The role of membrane water permeability in characterization of pathologically altered human stomach tissues: NMR studies

Comparative NMR studies of normal and pathologically altered human stomach tissues were performed on the basis of proton T1 relaxation time measurements in the presence of high external concentrations of relaxation (contrast) agents manganese ethylenediaminetetraacetic acid (Mn-EDTA) and gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA). Diffusion permeability of the cell membrane to water, Pd, was determined by measuring the longest proton T1 component sensitive to the exchange of water molecules through the cell membrane. Pathologically altered tissues showed substantially higher (2 to 10 times) average cell membrane permeabilities to water.     

Murine lupus autoantibodies identify distinct subsets of apoptotic bodies

The specific modification of autoantigens and their redistribution into blebs at the surface of apoptotic cells contribute to the induction of autoimmune responses. Blebs containing fragments of the apoptotic nucleus separate from the remainder of the cell to form membrane-bound sub-cellular particles (SCPs), otherwise known as apoptotic bodies. To determine whether apoptotic bodies containing nuclear antigens represent a defined subset of SCPs, we examined the heterogeneity of particles generated by Jurkat cells following synchronization of the cell cycle by serum withdrawal and inhibition of topoisomerase I by camptothecin. Particles were purified by filtration, incubated in the presence of antinucleosome or anti-cardiolipin autoantibodies, annexin V, and Sytox Orange and analyzed by flow cytometry and confocal microscopy. We demonstrate that nuclear autoantigens are associated with one clearly defined subset of SCPs that can be distinguished from other products of late apoptosis. Our experiments represent an important step towards characterizing the heterogeneity of SCPs that are generated in late apoptosis and identifying their contributions to tolerance and autoimmunity.     

Apoptosis, subcellular particles, and autoimmunity

Firm evidence links the process of apoptosis to the induction of autoimmune disease. However, questions remain regarding the precise interactions of dying cells with the immune system. Genetic analyses indicate that deficiencies in serum proteins or receptors that mediate clearance of apoptotic cells increase the risk of autoimmunity. Moreover, administration of apoptotic cells to naive animals elicits transient autoimmune responses. Because known autoantigens are covalently modified and redistributed to cell surface blebs during the execution stage of apoptosis, increasing attention is being directed at this stage of programmed cell death, and researchers have identified a variety of autoantigens that are sequestered within blebs. However, blebs are merely a transition stage toward the complete cellular fragmentation, as blebs quickly convert into apoptotic bodies, subcellular particles (SCPs) of heterogeneous size, surface composition, and cargo. Because certain types of subcellular particles represent packets of highly enriched autoantigens, we propose that they are relevant to our understanding of autoimmunity.     

Atmospheric pressure as a force that fills developing bones with marrow and air

Many theories try to explain the existence and function of paranasal sinuses. This paper is an attempt to correlate process of paranasal sinus development in human with bone pneumatization processes in animals. It is here proposed that this mechanism starts in utero and continues after birth. During endochondral development, a solid hyaline cartilage model transforms into long bones. Central chondrocytes hypertrophy and their lacunae become confluent. Dissolving of the cartilage intercellular matrix forms a primitive marrow cavity. It is soon invaded by the periostal bud. Once circulation is established in the developing bone, the dissolved hyaline matrix can be slowly washed away from the bone cavity. Circulation in the bone cavity can develop slight subatmospheric pressures, similar to negative interstitial pressures in subcutaneous tissues. The amniotic fluid conducts atmospheric pressure to the fetal body. The pressure is trying to fill enlarging bone cavities through the existing vascular openings, or to create new openings. Bone walls of developing paranasal bones are to weak to resist the pressure gradient on their walls. New openings form on the weakest spots allowing airway mucosa to form initial paranasal sinuses. The enlarging cavities of long bones that are remote from the body surface and airway also develop a slightly subatmospheric pressure that fills them with cellular elements. These elements enter bone through the feeding vessels and form bone marrow. During after birth skeletal growth, bone remodeling shapes paranasal sinuses in a process of slow evolution that do not require measurable pressure gradients. When two sinuses come in vicinity, their growth rate declines, since the remaining thin and fragile bone lamella between them does not retract anymore.     

Focus on ulcerative colitis: stable gastric pentadecapeptide BPC 157

Stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419) may be the new drug stable in human gastric juice, effective both in the upper and lower GI tract, and free of side effects. BPC 157, in addition to an antiulcer effect efficient in therapy of inflammatory bowel disease (IBD) (PL 14736) so far only tested in clinical phase II, has a very safe profile, and exhibited a particular wound healing effect. It also has shown to interact with the NO-system, providing endothelium protection and angiogenic effect, even in severely impaired conditions (i.e., it stimulated expression of early growth response 1 gene responsible for cytokine and growth factor generation and early extracellular matrix (collagen) formation (but also its repressor nerve growth factor 1-A binding protein-2)), important to counteract severe complications of advanced and poorly controlled IBD. Hopefully, the lessons from animal studies, particularly advanced intestinal anastomosis healing, reversed short bowel syndrome and fistula healing indicate BPC 157's high significance in further IBD therapy. Also, this supportive evidence (i.e., no toxic effect, limit test negative, LD1 not achieved, no side effect in trials) may counteract the problems commonly exercised in the use of peptidergic agents, particularly those used on a long-term basis.     

From the Cover: The multimillennial sea-level commitment of global warming

Global mean sea level has been steadily rising over the last century, is projected to increase by the end of this century, and will continue to rise beyond the year 2100 unless the current global mean temperature trend is reversed. Inertia in the climate and global carbon system, however, causes the global mean temperature to decline slowly even after greenhouse gas emissions have ceased, raising the question of how much sea-level commitment is expected for different levels of global mean temperature increase above preindustrial levels. Although sea-level rise over the last century has been dominated by ocean warming and loss of glaciers, the sensitivity suggested from records of past sea levels indicates important contributions should also be expected from the Greenland and Antarctic Ice Sheets. Uncertainties in the paleo-reconstructions, however, necessitate additional strategies to better constrain the sea-level commitment. Here we combine paleo-evidence with simulations from physical models to estimate the future sea-level commitment on a multimillennial time scale and compute associated regional sea-level patterns. Oceanic thermal expansion and the Antarctic Ice Sheet contribute quasi-linearly, with 0.4 m °C⁻¹ and 1.2 m °C⁻¹ of warming, respectively. The saturation of the contribution from glaciers is overcompensated by the nonlinear response of the Greenland Ice Sheet. As a consequence we are committed to a sea-level rise of approximately 2.3 m °C⁻¹ within the next 2,000 y. Considering the lifetime of anthropogenic greenhouse gases, this imposes the need for fundamental adaptation strategies on multicentennial time scales.