with a 3-Ethyl-1,1-diisopentyl-4-methylcyclopentane Skeleton from Evodia lepta.

Two polyprenylated acylcyclopentanone racemates, evodialones A (1) and B (2), featuring a 3-ethyl-1,1-diisopentyl-4-methylcyclopentane skeleton, were isolated from an extract of the aerial parts of Evodia lepta. Evodialone A (1) was resolved by chiral-phase HPLC to afford a pair of enantiomers, (+)- and (-)-evodialones A (1b/1a), while evodialone B (2) could not be resolved. Their structures were elucidated by spectroscopic analysis and a combination of computational techniques including gauge-independent atomic orbital calculation of 1D NMR data and experimental and TDDFT-calculated ECD spectra. A putative biosynthetic pathway of 1 and 2 starting from the monocyclic polyprenylated acylphloroglucinols is proposed. All the isolates were screened for the antimicrobial activity in vitro, and 1a and 1b showed moderate inhibitory activities against several pathogenic fungi with MICs values of 17.1-68.3 µM.

ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions.

Cell plasticity sustains intra-tumor heterogeneity and treatment resistance in melanoma. Deciphering the transcriptional mechanisms governing reversible phenotypic transitions between proliferative/differentiated and invasive/stem-like states is required. Expression of the ZEB1 transcription factor is frequently activated in melanoma, where it fosters adaptive resistance to targeted therapies. Here, we performed a genome-wide characterization of ZEB1 transcriptional targets, by combining ChIP-sequencing and RNA-sequencing, upon phenotype switching in melanoma models. We identified and validated ZEB1 binding peaks in the promoter of key lineage-specific genes crucial for melanoma cell identity. Mechanistically, ZEB1 negatively regulates SOX10-MITF dependent proliferative/melanocytic programs and positively regulates AP-1 driven invasive and stem-like programs. Comparative analyses with breast carcinoma cells revealed lineage-specific ZEB1 binding, leading to the design of a more reliable melanoma-specific ZEB1 regulon. We then developed single-cell spatial multiplexed analyses to characterize melanoma cell states intra-tumoral heterogeneity in human melanoma samples. Combined with scRNA-Seq analyses, our findings confirmed increased ZEB1 expression in Neural-Crest-like cells and mesenchymal cells, underscoring its significance in vivo in both populations. Overall, our results define ZEB1 as a major transcriptional regulator of cell states transitions and provide a better understanding of lineage-specific transcriptional programs sustaining intra-tumor heterogeneity in melanoma.

Microcystin­leucine arginine promotes colorectal cancer cell proliferation by activating the PI3K/Akt/Wnt/ß­catenin pathway.

Microcystin­leucine arginine (MC­LR) is an environmental toxin produced by cyanobacteria and is considered to be a potent carcinogen. However, to the best of our knowledge, the effect of MC­LR on colorectal cancer (CRC) cell proliferation has never been studied. The aim of the present study was to investigate the effect of MC­LR on CRC cell proliferation and the underlying mechanisms. Firstly, a Cell Counting Kit­8 (CCK­8) assay was conducted to determine cell viability at different concentrations, and 50 nM MC­LR was chosen for further study. Subsequently, a longer CCK­8 assay and a cell colony formation assay showed that MC­LR promoted SW620 and HT29 cell proliferation. Furthermore, western blotting analysis showed that MC­LR significantly upregulated protein expression of PI3K, p­Akt (Ser473), p­GSK3ß (Ser9), ß­catenin, c­myc and cyclin D1, suggesting that MC­LR activated the PI3K/Akt and Wnt/ß­catenin pathways in SW620 and HT29 cells. Finally, the pathway inhibitors LY294002 and ICG001 were used to validate the role of the PI3K/Akt and Wnt/ß­catenin pathways in MC­LR­accelerated cell proliferation. The results revealed that MC­LR activated Wnt/ß­catenin through the PI3K/Akt pathway to promote cell proliferation. Taken together, these data showed that MC­LR promoted CRC cell proliferation by activating the PI3K/Akt/Wnt/ß­catenin pathway. The present study provided a novel insight into the toxicological mechanism of MC­LR.

A small-diameter vascular graft immobilized peptides for capturing endothelial colony-forming cells.

Combining synthetic polymers and biomacromolecules prevents the occurrence of thrombogenicity and intimal hyperplasia in small-diameter vascular grafts (SDVGs). In the present study, an electrospinning poly (L)-lactic acid (PLLA) bilayered scaffold is developed to prevent thrombosis after implantation by promoting the capture and differentiation of endothelial colony-forming cells (ECFCs). The scaffold consists of an outer PLLA scaffold and an inner porous PLLA biomimetic membrane combined with heparin (Hep), peptide Gly-Gly-Gly-Arg-Glu-Asp-Val (GGG-REDV), and vascular endothelial growth factor (VEGF). Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), and contact angle goniometry were performed to determine successful synthesis. The tensile strength of the outer layer was obtained using the recorded stress/strain curves, and hemocompatibility was evaluated using the blood clotting test. The proliferation, function, and differentiation properties of ECFCs were measured on various surfaces. Scanning electronic microscopy (SEM) was used to observe the morphology of ECFCs on the surface. The outer layer of scaffolds exhibited a similar strain and stress performance as the human saphenous vein via the tensile experiment. The contact angle decreased continuously until it reached 56° after REDV/VEGF modification, and SEM images of platelet adhesion showed a better hemocompatibility surface after modification. The ECFCs were captured using the REDV + VEGF + surface successfully under flow conditions. The expression of mature ECs was constantly increased with the culture of ECFCs on REDV + VEGF + surfaces. SEM images showed that the ECFCs captured by the REDV + VEGF + surface formed capillary-like structures after 4 weeks of culture. The SDVGs modified by REDV combined with VEGF promoted ECFC capture and rapid differentiation into ECs, forming capillary-like structures in vitro. The bilayered SDVGs could be used as vascular devices that achieved a high patency rate and rapid re-endothelialization.

EGCG promotes the sensory function recovery in rats after dorsal root crush injury by upregulating KAT6A and inhibiting pyroptosis.

Dorsal root injury usually leads to irreversible sensory function loss and lacks effective treatments. (-)-epigallocatechin-3-gallate (EGCG) is reported to exert neuroprotective roles in the nervous systems. However, the function of EGCG in treating dorsal root injury remains unclear. Hence, we built the dorsal root crush injury (DRCI) rat model to be treated with EGCG, followed by the western blot, Enzyme-linked immunosorbent assay, and sensory behavior tests. We observed that EGCG can upregulate the Lysine acetyltransferase 6A (KAT6A) level and inhibit the pyroptosis, indicated by downregulated gasdermin-D, caspase-1, and interleukin 18 protein levels, and alleviate the neuropathic pain, indicated by the decreased paw withdraw threshold in Plantar test and decreased paw withdraw latency in von Frey test, and downregulated calcitonin gene-related peptide, nerve growth factor, and c-Fos protein levels. But EGCG cannot alleviate the neuropathic pain when the KAT6A was inhibited by CTX-0124143 and pyroptosis was activated by Miltirone. These combined results indicated that EGCG can promote the sensory function recovery in rats after DRCI via upregulating KAT6A and inhibiting pyroptosis, laying the foundation for EGCG to be a novel candidate for the treatment of dorsal root injury.

An in vivo avian model of human melanoma to perform rapid and robust preclinical studies.

Metastatic melanoma patients carrying a BRAFV600 mutation can be treated with a combination of BRAF and MEK inhibitors (BRAFi/MEKi), but innate and acquired resistance invariably occurs. Predicting patient response to targeted therapies is crucial to guide clinical decision. We describe here the development of a highly efficient patient-derived xenograft model adapted to patient melanoma biopsies, using the avian embryo as a host (AVI-PDXTM ). In this in vivo paradigm, we depict a fast and reproducible tumor engraftment of patient samples within the embryonic skin, preserving key molecular and phenotypic features. We show that sensitivity and resistance to BRAFi/MEKi can be reliably modeled in these AVI-PDXTM , as well as synergies with other drugs. We further provide proof-of-concept that the AVI-PDXTM models the diversity of responses of melanoma patients to BRAFi/MEKi, within days, hence positioning it as a valuable tool for the design of personalized medicine assays and for the evaluation of novel combination strategies.

The change in pediatric subject symptoms during the COVID-19 pandemic in China: an increase in cardiac consultation.

BACKGROUND: It is reported that the adverse impact of nonpharmaceutical interventions (NPIs) on the mental health of children and adolescents may lead to psychologically related disorders during the coronavirus disease 2019 (COVID-19) period. Subject symptoms such as chest pain, chest tightness, and palpitation may be related to increased stress and anxiety in children and adolescents. The present research aimed to determine the number of pediatric consults and etiology of subject symptoms during the COVID-19 pandemic period and compared it with the same timelines in 2019 and 2021 to discuss the impact of different periods on the organic disease onset of children with subject symptoms, especially in cardiac involvement. METHODS: Children who visited Qingdao Women and Children's Hospital, Qingdao University between January 23 to April 30, 2019 (pre-COVID-19 period), January 23 to April 30, 2020 (COVID-19 period), and January 23 to April 30, 2021 (post-COVID-19 period) presenting chest pain, chest tightness, and palpitation were recruited. Information to determine gender, age, medical history, department for the initial visit, clinical manifestations, time from the latest onset to the visit, and diagnosis were recorded. RESULT: A total of 891 patients were enrolled in the present study (514 males; median age: 7.72). One hundred twenty-three patients presented during the pre-COVID-19 period while 130 during the COVID-19 period, nevertheless, the number substantially increased during the post-COVID-19 period (n = 638). Cardiac etiology accounted for 1.68% (n = 15) of the patient population, including arrhythmias (n = 10, 1.12%), myocarditis (n = 4, 0.44%), and atrial septal defect (n = 1, 0.11%). There was no significant difference among groups in the distribution of organic etiology. The median time from the latest onset to the visit during the pre-COVID-19 period was 7 days compared to 10 days during the COVID-19 period and 3 days during the post-COVID period. CONCLUSION: During the post-COVID-19 period, the median time from the latest onset to the visit was significantly shorter than that in the pre-COVID-19 period or COVID-19 period. The pediatric consult of children with subject symptoms presented increased substantially during the post-COVID-19 period, while there was no significant difference in the number of patients involving the cardiac disease. Clinicians ought to be more careful to screen heart diseases to prevent missed diagnosis and misdiagnosis during special periods.

Euphopanes A-C, three new diterpenoids from Euphorbia pekinensis.

Three new diterpenoids, euphopanes A-C (1-3), including one ent-isopimarane (1), one ent-abietane (2) and one cembrane (3), along with five known compounds (4-8) were isolated from the roots of Euphorbia pekinensis. Their structures were elucidated by extensive spectroscopic analysis, and the absolute configurations of compounds 1-3 were determined by ECD calculations. All the isolates were screened for the cytotoxicity against three cancer cell lines (C4-2B, C42B/ENZR, and MDA-MB-231), and compounds 1, 2, and 4 showed significant cytotoxicity against human prostate cancer cells C4-2B with IC50 values of 14.3, 16.9, and 15.3 µM, respectively.

Microcystin-LR induced microfilament rearrangement and cell invasion by activating ERK/VASP/ezrin pathway in DU145 cells.

Microcystin-LR (MC-LR) is an environmental toxin that is synthesized by cyanobacteria and considered a potential human carcinogen. However, the role of MC-LR in prostate cancer progression has not been elucidated. The purpose of this study was to investigate the effect of MC-LR on prostate cancer cell invasion and its underlying mechanisms. Transwell assay was performed, and the result showed that MC-LR increased DU145 cell invasion in a concentration-dependent manner. The result of Western blot showed that MC-LR promoted ERK phosphorylation, while enhancing VASP and ezrin phosphorylation. Moreover, PD0325901 was used to verify the role of the ERK/VASP/ezrin axis in MC-LR-promoted cell invasion. The results revealed that MC-LR promoted microfilament rearrangement and cell invasion by activating the ERK/VASP/ezrin pathway in DU145 cells. Finally, in vivo assay was performed, and the result suggested that MC-LR promoted p-ERK, p-VASP and p-ezrin expression and local invasion in nude mice model. Taken together, our data proved that MC-LR induced microfilament rearrangement and cell invasion by activating the ERK/VASP/ezrin pathway in DU145 cells.

A central circadian oscillator confers defense heterosis in hybrids without growth vigor costs.

Plant immunity frequently incurs growth penalties, which known as the trade-off between immunity and growth. Heterosis, the phenotypic superiority of a hybrid over its parents, has been demonstrated for many traits but rarely for disease resistance. Here, we report that the central circadian oscillator, CCA1, confers heterosis for bacterial defense in hybrids without growth vigor costs, and it even significantly enhances the growth heterosis of hybrids under pathogen infection. The genetic perturbation of CCA1 abrogated heterosis for both defense and growth in hybrids. Upon pathogen attack, the expression of CCA1 in F1 hybrids is precisely modulated at different time points during the day by its rhythmic histone modifications. Before dawn of the first infection day, epigenetic activation of CCA1 promotes an elevation of salicylic acid accumulation in hybrids, enabling heterosis for defense. During the middle of every infection day, diurnal epigenetic repression of CCA1 leads to rhythmically increased chlorophyll synthesis and starch metabolism in hybrids, effectively eliminating the immunity-growth heterosis trade-offs in hybrids.