Interaction of Protein C Inhibitor with the Type II Transmembrane Serine Protease Enteropeptidase

The serine protease inhibitor protein C inhibitor (PCI) is expressed in many human tissues and exhibits broad protease reactivity. PCI binds glycosaminoglycans and certain phospholipids, which modulate its inhibitory activity. Enteropeptidase (EP) is a type II transmembrane serine protease mainly found on the brush border membrane of epithelial cells in the duodenum, where it activates trypsinogen to initiate the digestion of food proteins. Some active EP is also present in duodenal fluid and has been made responsible for causing pancreatitis in case of duodeno-pancreatic reflux. Together with its substrate trypsinogen, EP is furthermore present in the epidermis and in some cancer cells. In this report, we show that PCI inhibited EP with an apparent 2nd order rate constant of 4.48×104 M−1 s−1. Low molecular weight (LMWH) and unfractionated heparin (UFH) slightly reduced the inhibitory effect of PCI. The SI (stoichiometry of inhibition) value for the inhibition of EP by PCI was 10.8 in the absence and 17.9 in the presence of UFH (10 U/ml). By inhibiting trypsin, chymotrypsin, and additionally EP, PCI might play a role in the protection of the pancreas from autodigestion. Furthermore the interaction of PCI with EP may influence the regulation of epithelial differentiation

Specific IgG decline after successful treatment of Helicobacter pylori infection according to treatment protocol with azithromycin

Budući da do sada, ni jednim terapijskim protokolom, nije zabilježen 100 % učinak na eradikaciju Helicobacter pylori (HP), uspješnost liječenja treba provjeriti i pratiti. Najpristupačnije su kvantitativne serološke metode, koje su brze, točne, relativno jeftine i jednostavne za izvođenje, a za pacijente sigurne i prihvatljivije od invazivnih pretraga koje zahtijevaju gastroskopiju. Prednost ima imunoenzimsko određivanje (ELISA) visine titra specifičnih IgG-protutijela u serumu bolesnika. Svrha ovog istraživanja bila je pratiti i prikazati kretanje titra tih protutijela u bolesnika, koji su pri prvom pregledu bili seropozitivni, a nakon liječenja eradikacija uzročnika je uspjela. Prikazane su značajke 90 liječenih bolesnika, prosječne dobi 50 godina (16–79), od toga 52 s vrijedom dvanaesnika, 9 s vrijedom želuca i 29 s gastritisom bez vrijeda. Serološke pretrage rađene su imunoenzimskom tehnikom (ELISA), pomoću Pyloriset EIA-G komercijalnog pripravka (Orion Diagnostica, Finland), po uputama proizvođača. Početne vrijednosti titra kretale su se između 280 i 11 875 (srednja vrijednost 2808 ), uz granični titar 280 ±20. Nakon liječenja, u svim kontrolnim uzorcima seruma, razine specifičnih IgG protutijela postupno su padale za sve vrijeme pra}enja. Svi bolesnici čiji početni titar nije prelazio 1200, tijekom godinu dana praćenja postali su seronegativni. Srednji postotak pada titra anti-HP-IgG ispitivane populacije, bio je nakon dva mjeseca 56, nakon četiri mjeseca 68, nakon šest mjeseci 75, nakon godinu dana 87 (relativni titar bio je 13). Kao indikator uspješnog liječenja smatra se pad titra IgG najmanje za 40 % do četvrtog mjeseca po završenoj terapiji, odnosno najmanje 50 % šest mjeseci nakon zadnje doze antibiotika.As no treatment protocol for Helicobacter pylori (HP) eradication described to date, has a 100 % success rate, treatment monitoring is necessary. The ELISA specific IgG-serology is simple, accurate, safe, quick, relatively inexpensive and generally available technique. The aim of this study was to monitor the serology pattern in seropositive patients after successful eradication of HP with triple therapy. Characteristics of 90 treated patients, mean age 50 (16–79), on short-term serological monitoring are presented. The study group involved 52 patients with duodenal ulcer, 9 with gastric ulcer and 29 patients with gastritis but without ulcer. With Pyloriset EIA-G (Orion, Finland) immunoassay, anti-HP IgG-antibody titres were estimated. The pretreatment values varied between 280 and 11 875 (mean 2808) with cut-off level of 280 ±20. After treatment in every follow-up specimen IgG-levels declined gradually. The mean percentage of anti-HP IgG--decline in the group as a whole, if measured 2, 4, 6 and 12 months after treatment, was 56, 68, 75 and 87 respectively. During the first year of monitoring after treatment, all patients with pretreatment IgG-level less than 1200 (low titres) became seronegative. Decrease in the titre at 4 (40 %) or 6 (50 %) months after the last dose of antibiotics, can be used as a marker for HP-eradication

Abrupt change in tropical Pacific climate mean state during the Little Ice Age

The mean state of the tropical Pacific ocean-atmosphere climate, in particular its east-west asymmetry, has profound consequences for regional climates and for the El Niño/Southern Oscillation variability. Here we present a new high-resolution paleohydrological record using the stable-hydrogen-isotopic composition of terrestrial-lipid biomarkers (δDwax) from a 1,400-year-old lake sedimentary sequence from northern Philippines. Results show a dramatic and abrupt increase in δDwax values around 1630 AD with sustained high values until around 1900 AD. We interpret this change as a shift to significantly drier conditions in the western tropical Pacific during the second half of the Little Ice Age as a result of a change in tropical Pacific mean state tied to zonal sea surface temperature (SST) gradients. Our findings highlight the prominent role of abrupt shifts in zonal SST gradients on multidecadal to multicentennial timescales in shaping the tropical Pacific hydrology of the last millennium, and demonstrate that a marked transition in the tropical Pacific mean state can occur within a period of a few decades.publishedVersio

Differential Expression of Novel Potential Regulators in Hematopoietic Stem Cells

The hematopoietic system is an invaluable model both for understanding basic developmental biology and for developing clinically relevant cell therapies. Using highly purified cells and rigorous microarray analysis we have compared the expression pattern of three of the most primitive hematopoietic subpopulations in adult mouse bone marrow: long-term hematopoietic stem cells (HSC), short-term HSC, and multipotent progenitors. All three populations are capable of differentiating into a spectrum of mature blood cells, but differ in their self-renewal and proliferative capacity. We identified numerous novel potential regulators of HSC self-renewal and proliferation that were differentially expressed between these closely related cell populations. Many of the differentially expressed transcripts fit into pathways and protein complexes not previously identified in HSC, providing evidence for new HSC regulatory units. Extending these observations to the protein level, we demonstrate expression of several of the corresponding proteins, which provide novel surface markers for HSC. We discuss the implications of our findings for HSC biology. In particular, our data suggest that cell–cell and cell–matrix interactions are major regulators of long-term HSC, and that HSC themselves play important roles in regulating their immediate microenvironment

Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice.

Oxidized phospholipids (OxPL) are ubiquitous, are formed in many inflammatory tissues, including atherosclerotic lesions, and frequently mediate proinflammatory changes 1 . Because OxPL are mostly the products of non-enzymatic lipid peroxidation, mechanisms to specifically neutralize them are unavailable and their roles in vivo are largely unknown. We previously cloned the IgM natural antibody E06, which binds to the phosphocholine headgroup of OxPL, and blocks the uptake of oxidized low-density lipoprotein (OxLDL) by macrophages and inhibits the proinflammatory properties of OxPL2-4. Here, to determine the role of OxPL in vivo in the context of atherogenesis, we generated transgenic mice in the Ldlr-/- background that expressed a single-chain variable fragment of E06 (E06-scFv) using the Apoe promoter. E06-scFv was secreted into the plasma from the liver and macrophages, and achieved sufficient plasma levels to inhibit in vivo macrophage uptake of OxLDL and to prevent OxPL-induced inflammatory signalling. Compared to Ldlr-/- mice, Ldlr -/- E06-scFv mice had 57-28% less atherosclerosis after 4, 7 and even 12 months of 1% high-cholesterol diet. Echocardiographic and histologic evaluation of the aortic valves demonstrated that E06-scFv ameliorated the development of aortic valve gradients and decreased aortic valve calcification. Both cholesterol accumulation and in vivo uptake of OxLDL were decreased in peritoneal macrophages, and both peritoneal and aortic macrophages had a decreased inflammatory phenotype. Serum amyloid A was decreased by 32%, indicating decreased systemic inflammation, and hepatic steatosis and inflammation were also decreased. Finally, the E06-scFv prolonged life as measured over 15 months. Because the E06-scFv lacks the functional effects of an intact antibody other than the ability to bind OxPL and inhibit OxLDL uptake in macrophages, these data support a major proatherogenic role of OxLDL and demonstrate that OxPL are proinflammatory and proatherogenic, which E06 counteracts in vivo. These studies suggest that therapies inactivating OxPL may be beneficial for reducing generalized inflammation, including the progression of atherosclerosis, aortic stenosis and hepatic steatosis

A convergent spectroscopy-based approach for Vcmax across leaf age and growth environments.

Abstract OOS 2-2

Anisotrope Materialmodellierung für den menschlichen Unterkiefer

Im Rahmen der biomechanischen Simulation knöcherner menschlicher Organe ist die Frage nach einer befriedigenden Materialbeschreibung nach wie vor ungelöst. Computertomographische Datensätze liefern eine räumliche Verteilung der (Röntgen-) Dichte und ermöglichen damit eine gute Darstellung der individuellen Geometrie. Weiter können die verschiedenen Materialbestandteile des Knochens, Spongiosa und Kortikalis, voneinander getrennt werden. Aber die richtungsabhängige Information der Materialanisotropie ist verloren. In dieser Arbeit wird ein Ansatz für eine anisotrope Materialbeschreibung vorgestellt, die es ermöglicht, den Einfluss der individuellen knöchernen Struktur auf das makroskopische Materialverhalten abzuschätzen

Defining genes: a computational framework

The precise elucidation of the gene concept has become the subject of intense discussion in light of results from several, large high-throughput surveys of transcriptomes and proteomes. In previous work, we proposed an approach for constructing gene concepts that combines genomic heritability with elements of function. Here, we introduce a definition of the gene within a computational framework of cellular interactions. The definition seeks to satisfy the practical requirements imposed by annotation, capture logical aspects of regulation, and encompass the evolutionary property of homology