A Coupling-Induced Assembly Strategy for Constructing Artificial Shell on Mitochondria in Living Cells.

The strategy of in vivo self-assembly has been developed for improved enrichment and long-term retention of anticancer drug in tumor tissues. However, most self-assemblies with non-covalent bonding interactions are susceptible to complex physiological environments, leading to weak stability and loss of biological function. Here, we develop a coupling-induced assembly (CIA) strategy to generate covalently crosslinked nanofibers, which is applied for in situ constructing artificial shell on mitochondria. The oxidation-responsive peptide-porphyrin conjugate P1 is synthesized, which self-assemble into nanoparticles. Under the oxidative microenvironment of mitochondria, the coupling of thiols in P1 causes the formation of dimers, which is further ordered and stacked into crosslinked nanofibers. As a result, the artificial shell is constructed on the mitochondria efficiently through multivalent cooperative interactions due to the increased binding sites. Under ultrasound (US) irradiation, the porphyrin molecules in the shell produce a large amount of reactive oxygen species (ROS) that act on the adjacent mitochondrial membrane, exhibiting ~2-fold higher antitumor activity than nanoparticles in vitro and in vivo. Therefore, the mitochondria-targeted CIA strategy provides a novel perspective on improved sonodynamic therapy (SDT) and shows potential applications in antitumor therapies.

Terahertz s-SNOM Imaging of a Single Cell with Nanoscale Resolution.

Terahertz scattering scanning near-field optical microscopy is a robust spectral detection technique with a nanoscale resolution. However, there are still major challenges in investigating the heterogeneity of cell membrane components in individual cells. Here, we present a novel and comprehensive analytical approach for detecting and investigating heterogeneity in cell membrane components at the single-cell level. In comparison to the resolution of the topographical atomic force microscopy image, the spatial resolution of the terahertz near-field amplitude image is 3 times that of the former. This ultrafine resolution enables the compositional distribution in the cell membrane, such as the distribution of extracellular vesicles, to be finely characterized. Furthermore, via extraction of the near-field absorption images at specific frequencies, the visualization and compositional difference analysis of cell membrane components can be presented in detail. These findings have significant implications for the intuitive and visual analysis of cell development and disease evolutionary pathways.

Nanomechanical collective vibration of SARS-CoV-2 spike proteins.

The development of effective therapeutics against COVID-19 requires a thorough understanding of the receptor recognition mechanism of the SARS-CoV-2 spike (S) protein. Here the multidomain collective dynamics on the trimer of the spike protein has been analyzed using normal mode analysis (NMA). A common nanomechanical profile was identified in the spike proteins of SARS-CoV-2 and its variants. The profile involves collective vibrations of the receptor-binding domain (RBD) and the N-terminal domain (NTD), which may mediate the physical interaction process. Quantitative analysis of the collective modes suggests a nanomechanical property involving large-scale conformational changes, which explains the difference in receptor binding affinity among different variants. These results support the use of intrinsic global dynamics as a valuable perspective for studying the allosteric and functional mechanisms of the S protein. This approach also provides a low-cost theoretical toolkit for screening potential pathogenic mutations and drug targets.

Detecting mental and physical disorders using multi-task learning equipped with knowledge graph attention network.

Mental and physical disorders (MPD) are inextricably linked in many medical cases; psychosomatic diseases can be induced by mental concerns and psychological discomfort can ensue from physiological diseases. However, existing medical informatics studies focus on identifying mental or physical disorders from a unilateral perspective. Consequently, no existing domain knowledge base, corpus, or detection modeling approach considers mental as well as physical aspects concurrently. This paper proposes a joint modeling approach to detect MPD. First, we crawl through online medical consultation records of patients from websites and build an MPD knowledge ontology by extracting the core conceptual features of the text. Based on the ontology, an MPD knowledge graph containing 12,673 nodes and 82,195 relations is obtained using term matching with a domain thesaurus of each concept. Subsequently, an MPD corpus with fine-grained severities (None, Mild, Moderate, Severe, Dangerous) and 8909 records is constructed by formulating MPD classification criteria and a data annotation process under the guidance of domain experts. Taking the knowledge graph and corpus as the dataset, we design a multi-task learning model to detect the MPD severity, in which a knowledge graph attention network (KGAT) is embedded to better extract knowledge features. Experiments are performed to demonstrate the effectiveness of our model. Furthermore, we employ ontology-based and centrality-based methods to discover additional potential inferred knowledge, which can be captured by KGAT so as to improve the prediction performance and interpretability of our model. Our dataset has been made publicly available, so it can be further used as a medical informatics reference in the fields of psychosomatic medicine, psychiatrics, physical co-morbidity, and so on.

Neutralization of SARS-CoV-2 BA.2.86 and JN.1 by CF501 adjuvant-enhanced immune responses targeting the conserved epitopes in ancestral RBD.

The emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants BA.2.86 and JN.1 raise concerns regarding their potential to evade immune surveillance and spread globally. Here, we test sera from rhesus macaques immunized with 3 doses of wild-type SARS-CoV-2 receptor-binding domain (RBD)-Fc adjuvanted with the STING agonist CF501. We find that the sera can potently neutralize pseudotyped XBB.1.5, XBB.1.16, CH.1.1, EG.5, BA.2.86, and JN.1, with 50% neutralization titers ranging from 3,494 to 7,424. We also demonstrate that CF501, but not Alum, can enhance immunogenicity of the RBD from wild-type SARS-CoV-2 to improve induction of broadly neutralizing antibodies (bnAbs) with binding specificity and activity similar to those of SA55, BN03, and S309, thus exhibiting extraordinary broad-spectrum neutralizing activity. Overall, the RBD from wild-type SARS-CoV-2 also contains conservative epitopes. The RBD-Fc adjuvanted by CF501 can elicit potent bnAbs against JN.1, BA.2.86, and other XBB subvariants. This strategy can be adopted to develop broad-spectrum vaccines to combat future emerging and reemerging viral infectious diseases.

Clinical development of antivirals against SARS-CoV-2 and its variants.

The unceasing global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) calls for the development of novel therapeutics. Although many newly developed antivirals and repurposed antivirals have been applied to the treatment of coronavirus disease 2019 (COVID-19), antivirals showing satisfactory clinical efficacy are few in number. In addition, the loss of sensitivity to variants of concern (VOCs) and lack of oral bioavailability have also limited the clinical application of some antivirals. These facts remind us to develop more potent and broad-spectrum antivirals with better pharmacokinetic/pharmacodynamic properties to fight against infections from SARS-CoV-2, its variants, and other human coronaviruses (HCoVs). In this review, we summarize the latest advancements in the clinical development of antivirals against infections by SARS-CoV-2 and its variants.

All-temperature area battery application mechanism, performance, and strategies.

Further applications of electric vehicles (EVs) and energy storage stations are limited because of the thermal sensitivity, volatility, and poor durability of lithium-ion batteries (LIBs), especially given the urgent requirements for all-climate utilization and fast charging. This study comprehensively reviews the thermal characteristics and management of LIBs in an all-temperature area based on the performance, mechanism, and thermal management strategy levels. At the performance level, the external features of the batteries were analyzed and compared in cold and hot environments. At the mechanism level, the heat generation principles and thermal features of LIBs under different temperature conditions were summarized from the perspectives of thermal and electrothermal mechanisms. At the strategy level, to maintain the temperature/thermal consistency and prevent poor subzero temperature performance and local/global overheating, conventional and novel battery thermal management systems (BTMSs) are discussed from the perspective of temperature control, thermal consistency, and power cost. Moreover, future countermeasures to enhance the performance of all-climate areas at the material, cell, and system levels are discussed. This study provides insights and methodologies to guarantee the performance and safety of LIBs used in EVs and energy storage stations.

A pan-sarbecovirus vaccine based on RBD of SARS-CoV-2 original strain elicits potent neutralizing antibodies against XBB in non-human primates.

The recently emerged Omicron subvariants XBB and BQ.1.1 have presented striking immune evasion against most monoclonal neutralizing antibodies and convalescent plasma. Therefore, it is essential to develop broad-spectrum COVID-19 vaccines to combat current and future emerging variants. Here, we found that the human IgG Fc-conjugated RBD of the original SARS-CoV-2 strain (WA1) plus a novel STING agonist-based adjuvant CF501 (CF501/RBD-Fc) could induce highly potent and durable broad-neutralizing antibody (bnAb) responses against Omicron subvariants, including BQ.1.1 and XBB in rhesus macaques with NT50s ranging from 2,118 to 61,742 after three doses. A decline of 0.9- to 4.7-fold was observed in the neutralization activity of sera in the CF501/RBD-Fc group against BA.2.2, BA.2.9, BA.5, BA.2.75, and BF.7 relative to D614G after three doses, while a significant decline of NT50 against BQ.1.1 (26.9-fold) and XBB (22.5-fold) relative to D614G. However, the bnAbs were still effective in neutralizing BQ.1.1 and XBB infection. These results suggest that the conservative but nondominant epitopes in RBD could be stimulated by CF501 to generate bnAbs, providing a proof-of-concept for using "nonchangeable against changeables" strategy to develop pan-sarbecovirus vaccines against sarbecoviruses, including SARS-CoV-2 and its variants.

Cost-effective duplex Kompetitive Allele Specific PCR markers for homologous genes facilitating wheat breeding.

BACKGROUND: Owing to successful cloning of wheat functional genes in recent years, more traits can be selected by diagnostic markers, and consequently, effective molecular markers will be powerful tools in wheat breeding programs. RESULTS: The present study proposed a cost-effective duplex Kompetitive Allele Specific PCR (dKASP) marker system that combined multiplex PCR and KASP™ technology to yield twice the efficiency at half the cost compared with the common KASP™ markers and provide great assistance in breeding selection. Three dKASP markers for the major genes controlling plant height (Rht-B1/Rht-D1), grain hardness (Pina-D1/Pinb-D1), and high-molecular-weight glutenin subunits (Glu-A1/Glu-D1) were successfully developed and applied in approved wheat varieties growing in the middle and lower reaches of the Yangtze River and advanced lines from our breeding program. Three markers were used to test six loci with high efficiency. In the approved wheat varieties, Rht-B1b was the most important dwarfing allele, and the number of accessions carrying Pinb-D1b was much greater than that of the accessions carrying Pina-D1b. Moreover, the number of accessions carrying favorable alleles for weak-gluten wheat (Null/Dx2) was much greater than that of the accessions carrying favorable alleles for strong-gluten wheat (Ax1 or Ax2*/Dx5). In the advanced lines, Rht-B1b and Pinb-D1b showed a significant increase compared with the approved varieties, and the strong-gluten (Ax1 or Ax2*/Dx5) and weak-gluten (Null/Dx2) types also increased. CONCLUSION: A cost-effective dKASP marker system that combined multiplex PCR and KASP™ technology was proposed to achieve double the efficiency at half the cost compared with the common KASP™ markers. Three dKASP markers for the major genes controlling PH (Rht-B1/Rht-D1), GH (Pina-D1/Pinb-D1), and HMW-GS (Glu-A1/Glu-D1) were successfully developed, which would greatly improve the efficiency of marker-assisted selection of wheat.

Development of variant-proof severe acute respiratory syndrome coronavirus 2, pan-sarbecovirus, and pan-ß-coronavirus vaccines.

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with high transmission rates and striking immune evasion have posed a serious challenge to the application of current first-generation SARS-CoV-2 vaccines. Other sarbecoviruses, such as SARS-CoV and SARS-related coronaviruses (SARSr-CoVs), have the potential to cause outbreaks in the future. These facts call for the development of variant-proof SARS-CoV-2, pan-sarbecovirus or pan-ß-CoV vaccines. Several novel vaccine platforms have been used to develop vaccines with broad-spectrum neutralizing antibody responses and protective immunity to combat the current SARS-CoV-2 and its variants, other sarbecoviruses, as well as other ß-CoVs, in the future. In this review, we discussed the major target antigens and protective efficacy of current SARS-CoV-2 vaccines and summarized recent advances in broad-spectrum vaccines against sarbecoviruses and ß-CoVs.

Genome-wide evolutionary analysis of AUX/IAA gene family in wheat identifies a novel gene TaIAA15-1A regulating flowering time by interacting with ARF.

Flowering time is a critical agronomic trait that has strong effects on crop yields. Auxin signaling pathway plays an important role in various development processes, such as flowering, grain development. However, no Aux/IAA gene had been reported to have functions involving in wheat flowering time. Here, we systematically performed genome-wide identification, classification, domain distribution, exon-intron structure, chromosome locations and global expression pattern of Aux/IAA gene family in 14 plant genomes (including Triticum aestivum). A phylogenetic model was proposed to infer the Aux/IAA evolutionary history involving in a central exon-intron structure "2121" during evolution. Overexpression of TaIAA15-1A caused an early flowering time in Brachypodium. RNA-seq analysis showed that TaIAA15-1A overexpression alters various pathways including phytohormone signaling pathway, flowering-related pathway, and polyamine biosynthesis pathway. Screening of auxin response factor (ARF) genes identified BdARF16 that interacted with TaIAA15-1A. Exogenous polyamine (spermidine and spermine) treatments promoted early flowering and (putrescine and DCHA) delayed flowering time of WT plants. Our finding will provide insights on mechanisms of Aux/IAAs gene family and TaIAA15-1A, illustrating the potential during crop improvement programs.

Heat Generation and Degradation Mechanism of Lithium-Ion Batteries during High-Temperature Aging.

High-temperature aging has a serious impact on the safety and performance of lithium-ion batteries. This work comprehensively investigates the evolution of heat generation characteristics upon discharging and electrochemical performance and the degradation mechanism during high-temperature aging. Post-mortem characterization analysis revealed that lithium plating is the main degradation mechanism. The occurrence of side reactions leads to cell capacity fading and electrochemical performance degradation. The DC resistance and AC impedance increase significantly, and the severe internal polarization makes the incremental capacity curve shift to lower voltage. In the early aging stage, the cell degrades slightly, and the temperature rise rate has not changed significantly upon discharging. The cell capacity plays a leading role, whose degradation makes the temperature rise decrease. With the aging deepening, the severe cell degradation makes the temperature rise rate increase significantly. Even if the capacity fading, the temperature rise still increases significantly compared to the fresh state. Furthermore, irreversible heat and reversible heat increase significantly with the aging deepening and current rate increasing.

Exceptional soft tissue preservation reveals a cnidarian affinity for a Cambrian phosphatic tubicolous enigma.

Exoskeletal dwelling tubes are widespread among extant animals and early fossil assemblages. Exceptional fossils from the Cambrian reveal independent origins of tube dwelling by several clades including cnidarians, lophophorates, annelids, scalidophorans, panarthropods and ambulacrarians. However, most fossil tubes lack preservation of soft parts, making it difficult to understand their affinities and evolutionary significance. Gangtoucunia aspera (Wulongqing Formation, Cambrian Stage 4) was an annulated, gradually expanding phosphatic tube, with occasional attachments of multiple, smaller juveniles and has previously been interpreted as the dwelling tube of a 'worm' (e.g. a scalidophoran), lophophorate or problematicum. Here, we report the first soft tissues from Gangtoucunia that reveal a smooth body with circumoral tentacles and a blind, spacious gut that is partitioned by septa. This is consistent with cnidarian polyps and phylogenetic analysis resolves Gangtoucunia as a total group medusozoan. The tube of Gangtoucunia is phenotypically similar to problematic annulated tubular fossils (e.g. Sphenothallus, Byronia, hyolithelminths), which have been compared to both cnidarians and annelids, and are among the oldest assemblages of skeletal fossils. The cnidarian characters of G. aspera suggest that these early tubular taxa are best interpreted as cnidarians rather than sessile bilaterians in the absence of contrary soft tissue evidence.

Baseline Hemodynamic Impairment and Revascularization Outcome in Newly Diagnosed Adult Moyamoya Disease Determined by Pseudocontinuous Arterial Spin Labeling.

OBJECTIVE: The study aimed to investigate the hemodynamic features and independent predictors of neoangiogenesis after revascularization in moyamoya disease (MMD) by pseudocontinuous arterial spin labeling magnetic resonance imaging (pCASL MRI). METHODS: Thirty-nine MMD patients were categorized into infarction group, hemorrhagic group, and atypical group. All patients underwent combined bypass surgery and pCASL MRI with postlabeling delays (PLD) of 1525 ms and 2525 ms. Absolute CBFMCA (cerebral blood flow in middle cerebral artery territory), relative CBFMCA (CBFMCA 2525 ms/CBFMCA 1525 ms), and spatial coefficient of variation of MCA (CoVMCA) were analyzed. Relationships between CBFMCA and the following clinical parameters were assessed: Suzuki stage, modified Rankin scale (mRS), cerebrovascular accident lesion score, and deep medullary veins score. Potential predictors for favorable neoangiogenesis and hemodynamic changes were explored as well. RESULTS: Preoperative CBFMCA differed among MMD patients with variable clinical presentations, Matsushima stages, modified Rankin Scale scores, CVA scores, and deep medullary vein scores. After bypass surgery, mean CBFMCA increased significantly in the infarction group (P = 0.027) and decreased in the hemorrhagic group (P = 0.043), while spatial CoVMCA was observed to decline in all groups. Higher preoperative relative CBFMCA and spatial CoVMCA were independent predictors for robust neoangiogenesis after bypass. The cutoff value of 0.330 of spatial CoVMCA at long PLD yielded the best sensitivity at 82.1% and specificity at 81.8%. Furthermore, both preoperative relative CBFMCA and spatial CoVMCA showed mild positive correlations with ΔmRS in MMD patients. CONCLUSIONS: pCASL-MRI with multiple PLDs could reflect preoperative hemodynamic impairment and predict the neoangiogenesis after combined bypass surgery in moyamoya patients.

Caveolin-1 Promoted Collateral Vessel Formation in Patients With Moyamoya Disease.

Background: Caveolin-1 (Cav-1) plays pivotal roles in the endothelial function and angiogenesis postischemia. Moyamoya disease (MMD) is characterized by progressive artery stenosis with unknown etiology. We aim to determine whether serum Cav-1 levels of patients with MMD were associated with collateral vessel formation after bypass surgery. Methods: We studied serum Cav-1 levels of 130 patients with MMD (16 with RNF213 p.R4810K mutation and 114 without RNF213 p.R4810K mutation), 15 patients with acute stroke, and 33 healthy controls. Cerebral perfusion and collateral circulation were evaluated preoperation and at 6 months after operation using pseudocontinuous arterial spin labeling MRI (pCASL-MRI) and digital subtraction angiography (DSA), respectively. Endothelial expression of Cav-1 was verified in the superficial temporal artery (STA) wall of patients with MMD by immunofluorescence double staining. We also investigated whether overexpression of Cav-1 affects cell migration and tube formation using human microvascular endothelial cells (HMECs). Results: The serum Cav-1 level of patients with MMD intermediated between the stroke group and healthy controls and it was enhanced after the bypass surgery (681.87 ± 311.63 vs. 832.91 ± 464.41 pg/ml, p = 0.049). By 6 months after bypass surgery, patients with MMD with better collateral compensation manifested higher postoperative/preoperative Cav-1 ratio (rCav-1) than bad compensation patients. Consistently, cerebral blood flow (CBF) determined by pCASL-MRI (nCBFMCA ratio) was positively in line with rCav-1 ratio (r = 0.8615, p < 0.0001). Cav-1 was expressed in the endothelial cells of the STA vessels of patients with MMD. Overexpression of Cav-1 by plasmid transfection in HMECs promoted tube formation and cell migration. Conclusion: This study indicated that Cav-1 may be a potential driver to promote angiogenesis and collateral formation after bypass surgery in patients with MMD, providing a better understanding of MMD pathophysiology and potential non-surgical targets of MMD.

QTL detection for bread wheat processing quality in a nested association mapping population of semi-wild and domesticated wheat varieties.

BACKGROUND: Wheat processing quality is an important factor in evaluating overall wheat quality, and dough characteristics are important when assessing the processing quality of wheat. As a notable germplasm resource, semi-wild wheat has a key role in the study of wheat processing quality. RESULTS: In this study, four dough rheological characteristics were collected in four environments using a nested association mapping (NAM) population consisting of semi-wild and domesticated wheat varieties to identify quantitative trait loci (QTL) for wheat processing quality. A total of 49 QTL for wheat processing quality were detected, explaining 0.36-10.82% of the phenotypic variation. These QTL were located on all wheat chromosomes except for 2D, 3A, 3D, 6B, 6D and 7D. Compared to previous studies, 29 QTL were newly identified. Four novel QTL, QMlPH-1B.4, QMlPH-3B.4, QWdEm-1B.2 and QWdEm-3B.2, were stably identified in three or more environments, among which QMlPH-3B.4 was a major QTL. Moreover, eight important genetic regions for wheat processing quality were identified on chromosomes 1B, 3B and 4D, which showed pleiotropy for dough characteristics. In addition, out of 49 QTL, 15 favorable alleles came from three semi-wild parents, suggesting that the QTL alleles provided by the semi-wild parent were not utilized in domesticated varieties. CONCLUSIONS: The results show that semi-wild wheat varieties can enrich the existing wheat gene pool and provide broader variation resources for wheat genetic research.

A Palmitic Acid-Conjugated, Peptide-Based pan-CoV Fusion Inhibitor Potently Inhibits Infection of SARS-CoV-2 Omicron and Other Variants of Concern.

Our previous studies have shown that cholesterol-conjugated, peptide-based pan-coronavirus (CoV) fusion inhibitors can potently inhibit human CoV infection. However, only palmitic acid (C16)-based lipopeptide drugs have been tested clinically, suggesting that the development of C16-based lipopeptide drugs is feasible. Here, we designed and synthesized a C16-modified pan-CoV fusion inhibitor, EK1-C16, and found that it potently inhibited infection by SARS-CoV-2 and its variants of concern (VOCs), including Omicron, and other human CoVs and bat SARS-related CoVs (SARSr-CoVs). These results suggest that EK1-C16 could be further developed for clinical use to prevent and treat infection by the currently circulating MERS-CoV, SARS-CoV-2 and its VOCs, as well as any future emerging or re-emerging coronaviruses.

Membrane phosphatidylserine allosterically regulates the cytosolic phospholipase A2 activity via an electrostatic-switch mechanism.

Phospholipase A2 (PLA2) is a peripheral membrane protein that plays an essential role in many inflammatory responses. However, the activation mechanisms of PLA2 on the membrane surface have not been fully understood. Herein, we have combined experimental techniques and theoretical approaches to investigate the activation and association of the PLA2 protein on an artificial phospholipid membrane. Using a phosphatidylserine (PS) nanodomain containing membrane to mimic the inflammatory conditions, we found that the activity of cytosolic PLA2s (cPLA2s) increases with higher ratios of PS in the membrane. Molecular dynamics simulations reveal that significant changes in the protein structure are related to negatively charged membranes. In particular, the alteration of negatively charged residues in the C2 domain brings about an opened binding pocket and the catalytic site access to the substrate phospholipid. Meanwhile, the negative residues in the loop 650-665 facilitate the optimal interfacial orientation of the protein with a closed binding pocket on the membrane surface. These results lead us to suggest an electrostatic-switch allosteric mechanism for cPLA2 activation on the cell membrane surface under the inflammatory state.

LncRNA-mRNA Co-expression Profiles Relative to Vascular Remodeling in Moyamoya Patients Without RNF213 Mutation.

OBJECTIVE: Moyamoya disease (MMD) is an idiopathic cerebrovascular disease with unknown etiology. Long noncoding RNA (lncRNA) and messenger RNA (mRNA) profiles in MMD remain unknown. In this current study, we aim to investigate lncRNA-mRNA co-expression pattern and their biological functions in superficial temporal artery (STA) of MMD. METHODS: STA of 3 MMD patients without RNF213 mutation and 3 age-matched controls were obtained for transcriptomic RNA sequencing. Bioinformatics analysis was performed to investigate their molecular functions and interactions. Then, differentially expressed genes relative to vascular remodeling were further validated by quantitative real-time polymerase chain reaction and immunofluorescence. WNT5A functions were tested by tube formation assay and wound scratching assay in human microvascular endothelial cells (HMECs). RESULTS: We detected 6235 different lncRNAs and 2065 different mRNAs from the RNA-sequencing between MMD patients and controls (P < 0.05; fold change >2.0). Gene ontology showed that altered mRNAs were enriched for endothelial cell morphogenesis and positive regulation of angiogenesis, which were closely related with vascular remodeling. We then searched 76 altered genes related with vascular remodeling and applied Kyoto Encyclopedia of Genes and Genomes analysis. Integrated analysis of lncRNA-TF-mRNA co-expression networks and gene verifications indicated that molecular including WNT5A, TEK, and GATA2 may contribute to the vascular malformation of MMD. Overexpression of WNT5A in HMECs promoted tube formation and cell migration. CONCLUSIONS: In MMD patients, genes related to vascular remodeling including WNT5A and their regulators were aberrantly disrupted. These results will help elucidate the complicated pathogenic mechanism of MMD and develop potential therapeutic targets facilitating MMD angiogenesis in the future.