Pathways of human T lymphocyte development and activation

The T lymphocyte receptor for antigen, which operates in conjunction with gene products of the major histocompatibility complex (MHC), is a molecular complex comprised of five polypeptide chains. Both the 49 kDa alpha and 43 kDa beta chains are immunoglobulin-like and thus contain variable domains responsible for ligand binding. In contrast, the 20–25 kDa T3 gamma, delta and epsilon chains are monomorphic structures presumably involved in transmembrane signalling. The alpha and beta subunits are disulfide bonded to each other and held in noncovalent association with the T3 chains. T3-Ti receptor crosslinking leads to conformational modification of a second T lineage specific molecule, termed the 50 kDa T11 structure which in turn leads to protein kinase C activation, elevation in intracytoplasmic free calcium and Na⁺/H⁺ antiport stimulation.     

Pathways for phosphoinositide synthesis.

In eukaryotic cells, phosphatidylinositol can be phosphorylated on the inositol ring by a series of kinases to produce at least seven distinct phosphoinositides. These lipids have been implicated in a variety of cellular processes, including calcium regulation, actin rearrangement, vesicle trafficking, cell survival and mitogenesis. The phosphorylated lipids can act as precursors of second messengers or act directly to recruit specific signaling proteins to the membrane. A number of the kinases responsible for producing these lipids have been purified and their cDNA clones have been isolated. The most well characterized of these enzymes are the phosphoinositide 3-kinases. However, progress has also been made in the characterization of phosphatidylinositol 4-kinases and phosphatidylinositol-4-phosphate 5-kinases. In addition, new pathways involving phosphatidylinositol-5-phosphate 4-kinases, phosphatidylinositol-3-phosphate 5-kinases and phosphatidylinositol-3-phosphate 4-kinases have recently been described. The various enzymes and pathways involved in the synthesis of cellular phosphoinositides will be discussed.     

Differential Expression Analysis for Pathways

Life science technologies generate a deluge of data that hold the keys to unlocking the secrets of important biological functions and disease mechanisms. We present DEAP, Differential Expression Analysis for Pathways, which capitalizes on information about biological pathways to identify important regulatory patterns from differential expression data. DEAP makes significant improvements over existing approaches by including information about pathway structure and discovering the most differentially expressed portion of the pathway. On simulated data, DEAP significantly outperformed traditional methods: with high differential expression, DEAP increased power by two orders of magnitude; with very low differential expression, DEAP doubled the power. DEAP performance was illustrated on two different gene and protein expression studies. DEAP discovered fourteen important pathways related to chronic obstructive pulmonary disease and interferon treatment that existing approaches omitted. On the interferon study, DEAP guided focus towards a four protein path within the 26 protein Notch signalling pathway.     

Prospects for a bio-based succinate industry

Bio-based succinate is receiving increasing attention as a potential intermediary feedstock for replacing a large petrochemical-based bulk chemical market. The prospective economical and environmental benefits of a bio-based succinate industry have motivated research and development of succinate-producing organisms. Bio-based succinate is still faced with the challenge of becoming cost competitive against petrochemical-based alternatives. High succinate concentrations must be produced at high rates, with little or no by-products to most efficiently use substrates and to simplify purification procedures. Herein are described the current prospects for a bio-based succinate industry, with emphasis on specific bacteria that show the greatest promise for industrial succinate production. The succinate-producing characteristics and the metabolic pathway used by each bacterial species are described, and the advantages and disadvantages of each bacterial system are discussed.     

Neurogenesis: Pathways for population balance

EGFR–Notch 1 pathway interactions balance neural stem cell and progenitor cell populations.     

Pathways to inflammation induced by immune complexes: development of the Arthus reaction

The changes associated with inflammation induced by immune complexes (reversed passive Arthus reaction induced with egg albumin-anti-egg albumin) were quantitated and the kinetics of the various vascular phenomena were ascertained. Hyperemia, increase in vascular permeability, platelet accumulation, and polymorphonuclear (PMN) leukocyte accumulation occurred relatively early after induction of the inflammatory lesions, and peaked in 2-4 h. Hemorrhage peaked in 6-h-old lesions. Morphological studies confirmed that almost all infiltrating cells were PMN leukocytes and immunofluorescent tracer studies showed immune complexes in vessel walls as early as 15 min after i.v. injection of the fluoresceinated antigen and the intradermal injection of antibody. By 8 h the progression of the lesions had subsided and by 24 h there were signs of resolution. A pathway for the development of the inflammatory lesions induced with immune complexes is proposed.     

Multiple Pathways for Apoptotic Nuclear Fragmentation

We analyzed the ultrastructure of apoptotic nuclear fragmentation in U937 cells treated with many different apoptogenic agents. We found that this characteristic apoptotic feature can be achieved through multiple alternative pathways, depending on the apoptogenic inducer, leading to slightly different final nuclear morphologies. In most instances, the irregularly shaped nucleus of U937 rounds up; then, chromatin condenses at the nuclear periphery. Condensed chromatin can form protruding patches, which eventually bud from the nucleus in sealed vesicles through a process which is actin-dependent, since it could be blocked by cytochalasins. Alternatively, chromatin condenses in tiny, nonprotruding crescents, and a cleavage in the nuclear sap forms, beginning from the inner nuclear membrane and growing inward, thus splitting the nucleus. In U937 induced to apoptosis by hydrogen peroxide in the presence of ADP-ribosylation inhibitors, the nuclei fragment in many vesicles before chromatin even begins to condense: chromatin condensation probably occurs as a consequence. While all the apoptotic morphologies described above evolve from interphase cells, a peculiar apoptotic morphology, possibly deriving from mitotic cells, is detected upon oxidative stress, recalling the formation of micronuclei by clastogenic treatments; it shows partially membrane-bound chromatin patches, which look midway between condensed chromosomes and apoptotic condensed chromatin. The existence of these multiple pathways for nuclear fragmentation may indicate an evolutionary convergence, suggesting that this event may play an important physiological role in apoptosis.     

武汉生物制药产业的发展及建议

在简要分析了国内外生物制药产业发展的同时,也对武汉生物制药产业的发展作了基本条件分析,并对今后重点发展的技术方向及对策提出了建议。     

Pathways for Virus Assembly around Nucleic Acids

Understanding the pathways by which viral capsid proteins assemble around their genomes could identify key intermediates as potential drug targets. In this work, we use computer simulations to characterize assembly over a wide range of capsid protein–protein interaction strengths and solution ionic strengths. We find that assembly pathways can be categorized into two classes, in which intermediates are either predominantly ordered or disordered. Our results suggest that estimating the protein–protein and the protein–genome binding affinities may be sufficient to predict which pathway occurs. Furthermore, the calculated phase diagrams suggest that knowledge of the dominant assembly pathway and its relationship to control parameters could identify optimal strategies to thwart or redirect assembly to block infection. Finally, analysis of simulation trajectories suggests that the two classes of assembly pathways can be distinguished in single-molecule fluorescence correlation spectroscopy or bulk time-resolved small-angle X-ray scattering experiments.     

Mitoptosis: Different Pathways for Mitochondrial Execution

Mitoptosis was described as a sort of mitochondrial death program. It could be associated with both necrosis and apoptosis, although degenerating mitochondria are also found in autophagic vacuoles. It was demonstrated that several molecules might contribute to the remodeling and rearrangement of mitochondrial membranes, leading to mitochondria rupture and disruption. Here, we hypothesize that, at least in T cells, two main pathways of mitoptosis can occur: an inner membrane mitoptosis (IMM), in which only the internal matrix and cristae are lost while the external mitochondrial envelope remains unaltered, and an outer membrane mitoptosis (OMM) where only swollen internal cristae are detected as remnants. We suggest that the study of these processes could provide useful insights not only to the field of cell death but also to the study of the pathogenic mechanisms of mitochondria-associated human diseases.

Addendum to:

Death Receptor Ligation Triggers Membrane Scrambling Between Golgi and Mitochondria

S. Ouasti, P. Matarrese, R. Paddon, R. Khosravi-Far, M. Sorice, A. Tinari, W. Malorni, M. Degli Esposti

Cell Death Differ 2006; Epub ahead of print