An RRM domain protein SOE suppresses transgene silencing in rice.

Gene expression is regulated at multiple levels, including RNA processing and DNA methylation/demethylation. How these regulations are controlled remains unclear. Here, through analysis of a suppressor for the OsEIN2 over-expressor, we identified an RNA recognition motif protein SUPPRESSOR OF EIN2 (SOE). SOE is localized in nuclear speckles and interacts with several components of the spliceosome. We find SOE associates with hundreds of targets and directly binds to a DNA glycosylase gene DNG701 pre-mRNA for efficient splicing and stabilization, allowing for subsequent DNG701-mediated DNA demethylation of the transgene promoter for proper gene expression. The V81M substitution in the suppressor mutant protein mSOE impaired its protein stability and binding activity to DNG701 pre-mRNA, leading to transgene silencing. SOE mutation enhances grain size and yield. Haplotype analysis in c. 3000 rice accessions reveals that the haplotype 1 (Hap 1) promoter is associated with high 1000-grain weight, and most of the japonica accessions, but not indica ones, have the Hap 1 elite allele. Our study discovers a novel mechanism for the regulation of gene expression and provides an elite allele for the promotion of yield potentials in rice.

The GDSL Lipase MHZ11 Modulates Ethylene Signaling in Rice Roots.

Ethylene plays important roles in plant growth and development, but the regulation of ethylene signaling is largely unclear, especially in crops such as rice (Oryza sativa). Here, by analysis of the ethylene-insensitive mutant mao huzi 11 (mhz11), we identified the GDSL lipase MHZ11, which modulates ethylene signaling in rice roots. MHZ11 localized to the endoplasmic reticulum membrane and has acyl-hydrolyzing activity. This activity affects the homeostasis of sterols in rice roots and is required for root ethylene response. MHZ11 overexpression caused constitutive ethylene response in roots. Genetically, MHZ11 acts with the ethylene receptor ETHYLENE RESPONSE SENSOR2 (OsERS2) upstream of CONSTITUTIVE TRIPLE RESPONSE2 (OsCTR2) and ETHYLENE INSENSITIVE2 (OsEIN2). The mhz11 mutant maintains more OsCTR2 in the phosphorylated form whereas MHZ11 overexpression promotes ethylene-mediated inhibition of OsCTR2 phosphorylation. MHZ11 colocalized with the ethylene receptor OsERS2, and its effect on OsCTR2 phosphorylation requires ethylene perception and initiation of ethylene signaling. The mhz11 mutant overaccumulated sterols and blocking sterol biosynthesis partially rescued the mhz11 ethylene response, likely by reducing receptor-OsCTR2 interaction and OsCTR2 phosphorylation. We propose that MHZ11 reduces sterol levels to impair receptor-OsCTR2 interactions and OsCTR2 phosphorylation for triggering ethylene signaling. Our study reveals a mechanism by which MHZ11 participates in ethylene signaling for regulation of root growth in rice.

Single Transverse Spin Asymmetry as a New Probe of Standard-Model-Effective-Field-Theory Dipole Operators.

Electroweak dipole operators in the standard-model-effective-field theory (SMEFT) are important indirect probes of quantum effects of new physics beyond the standard model (SM), yet they remain poorly constrained by current experimental analyses for lack of interference with the SM amplitudes in constructing cross section observables. In this Letter, we point out that dipole operators flip fermion helicities and so are ideally studied through single transverse spin asymmetries. We illustrate this at a future electron-positron collider with transversely polarized beams, where such an effect exhibits as azimuthal cosϕ and sinϕ distributions which originate from the interference of the electron dipole operators with the SM and are linearly dependent on their Wilson coefficients. This new method can improve the current constraints on the electron dipole couplings by 1-2 orders of magnitude, without depending on other new physics operators, and can also simultaneously constrain both their real and imaginary parts, offering a new opportunity for probing potential CP-violating effects.

Nanopore Deciphering Single Digital Polymers Towards High-Density Data Storage.

Sequence-defined polymer is one of the most promising alternative media for high-density data storage. It could be used to alleviate the problem of insufficient storage capacity of conventional silicon-based devices for the explosively increasing data. To fulfil the goal of polymer data storage, suitable methods should be developed to accurately read and decode the information-containing polymers, especially for those composed by a combination of the natural and unnatural monomers. Nanopore-based approaches have become one of the most competitive analysis and sequencing techniques, which are expected to read both natural and synthetic polymers with single-molecule precision and monomeric resolution. Herein, this work emphasizes the advances being made in nanopore reading and decoding of information stored in the man-made polymers and DNA nanostructures, and discusses the challenges and opportunities towards the development and realization of high-density data storage.

Streptomonospora mangrovi sp. nov., isolated from mangrove soil showing similar metabolic capabilities, but distinct secondary metabolites profiles.

A novel actinomycete, designated strain S1-112 T, was isolated from a mangrove soil sample from Hainan, China, and characterized using a polyphasic approach. Strain S1-112 T showed the highest similarity of the 16S rRNA gene to Streptomonospora nanhaiensis 12A09T (99.24%). Their close relationship was further supported by phylogenetic analyses, which placed these two strains within a stable clade. The highest values of digital DNA-DNA hybridization (dDDH, 41.4%) and average nucleotide identity (ANI, 90.55%) were detected between strain S1-112 T and Streptomonospora halotolerans NEAU-Jh2-17 T. Genotypic and phenotypic characteristics demonstrated that strain S1-112 T could be distinguished from its closely related relatives. We also profiled the pan-genome and metabolic features of genomic assemblies of strains belonging to the genus Streptomonospora, indicating similar functional capacities and metabolic activities. However, all of these strains showed promising potential for producing diverse types of secondary metabolites. In conclusion, strain S1-112 T represents a novel species of the genus Streptomonospora, for which the name Streptomonospora mangrovi sp. nov. was proposed. The type strain is S1-112 T (= JCM 34292 T).

Cardiolipin-Targeted NIR-II Fluorophore Causes "Avalanche Effects" for Re-Engaging Cancer Apoptosis and Inhibiting Metastasis.

Restoring innate apoptosis and simultaneously inhibiting metastasis by a molecular drug is an effective cancer therapeutic approach. Herein, a large rigid and V-shaped NIR-II dye, DUT850, is rationally designed for potential cardiolipin (CL)-targeted chemo-phototheranostic application. DUT850 displays moderate NIR-II fluorescence, excellent photodynamic therapy (PDT) and photothermal therapy (PTT) performance, and ultra-high photostability. More importantly, the unique rigid V-shaped backbone, positive charge, and lipophilicity of DUT850 afford its specific recognition and efficient binding to CL; such an interaction of DUT850-CL induced a spectrum of physiological disruptions, including translocation of cytochrome c, Ca2+ overload, reactive oxygen species burst, and ATP depletion, which not only activated cancer cell apoptosis but also inhibited tumor metastasis both in vitro and in vivo. Furthermore, the tight binding of DUT850-CL improves the phototoxicity of DUT850 toward cancer cells (IC50 as low as 90 nM) under safe 808 nm laser irradiation (330 mW cm-2). Upon encapsulation into bovine serum albumin (BSA), DUT850@BSA exerted a synergetic chemo-PDT-PTT effect on the 4T1 tumor mouse model, eventually leading to solid tumor annihilation and metastasis inhibition, which could be followed in real time with the NIR-II fluorescence of DUT850. This work contributed a promising approach for simultaneously re-engaging cancer cell apoptotic networks and activating the anti-metastasis pathway by targeting a pivotal upstream effector, which will bring a medical boon for inhibition of tumor proliferation and metastasis.

Near-infrared ITO-based photonic hypercrystals with large angle-insensitive bandgaps.

The angle-sensitive photonic bandgap (PBG) is one of the typical features of one-dimensional photonic crystals. Based on the phase-variation compensation effect between the dielectric and hyperbolic metamaterials (HMMs), angle-insensitive PBGs can be realized in photonic hypercrystals. However, since hypercrystals are usually constructed using metal components, these angle-insensitive PBGs are mostly limited to narrow bandwidths in visible range. Here, we replace metal with indium tin oxide (ITO) to construct HMMs in the near-infrared range. In these ITO-based HMMs, we experimentally demonstrate the negative refraction of light in transverse magnetic polarization. With this HMM component, we realize a photonic hypercrystal with an angle-insensitive PBG in the wavelength range of 1.15-2.02 µm. These ITO-based hypercrystals with large angle-insensitive PBGs can find applications in near-infrared reflectors or filters.

Theoretical Exploration of Peculiar Sandwich-Type Clusters Formed by the Coordination of E92- (E = Si, Ge, Sn) Zintl Clusters: Structural Properties, Active Sites, and Hydrogen Storage.

A peculiar heterogeneous metal sandwich fragment {(Ge9)2[η6-Ge(PdPPh3)3]}4- anion cluster was synthesized for the first time by Xu et al. (Xu, H. L.; Tkachenko, N. V.; Wang, Z. C.; Chen, W. X.; Qiao, L.; Munoz-Castro, A.; Boldyrev, A. I.; Sun, Z. M. Nat. Commun.2020, 11, 5286). In this work, novel analogous sandwich compounds ({(E9)2[η6-E(PdPH3)3]}4- (E = Si (1), Ge (2), Sn (3)) were studied using quantum chemical calculations and wave function analysis to determine the geometry, bonding nature, aromaticity, active sites, and hydrogen storage. Structural analysis revealed that the clusters were compounds formed by the coordination of two E92- (E = Si, Ge, Sn) Zintl clusters with a central E@Pd3 (E = Si, Ge, Sn) interlayer. The steric hindrance at both ends is small, facilitating facile attachment to other molecules. The valence states of the central atom E (E = Si, Ge, Sn) are close to zero, indicating that they are stable novel heterometallic sandwich compounds, and the Zintl ligands at both ends are negative, thus they can react with Lewis acids. Bonding analysis showed that the E92- (E = Si, Ge, Sn) cluster has a delocalized framework bonding mode. For aromaticity analysis, we used AdNDP, ELF, LOL, ICSS, and NICS to qualitatively and quantitatively clarify that these clusters possess the characteristics of overall delocalization, σ aromaticity, and remarkable stability. By analyzing the unique structure and predicting the reaction sites, we concluded that the E92- ligand reacts with Lewis acids. Finally, through the adsorption of hydrogen molecules, the average adsorption energies of 1-3 were 0.387, 0.374, and 0.325 eV per H2 molecule, respectively, meeting the physical adsorption standard, with the adsorption effect of 3 being slightly more superior than that of 1 and 2. Our study represents a substantial step forward in the study of high-density materials for volumetric H2 storage applications.

Plasma TIGIT Level Is a Possible Marker in HIV-Related Liver Damage.

T cell immunoglobulin and ITIM domain (TIGIT), has a key role in immunopathogenesis of HIV. Previous studies on immune checkpoint receptors had mainly focused on the membrane form. To evaluate clinical significance of soluble form of TIGIT (sTIGIT) in people living with HIV. Blood samples of 61 untreated HIV-infected patients and 24 healthy individuals were collected and TIGIT concentrations in plasma were measured by ELISA method. A decreased level of plasma TIGIT in HIV-infected patients was found to be negatively associated with AST/ALT ratio (r = -0.5358, p = 0.0483) that was indicative of liver damage. Moreover, the proportion of TIGIT on CD3+CD4+ cells in HIV-infected individuals increased (47.12 ± 5.051%) compared with in healthy controls (22.13 ± 4.426%, p < 0.01), which indicated change in plasma TIGIT level was at least partially attributed to CD3+CD4+ T cells. Furthermore, there was a strong positive correlation between TIGIT plasma levels and lymphocyte activation gene-3 (LAG-3) plasma levels in HIV-infected patients with a linear correlation coefficient r = 0.904. Therefore, plasma TIGIT level is a possible marker in HIV-related liver damage and LAG-3 closely related to TIGIT possibly plays a co-ordinated role in HIV-related liver damage.

3D Blockage Mapping for Identifying Familial Point Mutations in Single Amyloid-ß Peptides with a Nanopore.

Accurate discrimination of amyloid-ß (Aß) peptides containing familial point mutations would advance the knowledge of their roles in early-onset Alzheimer's disease. Herein, we simultaneously identified the mutant A21G, E22G, E22Q, and the wild-type (WT) Aß18-26 peptides with aerolysin nanopore using a 3D blockage mapping strategy. The standard deviation of current blockade fluctuations (σb ) was proposed as a new supplement to current blockage (Ib /I0 ) and duration time (tD ) to profile the blockage characteristics of single molecules. Although the WT and A21G Aß18-26 are indistinguishable in a traditional Ib /I0 -tD 2D description, ∼87 % of the blockade events can be accurately classified with half reduction of false identification using a combination of Ib /I0 , tD, and σb . This work offers an easy and reliable strategy to promote nanopore sensitivity of peptide mutants, leading to a more precise analysis of pathogenic mutations for developing effective diagnosis and treatment.

Tailored Engineering of Novel Xanthonium Polymethine Dyes for Synergetic PDT and PTT Triggered by 1064 nm Laser toward Deep-Seated Tumors.

Small molecular dye that simultaneously exerts dual PDT/PTT effects as well as florescence imaging triggered by a single NIR-II light has never been reported to date. Apart from the huge challenge in pushing absorption profile into NIR-II region, fine-tuning dyes' excited state via rational structure design to meet all three functions, especially oxygen photosensitization, remains the most prominent throttle. Herein, five novel NIR-II dyes (BHs) are productively developed by strategically conjugating dyad innovative xanthonium with sequentially extended polymethine bridges, enabling intense absorption from 890 to 1206 nm, significantly 400 nm longer than conventional cyanine dyes with same polymethines. More importantly, owning to high resonance and favorable excited state energy population induced by greater rigidity via ring-fused amino, BH 1024 exhibits best singlet oxygen generation capability, moderate photothermal heating, and considerable fluorescence under 1064 nm laser irradiation. Furthermore, BH 1024 is encapsulated into folate-functionalized polymer, which demonstrated a synergetic PDT/PTT effect in vitro and in vivo, eventually achieving solid tumors elimination under NIR-II fluorescence guide. As far as it is known, this is the first time small molecular dyes for NIR-II PDT or NIR-II PDT/PTT are explored and designed.

Nonreciprocal Tamm plasmon absorber based on lossy epsilon-near-zero materials.

Contrary to conventional Tamm plasmon (TP) absorbers of which narrow absorptance peaks will shift toward short wavelengths (blueshift) as the incident angle increases for both transverse magnetic (TM) and transverse electric (TE) polarizations, here we theoretically and experimentally achieve nonreciprocal absorption in a planar photonic heterostructure composed of an isotropic epsilon-near-zero (ENZ) slab and a truncated photonic crystal for TM polarization. This exotic phenomenon results from the interplay between ENZ and material loss. And the boundary condition across the ENZ interface and the confinement effect provided by the TP can enhance the absorption in the ENZ slab greatly. As a result, a strong and nonreciprocal absorptance peak is observed experimentally with a maximum absorptance value of 93% in an angle range of 60∼70°. Moreover, this TP absorber shows strong angle-independence and polarization-dependence. As the characteristics above are not at a cost of extra nanopatterning, this structure is promising to offer a practical design in narrowband thermal emitter, highly sensitive biosensing, and nonreciprocal nonlinear optical devices.

Steroidobacter gossypii sp. nov., isolated from cotton field soil.

A Gram-negative bacterium, designated S1-65T, was isolated from soil samples collected from a cotton field located in the Xinjiang region of PR China. Results of 16S rRNA gene sequence analysis revealed that strain S1-65T was affiliated to the genus Steroidobacter with its closest phylogenetic relatives being 'Steroidobacter cummioxidans' 35Y (98.4 %), 'Steroidobacter agaridevorans' SA29-B (98.3 %) and Steroidobacter agariperforans KA5-BT (98.3 %). 16S rRNA-directed phylogenetic analysis showed that strain S1-65T formed a unique phylogenetic subclade next to 'S. agaridevorans' SA29-B and S. agariperforans KA5-BT, suggesting that strain S1-65T should be identified as a member of the genus Steroidobacter. Further, substantial differences between the genotypic properties of strain S1-65T and the members of the genus Steroidobacter, including average nucleotide identity and digital DNA-DNA hybridization, resolved the taxonomic position of strain S1-65T and suggested its positioning as representing a novel species of the genus Steroidobacter. The DNA G+C content of strain S1-65T was 62.5 mol%, based on its draft genome sequence. The predominant respiratory quinone was ubiquinone-8. The main fatty acids were identified as summed feature 3 (C16:1ω6c/C16:1ω7c), C16 : 0 and iso-C15 : 0. In addition, its polar lipid profile was composed of aminophospholipid, diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. Here, we propose a novel species of the genus Steroidobacter: Steroidobacter gossypii sp. nov. with the type strain S1-65T (=JCM 34287T=CGMCC 1.18736T).

Genomic molecular signatures determined characterization of Mycolicibacterium gossypii sp. nov., a fast-growing mycobacterial species isolated from cotton field soil.

A Gram-positive, acid-fast and rapidly growing rod, designated S2-37 T, that could form yellowish colonies was isolated from one soil sample collected from cotton cropping field located in the Xinjiang region of China. Genomic analyses indicated that strain S2-37 T harbored T7SS secretion system and was very likely able to produce mycolic acid, which were typical features of pathogenetic mycobacterial species. 16S rRNA-directed phylogenetic analysis referred that strain S2-37 T was closely related to bacterial species belonging to the genus Mycolicibacterium, which was further confirmed by pan-genome phylogenetic analysis. Digital DNA-DNA hybridization and the average nucleotide identity presented that strain S2-37 T displayed the highest values of 39.1% (35.7-42.6%) and 81.28% with M. litorale CGMCC 4.5724 T, respectively. And characterization of conserved molecular signatures further supported the taxonomic position of strain S2-37 T belonging to the genus Mycolicibacterium. The main fatty acids were identified as C16:0, C18:0, C20:3ω3 and C22:6ω3. In addition, polar lipids profile was mainly composed of diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylinositol. Phylogenetic analyses, distinct fatty aids and antimicrobial resistance profiles indicated that strain S2-37 T represented genetically and phenotypically distinct from its closest phylogenetic neighbour, M. litorale CGMCC 4.5724 T. Here, we propose a novel species of the genus Mycolicibacterium: Mycolicibacterium gossypii sp. nov. with the type strain S2-37 T (= JCM 34327 T = CGMCC 1.18817 T).

Effect of urban underlying surface on PM2.5 vertical distribution based on UAV in Xi'an, China.

Fine particulate matter (PM2.5) has become a significant issue of ecological environment. However, few studies have explored the vertical distribution of PM2.5 in cities. The objectives of this paper are to reveal the vertical distribution regular pattern of PM2.5 over urban underlying surfaces near the ground with a hexacopter-type unmanned aerial vehicle (UAV) in winter. Results showed that the maximum vertical gradient of PM2.5 near the ground was typically the greatest in the morning as the stable atmospheric conditions. Moreover, regression model illustrated that relative humidity had the greatest impact on the vertical profile of PM2.5 compared to air temperature and altitude as hygroscopic of PM2.5 aerosols. Curve model shown that vertical profile of PM2.5 over the surfaces of water and green space first increased slowly and then declined, besides, the highest concentration inflection of PM2.5 above the water body (23.7 m) is higher than the green space (14.3 m). Thus, suggesting residents living vertical of 10-30 m from the ground around large water bodies and green spaces should not open windows for ventilation in the morning. Therefore, this study provides insights into the vertical distributions of PM2.5 over different underlying surfaces and should be of reference value to urban planners for designing urban spaces to optimize atmosphere environment to provide a healthy living environment.

Metabolic engineering of ß-carotene biosynthesis in Yarrowia lipolytica.

OBJECTIVE: Carotenoids, as potent antioxidant compounds, have gained extensive attention, especially in human health. In this study, the combination of CRISPR/Cas9 integration strategy and fermenter cultivation was utilized to obtain efficient ß-carotene-producing Yarrowia lipolytica cell factories for potential industrial application. RESULTS: The introduction of the genes of Mucor circinelloides, encoding phytoene dehydrogenase (carB) and bifunctional phytoene synthase/lycopene cyclase (carRP), contributed to the heterologous production of ß-carotene in Y. lipolytica XK2. Furthermore, ß-carotene production was efficiently enhanced by increasing the copy numbers of the carB and carRP genes and overexpressing of GGS1, ERG13, and HMG, the genes related to the mevalonate (MVA) pathway. Thus, the optimized strain overexpressed a total of eight genes, including three copies of carRP, two copies of carB, and single copies of GGS1, HMG, and ERG13. As a consequence, strain Y. lipolytica XK19 accumulated approximately 408 mg/L ß-carotene in shake flask cultures, a twenty-four-fold increase compared to the parental strain Y. lipolytica XK2. CONCLUSIONS: 4.5 g/L ß-carotene was obtained in a 5-L fermenter through a combination of genetic engineering and culture optimization, suggesting a great capacity and flexibility of Y. lipolytica in the production of carotenoids.

Effects of parental genetic divergence on gene expression patterns in interspecific hybrids of Camellia.

BACKGROUND: The merging of two divergent genomes during hybridization can result in the remodeling of parental gene expression in hybrids. A molecular basis underling expression change in hybrid is regulatory divergence, which may change with the parental genetic divergence. However, there still no unanimous conclusion for this hypothesis. RESULTS: Three species of Camellia with a range of genetic divergence and their F1 hybrids were used to study the effect of parental genetic divergence on gene expression and regulatory patterns in hybrids by RNA-sequencing and allelic expression analysis. We found that though the proportion of differentially expressed genes (DEGs) between the hybrids and their parents did not increase, a greater proportion of DEGs would be non-additively (especially transgressively) expressed in the hybrids as genomes between the parents become more divergent. In addition, the proportion of genes with significant evidence of cis-regulatory divergence increased, whereas with trans-regulatory divergence decreased with parental genetic divergence. CONCLUSIONS: The discordance within hybrid would intensify as the parents become more divergent, manifesting as more DEGs would be non-additively expressed. Trans-regulatory divergence contributed more to the additively inherited genes than cis, however, its contribution to expression difference would be weakened as cis mutations accumulated over time; and this might be an important reason for that the more divergent the parents are, the greater proportion of DEGs would be non-additively expressed in hybrid.

Hydrogen Sulfide-Activatable Second Near-Infrared Fluorescent Nanoassemblies for Targeted Photothermal Cancer Therapy.

Near-infrared (NIR)-II fluorescence agents hold great promise for deep-tissue photothermal therapy (PTT) of cancers, which nevertheless remains restricted by the inherent nonspecificity and toxicity of PTT. In response to this challenge, we herein develop a hydrogen sulfide (H2S)-activatable nanostructured photothermal agent (Nano-PT) for site-specific NIR-II fluorescence-guided PTT of colorectal cancer (CRC). Our in vivo studies reveal that this theranostic Nano-PT probe is specifically activated in H2S-rich CRC tissues, whereas it is nonfunctional in normal tissues. Activation of Nano-PT not only emits NIR-II fluorescence with deeper tissue penetration ability than conventional fluorescent probes but also generates high NIR absorption resulting in efficient photothermal conversion under NIR laser irradiation. Importantly, we establish NIR-II imaging-guided PTT of CRC by applying the Nano-PT agent in tumor-bearing mice, which results in complete tumor regression with minimal nonspecific damages. Our studies thus shed light on the development of cancer biomarker-activated PTT for precision medicine.

Transcriptome analysis reveals hybridization-induced genome shock in an interspecific F1 hybrid from Camellia.

The combination of two divergent genomes during hybridization can result in "genome shock". Although genome shock has been reported in the hybrids of some herbaceous plants, the pattern and the principle it follows are far from understood, especially in woody plants. Here, the gene expression patterns were remodeled in the F1 hybrid from the crossing of Camellia azalea × Camellia amplexicaulis compared with the parents as revealed by RNA-seq. About 54.5% of all unigenes were differentially expressed between the F1 hybrid and at least one of the parents, including 6404 unigenes with the highest expression level in the F1 hybrid. A series of genes, related to flower development, essential for RNA-directed DNA methylation and histone methylation, as well as 223 transposable elements, were enriched; and most of them exhibited a higher level of expression in the F1 hybrid. These results indicated that the genome shock induced by interspecific hybridization in Camellia could indeed result in changes of gene expression patterns, potentially through regulating DNA methylation and histone methylation which may be helpful for the maintaining of genome stability and even related to the unique phenotype of the F1 hybrid.

MEF2C loss-of-function mutation associated with familial dilated cardiomyopathy.

BACKGROUND: The MADS-box transcription factor myocyte enhancer factor 2C (MEF2C) is required for the cardiac development and postnatal adaptation and in mice-targeted disruption of the MEF2C gene results in dilated cardiomyopathy (DCM). However, in humans, the association of MEF2C variation with DCM remains to be investigated. METHODS: The coding regions and splicing boundaries of the MEF2C gene were sequenced in 172 unrelated patients with idiopathic DCM. The available close relatives of the index patient harboring an identified MEF2C mutation and 300 unrelated, ethnically matched healthy individuals used as controls were genotyped for MEF2C. The functional effect of the mutant MEF2C protein was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. RESULTS: A novel heterozygous MEF2C mutation, p.Y157X, was detected in an index patient with adult-onset DCM. Genetic screen of the mutation carrier's family members revealed that the mutation co-segregated with DCM, which was transmitted as an autosomal dominant trait with complete penetrance. The non-sense mutation was absent in 300 control individuals. Functional analyses unveiled that the mutant MEF2C protein had no transcriptional activity. Furthermore, the mutation abolished the synergistic transactivation between MEF2C and GATA4 as well as HAND1, two other transcription factors that have been associated with DCM. CONCLUSIONS: This study indicates MEF2C as a new gene responsible for human DCM, which provides novel insight into the mechanism underpinning DCM, suggesting potential implications for development of innovative prophylactic and therapeutic strategies for DCM, the most prevalent form of primary myocardial disease.