The physicochemical properties of lipopolysaccharide chemotypes regulate activation of the contact pathway of blood coagulation.

Lipopolysaccharide (LPS) is the primary pathogenic factor in Gram-negative sepsis. While the presence of LPS in the bloodstream during infection is associated with disseminated intravascular coagulation, the mechanistic link between LPS and blood coagulation activation remains ill-defined. The contact pathway of coagulation-a series of biochemical reactions that initiates blood clotting when plasma factors XII (FXII) and XI (FXI), prekallikrein (PK) and high molecular weight kininogen (HK) interact with anionic surfaces-has been shown to be activated in Gram-negative septic patients.

Endothelial Chromatin-Remodeling Enzymes Regulate the Production of Critical ECM Components During Murine Lung Development.

Background: The chromatin-remodeling enzymes BRG1 (brahma-related gene 1) and CHD4 (chromodomain helicase DNA-binding protein 4) independently regulate the transcription of genes critical for vascular development, but their coordinated impact on vessels in late-stage embryos has not been explored.

Methods: In this study, we genetically deleted endothelial and in mixed background mice (), and littermates that were negative for Cre recombinase were used as controls. Tissues were analyzed by immunostaining, immunoblot, and flow cytometry.

Clearance of VWF by hepatic macrophages is critical for the protective effect of ADAMTS13 in sickle cell anemia mice.

Although it is caused by a single-nucleotide mutation in the β-globin gene, sickle cell anemia (SCA) is a systemic disease with complex, incompletely elucidated pathologies. The mononuclear phagocyte system plays critical roles in SCA pathophysiology. However, how heterogeneous populations of hepatic macrophages contribute to SCA remains unclear.

PROX1 Inhibits PDGF-B Expression to Prevent Myxomatous Degeneration of Heart Valves.

Background: Cardiac valve disease is observed in 2.5% of the general population and 10% of the elderly people. Effective pharmacological treatments are currently not available, and patients with severe cardiac valve disease require surgery.

Anti-miR-93-5p therapy prolongs sepsis survival by restoring the peripheral immune response.

Sepsis remains a leading cause of death for humans and currently has no pathogenesis-specific therapy. Hampered progress is partly due to a lack of insight into deep mechanistic processes. In the past decade, deciphering the functions of small noncoding miRNAs in sepsis pathogenesis became a dynamic research topic.

Internalization of Polymeric Bacterial Peptidoglycan Occurs through Either Actin or Dynamin Dependent Pathways.

Peptidoglycan (PGN), a polymeric glycan macromolecule, is a major constituent of the bacterial cell wall and a conserved pathogen-associated molecular pattern (PAMP) that triggers immune responses through cytosolic sensors. Immune cells encounter both PGN polymers and hydrolyzed muropeptides during infections, and primary human innate immune cells respond better to polymeric PGN than the minimal bioactive subunit muramyl dipeptide (MDP). While MDP is internalized through macropinocytosis and/or clathrin-mediated endocytosis, the internalization of particulate polymeric PGN is unresolved.

Early Antibiotic Exposure Alters Intestinal Development and Increases Susceptibility to Necrotizing Enterocolitis: A Mechanistic Study.

Increasing evidence suggests that prolonged antibiotic therapy in preterm infants is associated with increased mortality and morbidities, such as necrotizing enterocolitis (NEC), a devastating gastrointestinal pathology characterized by intestinal inflammation and necrosis. While a clinical correlation exists between antibiotic use and the development of NEC, the potential causality of antibiotics in NEC development has not yet been demonstrated. Here, we tested the effects of systemic standard-of-care antibiotic therapy for ten days on intestinal development in neonatal mice.

Complement C5 inhibition protects against hemolytic anemia and acute kidney injury in anthrax peptidoglycan-induced sepsis in baboons.

Late-stage anthrax infections are characterized by dysregulated immune responses and hematogenous spread of , leading to extreme bacteremia, sepsis, multiple organ failure, and, ultimately, death. Despite the bacterium being nonhemolytic, some fulminant anthrax patients develop a secondary atypical hemolytic uremic syndrome (aHUS) through unknown mechanisms. We recapitulated the pathology in baboons challenged with cell wall peptidoglycan (PGN), a polymeric, pathogen-associated molecular pattern responsible for the hemostatic dysregulation in anthrax sepsis.

Acceleration of Small Intestine Development and Remodeling of the Microbiome Following Hyaluronan 35 kDa Treatment in Neonatal Mice.

The beneficial effects of human milk suppressing the development of intestinal pathologies such as necrotizing enterocolitis in preterm infants are widely known. Human milk (HM) is rich in a multitude of bioactive factors that play major roles in promoting postnatal maturation, differentiation, and the development of the microbiome. Previous studies showed that HM is rich in hyaluronan (HA) especially in colostrum and early milk.

Factor XII plays a pathogenic role in organ failure and death in baboons challenged with Staphylococcus aureus.

Activation of coagulation factor (F) XI promotes multiorgan failure in rodent models of sepsis and in a baboon model of lethal systemic inflammation induced by infusion of heat-inactivated Staphylococcus aureus. Here we used the anticoagulant FXII-neutralizing antibody 5C12 to verify the mechanistic role of FXII in this baboon model. Compared with untreated control animals, repeated 5C12 administration before and at 8 and 24 hours after bacterial challenge prevented the dramatic increase in circulating complexes of contact system enzymes FXIIa, FXIa, and kallikrein with antithrombin or C1 inhibitor, and prevented cleavage and consumption of high-molecular-weight kininogen.

CD14 inhibition improves survival and attenuates thrombo-inflammation and cardiopulmonary dysfunction in a baboon model of Escherichia coli sepsis.

Background: During sepsis, gram-negative bacteria induce robust inflammation primarily via lipopolysacharride (LPS) signaling through TLR4, a process that involves the glycosylphosphatidylinositol (GPI)-anchored receptor CD14 transferring LPS to the Toll-like receptor 4/myeloid differentiation factor 2 (TLR4/MD-2) complex. Sepsis also triggers the onset of disseminated intravascular coagulation and consumptive coagulopathy.

Objectives: We investigated the effect of CD14 blockade on sepsis-induced coagulopathy, inflammation, organ dysfunction, and mortality.

Fondaparinux pentasaccharide reduces sepsis coagulopathy and promotes survival in the baboon model of Escherichia coli sepsis.

Background: Sepsis triggers dysfunction of coagulation and fibrinolytic systems leading to disseminated intravascular coagulation (DIC) that contributes to organ failure and death. Fondaparinux (FPX) is a synthetic pentasaccharide that binds to antithrombin (AT) and selectively inhibits factor (F) Xa and other upstream coagulation proteases but not thrombin (T).

Objectives: We used a baboon model of lethal Escherichia coli sepsis to investigate the effects of FPX treatment on DIC, organ function, and outcome.

Inhibition of contact-mediated activation of factor XI protects baboons against -induced organ damage and death.

infections can produce systemic bacteremia and inflammation in humans, which may progress to severe sepsis or septic shock, even with appropriate antibiotic treatment. Sepsis may be associated with disseminated intravascular coagulation and consumptive coagulopathy. In some types of mouse infection models, the plasma coagulation protein factor XI (FXI) contributes to the pathogenesis of sepsis.

Role of ADTRP (Androgen-Dependent Tissue Factor Pathway Inhibitor Regulating Protein) in Vascular Development and Function.

Background The physiological function of ADTRP (androgen-dependent tissue factor pathway inhibitor regulating protein) is unknown. We previously identified ADTRP as coregulating with and supporting the anticoagulant activity of tissue factor pathway inhibitor in endothelial cells in vitro. Here, we studied the role of ADTRP in vivo, specifically related to vascular development, stability, and function.

Factor XII Activation Promotes Platelet Consumption in the Presence of Bacterial-Type Long-Chain Polyphosphate In Vitro and In Vivo.

Objective- Terminal complications of bacterial sepsis include development of disseminated intravascular consumptive coagulopathy. Bacterial constituents, including long-chain polyphosphates (polyP), have been shown to activate the contact pathway of coagulation in plasma. Recent work shows that activation of the contact pathway in flowing whole blood promotes thrombin generation and platelet activation and consumption distal to thrombus formation ex vivo and in vivo.

Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways.

Anthrax infections exhibit progressive coagulopathies that may contribute to the sepsis pathophysiology observed in fulminant disease. The hemostatic imbalance is recapitulated in primate models of late-stage disease but is uncommon in toxemic models, suggesting contribution of other bacterial pathogen-associated molecular patterns (PAMPs). Peptidoglycan (PGN) is a bacterial PAMP that engages cellular components at the cross talk between innate immunity and hemostasis.

In vivo-generated thrombin and plasmin do not activate the complement system in baboons.

Sepsis concurrently activates both coagulation and complement systems. Although complement activation by bacteria is well documented, work in mice and in vitro suggests that coagulation proteases can directly cleave complement proteins. We aimed to determine whether generation of coagulation proteases in vivo can activate the complement cascade in 2 highly coagulopathic models.

Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of sepsis.

Bacterial sepsis triggers robust activation of the complement system with subsequent generation of anaphylatoxins (C3a, C5a) and the terminal complement complex (TCC) that together contribute to organ failure and death. Here we tested the effect of RA101295, a 2-kDa macrocyclic peptide inhibitor of C5 cleavage, using in vitro whole-blood assays and an in vivo baboon model of sepsis. RA101295 strongly inhibited induced complement activation both in vitro and in vivo by blocking the generation of C5a and the soluble form of TCC, sC5b-9.

Use of pattern recognition techniques for early detection of morbidity in receiving feedlot cattle.

Two groups of cattle were used to develop (model data set: 384 heifers, 228 ± 22.7 kg BW, monitored over a 225-d feeding period) and to validate (naïve data set: 384 heifers, 322 ± 34.7 kg BW, monitored over a 142-d feeding period) the use of feeding behavior pattern recognition techniques to predict morbidity in newly arrived feedlot cattle.

Space allowance during commercial long distance transport of cattle in North America.

The objective of the present work was to study space allowance in cattle during commercial long haul transport (≥400 km; n = 6,152 journeys). Surveys, delivered to livestock transport carriers, gathered information on the number, BW, and distribution of cattle by trailer compartment as well as the characteristics of the transport vehicles used. Space allowance (SA; m(2)/animal), allometric coefficient (k = SA / BW(0.

Relationships between transport conditions and welfare outcomes during commercial long haul transport of cattle in North America.

The objective of the present study was to document the relationships between selected welfare outcomes and transport conditions during commercial long haul transport of cattle (≥400 km; 6,152 journeys; 290,866 animals). Surveys were delivered to transport carriers to collect information related to welfare outcomes including the number of dead, non-ambulatory (downer) and lame animals during each journey. Transport conditions surveyed included the length of time animals spent on truck, ambient temperature, animal density, shrinkage, loading time, cattle origin, season, experience of truck drivers, and vehicle characteristics.

Factors affecting body weight loss during commercial long haul transport of cattle in North America.

The objective of the present study was to identify and quantify several factors affecting shrink in cattle during commercial long-haul transport (≥400 km; n = 6,152 journeys). Surveys were designed and delivered to transport carriers to collect relevant information regarding the characteristics of animals, time of loading, origin and destination, and loaded weight before and after transport. In contrast to fat cattle, feeder cattle exhibited greater shrink (4.

Benchmarking study of industry practices during commercial long haul transport of cattle in Alberta, Canada.

The objective of the present study was to document current commercial practices during long haul transport (≥400 km) of cattle in Alberta through surveys delivered to truck drivers (6,152 journeys that transported 290,362 animals). The live beef export industry to the United States (89% of all journeys) had a large influence on long haul transport. This was particularly true for fat cattle going to slaughter (82%) and backgrounded feeders going to feed yards (15%).

Relationship between feeding behavior and performance of feedlot steers fed barley-based diets.

The relationship between feeding behavior and performance of 274 feedlot cattle was evaluated using Charolais cross steers from 2 consecutive years averaging 293 ± 41 kg for yr 1 (n = 115) and 349 ± 41 for yr 2 (n = 159). Steers were blocked by BW and assigned to 3 (yr 1) or 4 (yr 2) feedlot pens equipped with a radio frequency identification system (GrowSafe Systems). Each pen contained 5 feeding stalls that allowed individual animal access to a feed tub suspended on load cells.