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Heterostyly, a plant sexual polymorphism controlled by the S-locus supergene, has evolved numerous times among angiosperm lineages and represents a classic example of convergent evolution in form and function. Determining whether underlying molecular convergence occurs could provide insights on constraints to floral evolution. Here, we investigated S-locus genes in distylous Gelsemium (Gelsemiaceae) to determine whether there is evidence of molecular convergence with unrelated distylous species. We used several approaches, including anatomical measurements of sex-organ development and transcriptome and whole-genome sequencing, to identify components of the S-locus supergene. We also performed evolutionary analysis with candidate S-locus genes and compared them with those reported in Primula and Turnera. The candidate S-locus supergene of Gelsemium contained four genes, of which three appear to have originated from gene duplication events within Gelsemiaceae. The style-length genes GeCYP in Gelsemium and CYP734A50 in Primula likely arose from duplication of the same gene, CYP734A1. Three out of four S-locus genes in Gelsemium elegans were hemizygous, as previously reported in Primula and Turnera. We provide genomic evidence on the genetic convergence of the supergene underlying distyly among distantly related angiosperm lineages and help to illuminate the genetic architecture involved in the evolution of heterostyly.

Koumine, an indole alkaloid extracted from Gelsemium elegans Benth, exerts anti-inflammation and antioxidant activities. However, the effects of koumine on intestinal injury induced by HWe established an IPEC-J2 cell damage model induced by HIn the experiment, cell damage models were made with hydrogen peroxide. To assess the protective effect of koumine on HThe results of CCK-8 and LDH implied that koumine has a mitigative effect on HThis in vitro experimental study suggests that koumine suppresses the H

Antibiotics have been extensively used to ensure the productivity of animals on intensive livestock farms. Accordingly, antimicrobial-resistant organisms, which can be transmitted to humans via the food chain, pose a threat to public health. The Enterobacterium antimicrobial resistance gene

To investigate the post-liquefaction shearing behaviour of saturated gravelly soil, laboratory tests were conducted using a static-dynamic multi-purpose triaxial apparatus. In addition, numerical simulations using the discrete element method (DEM) were performed to preliminarily understand the micro-mechanism of gravelly soil in monotonic loading after liquefaction. The influences of dry density, initial confining stress and degree of liquefaction on the post-liquefaction shearing behaviour of gravelly soil were discussed, and the evolution of the micro-parameters of the granular system was also analysed. The results show that the stress-strain responses of gravelly soil after liquefaction can be divided into three stages: (1) low strength stage, (2) super-linear strength recovery stage, and (3) sublinear strength recovery stage, which are distinctly different from those of the general saturated gravelly soil without previous cyclic loading. The initial state and prior dynamic stress history have significant influences on the post-liquefaction shearing behaviour of gravelly soil. The DEM simulation revealed that the average coordination number sharply increases, the contact normal shows an obvious orientation distribution, and the destroyed force chain backbones are reconstructed in the monotonic reloading process after liquefaction. The evolution of the micro-parameters of the granular system clearly reflects the interior interaction process and micro-mechanisms in the particles during the three different stages of the macro-mechanical behaviour of gravelly soil.

Objective: Angiocrine factors, mediating the endothelial-mural cell interaction in vascular wall construction as well as maintenance, are incompletely characterized. This study aims to investigate the role of endothelial cell–derived FSTL1 (follistatin-like protein 1) in vascular homeostasis. Approach and Results: Using conditional knockout mouse models, we show that loss of FSTL1 in endothelial cells ( Fstl1 ECKO ) led to an increase of pulmonary vascular resistance, resulting in the heart regurgitation especially with tricuspid valves. However, this abnormality was not detected in mutant mice with Fstl1 knockout in smooth muscle cells or hematopoietic cells. We further showed that there was excessive αSMA (α-smooth muscle actin) associated with atrial endocardia, heart valves, veins, and microvessels after the endothelial FSTL1 deletion. There was also an increase in collagen deposition, as demonstrated in livers of Fstl1 ECKO mutants. The SMAD3 (mothers against decapentaplegic homolog 3) phosphorylation (pSMAD3) was significantly enhanced, and pSMAD3 staining was colocalized with αSMA in vein walls, suggesting the activation of TGFβ (transforming growth factor β) signaling in vascular mural cells of Fstl1 ECKO mice. Consistently, treatment with a TGFβ pathway inhibitor reduced the abnormal association of αSMA with the atria and blood vessels in Fstl1 ECKO mutant mice. Conclusions: The findings imply that endothelial FSTL1 is critical for the homeostasis of vascular walls, and its insufficiency may favor cardiovascular fibrosis leading to heart failure.

Partially submerged deposit slopes are often encountered in practical engineering applications. However, studies on evaluating their stability under seismic loading are still rare. In order to understand the seismic behavior of partially submerged deposit slopes, centrifuge shaking table model tests (50g) were employed. The responses of horizontal accelerations, accumulated excess pore pressures, deformation mode, and failure mode of the partially submerged deposit slope model were analyzed. In dynamic centrifuge model tests, EQ5 shaking event was applied numerically. The results indicated that in the saturated zone of the deposit slope, liquefaction did not occur, and the measured horizontal accelerations near the water table were amplified as a layer-magnification effect. It was also shown that the liquefaction-resistance of the deposit slope increased under multiple sequential ground motions, and the deformation depth of the deposit slope induced by earthquake increased gradually with increasing dynamic load amplitude. Except for the excessive crest settlement generated by strong shaking, an additional vertical permanent displacement was initiated at the slope crest due to the dissipation of excess pore pressure under seismic loading. The result of particle image velocimetry (PIV) analysis showed that an obvious internal arc-slip was generated around the water table of the partially submerged deposit slope under seismic loading. Keywords: Centrifuge model test, Acceleration responses, Excess pore pressure, Deposit slope

Background: Naja atra is a venomous snake species medically relevant in China. In the current study, we evaluated the composition and toxicological profile of venom collected from farm-raised N. atra. Methods: Venom was collected from third-generation captive bred N. atra on a snake farm in Hunan Province, China. The venom was analyzed using sodium dodecyl sulfate polyacrylamide gel electrophoresis and nano-liquid chromatography with electrospray ionization tandem mass spectrometry. In addition, hemolytic activity, median lethal dose, serum biochemical and histopathological parameters were accessed. Results: N. atra venom proteome was dominated by phospholipase A2 (46.5%) and three-finger toxins (41.4 %), and a set of common low relative abundance proteins, including cysteine-rich secretory proteins (4.7%), NGF-beta (2.4%), snake venom metalloproteinase (1.5%), glutathione peroxidase (0.6%), vespryn (0.3%), and 5ʹ-nucleotidases (0.2%) were also found. Furthermore, the venom exhibited direct hemolytic activity, neurotoxicity, myotoxicity, and high lethal potency in mice, with a subcutaneous median lethal dose of 1.02 mg/kg. Histopathological analysis and serum biochemical tests revealed that venom caused acute hepatic, pulmonary and renal injury in mice. Conclusion: This study revealed the composition and toxicity of venom collected from farm-raised N. atra, thereby providing a reference for the analysis of venom samples collected from captive-born venomous snakes in the future.

Colistin is one of the last-line drugs against difficult to treat and multidrug-resistant Gram-negative bacteria. The emergence of mobile colistin resistance gene m

Aeromonas hydrophila, a heterotrophic and Gram-negative bacterium, has attracted considerable attention owing to the increasing prevalence of reported infections. Colistin is a last-resort antibiotic that can treat life-threatening infections caused by multidrug-resistant Gram-negative bacteria. However, the mechanisms underlying colistin resistance in A. hydrophila remain unclear. The present study reveals four novel colistin resistance mechanisms in A. hydrophila: (i) EnvZ/OmpR upregulates the expression of the arnBCADTEF operon to mediate lipopolysaccharide (LPS) modification by 4-amino-4-deoxy-l-arabinose, (ii) EnvZ/OmpR regulates the expression of the autotransporter gene3832 to decrease outer membrane permeability in response to colistin, (iii) deletion of envZ/ompR activates PhoP/PhoQ, which functions as a substitute two-component system to mediate the addition of phosphoethanolamine to lipid A via pmrC, and (iv) the mlaFD173A mutant confers high-level colistin resistance via upregulation of the Mla pathway. The EnvZ/OmpR two-component system-mediated resistance mechanism is the leading form of colistin resistance in A. hydrophila, which enables it to rapidly generate low- to medium-level colistin resistance. As colistin concentrations in the environment continue to rise, antibiotic resistance mediated by EnvZ/OmpR becomes insufficient to ensure bacterial survival. Consequently, A. hydrophila has developed an mlaF mutation that results in high-level colistin resistance. Our findings indicate that A. hydrophila can thrive in a complex environment through various colistin resistance mechanisms.

Venom was collected from third-generation captive bredThis study revealed the composition and toxicity of venom collected from farm-raised

The seismic performance of stabilising piles used to reinforce underlying bedrock in a deposit slope is a complex soil-structure interaction problem, on which there is limited design guidance on the optimum use of a single row of rock-socketed piles to reinforce such slopes. Two centrifuge shaking-table model tests at a geometric scale of 1:50 were conducted to ascertain the dynamic responses of the underlying bedrock deposit slopes without and with the use of stabilising piles during an earthquake. Multi-stage seismic waves with various peak accelerations were applied from the bottom of each model. Under seismic excitation, the differences in the response accelerations between the deposit and bedrock increase significantly with the increase in amplitude of the input seismic waves. The two are prone to uncoordinated movement, which leads to slope instability. Setting stabilising piles reduces the crest settlement and angular deformation and changes the natural frequency of the slope crest. The presence of the rock-socketed stabilising piles can bridge the uncoordinated movement of the bedrock and the overlying deposit to some extent. According to the mobilised pile bending moment, shear force, lateral pile-soil load distribution, and pile displacement, the dynamic response characteristics of stabilising piles under continuous multi-level seismic excitation were analysed. The resultant force arising from a distributed load increment on the piles caused by an earthquake is mainly concentrated in the upper part (the point of action of the resultant force is 1.54m below the slope surface). With increases in the peak ground acceleration (PGA) of the input motion, the resistance of the bedrock in front of the stabilising piles increases; moreover, with the increase of PGA, the peak resistance under the bedrock surface of the stabilising piles gradually moves downwards. This finding indicates that the strong seismic motion significantly changes the embedded working state of the stabilising pile.

A series of indoor tests was performed to obtain the physical and mechanical properties and structural characterization of granite residual soil. Experimental results indicated that clot and flocculation are the primary forms of microstructure, and the residual appearance of the parent rock’s crystal pattern is reserved. Structural strength is provided by strong cementation and residual chemical bond force. The clay mineral is mostly kaolin, which exhibits a laminated structure. The grain particle of granite residual soil presents the mixed features of sand and clay. The coefficient of compressibility is mostly distributed with in the range of 0.30–0.35 MPa−1, which is for medium compressible soil. Granite residual soil demonstrates good mechanical performance even under saturation condition. However, strength variability is notable. Drying and wetting cycles reduce the strength of granite residual soil, and strength decreases by approximately 30% after two drying and wetting cycles.

The prevalence and antimicrobial susceptibility of Clostridium perfringens (C. perfringens) in chickens and pigs were investigated in Beijing and Shanxi, China. In total, 322 C. perfringens (chicken n = 60 and pig n = 262) were obtained from 620 feces of chickens (n = 256) and pigs (n = 364). Multiplex PCR for toxin typing of C. perfringens revealed that all the isolates belong to type A, with 45.7 % (147/322) isolates carrying beta-2 toxin-encoding gene cpb2. Minimum inhibitory concentrations of 27 antimicrobial agents showed that 91.0 % of the tested C. perfringens isolates were resistant to gentamicin and sulfonamides (sulfisoxazole and trimethoprim-sulfamethoxazole), and little resistance was showed to amoxicillin-clavulanate, ceftiofur, doxycycline, vancomycin and linezolid. Additionally, nosiheptide, avilamycin, virginiamycin and bacitracin exhibited good activity against the tested C. perfringens with low MIC50 (0.06 to ≤4 μg/mL) and MIC90 values (0.25-8 μg/mL). Whole genome sequencing (WGS) of 48 representative isolates from each farm indicated that the C. perfringens contained diverse antimicrobial resistance genes [tetA(P), ant(6)-Ib, erm(Q), etc.] and toxin genes (cpb2, colA, cloSI, pfoA, etc.). By comparative analysis, four C. perfringens isolates from three different pig farms harboured cpb2-carrying plasmid p1 with 100 % nucleotide sequence identity, suggesting horizontal gene transfer among these microorganisms. The further phylogenomic reconstruction, based on the core-genome single nucleotide polymorphisms (SNPs) of the representatives, demonstrating that C. perfringens from the same farms and regions were closely related. These findings expanded our knowledge of C. perfringens isolated from animals in China, which provided scientific basis for efficient intervention or prevention measures of antimicrobial resistance in animal husbandry in China.

The micropile-cantilever retaining wall (CRW) combined retaining structures are widely used in slope reinforcement design. While the landslide thrust distributed between the micropiles and the CRW remains unclear. In this work, the seismic response of a micropile-reinforced cut slope behind a CRW are studied by means of a centrifuge shaking-table model test. The proportion of slope sliding force borne by CRW and micropiles under multistage earthquakes is revealed. When the backfill has a large slope angle and loads are applied to the upper part of the slope crest, the dynamic earth pressure coefficient is much larger than that when the backfill surface is horizontal and no additional loads are applied. The current data show that the residual bending moment accumulates significantly on the CRW and micropiles after an earthquake, which must be considered during the seismic design of the micropile-CRW combined retaining structures.

Deinagkistrodon acutus is a venomous pit viper commonly used in traditional Chinese medicine; farming these snakes has become a major industry. In 2017, an outbreak of fatal diarrhoea among farm-raised D. acutus in Hunan Province caused the deaths of 5,600 snakes within 3 weeks. We isolated a brand-new sequence type of Aeromonas hydrophila (ST516) from lesions and confirmed that this bacterium was the causal agent of the outbreak. Snakes infected with the bacterium in the laboratory showed similar clinical symptoms to those of snakes in the original outbreak. We also tested bacterial virulence in Kunming mice to examine the likelihood of zoonosis. Isolates were pathogenic to mice, causing diarrhoea within 4 hr post-challenge, which indicates that the bacterium can potentially infect mammals. Environmental analysis showed that polluted spring water likely caused the diarrhoea in snakes. This study is the first to report on a large-scale outbreak of fatal diarrhoea in farm-raised snakes, originating in a pathogen that can infect mammals. These results should raise awareness regarding potential anthropozoonosis among poikilotherms, mammals, and humans; appropriate prevention or control methods should be developed.

Inertial instability-induced slope failure is one of the most destructive seismic hazards encountered in China. Depositional slopes are widely distributed across the south-western part of China. To study the seismic performance of rock–soil mixture deposit (RSMD) slopes in detail, physical and mechanical tests of air-dried RSMD, and a 1:50 geometric scale, generalised RSMD slope centrifugal shaking table modelling tests were conducted. The acceleration response, slope deformation, and instability mode of the air-dried RSMD slope under the continuous action of four earthquakes with different intensities are analysed. Besides, the dynamic finite-difference numerical simulations were performed with FLAC to simulate the centrifuge model test. The numerical simulation results were compared with the test results in terms of the horizontal acceleration response, time history of crest settlements, and the slope failure characteristics. The results show that the horizontal peak ground acceleration (PGA) amplification factors of the RSMD slope reflect typical elevation, and surface, amplification effects. In addition, the spectral distribution of the seismic wave has changed significantly with propagation along the slope elevation. The energy of input seismic wave in a frequency range close to the natural frequency of an RSMD slope is significantly amplified. During the test, it was observed that the failure of an air-dried RSMD slope occurred when the PGA reached 0.216 g, and the settlement at the crest of the slope was obvious. The failure mode was dominated by shallow collapse.

Background Long non-coding RNAs (lncRNAs) participate in many biological dynamics and play significant roles in gene regulation. LncRNA expression is altered in many cancers; however, the expressions and functions of lncRNA genes in lung adenocarcinoma (LAD) remain unknown. Methods LncRNA and messenger RNA (mRNA) expression in LAD without lymphatic metastasis versus paired adjacent non-tumor (ANT) lung tissues and LAD with versus without lymphatic metastasis were analyzed using Human LncRNA Arraystar V3.0. The expression levels of four downregulated and four upregulated lncRNAs were verified using quantitative real-time PCR in cells and tissue specimens. Results In this study, 949 lncRNAs and 681 mRNAs had differential expression in LAD without lymphatic metastasis compared to ANT lung tissues, while 2740 lncRNAs and 1714 mRNAs were differentially expressed in LAD with lymphatic metastasis compared to LAD without lymphatic metastasis. The expression patterns of selected lncRNAs (LINC00113, AC005009.1, ARHGAP22-IT1, AC009411.1, SRGAP3-AS2, EGFEM1P, FAM66E, and HLA-F-AS1) were consistent with microarray data. Differentially expressed mRNA genes were enriched in crucial Gene Ontology terms and pathways. Conclusion Our results revealed differentially expressed lncRNAs in LAD, suggesting lncRNAs may be potential indicators for LAD diagnosis and therapy.

Background Gelsemium elegans (G. elegans) (2n = 2x = 16) is genus of flowering plants belonging to the Gelsemicaeae family. Method Here, a high-quality genome assembly using the Oxford Nanopore Technologies (ONT) platform and high-throughput chromosome conformation capture techniques (Hi-C) were used. Results A total of 56.11 Gb of raw GridION X5 platform ONT reads (6.23 Gb per cell) were generated. After filtering, 53.45 Gb of clean reads were obtained, giving 160 × coverage depth. The de novo genome assemblies 335.13 Mb, close to the 338 Mb estimated by k-mer analysis, was generated with contig N50 of 10.23 Mb. The vast majority (99.2%) of the G. elegans assembled sequence was anchored onto 8 pseudo-chromosomes. The genome completeness was then evaluated and 1338 of the 1440 conserved genes (92.9%) could be found in the assembly. Genome annotation revealed that 43.16% of the G. elegans genome is composed of repetitive elements and 23.9% is composed of long terminal repeat elements. We predicted 26,768 protein-coding genes, of which 84.56% were functionally annotated. Conclusion The genomic sequences of G. elegans could be a valuable source for comparative genomic analysis in the Gelsemicaeae family and will be useful for understanding the phylogenetic relationships of the indole alkaloid metabolism., Graphical abstract Here, we report a high-quality Gelsemium elegans genome assembly using the ONT platform and Hi-C. The de novo genome assemblies 335.13 Mb, was generated with contig N50 of 10.23 Mb. The vast majority (99.2%) of the G. elegans assembled sequence was anchored onto the 8 pseudo-chromosomes.Image 1

Epithelial-mesenchymal transition (EMT) is one of important steps that lead to cancer metastasis. Interleukin-22 (IL-22) is a T helper 17 (Th17) cells-secreted cytokine, it can promote invasion and metastasis of many cancers. MiR-486-5p is a microRNA that known to function as a tumor suppressor, and bioinformatics analysis predicts that Dock-1 has a binding site of miR-486-5p. In current research, we examined the relative expression levels of miR-486-5p and Dock-1 in 80 pairs of breast cancer tissues and corresponding adjacent normal tissues, also the effects of modifying their levels in cultured cells. We illustrated that IL-22 and Dock1 promote the invasion, metastasis, and EMT of breast cancer using Transwell invasion assay, western blot and immunofluorescence. MiR-486-5p directly bound the Dock1 mRNA 3' untranslated region and inhibited IL-22-induced EMT of breast cancer cells via the Dock1/NF-κB/Snail signaling pathway. Dock1 overexpression reversed the effect caused by the overexpression of miR-486-5p. Overexpression of miR-486-5p or downregulation of Dock1 reduced pulmonary metastasis in mice. This study provided insight into a potential mechanism where miRNAs regulate breast cancer metastasis and provided a novel therapeutic target for breast cancer treatment.

Background Long non‐coding RNAs (lncRNAs) participate in many biological dynamics and play significant roles in gene regulation. LncRNA expression is altered in many cancers; however, the expressions and functions of lncRNA genes in lung adenocarcinoma (LAD) remain unknown. Methods LncRNA and messenger RNA (mRNA) expression in LAD without lymphatic metastasis versus paired adjacent non‐tumor (ANT) lung tissues and LAD with versus without lymphatic metastasis were analyzed using Human LncRNA Arraystar V3.0. The expression levels of four downregulated and four upregulated lncRNAs were verified using quantitative real‐time PCR in cells and tissue specimens. Results In this study, 949 lncRNAs and 681 mRNAs had differential expression in LAD without lymphatic metastasis compared to ANT lung tissues, while 2740 lncRNAs and 1714 mRNAs were differentially expressed in LAD with lymphatic metastasis compared to LAD without lymphatic metastasis. The expression patterns of selected lncRNAs (LINC00113, AC005009.1, ARHGAP22‐IT1, AC009411.1, SRGAP3‐AS2, EGFEM1P, FAM66E, and HLA‐F‐AS1) were consistent with microarray data. Differentially expressed mRNA genes were enriched in crucial Gene Ontology terms and pathways. Conclusion Our results revealed differentially expressed lncRNAs in LAD, suggesting lncRNAs may be potential indicators for LAD diagnosis and therapy.

This paper presents an intensive review of the constitutive models for frozen soil. The models are classified into five categories, namely, empirically fitted model, classical plastic model, rate process model, element assembly model, and hypo-plastic model. The background and relative merits of each type of the models are elucidated.

Recent studies show that mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) signaling pathways are two pivotal roles contributing to the development of lipopolysaccharide (LPS)-induced acute lung injury (ALI). The present study aimed to investigate the protective effect of kaempferol (Kae), a naturally occurring flavonoid compound, on ALI and explore its possible mechanisms. Male BALB/c mice with ALI, induced by intranasal instillation of LPS, were treated or not with Kae (100 mg/kg, intragastrically) 1h prior to LPS exposure. Kae treatment attenuated pulmonary edema of mice with ALI after LPS challenge, as it markedly decreased the lung W/D ratio of lung samples, protein concentration and the amounts of inflammatory cells in BALF. Similarly, LPS mediated overproduction of proinflammatory cytokines in BALF, including TNF-α, IL-1β and IL-6, was strongly reduced by Kae. Histological studies demonstrated that Kae substantially inhibited LPS-induced alveolar wall thickness, alveolar hemorrhage and leukocytes infiltration in lung tissue with evidence of reduced myeloperoxidase (MPO) activity. Kae also efficiently increased superoxide dismutase (SOD) activity of lung sample when compared with LPS group, which was obviously reduced by LPS administration. In addition, Western blot analysis indicated that the activation of MAPKs and NF-κB signaling pathways stimulated by LPS was significantly blocked by Kae. Taken together, our results suggest that Kae exhibits a protective effect on LPS-induced ALI via suppression of MAPKs and NF-κB signaling pathways, which may involve the inhibition of tissue oxidative injury and pulmonary inflammatory process.

Decades of intensive irrigation of farmlands in the oasis irrigated areas of Xinjiang, Northwest China has caused secondary salinization of vast areas of land since the mid-1980s. Based on the systematic analysis of the monitoring data of hydrology, soil, irrigation and salinity at two different scales in the case of Weigan River Plain Oasis in Xinjiang Province, algorithms derived from hydrosalinity balance principle were developed to estimate the salt mobilization and characteristics; salt and water mobilization and distribution were closely examined both in catchment scale and in field scale. The critical ratio of drainage to irrigation of Weigan River Plain Oasis was estimated to be 9.19%. Furthermore, analysis of the relationship between the two different scaling issues was illustrated. Finally, corresponding countermeasures for secondary soil salinization were proposed according to the different developmental stages and salinization status of water and soil resources.The findings of this paper is helpful in controlling the local hydrology, in limiting or diminishing salinization trends, as well as in providing academic and instructive meaning for the sustainable development of agriculture in oasis irrigation areas.

Conjugates of the Escherichia coli serum antibody (Ab) with the gentamicin sulfate (GM sulfate) have been evaluated for the assessment of their ability to eradicate E. coli in vitro. The combination of every component in the targeted drug is the amino of serum antibody and gentamicin sulfate combined with the hydroxyl of PEG6000 by hydrogen bond, which forms stable complexes. The half-life of this complex is 4.83 h, and it is non-toxic side effects and low immunogenic. After the combination of antibody and gentamicin sulfate, the targeting of antibody is quite good. In vitro anti-bacterial activity of gentamicin sulfate increased 1000 times, and the clinical curative effect enhanced 100 times, this means higher efficacy and safety.

Publisher Copyright: © 2022 American Society for Clinical Investigation. All rights reserved. Vascular endothelial growth factor C (VEGF-C) induces lymphangiogenesis via VEGF receptor 3 (VEGFR3), which is encoded by the most frequently mutated gene in human primary lymphedema. Angiopoietins (Angs) and their Tie receptors regulate lymphatic vessel development, and mutations of the ANGPT2 gene were recently found in human primary lymphedema. However, the mechanistic basis of Ang2 activity in lymphangiogenesis is not fully understood. Here, we used gene deletion, blocking Abs, transgene induction, and gene transfer to study how Ang2, its Tie2 receptor, and Tie1 regulate lymphatic vessels. We discovered that VEGF-C-induced Ang2 secretion from lymphatic endothelial cells (LECs) was involved in full Akt activation downstream of phosphoinositide 3 kinase (PI3K). Neonatal deletion of genes encoding the Tie receptors or Ang2 in LECs, or administration of an Ang2-blocking Ab decreased VEGFR3 presentation on LECs and inhibited lymphangiogenesis. A similar effect was observed in LECs upon deletion of the PI3K catalytic p110α subunit or with smallmolecule inhibition of a constitutively active PI3K located downstream of Ang2. Deletion of Tie receptors or blockade of Ang2 decreased VEGF-C-induced lymphangiogenesis also in adult mice. Our results reveal an important crosstalk between the VEGF-C and Ang signaling pathways and suggest new avenues for therapeutic manipulation of lymphangiogenesis by targeting Ang2/Tie/PI3K signaling.