Liquid metal for high-entropy alloy nanoparticles synthesis.

High-entropy alloy nanoparticles (HEA-NPs) show great potential as functional materials1-3. However, thus far, the realized high-entropy alloys have been restricted to palettes of similar elements, which greatly hinders the material design, property optimization and mechanistic exploration for different applications4,5. Herein, we discovered that liquid metal endowing negative mixing enthalpy with other elements could provide a stable thermodynamic condition and act as a desirable dynamic mixing reservoir, thus realizing the synthesis of HEA-NPs with a diverse range of metal elements in mild reaction conditions. The involved elements have a wide range of atomic radii (1.24-1.97 Å) and melting points (303-3,683 K). We also realized the precisely fabricated structures of nanoparticles via mixing enthalpy tuning. Moreover, the real-time conversion process (that is, from liquid metal to crystalline HEA-NPs) is captured in situ, which confirmed a dynamic fission-fusion behaviour during the alloying process.

The effect of the bgs13 mutation on the structure of the reporter protein beta-lactoglobulin: Influence on folding and aggregation in Pichia pastoris.

Pichia pastoris, a methylotrophic yeast used for recombinant protein expression, has the capability of performing many eukaryotic post-translational modifications, growing to high cell densities, and producing proteins in a cost-effective manner. However, P. pastoris's secretion properties are not always efficient, and its secretory pathway mechanisms have not been thoroughly elucidated. A previously identified mutant strain, bgs13, was found to efficiently secrete most recombinant proteins tested, raising the possibility that this bgs13 mutant is a universal super secreter. In this study, we used a reporter protein, ß-lactoglobulin (b-LG), to perform structural analysis of the protein secreted from wild type and mutant bgs13 strains to investigate the secretory mechanism. Primary, secondary, and tertiary structures of b-LG were examined using Edman sequencing, circular dichroism, tryptophan fluorescence, and temperature induced aggregation analysis. Our results demonstrate that the bgs13 produced more b-LG than the wt strain and that this protein was functionally folded similar to the wt. Surprisingly, we also found that the bgs13 b-LG was more resistant to aggregation, providing another example of the superior qualities of this strain for enhanced secreted protein production.

MTM-HCC at Previous Liver Resection as a Predictor of Overall Survival in Salvage Liver Transplantation.

OBJECTIVES: Salvage liver transplantation (sLT) is considered an effective method to treat hepatocellular carcinoma (HCC) recurrence. This multicenter research aimed to identify the prognostic factors associated with recurrence-free survival (RFS) and overall survival (OS) after sLT. MATERIAL AND METHODS: A retrospective analysis of 114 patients who had undergone sLT for recurrent HCC between February 2012 and September 2020 was performed. The baseline and clinicopathological data of the patients were collected. RESULTS: The 1-, 3-, and 5-year RFS rates after sLT were 88.9%, 75.2%, and 69.2%, respectively, and the OS rates were 96.4%, 78.3%, and 70.8%. A time from liver resection (LR) to recurrence < 1 year, disease beyond the Milan criteria at sLT and macrotrabecular massive (MTM)-HCC were identified as risk factors for RFS and were further identified as independent risk factors. A time from LR to recurrence < 1 year, disease beyond the Milan criteria at sLT and MTM-HCC were also risk factors for OS and were further identified as independent risk factors. CONCLUSIONS: Compared with primary liver transplantation (pLT), more prognostic factors are available from patients who had undergone LR. We suggest that in cases of HCC recurrence within 1 year after LR, disease beyond the Milan criteria at sLT and MTM-HCC patients, sLT should be used with caution.

A Cadaveric Limb Analysis of the Posterior Tibial Musculotendinous Junction to determine the feasibility of Interosseous Membrane Tendon Transfer.

The transfer of the posterior tibial tendon through the interosseous membrane is potentially an effective treatment to correct the deformity of the foot and ankle. Our study aimed to evaluate the anatomical feasibility of anterior transfer of the posterior tibial tendon through the interosseous membrane route using the musculotendinous junction (MTJ). Eighteen adult cadavers were used. The width and thickness of the tibial posterior MTJ, width of the interosseous membrane at the corresponding level, and the window size of the interosseous membrane were measured. Additionally, the distance between the distal end of the MTJ and the tip of the medial malleolus were recorded. The mean length of the posterior tibial tendon was 83.60 mm, the mean distance of the posterior tibial MTJ to medial malleolus tip was 45.48 mm and the mean length of MTJ was 31.74 mm. The mean width of distal end of MTJ was 7.76 mm, thickness of distal end of MTJ was 4.07 mm and the mean width of the interosseous membrane at the distal end of MTJ was 4.76 mm. We found the mean width of the proximal end of MTJ was 20.68 mm, the mean thickness of proximal end of MTJ was 5.52 mm, and mean width of interosseous membrane at the proximal end of MTJ was 8.76 mm. Our study has demonstrated that a 31 mm length incision made at approximately 45 mm from the proximal end of the medial malleolus can safely reach the MTJ. We recommend an opening length of the interosseous membrane of at least 20 mm.

Effects of oral stimulation with breast milk in preterm infants oral feeding: a randomized clinical trial.

OBJECTIVES: This study was performed to evaluate the effect of oral stimulation with breast milk for preterm infants. METHODS: A total of 68 subjects form neonatal intensive care unit were randomly assigned into control group (n=20), premature infant oral motor intervention (PIOMI) group (n=25) and premature infant oral motor intervention with breast milk (BM-PIOMI) group (n=23). RESULTS: BM-PIOMI group had significant shorter initiation of oral feeding (IOF) time compared to PIOMI group (2.95 days, 95% CI [0.42-5.48]) or control group (9.79 days, 95% CI [7.07-12.51]). BM-PIOMI group had significant sooner transition time from IOF to full oral feeding (FOF) compared to control group (6.68 days, 95% CI [2.2-11.16]), but not to PIOMI group (2.09 days, 95% CI [-2.07 to 6.25]). Length of hospital stay (LOS) did not show statistical different between three groups (control 38.85 ± 14.40 vs. PIOMI 38.48 ± 11.76 vs. BM-PIOMI 38.04 ± 12.2). Growth mixture model identified improvement in non-nutritive sucking (NNS) score in BM-PIOMI group compared to control and PIOMI group (0.8293, p<0.0001, and 0.8296, p<0.0001, respectively). CONCLUSIONS: Oral stimulation with breast milk can better promotes the oral feeding process of premature infants than the simple oral stimulation, by shorten IOF time and improve early NNS score, but does not shorten transition time from IOF to FOF and LOS.

A New C22-Quassinoid with Anti-Pancreatic Adenocarcinoma Activity from Seeds of Brucea javanica.

An undescribed C22-quassinoid named sergeolide A (1) and fifteen known quassinoids (2-16) were obtained from the seeds of Brucea javanica (Simaroubaceae). All chemical structures were established based on spectroscopic data and X-ray diffraction analysis. Sergeolide A (1) is the first example of a naturally occurring C22-quassinoid bearing a butenolide group fused the A ring of the bruceolide skeleton from Brucea genus. And this is the first report of the NMR data for desmethyl-bruceines B (2) and C (3) and the crystal structure for bruceolide (11). In addition, all isolates were evaluated for their anti-pancreatic adenocarcinoma activity by measuring the growth inhibitory of the MIA PaCa-2 cell lines. Consequently, compounds 1, 7-10, and 12-16 exhibited potent anti-pancreatic cancer activity in vitro (IC50 =0.054∼0.357 µM).

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

Bruceine A induces cell growth inhibition and apoptosis through PFKFB4/GSK3ß signaling in pancreatic cancer.

Pancreatic cancer is one of the most aggressive cancers with a poor prognosis and 5-year low survival rate. In the present study, we report that bruceine A, a quassinoid found in Brucea javanica (L.) Merr. has a strong antitumor activity against human pancreatic cancer cells both in vitro and in vivo. Human proteome microarray reveals that 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is the candidate target of bruceine A and both fluorescence measurement and microscale thermophoresis suggest bruceine A binds to PFKFB4. Bruceine A suppresses glycolysis by inhibiting PFKFB4, leading to cell cycle arrest and apoptosis in MIA PaCa-2 cells. Furthermore, glycogen synthase kinase-3 ß (GSK3ß) is identified as a downstream target of PFKFB4 and an PFKFB4-interacting protein. Moreover, bruceine A induces cell growth inhibition and apoptosis through GSK3ß, which is dysregulated in pancreatic cancer and closely related to the prognosis. In all, these findings suggest that bruceine A inhibits human pancreatic cancer cell growth via PFKFB4/GSK3ß-mediated glycolysis, and it may serve as a potent agent for curing human pancreatic cancer.

Important role of surface plasmon coupling with the quantum wells in a surface plasmon enhanced color-converting structure of colloidal quantum dots on quantum wells.

To improve the color-conversion efficiency based on a quantum-well (QW) light-emitting diode (LED), a more energy-saving strategy is needed to increase the energy transfer efficiency from the electrical input power of the LED into the emission of over-coated color-converter, not just from LED emission into converted light. In this regard, the efficiency of energy transfer of any mechanism from LED QW into the color-converter is an important issue. By overlaying blue-emitting QW structures and GaN templates with both deposited metal nanoparticles (DMNPs) and color-converting quantum dot (QD) linked synthesized metal nanoparticles (SMNPs) of different localized surface plasmon (LSP) resonance wavelengths for producing multiple surface plasmon (SP) coupling mechanisms with the QW and QD, we study the enhancement variations of their internal quantum efficiencies and photoluminescence decay times. By comparing the QD emission efficiencies between the samples with and without QW, one can observe the advantageous effect of QW coupling with LSP resonances on QD emission efficiency. Also, with the LSP resonance wavelengths of both DMNPs and SMNPs close to the QW emission wavelength for producing strong SP coupling with the QW and hence QD absorption, a higher QD emission or color-conversion efficiency can be obtained.

Options for the treatment of intrahepatic recurrent hepatocellular carcinoma: Salvage liver transplantation or rehepatectomy?

OBJECTIVE: To explore prognostic factors by comparing the efficacy of salvage liver transplantation (sLT) and rehepatectomy (RH) for the treatment of recurrent hepatocellular carcinoma after hepatectomy. METHODS: Clinical data were collected for 124 patients treated at our center from January 2012 to August 2018. The median follow-up time for the patients was 39 months. By analyzing the clinical data between the sLT group (46 cases) and RH group (78 cases), the factors affecting the prognosis of patients were compared. RESULTS: The proportion of alpha-fetoprotein (AFP) ≥ 100 µg/L in the recurrence group was significantly higher than that in the recurrence-free group (70.0% vs 22.2%, P = .014). The postoperative overall survival (OS) and recurrence-free survival (RFS) were better in the sLT group than in the RH group (81.2% vs 36.9%, P < .01; 77.1% vs 55.6%, P = .019). In the sLT group, the OS and RFS in the AFP < 100 µg/L group were superior to those in the AFP ≥ 100 µg/L group (P = .046 and P = .002). CONCLUSION: The sLT group had achieved better efficacy than RH group, but when AFP ≥ 100 µg/L, sLT did not achieve better efficacy than RH.

Preparation of ultrathin carbon-coated CdS nanobelts for advanced Li and Na storage.

In this paper, we report a simple hydrothermal method for preparation of ultrathin carbon-coated CdS (CdS@C) nanobelts. The CdS@C nanobelts show superior electrochemical properties as an anode material for Li-ion batteries. The optimized CdS@C composites deliver a reversible capacity around 910 mAhg-1 and 48 mAhg-1 at 0.1 Ag-1 and 30.0 Ag-1, respectively. Moreover, the optimized nanobelts are also potential materials for Na storage. A stable capacity around 240 mAhg-1 is obtained at 0.1 Ag-1, even after 100 cycles.

Spatial range of the plasmonic Dicke effect in an InGaN/GaN multiple quantum well structure.

The plasmonic Dicke effect means a cooperative emission mechanism of multiple light emitters when they are simultaneously coupled with the same surface plasmon (SP) mode of a metal nanostructure to achieve a higher collective emission efficiency. Here, we compare the enhancements of emission efficiency among a series of SP-coupled InGaN/GaN quantum-well (QW) structures of different QW period numbers to show an emission behavior consistent with the plasmonic Dicke effect. The relative enhancement of overall emission efficiency increases with QW period number until it reaches a critical value, beyond which the enhancement starts to decrease. This critical QW period number corresponds to the effective depth range of the plasmonic Dicke effect in a multiple-QW system. It also represents an optimized QW structure for maximizing the SP coupling effect. Internal quantum efficiency and time-resolved photoluminescence are measured for comparing the enhanced emission efficiencies of blue and green QW structures with different QW period numbers through SP coupling induced by surface Ag nanoparticles.

Enhanced ion diffusion induced by structural transition of Li-modified borophosphene.

Density functional theory (DFT) calculations have been carried out to investigate the performance of borophosphene in lithium-ion batteries. Our study has revealed the following: (1) the Dirac cone in the electronic structure demonstrates the metallic nature of borophosphene, implying the enhanced electronic conductivity of the anode electrodes; (2) borophosphene shows high adsorption of Li ions with binding energies in the range of -0.6 to -1.1 eV; (3) the theoretical storage capacity is significantly high, up to 1282.7 mA h g-1, and more interestingly, a structural transition is observed in the host borophosphene at a high density of Li ions; (4) at low concentrations, graphene-like borophosphene shows isotropic diffusion of Li atoms with a barrier around 0.5 eV, while at high density, the phosphorene-like borophosphene exhibits a reduced barrier in the range of 0.12-0.14 eV along the zigzag direction, suggesting strong promotion of Li-ion transportation; (5) meanwhile, owing to the structural transition, phosphorene-like borophosphene exhibits highly anisotropic migration of Li ions along the zigzag and armchair directions. These new findings present the great advantages of borophosphene as an anode material in lithium-ion batteries.

Dynamics of greenhouse gas emission induced by different burrowing activities of fossorial vertebrates in the Qinghai-Tibetan Plateau alpine meadow ecosystem.

Plateau zokor (Myospalax baileyi) and plateau pika (Ochotona curzoniae) are endemic fossorial vertebrates in the Qinghai-Tibetan Plateau alpine meadow ecosystem. Their different burrowing activities together transform soil structure and then significantly change the landscape of meadow ecosystem. However, how their burrowing activities impact greenhouse gas (GHG) emissions and the pattern of GHG emissions between different types of tunnel burrowing still remain obscure. In this study, we conducted in situ measurements quantitatively investigating the impacts of the different burrowing activities of zokors and pikas on three main GHG CO2, CH4, and N2O from an alpine meadow ecosystem in southeastern Qinghai-Tibetan Plateau. Our results showed that zokor hummocks and pika burrows were sources of CO2 and N2O and sinks of CH4. Zokors burrowing increased N2O in the atmosphere, decreased CO2, and enhanced CH4 absorbing, while pikas burrowing increased N2O in the atmosphere and enhanced CH4 absorbing. Considering the controversial role of fossorial vertebrates in Qinghai-Tibetan Plateau, this study also shed lights on effective management of animal activities with the aim of stabilizing or increasing ecosystem carbon sequestration.

Identification, characterization and expression profiles of PSEN2 in the Chinese tree shrew (Tupaia belangeri chinensis).

The gene PSEN2 encodes presenilin-2, a subunit of γ-secretase. Mutations in PSEN2 are not only related to Alzheimer's disease but are also involved in other diseases. The Chinese tree shrew (Tupaia belangeri chinensis) is a potential animal model for Alzheimer's disease, although little is known about its cDNA sequence, protein structure, and PSEN2 expression. To better understand PSEN2 in the tree shrew, we cloned this gene by rapid amplification of cDNA ends technology. Hence, we analyzed the sequence and molecular characteristics of PSEN2 mRNA, predicted its spatial structure, and analyzed its expression profiles. We found that tree shrew PSEN2 is 1539 base pairs in length and encodes 330 amino acids. It is homologous and genetically similar to humans (97.64% identity). The protein structure of tree shrew PSEN2 indicated similarities to human PSEN2, both being comprised of numerous transmembrane helices. However, tree shrew PSEN2 possesses seven α-helices, and thus lacks three compared with human PSEN2. Tree shrew PSEN2 mRNAs were ubiquitously detected in all tissues, with a tissue- and temporal-specific pattern. These results pave the way towards the function of tree shrew PSEN2, which will give insights into the mechanisms leading to neurodegenerative and other diseases in humans.

[16-gauge vs 18-gauge puncture needle for transrectal ultrasound-guided prostate biopsy in the diagnosis of prostate cancer: Effect and complications].

OBJECTIVE: To compare the efficiency and complications of transrectal ultrasound (TRUS)-guided prostate biopsy with a 16-gauge (16G) or an 18G puncture needle in the diagnosis of PCa. METHODS: This prospective randomized controlled study included 142 male patients undergoing TRUS-guided prostate biopsy in our hospital, 71 with the 16G and the other 71 with the 18G puncture needle. We compared the post-puncture incidence rates of hematuria, bleeding and infection between the two groups of patients and classified the complications according to the Clavien-Dindo scores. RESULTS: The detection rate of PCa was significantly lower in the 18G than in the 16G group (12.68% vs 36.62%, χ2 = 10.958, P = 0.001), even with f/tPSA ≤ 0.15 (8.51% vs 44.44%, χ2 = 12.617, P = 0.001), but showed no statistically significant difference between the two groups with f/tPSA > 0.15 (P<0.05). No post-puncture infection was observed in any of the patients. There were no statistically significant differences between the 18G and 16G groups in the incidence rates of rectal bleeding (21.13% vs 15.49%, χ2 = 0.753, P = 0.385) and urethral bleeding (18.31% vs 16.90%, χ2 = 0.049, P = 0.826), nor in Clavien-Dindo grades (26 vs 20 cases of grade I; no grade II in either group; 2 vs 3 cases of grade III ; Z = －0.698, P = 0.458). CONCLUSIONS: The 16G puncture needle can achieve a higher detection rate of PCa than the 18G needle in TRUS-guided prostate biopsy without increasing the incidence of complications.

Expression of VEGFR-2 and Meis1 in the early stage of kidney cancers and its clinical significance. / Meis1与VEGFR-2åœ¨æ—©æœŸè‚¾ç™Œç»„ç»‡ä¸­çš„è¡¨è¾¾åŠå ¶ä¸´åºŠæ„ä¹‰.

OBJECTIVES: To evaluate the expression of myeloid ecotropic viral integration site 1 (Meis1) and vascular endothelial growth factor receptor 2 (VEGFR-2) in early-stage kidney cancers and the clinical significance. METHODS: The cancer tissues and the matched adjacent normal tissues in patients with kidney cancer, who received surgical treatment from April 2005 to September 2018 in the Haikou Hospital Affiliated to Xiangya School of Medicine, Central South University, were collected. The samples included 80 pairs of paraffin specimen, 15 pairs of fresh cancer and the matched adjacent normal tissues from these patients. Real-time PCR and immunohistochemical method were used to detect the expression levels of Meis1 and VEGFR-2 mRNA and protein in kidney tissues and adjacent normal tissues, and the correlation of clinical pathology parameters and the prognosis were analyzed in the patients. RESULTS: The expression levels of Meis1 and VEGFR-2 mRNA and protein in the renal carcinoma tissues were lower than those in the matched adjacent normal tissues (both P<0.01), and the expression levels of Meis1 were positively correlated with that of VEGFR-2 (r=0.681, P<0.01). The analysis of relevant clinical-pathological parameters in the patients showed that: the expression positive rate of Meis1 was significantly related with the pathological type of renal cancer (P<0.01), while the positive rate of Meis1 and VEGFR-2 expression was not related with the gender, age, T stage of patients (all P>0.05), but it was significantly related with the prognosis in the patients (P<0.05). Cox regression analysis showed that: Meis1 was an independent factor for the prognosis of patients (P<0.05). CONCLUSIONS: The mRNA and protein expression levels of Meis1 and VEGFR-2 in the early-stage kidney cancer tissues are significantly decreased compared with those in the adjacent normal tissues. Meis1 may be served as a tumor suppressor to affect the occurrence and development of kidney cancer. Therefore, Meis1 may be used as a biomarker to predict the prognosis of patients with kidney cancer.

DNA damage-induced activation of ATM promotes ß-TRCP-mediated ARID1A ubiquitination and destruction in gastric cancer cells.

BACKGROUND: AT-rich interactive domain-containing protein 1A (ARID1A) is a subunit of the mammary SWI/SNF chromatin remodeling complex and a tumor suppressor protein. The loss of ARID1A been observed in several types of human cancers and associated with poor patient prognosis. Previously, we have reported that ARID1A protein was rapidly ubiquitinated and destructed in gastric cancer cells during DNA damage response. However, the ubiquitin e3 ligase that mediated this process remains unclear. MATERIALS AND METHODS: The interaction between ARID1A and ß-TRCP was verified by co-immunoprecipitation (Co-IP) assay. The degron site of ARID1A protein was analyzed by bioinformatics assay. Short hairpin RNAs (shRNAs) were used to knockdown (KD) gene expression. RESULTS: Here we show that DNA damage promotes ARID1A ubiquitination and subsequent destruction via the ubiquitin E3 ligase complex SCFß-TRCP. ß-TRCP recognizes ARID1A through a canonical degron site (DSGXXS) after its phosphorylation in response to DNA damage. Notably, genetic inactivation of the Ataxia Telangiectasia Mutated (ATM) kinase impaired DNA damage-induced ARID1A destruction. CONCLUSIONS: Our studies provide a novel molecular mechanism for the negative regulation of ARID1A by ß-TRCP and ATM in DNA damaged gastric cancer cells.

Studies on the lipid-regulating mechanism of alisol-based compounds on lipoprotein lipase.

Studies on the lipid-regulating effects of alisol compounds are reported that include alisol B, alisol A 24-acetate (24A), alisol A and an alisol B - 24A - alisol A mixture (content ratio = 1:1:1). The effects on the activity of lipoprotein lipase (LPL), a key lipid-modulating enzyme, were studied to investigate the molecular mechanism of lipid-regulating activity of alisols. The effects of alisols on regulating blood lipids and the activities of LPL were determined using a reagent kit method. The structure of LPL was obtained by homology modeling and the interactive mechanism of alisol monomers and the mixture with LPL was investigated by molecular simulation. The alisol monomer and mixture were shown to regulate blood lipids, suggesting that alisols may decrease the level of triglyceride (TG) by improving the activity of LPL. The order of intensity was: mixture > alisol A > alisol B > 24A, indicating that alisols of alismatis rhizoma feature a synergistic effect on LPL. The N- and C-terminus of LPL both represented the catalytic active domains of this lipid-regulating effect. Cys306, Gln129 and Ser166 were the key amino acid residues resulting in the lipid-regulating effect of the alisol monomer while Ser166 and Arg18 were found to be responsible for the lipid-regulating effect of the mixture. The C-terminus of LPL was indirectly involved in the enzymatic process. A folded side chain of alisols or the parent ring was found to bind somewhat weaker to LPL than an open side chain or parent ring. The hydroxyl groups on the C14-, C22-, C28-, C30- and C31-terminus in the side chain, the ring ether structure in C23-position, and the acetyl group in C29-position represented the key sites for the lipid-regulating action of alisols. Meanwhile, the C30-site hydroxyl group played an important role in the synergistic effect of the alisol mixture.

A Novel MEF2C Loss-of-Function Mutation Associated with Congenital Double Outlet Right Ventricle.

Congenital heart defect (CHD) represents the most prevalent birth defect, and accounts for substantial morbidity and mortality in humans. Aggregating evidence demonstrates the genetic basis for CHD. However, CHD is a heterogeneous disease, and the genetic determinants underlying CHD in most patients remain unknown. In the present study, a cohort of 186 unrelated cases with CHD and 300 unrelated control individuals were recruited. The coding exons and flanking introns of the MEF2C gene, which encodes a transcription factor crucial for proper cardiovascular development, were sequenced in all study participants. The functional effect of an identified MEF2C mutation was characterized using a dual-luciferase reporter assay system. As a result, a novel heterozygous MEF2C mutation, p.R15C, was detected in an index patient with congenital double outlet right ventricle (DORV) as well as ventricular septal defect. Analysis of the proband's pedigree showed that the mutation co-segregated with CHD with complete penetrance. The missense mutation, which changed the evolutionarily conserved amino acid, was absent in 300 control individuals. Functional deciphers revealed that the mutant MEF2C protein had a significantly decreased transcriptional activity. Furthermore, the mutation significantly reduced the synergistic activation between MEF2C and GATA4, another transcription factor linked to CHD. This study firstly associates MEF2C loss-of-function mutation with DORV in humans, which provides novel insight into the molecular pathogenesis of CHD, suggesting potential implications for genetic counseling and personalized treatment of CHD patients.