Lymphatic mimicry in maternal endothelial cells promotes placental spiral artery remodeling

Molecular heterogeneity of endothelial cells underlies their highly-specialized functions during changing physiological conditions within diverse vascular beds. For example, placental spiral arteries (SAs) undergo remarkable remodeling to meet the ever-growing demands of the fetus-a process which is deficient in preeclampsia. The extent to which maternal endothelial cells coordinate with immune cells and pregnancy hormones to promote SA remodeling remains largely unknown. Here we found that remodeled SAs expressed the lymphatic markers PROX1, LYVE1, and VEGFR3, mimicking lymphatic identity. Uterine natural killer (uNK) cells, which are required for SA remodeling and secrete VEGFC, were both sufficient and necessary for VEGFR3 activation in vitro and in mice lacking uNK cells, respectively. Using Flt4Chy/+ mice with kinase inactive VEGFR3 and Vegfcfl/fl;Vav1-Cre mice, we demonstrated that SA remodeling required VEGFR3 signaling, and that disrupted maternal VEGFR3 signaling contributed to late-gestation fetal growth restriction. Collectively, we identified a novel instance of lymphatic mimicry by which maternal endothelial cells promote SA remodeling, furthering our understanding of the vascular heterogeneity employed for the mitigation of pregnancy complications such as fetal growth restriction and preeclampsia

Data-Driven Approach to Assess Street Safety: Large-Scale Analysis of the Microscopic Design

Safety is an important quality of street space that affects people’s psychological state and behavior in many ways. Previous large-scale assessment of street safety focuses more on social and physical factors and has less correlation with spatial design, especially the microscopic design. Limited by data and methods, street safety assessment related to microscopic design is mostly conducted on the small scale. Based on multisource big data, this study conducts a data-driven approach to assess the safety of street microscope design on a large scale from the perspective of individual perception. An assessment system including four dimensions of walkability, spatial enclosure, visual permeability, and vitality is constructed, which reflects the individual perceptions of the street space. Intraclass correlation coefficient (ICC) and location-based service (LBS) data are used to verify the effectiveness of the assessment method. The results show that multisource big data can effectively measure the physical elements and design features of streets, reflecting street users’ perception of vision, function, architecture, and street form, as well as the spatial selectivity based on their judgment of safety. The measurement of multidimensional connotations and the fusion of multiple data mining technologies promote the accuracy and effectiveness of the assessment method. Street safety presents the spatial distribution of high-value aggregation and low-value dispersion. Street safety is relatively low in areas with a large scale, lack of street interface, large amount of transit traffic, and high-density vegetation cover. The proposed method and the obtained results can be a reference for humanized street design and sustainable urban traffic planning and management

Ag2S nanoparticles anchored on P-doped g-C3N4: a novel 0D/2D p-n 2 heterojunction for superior photocatalytic inactivation of 3 multidrug-resistant E. coli

Photocatalytic inactivation has been proved to be an effective strategy to eliminate pathogenic bacteria in water. Herein, a novel 0D/2D p-n heterojunction of Ag _2 S-anchored P-doped g-C _3 N _4 (Ag _2 S/PCN) were constructed by a simple two-step process coupling one-pot calcination and ultrasonic-assisted synthesis. The photocatalytic performance of as-prepared Ag _2 S/PCN composites was investigated by inactivating multidrug-resistant E. coli under visible light irradiation. The results indicated that Ag _2 S/PCN-5 possessed outstanding photocatalytic inactivation activity and superior stability, which could completely inactivate 7.0 log E. coli cells within 60 min. The enhanced photocatalytic activity of Ag _2 S/PCN-5 was mainly attributed to the elevated visible-light response and improved production and transfer of photoexcited charges. In addition, the free radicals trapping experiments results revealed that h ^+ and •O _2 ^− were predominantly responsible for the efficient inactivation activity. Finally, according to the 0D/2D structure and energy band configuration analysis, the enhanced p-n type heterojunction photocatalytic inactivation mechanism of Ag _2 S/PCN was discussed in detail

Association of metformin exposure with low risks of frailty and adverse outcomes in patients with diabetes

Abstract Background Diabetes is an independent risk factor of frailty, which increases adverse outcomes in patients with diabetes. Metformin is a common antidiabetic drug in clinical practice. Insulin resistance and chronic inflammation are the two common mechanisms of diabetes and frailty, as well as the main targets of metformin. Research suggested that metformin has anti-aging potential. However, few studies focus on the relationship between metformin and frailty. Thus, we aimed to explore whether metformin was associated with a low risk of frailty and other adverse outcomes in diabetic patients. Methods A total of 422 patients (≥ 40 years old) with type 2 diabetes were recruited. Frailty was defined by the Fried phenotype. General information and metformin exposure data were collected, and comprehensive geriatric assessment and laboratory tests were performed. Follow-up was conducted after 4.5 years. The primary outcome was the combined endpoint of cardiovascular events, cerebrovascular events, readmission, and death. Binary logistic regression analysis was used to analyze the association of metformin with frailty. Survival analysis was performed using Cox proportional hazards models. Results The total prevalence of frailty was 19.4% among the participants with diabetes. 13.1% of patients in the metformin group and 28.2% in the non-metformin group had frailty. Metformin was inversely associated with frailty after adjusting for age, sex, duration, blood glucose levels, target organ damage, comorbidities, and polypharmacy. Further longitudinal analysis showed that metformin was also independently associated with a low risk of combined primary outcomes after adjusting for multiple covariables, while frailty was related to an increased risk of the combined primary outcomes. In the non-frail group, metformin was associated with a decreased risk of combined primary outcomes after adjustment for age and sex. However, the protective effect of metformin on adverse outcomes was not found in frail participants with diabetes. Conclusions Metformin use is associated with a reduced risk of frailty. In addition, frailty may attenuate the protective effects of metformin on adverse outcomes in diabetic patients. The early identification and prevention of frailty progression may help enhance the benefits of metformin in patients with diabetes

A blood capillary plexus-derived population of progenitor cells contributes to genesis of the dermal lymphatic vasculature during embryonic development

Despite the essential role of the lymphatic vasculature in tissue homeostasis and disease, knowledge of the organ-specific origins of lymphatic endothelial progenitor cells remains limited. The assumption that most murine embryonic lymphatic endothelial cells (LECs) are venous derived has recently been challenged. Here, we show that the embryonic dermal blood capillary plexus constitutes an additional, local source of LECs that contributes to the formation of the dermal lymphatic vascular network. We describe a novel mechanism whereby rare PROX1-positive endothelial cells exit the capillary plexus in a Ccbe1-dependent manner to establish discrete LEC clusters. As development proceeds, these clusters expand and further contribute to the growing lymphatic system. Lineage tracing and analyses of Gata2-deficient mice confirmed that these clusters are endothelial in origin. Furthermore, ectopic expression of Vegfc in the vasculature increased the number of PROX1-positive progenitors within the capillary bed. Our work reveals a novel source of lymphatic endothelial progenitors employed during construction of the dermal lymphatic vasculature and demonstrates that the blood vasculature is likely to remain an ongoing source of LECs during organogenesis, raising the question of whether a similar mechanism operates during pathological lymphangiogenesis

Lymphoangiocrine signals promote cardiac growth and repair.

This work was supported by NIH grant (RO1HL073402-16) to G.O, AHA grant (18CDA34110356) to X.L, 5T32HL134633 to W.M, FPU grant from the Spanish Ministry of Education, Culture and Sports and EMBO ShortTerm Fellowship to E.C.C, Leducq TNE-17CVD and RD16/0011/0019 (ISCIII) from the Spanish Ministry of Science, Innovation, and Universities to M.T, NIH T32 GM008061 to C.L, HL63762, and NS093382 to J.H. We thank Dr. Gabriele M. Rune and Dr. Bianka Brunne for the Reln +/− strain. RNAseq work was supported by the Northwestern University NUSeq Core Facility. We thank the Robert H. Lurie Cancer Center Flow Cytometry facility supported by NCI CCSG P30 CA060553 for their invaluable assistance. Flow Cytometry Cell Sorting was performed on a BD FACSAria SORP system and BD FACSymphony S6 SORP system, purchased through the support of NIH 1S10OD011996-01 and 1S10OD026814-01. Imaging work was performed at the Northwestern University Center for Advanced Microscopy supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Spinning disk confocal microscopy was performed on an Andor XDI Revolution microscope, purchased through the support of NCRR 1S10 RR031680-01. Proteomics services were performed by the Northwestern Proteomics Core Facility supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center, instrumentation award (S10OD025194) from NIH Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569. We thank the George M. O’Brien Kidney Research Core Center (NU GoKidney, supported by a P30 DK114857 award from NIDDK) for the use of the Echocardiography machine. The myocardial infarction surgeries were performed by the comprehensive Transplant Center Microsurgery Core, partially supported by NIH NIAID P01AI112522. We thank Dr. Jing Jin and Dr. Pan Liu for help with the ELISA reagents and data analysis, Dr. Ruihua Ma for help with DNA polyploidy analysis, Ao Shi for the Mef2c antibodies, Dr. Michael Dellinger for the Prox1CreERT2 mice and Dr. Hossein Ardehali for the MhcCre mice. We specially thank Dr. Beatriz Sosa-Pineda for advice and valuable suggestions and Dr. Pilar Ruiz-Lozano for shearing her expertise in the preparation of the collagen patches.Recent studies have suggested that lymphatics help to restore heart function after cardiac injury1-6. Here we report that lymphatics promote cardiac growth, repair and cardioprotection in mice. We show that a lymphoangiocrine signal produced by lymphatic endothelial cells (LECs) controls the proliferation and survival of cardiomyocytes during heart development, improves neonatal cardiac regeneration and is cardioprotective after myocardial infarction. Embryos that lack LECs develop smaller hearts as a consequence of reduced cardiomyocyte proliferation and increased cardiomyocyte apoptosis. Culturing primary mouse cardiomyocytes in LEC-conditioned medium increases cardiomyocyte proliferation and survival, which indicates that LECs produce lymphoangiocrine signals that control cardiomyocyte homeostasis. Characterization of the LEC secretome identified the extracellular protein reelin (RELN) as a key component of this process. Moreover, we report that LEC-specific Reln-null mouse embryos develop smaller hearts, that RELN is required for efficient heart repair and function after neonatal myocardial infarction, and that cardiac delivery of RELN using collagen patches improves heart function in adult mice after myocardial infarction by a cardioprotective effect. These results highlight a lymphoangiocrine role of LECs during cardiac development and injury response, and identify RELN as an important mediator of this function.S