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Lymphangiogenesis is supported by 2 homologous VEGFR3 ligands, VEGFC and VEGFD. VEGFC is required for lymphatic development, while VEGFD is not. VEGFC and VEGFD are proteolytically cleaved after cell secretion in vitro, and recent studies have implicated the protease a disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3) and the secreted factor collagen and calcium binding EGF domains 1 (CCBE1) in this process. It is not well understood how ligand proteolysis is controlled at the molecular level or how this process regulates lymphangiogenesis, because these complex molecular interactions have been difficult to follow ex vivo and test in vivo. Here, we have developed and used biochemical and cellular tools to demonstrate that an ADAMTS3-CCBE1 complex can form independently of VEGFR3 and is required to convert VEGFC, but not VEGFD, into an active ligand. Consistent with these ex vivo findings, mouse genetic studies revealed that ADAMTS3 is required for lymphatic development in a manner that is identical to the requirement of VEGFC and CCBE1 for lymphatic development. Moreover, CCBE1 was required for in vivo lymphangiogenesis stimulated by VEGFC but not VEGFD. Together, these studies reveal that lymphangiogenesis is regulated by two distinct proteolytic mechanisms of ligand activation: one in which VEGFC activation by ADAMTS3 and CCBE1 spatially and temporally patterns developing lymphatics, and one in which VEGFD activation by a distinct proteolytic mechanism may be stimulated during inflammatory lymphatic growth.

Human vascular endothelial cells (EC) basally display class I and II MHC-peptide complexes on their surface and come in regular contact with circulating T cells. We propose that EC present microbial antigens to memory T cells as a mechanism of immune surveillance. Activated T cells, in turn, provide both soluble and contact-dependent signals to modulate normal EC functions, including formation and remodeling of blood vessels, regulation of blood flow, regulation of blood fluidity, maintenance of permselectivity, recruitment of inflammatory leukocytes, and antigen presentation leading to activation of T cells. T cell interactions with vascular EC are thus bidirectional and link the immune and circulatory systems.

Implants of collagen-fibronectin gels containing Bcl-2-transduced human umbilical vein endothelial cells (Bcl-2-HUVECs) induce the formation of human endothelial cell (EC)/murine vascular smooth muscle cell (VSMC) chimeric vessels in immunodeficient mice. Microfil casting of the vasculature 60 d after implantation reveals highly branched microvascular networks within the implants that connect with and induce remodeling of conduit vessels arising from the abdominal wall circulation. Approximately 85% of vessels within the implants are lined by Bcl-2-positive human ECs expressing VEGFR1, VEGFR2, and Tie-2, but not integrin αvβ3. The human ECs are seated on a well formed human laminin/collagen IV-positive basement membrane, and are surrounded by mouse VSMCs expressing SM-α actin, SM myosin, SM22α, and calponin, all markers of contractile function. Transmission electron microscopy identified well formed EC-EC junctions, chimeric arterioles with concentric layers of contractile VSMC, chimeric capillaries surrounded by pericytes, and chimeric venules. Bcl-2-HUVEC-lined vessels retain 70-kDa FITC-dextran, but not 3-kDa dextran; local histamine rapidly induces leak of 70-kDa FITC-dextran or India ink. As in skin, TNF induces E-selectin and vascular cell adhesion molecule 1 only on venular ECs, whereas intercellular adhesion molecule-1 is up-regulated on all human ECs. Bcl-2-HUVEC implants are able to engraft within and increase perfusion of ischemic mouse gastrocnemius muscle after femoral artery ligation. These studies show that cultured Bcl-2-HUVECs can differentiate into arterial, venular, and capillary-like ECs when implanted in vivo, and induce arteriogenic remodeling of the local mouse vessels. Our results support the utility of differentiated EC transplantation to treat tissue ischemia.

Orf, also known as contagious ecthyma, is a zoonotic infection caused by a dermatotropic parapoxvirus that commonly infects sheep and goats; it is transmitted to humans through contact with an infected animal or fomites. In humans, orf manifests as an ulcerative skin lesion sometimes resembling bacterial infection or neoplasm. Human infection typically is associated with occupational animal contact and has been reported in children after visiting petting zoos and livestock fairs. Cases lacking these exposure histories might be misdiagnosed, leading to unnecessary treatment of orf lesions, which do not usually require any specific treatment. This report describes four cases of human orf associated with household meat processing or animal slaughter, highlighting the importance of nontraditional risk factors. Orf should be included in the differential diagnosis of patients with clinically compatible skin lesions and a history of household meat processing or animal slaughter. Persons and communities with these exposure risks also should receive counseling regarding the use of nonpermeable gloves and hand hygiene to prevent infection.

▪ Abstract  Human vascular endothelial cells (EC) basally display class I and II MHC-peptide complexes on their surface and come in regular contact with circulating T cells. We propose that EC present microbial antigens to memory T cells as a mechanism of immune surveillance. Activated T cells, in turn, provide both soluble and contact-dependant signals to modulate normal EC functions, including formation and remodeling of blood vessels, regulation of blood flow, regulation of blood fluidity, maintenance of permselectivity, recruitment of inflammatory leukocytes, and antigen presentation leading to activation of T cells. T cell interactions with vascular EC are thus bidirectional and link the immune and circulatory systems.

Human umbilical vein endothelial cells (HUVEC) suspended in collagen/fibronectin gels and implanted subcutaneously in immunodeficient mice form simple vascular tubes that inosculate with the host circulation. Retroviral transduction of implanted HUVEC with caspase-resistant Bcl-2 (D34A) induces recruitment of murine vascular smooth muscle cells (VSMC) and formation of chimeric vessels within the implants. In this thesis, I characterize structural and functional properties of vessels lined by Bcl-2-transduced HUVEC (Bcl-2-HUVEC) and investigate the mechanism of Bcl-2-induced maturation. For comparison, I also evaluate a Bcl-2-independent survival pathway by overexpressing components of the Tie-2/Akt pathway in implanted EC. The principal findings are that Bcl-2-HUVEC induce remodeling and enlargement of conduit vessels arising from the host abdominal wall circulation. The engrafted vessels are quiescent and invested by VSMC expressing protein markers of contractile function. The vessels appropriately regulate vascular permeability and exhibit a TNF response consistent with differentiated arterioles and venules rather than cultured EC. Bcl-2HUVEC implants can engraft and increase blood flow in mouse gastrocnemius muscle following femoral artery ligation. These data suggest Bcl-2-HUVEC implants may be useful in treating ischemia. Overexpression of G145E mutant Bcl-2 confers reduced cytoprotective effect versus D34A or Bcl-2wt, and does not induce VSMC recruitment in vivo. Affymetrix arrays reveal that Bcl-2 causes transcriptome alteration in 3-D-cultured HUVEC absent in monolayer-cultured cells. Bcl-2 G145E induces smaller transcriptome alterations than Bcl-2wt at similar expression levels. These data demonstrate a novel role for Bcl-2 in influencing gene transcription, but do not implicate known proangiogenic factors in Bcl-2-induced maturation. Overexpression of Tie-2 wt, the activated mutant Tie-2 R849W, or downstream kinase Akt in cultured HUVEC increases levels of phospho-Akt and phospho-eNOS, and confers resistance to apoptosis. 14d after in vivo implantation, Tie-2 wt-, Tie-2 R849W-, and Akt-HUVEC form ectatic vessels with irregular VSMC investment. However, Tie-2 wt- or Tie-2 R849W-HUVEC show sustained proliferation in vivo, while Akt-HUVEC are largely quiescent after 14d. Treatment of animals with eNOS inhibitor L-NAME does not reverse Akt-induced ectasia; eNOS S1179D overexpression does not recapitulate Akt-induced morphologic change. These data suggest Tie-2 stimulates Akt dependent and independent pathways, and eNOS does not account for Akt-mediated effects.

Orf, also known as contagious ecthyma, is a zoonotic infection caused by a dermatotropic parapoxvirus that commonly infects sheep and goats; it is transmitted to humans through contact with an infected animal or fomites. In humans, orf manifests as an ulcerative skin lesion sometimes resembling bacterial infection or neoplasm. Bogoch et al describe four cases of human orf associated with household meat processing or animal slaughter, highlighting the importance of nontraditional risk factors. A CDC editorial note is presented.

The Laser Interferometer Space Antenna (LISA) has two scientific objectives of cosmological focus: to probe the expansion rate of the universe, and to understand stochastic gravitational-wave backgrounds and their implications for early universe and particle physics, from the MeV to the Planck scale. However, the range of potential cosmological applications of gravitational-wave observations extends well beyond these two objectives. This publication presents a summary of the state of the art in LISA cosmology, theory and methods, and identifies new opportunities to use gravitational-wave observations by LISA to probe the universe.

Background Diabetic ketoacidosis (DKA) is a serious complication of type 1 diabetes (T1D), arising from relative insulin deficiency and leading to hyperglycemia, ketonemia, and metabolic acidosis. Early detection and treatment are essential to prevent severe outcomes. This pediatric case–control study utilized plasma metabolomics to explore metabolic alterations associated with DKA and to identify predictive metabolite patterns. Methods We examined 34 T1D participants, including 17 patients admitted with severe DKA and 17 age- and sex-matched individuals in insulin-controlled states. A total of 215 plasma metabolites were analyzed using proton nuclear magnetic resonance and direct-injection liquid chromatography/mass spectrometry. Multivariate statistical methods, machine learning techniques, and bioinformatics were employed for data analysis. Results After adjusting for multiple comparisons, 65 metabolites were found to differ significantly between the groups (28 increased and 37 decreased). Metabolomics profiling demonstrated 100% accuracy in differentiating severe DKA from insulin-controlled states. Random forest analysis indicated that classification accuracy was primarily influenced by changes in ketone bodies, acylcarnitines, and phosphatidylcholines. Additionally, groups of metabolites (ranging in number from 8 to 18) correlated with key clinical and biochemical variables, including pH, bicarbonate, glucose, HbA1c, and Glasgow Coma Scale scores. Conclusions These findings underscore significant metabolic disturbances in severe DKA and their associations with critical clinical indicators. Future investigations should explore if metabolic alterations in severe DKA can identify patients at increased risk of complications and/or guide future therapeutic interventions.

Background In children with type 1 diabetes (T1D), diabetic ketoacidosis (DKA) triggers a significant inflammatory response; however, the specific effector proteins and signaling pathways involved remain largely unexplored. This pediatric case–control study utilized plasma proteomics to explore protein alterations associated with severe DKA and to identify signaling pathways that associate with clinical variables. Methods We conducted a proteome analysis of plasma samples from 17 matched pairs of pediatric patients with T1D; one cohort with severe DKA and another with insulin-controlled diabetes. Proximity extension assays were used to quantify 3072 plasma proteins. Data analysis was performed using multivariate statistics, machine learning, and bioinformatics. Results This study identified 214 differentially expressed proteins (162 upregulated, 52 downregulated; adj P < 0.05 and a fold change > 2), reflecting cellular dysfunction and metabolic stress in severe DKA. We characterized protein expression across various organ systems and cell types, with notable alterations observed in white blood cells. Elevated inflammatory pathways suggest an enhanced inflammatory response, which may contribute to the complications of severe DKA. Additionally, upregulated pathways related to hormone signaling and nitrogen metabolism were identified, consistent with increased hormone release and associated metabolic processes, such as glycogenolysis and lipolysis. Changes in lipid and fatty acid metabolism were also observed, aligning with the lipolysis and ketosis characteristic of severe DKA. Finally, several signaling pathways were associated with clinical biochemical variables. Conclusions Our findings highlight differentially expressed plasma proteins and enriched signaling pathways that were associated with clinical features, offering insights into the pathophysiology of severe DKA.