Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10?1? and P = 4.1 × 10??, respectively).     

Composition and functional role of the mucus layers in the intestine

In discussions on intestinal protection, the protective capacity of mucus has not been very much considered. The progress in the last years in understanding the molecular nature of mucins, the main building blocks of mucus, has, however, changed this. The intestinal enterocytes have their apical surfaces covered by transmembrane mucins and the whole intestinal surface is further covered by mucus, built around the gel-forming mucin MUC2. The mucus of the small intestine has only one layer, whereas the large intestine has a two-layered mucus where the inner, attached layer has a protective function for the intestine, as it is impermeable to the luminal bacteria.     

Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

Basal-like breast cancer (BBC) is a subtype of breast cancer with poor prognosis. Inherited mutations of BRCA1, a cancer susceptibility gene involved in double-strand DNA break (DSB) repair, lead to breast cancers that are nearly always of the BBC subtype; however, the precise molecular lesions and oncogenic consequences of BRCA1 dysfunction are poorly understood. Here we show that heterozygous inactivation of the tumor suppressor gene Pten leads to the formation of basal-like mammary tumors in mice, and that loss of PTEN expression is significantly associated with the BBC subtype in human sporadic and BRCA1-associated hereditary breast cancers. In addition, we identify frequent gross PTEN mutations, involving intragenic chromosome breaks, inversions, deletions and micro copy number aberrations, specifically in BRCA1-deficient tumors. These data provide an example of a specific and recurrent oncogenic consequence of BRCA1-dependent dysfunction in DNA repair and provide insight into the pathogenesis of BBC with therapeutic implications. These findings also argue that obtaining an accurate census of genes mutated in cancer will require a systematic examination for gross gene rearrangements, particularly in tumors with deficient DSB repair.     

Moisture Absorption, Mass Loss and Evaporative Resistance of Clothing in Transient Condition

The water vapour resistance of clothing ensembles is not as commonly determined as dry thermal insulation. The measurement techniques are more complicated and the measurement values differ among laboratories. Due to complicated moisture transfer process through clothing ensemble, the moisture absorbed and evaporated varies in transient and steady state phases depending on properties, thickness of clothing, and environmental conditions. The purpose of this study was to measure moisture gain inside hygroscopic underwear, and hydrophobic and permeable outer wear as a function of time, to investigate mass loss from ＂skin＂ as well as from the manikin, to quantify evaporative heat loss and total heat loss from the manikin, and to determine water vaponr resistance of clothing. Manikin Tore was used by wearing wet ＂skin＂ to simulate sweating condition. Moisture content in the inner garment gain shows an exponential relation against time. Moisture in the outer permeable layer shows little gain. On the contrary, mass loss directly from the wet skin decreases exponentially. The mass loss from the manikin is relatively stable throughout three test phases. The evaporative heat loss is about 2/3 of the total heat loss from the sweating manikin. While measuring the evaporative resistance of clothing ensembles with hygroscopic inner garment and permeable outer garment, unlike to measure ensembles with impermeable outer layer, one hour measurement time is enough to get relatively stable results. The variation between the 1^rt hour and the 3^nd hour is less than 5%. The length of transient period and measurement time is dependent on the permeability, thickness of clothing ensembles and environmental conditions.     

Iron deposits in the chronically inflamed central nervous system and contributes to neurodegeneration

Neurodegenerative disorders are characterized by the presence of inflammation in areas with neuronal cell death and a regional increase in iron that exceeds what occurs during normal aging. The inflammatory process accompanying the neuronal degeneration involves glial cells of the central nervous system (CNS) and monocytes of the circulation that migrate into the CNS while transforming into phagocytic macrophages. This review outlines the possible mechanisms responsible for deposition of iron in neurodegenerative disorders with a main emphasis on how iron-containing monocytes may migrate into the CNS, transform into macrophages, and die out subsequently to their phagocytosis of damaged and dying neuronal cells. The dying macrophages may in turn release their iron, which enters the pool of labile iron to catalytically promote formation of free-radical-mediated stress and oxidative damage to adjacent cells, including neurons. Healthy neurons may also chronically acquire iron from the extracellular space as another principle mechanism for oxidative stress-mediated damage. Pharmacological handling of monocyte migration into the CNS combined with chelators that neutralize the effects of extracellular iron occurring due to the release from dying macrophages as well as intraneuronal chelation may denote good possibilities for reducing the deleterious consequences of iron deposition in the CNS.     

Variants conferring risk of atrial fibrillation on chromosome 4q25

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart.     

The effects of non-thermal radio frequency radiation on human lymphocytes in vitro

Zusammenfassung Hypotonische Streuungen, die in radiobestrahlten Kulturen menschlicher Lymphozyten Chromosomenaberrationen erkennen liessen, traten dort siebenmal häufiger auf als in unbestrahlten Kulturen; offenbar das Ergebnis einer wärmefreien Bestrahlung. Trotz des Fehlens bedeutender Unterschiede in der DNA-Synthese, der Zellvergrösserung und im mitotischen Index zwischen bestrahlten und unbestrahlten Kulturen kam es zu Aberrationen.     

Rapid removal of Chernobyl fallout from Mediterranean surface waters by biological activity

The sinking of particulate organic matter from the euphotic zone is an important pathway for the vertical transport of many elements and organic compounds in the sea. Many natural and artificial radionuclides in surface waters are readily adsorbed onto suspended particles and are presumably scavenged and removed to depth on time scales commensurate with both particle sinking rate and retention time of the radionuclide on the particle. Previously, abyssal benthic organisms from the northeast Pacific were found to contain short-lived fission products which entered the sea surface as fallout from nuclear testing. The presence of these radionuclides at great depth could not be explained by Stokesian settling of small fallout particles and it was hypothesized that zooplankton grazing in the surface layers packaged these particle-reactive radionuclides into large, relatively dense faecal pellets which rapidly sank to depth. We report here data from a time-series sediment trap experiment and concomitant zooplankton collections which show conclusively that Chernobyl radioactivity, in particular the rare earth nuclides 141Ce and 144Ce, entering the Mediterranean as a single pulse, was rapidly removed from surface waters and transported to 200 m in a few days primarily by zooplankton grazing.     

Measurements of the flow of aqueous humor according to a new principle

Zusammenfassung Wird der Vorkammerinhalt des Auges von aussen mit Fluorescin gefärbt, so ist das aus der Pupille herausfliessende Kammerwasser kurzfristig als ungefärbte «Blase», deren Volumen photogrammetrisch bestimmbar ist, sichtbar. Das Minutenvolumen ist durch zwei zeitlich getrennte Messungen feststellbar.