Modulation of Extravascular Binding of Recombinant Factor IX Impacts the Duration of Efficacy in Mouse Models.

Background:  There is an emerging concept that in addition to circulating coagulation factor IX (FIX), extravascular FIX contributes to hemostasis.

Objective:  Our objective was to evaluate the efficacy of extravascular FIX using animal models of tail clip bleeding and ferric chloride-induced thrombosis.

Methods:  Mutant rFIX proteins with described enhanced (rFIX) or reduced (rFIX) binding to extracellular matrix were generated and characterized using aPTT, one-stage clotting, and modified FX assays.

Why are ACE2 binding coronavirus strains SARS-CoV/SARS-CoV-2 wild and NL63 mild?

Coronaviruses are responsible for several epidemics, including the 2002 SARS, 2012 MERS, and COVID-19. The emergence of recent COVID-19 pandemic due to SARS-CoV-2 virus in December 2019 has resulted in considerable research efforts to design antiviral drugs and other therapeutics against coronaviruses. In this context, it is crucial to understand the biophysical and structural features of the major proteins that are involved in virus-host interactions.

IVIG induces apoptotic cell death in CD56 NK cells resulting in inhibition of ADCC effector activity of human PBMC.

The mechanism of the efficacy of Intravenous immunoglobulins (IVIG) in autoimmune and inflammatory diseases is not well understood. This study aimed at understanding mechanisms of IVIG-mediated suppression of effector cell activities of peripheral blood mononuclear cells (PBMC) in antibody-dependent cellular cytotoxicity (ADCC). We were particularly interested in CD56 NK cells, the main ADCC effector cells in PBMC.

Angiotensin II synergizes with BAFF to promote atheroprotective regulatory B cells.

Angiotensin II (AngII) promotes hypertension, atherogenesis, vascular aneurysm and impairs post-ischemic cardiac remodeling through concerted roles on vascular cells, monocytes and T lymphocytes. However, the role of AngII in B lymphocyte responses is largely unexplored. Here, we show that chronic B cell depletion (Baffr deficiency) significantly reduces atherosclerosis in Apoe mice infused with AngII.

Indoleamine 2,3-Dioxygenase Fine-Tunes Immune Homeostasis in Atherosclerosis and Colitis through Repression of Interleukin-10 Production.

Indoleamine 2,3-dioxygenase 1 (Ido1) is a rate-limiting enzyme that catalizes the degradation of tryptophan along the kynurenine pathway. Here, we show that Ido1 activity sustains an immunostimulatory potential through inhibition of interleukin (Il)10. In atherosclerosis, Ido1-dependent inhibition of Il10 translates into disease exacerbation.

The intravenous injection of oxidized LDL- or Apolipoprotein B100--Coupled splenocytes promotes Th1 polarization in wildtype and Apolipoprotein E--Deficient mice.

Background: Th1 responses in atherosclerosis are mainly associated with the aggravation of atherosclerotic plaques, whereas Th2 responses lead to a less pronounced disease in mouse models. The fixation of antigens on cells by means of ethylene carbodiimide (ECDI), and subsequent injection of these antigen-coupled splenocytes (Ag-SP) to induce tolerance against the attached antigens, has been successfully used to treat murine type 1 diabetes or encephalomyelitis in. We analyzed this approach in a mouse model for atherosclerosis.

Effects of Proanthocyanidins on Adhesion, Growth, and Virulence of Highly Virulent Extraintestinal Pathogenic Escherichia coli Argue for Its Use to Treat Oropharyngeal Colonization and Prevent Ventilator-Associated Pneumonia.

Objective: In the context of increasing microbial resistance and limited new antimicrobials, we aimed to study the antimicrobial effects of cranberry proanthocyanidin extracts on Escherichia coli growth, adhesion to epithelial cells, and lung infection.

Design: Experimental in vitro and in vivo investigation.

Setting: University research laboratory.

Natural regulatory T cells limit angiotensin II-induced aneurysm formation and rupture in mice.

Objective: Abdominal aortic aneurysm is an inflammatory disease leading to destructive vascular remodeling and ultimately to lethal aortic rupture. Despite its frequent association with atherosclerosis, compelling studies have shown striking differences and potentially opposite roles of T-cell helper responses in aneurysm as compared with atherosclerosis, casting doubt on the relevance and suitability of T-cell-targeted therapies in this context.

Approach And Results: Here, we show that selective depletion of T regulatory (Treg) cells using a CD25-specific monoclonal antibody significantly enhances the susceptibility of C57Bl/6 mice to angiotensin II-induced abdominal aortic aneurysm and promotes aortic rupture (n=25-44 mice/group).

Perforated Meckel's Diverticulum Lithiasis: An Unusual Cause of Peritonitis.

Meckel's diverticulum is the commonest congenital malformation of gastrointestinal tract and represents a persistent remnant of the omphalomesenteric duct. Although it mostly remains silent, it can present as bleeding, perforation, intestinal obstruction, intussusception, and tumours. These complications, especially bleeding, tend to be more common in the paediatric group and intestinal obstruction in adults.

Overexpression of SOCS3 in T lymphocytes leads to impaired interleukin-17 production and severe aortic aneurysm formation in mice--brief report.

Objective: Mutations of signal transducer and activator of transcription 3 (STAT3) are responsible for autosomal dominant hyperimmunoglobulin E syndrome. Recently, we reported frequent vascular abnormalities, including aneurysms in these patients, and demonstrated that STAT3 inhibition promoted aneurysm in mice. The purpose of this study was to investigate the role of cell-specific STAT3 signaling in the susceptibility to aneurysm.

Humoral and cellular immune responses in atherosclerosis: spotlight on B- and T-cells.

Despite more than 1 million basic and clinical investigation reports on the mechanism and clinical outcome of cardiovascular events, the pathogenesis of this multi factorial disease is still incompletely understood, which is illustrated by the fact that it is still the leading cause of death in the western world. Over the decades it has been well approved that in addition to lipid dysfunction and arterial lipid accumulation, inflammation and autoimmune responses are major factors in directing the initiation and progression of atherosclerosis, the underlying cause of cardiovascular diseases. Atherosclerosis involves both humoral and cellular compartments of innate and adaptive immunity making it a very complex disease.

eNOS protects from atherosclerosis despite relevant superoxide production by the enzyme in apoE mice.

Background: All three nitric oxide synthase (NOS) isoforms are expressed in atherosclerotic plaques. NOS enzymes in general catalyse NO production. However, under conditions of substrate and cofactor deficiency, the enzyme directly catalyse superoxide formation.

Oxidative stress and compartment of gene expression determine proatherosclerotic effects of inducible nitric oxide synthase.

Genetic and pharmacological inhibition of inducible nitric oxide synthase (iNOS) decreases atherosclerosis development. Potential proatherogenic effects of iNOS include iNOS mediated oxidative stress and iNOS expression in different cellular compartments. Lesional iNOS can potentially produce nitric oxide radicals (NO), superoxide radicals (O2(-)), or both; these radicals may then react to form peroxynitrite.

Native C-reactive protein induces endothelial dysfunction in ApoE-/- mice: implications for iNOS and reactive oxygen species.

Objective: In addition to being a risk marker for cardiovascular disease, recent data suggests that C-reactive protein (CRP) induces endothelial dysfunction and promotes oxidative stress. We evaluated the effects of two conformers of CRP (pentameric, or native [nCRP], versus monomeric, or modified [mCRP]) on vessel function and production of reactive oxygen species (ROS) in an in-vivo model of atherosclerosis.

Methods And Results: Female ApoE(-/-) mice, fed a "western-type" diet, were treated with either human nCRP or mCRP (2.

Stability of DNA duplexes with Watson-Crick base pairs: a predicted model.

The conformational stability (difference between the free energies of the folded and unfolded states, DeltaG degrees ) of a DNA duplex is considered as a function of component energy terms, hydrophobic, base stacking, hydrogen bonding, van der Waals, and electrostatic, and a trinucleotide-level helix stiffness parameter measured in terms of its Young's modulus. Hydrophobic and base stacking energy components were determined with the use of the crystal structure data of 30 DNA duplexes judicially selected within a resolution of 1.5 A, and hydrogen bonding, van der Waals and electrostatic terms were determined through an extensive review of experimental and theoretical studies.

On the thermal unfolding character of globular proteins.

A theoretical model is presented to study the stepwise thermal unfolding of globular proteins using the stabilizing/destabilizing characters of amino acid residues in protein crystals. A multiple regression relation connecting the melting temperature and the amounts of stabilizing and destabilizing groups of residues in a protein, when used for the thermal behavior of peptide segments, provides reliable results on the stepwise unfolding nature of the protein. In ribonuclease A, the shell residues 16-22 are predicted to unfold earlier in the temperature range 30-45 degrees C; the beta-sheet structures undergo thermal denaturation as a single cooperative unit and there is evidence indicating the segment 106-118 as a nucleation site.

Note on fabric marks in motor vehicle collisions.

Two cases are described where motor vehicle accidents lead to fabric weave impressions and fibres being transferred to the paintwork of vehicles from the clothes of the victims.

Identification of membrane spanning beta strands in bacterial porins.

The membrane assembly of outer membrane proteins is more complex than that of transmembrane helical proteins owing to the intervention of many charged and polar residues in the membrane. Accordingly, the predictive accuracy of transmembrane beta strands is considerably lower than that of transmembrane alpha helices. In this paper we develop a set of conformational parameters for membrane spanning beta strands.

Hydrophobic distribution and spatial arrangement of amino acid residues in membrane proteins.

The analysis of known three-dimensional structures of membrane proteins provides an opportunity to understand their structure and stability. In this article we analyse the hydrophobic variation of amino acid residues at various ranges in membrane and aqueous parts of membrane proteins. The numerical indices for several properties of amino acid residues in membrane proteins, such as surrounding hydrophobicity, gain in surrounding hydrophobicity, hydrophobic gain ratio, accessible surface area, preference of amino acid residues in the interior and surface parts, solvent accessible reduction ratio and buriedness, were set up.

Internal packing conditions and fluctuations of amino acid residues in globular proteins.

In order to investigate the environmental conditions of amino acid residues in protein molecules, four kinds of packing studies (atomic, geometric, hydrophobic and hydration) were formulated and tested on two proteins; bovine pancreatic trypsin inhibitor (BPTI) and bovine pancreatic ribonuclease S (RNase S). The inter-relationship of these packings on the fluctuations of amino acid residues was analysed by comparing the packing results with the dynamical studies, such as the root-mean-square-deviation values of atomic displacements obtained from the trajectories of molecular dynamics simulation, temperature factor information from crystal structures and residue fluctuations in proteins from continuum model. These analyses yield information about the most fluctuating and most stabilizing residue sites.

Prediction of protein secondary structures from their hydrophobic characteristics.

Deciphering the native conformation of proteins from their amino acid sequences is one of the greatest challenges in the field of molecular biology. The successful prediction of structural class may help to improve the accuracy levels of structure (secondary and tertiary) predictive schemes in globular proteins. In our earlier works we developed a new surrounding hydrophobicity scale for the 20 amino acid residues applicable for both globular and membrane proteins and used it successfully to predict the transmembrane helical and strand segments in membrane proteins.

On the conformational stability of oligonucleotide duplexes and tRNA molecules.

Thermodynamic experiments provide a wealth of data about the conformational stability, viz., the free energy difference (delta G) between folded and unfolded states of DNA/RNA duplexes. However, there is no acceptable view about how the various non-covalent forces contribute individually to the observed stability.

Prediction of transmembrane beta-strands from hydrophobic characteristics of proteins.

The assembly of outer-membrane proteins consisting of beta-strands as transmembrane segments is somewhat more complex when compared to the assembly of inner membrane proteins having alpha-helices as transmembrane parts. This is probably due to the difference in the amino acid sequences of the transmembrane part strands and helices. Because of this feature, most predictive schemes which are successful in predicting transmembrane helical segments fail to predict transmembrane strand segments.