Rearrangements of nitrogen fixation (nif) genes in the heterocystous cyanobacteria

In the vegetative cells of heterocystous cyanobacteria, such as Anabaena, two Operons harbouring the nitrogen fixaton (nif) genes contain two separate intervening DNA elements resulting in the dispersion of genes and impaired gene expression. A 11 kb element disrupts thenifD gene in thenifH, D-K operon. It contains a 11 bp sequence (GGATTACTCCG) directly repeated at its ends and harbours a gene,xisA, which encodes a site-specific recombinase. A large 55 kb element interrupts thefdxN gene in thenifB fdxN-nifS-nifU operon. It contains two 5 bp direct repeats (TATTC) at its ends and accommodates at least one gene,xisF, which encodes another site-specific recombinase. During heterocyst differentiation both the discontinuities are precisely excised by two distinct site-specific recombination events. One of them is brought about by the XisA protein between the 11 bp direct repeats. The second one is caused by the XisF protein and occurs between the 5 bp direct repeats. As a consequence the 11kb and 55 kb elements are removed from the chromosome as circles and functional nif Operons are created. Nitrogenase proteins are then expressed from the rearranged genes in heterocysts and aerobic nitrogen fixation ensues. How these elements intruded thenif genes and how and why are they maintained in heterocystous cyanobacteria are exciting puzzles engaging considerable research effort currently. The unique developmental regulation of these gene rearrangements in heterocystous cyanobacteria is discussed

Angular Resolution of an EAS Array for Gamma Ray Astronomy at Energies Greater Than 5 x 10 (13) Ev

A 24 detector extensive air shower array is being operated at Ootacamund (2300 m altitude, 11.4 deg N latitude) in southern India for a study of arrival directions of showers of energies greater than 5 x 10 to the 13th power eV. Various configurations of the array of detectors have been used to estimate the accuracy in determination of arrival angle of showers with such an array. These studies show that it is possible to achieve an angular resolution of better than 2 deg with the Ooty array for search for point sources of Cosmic gamma rays at energies above 5 x 10 to the 13th power eV

Self Injection length in La0.7 Ca0.3 Mno3-YBa 2Cu3O7-d ferromagnet- superconductor multi layer thin films

We have carried out extensive studies on the self-injection problem in barrierless heterojunctions between La0.7Ca0.3MnO3 (LCMO) and YBa2Cu3O7-d (YBCO). The heterojunctions were grown in situ by sequentially growing LCMO and YBCO films on LaAlO3 (LAO) substrate using a pulsed laser deposition (PLD) system. YBCO micro-bridges with 64 microns width were patterned both on the LAO (control) and LCMO side of the substrate. Critical current, Ic, was measured at 77K on both the control side as well as the LCMO side for different YBCO film thickness. It was observed that while the control side showed a Jc of ~2 x 10E6 A/ cm2 the LCMO side showed about half the value for the same thickness (1800 A). The difference in Jc indicates that a certain thickness of YBCO has become 'effectively' normal due to self-injection. From the measurement of Jc at two different thickness' (1800 A and 1500 A) of YBCO both on the LAO as well as the LCMO side, the value of self-injection length (at 77K) was estimated to be ~900 A self-injection length has been quantified. A control experiment carried out with LaNiO3 deposited by PLD on YBCO did not show any evidence of self-injection.Comment: 6 pages, one figure in .ps forma

Deficiency and Also Transgenic Overexpression of Timp-3 Both Lead to Compromised Bone Mass and Architecture In Vivo

Tissue inhibitor of metalloproteinases-3 (TIMP-3) regulates extracellular matrix via its inhibition of matrix metalloproteinases and membrane-bound sheddases. Timp-3 is expressed at multiple sites of extensive tissue remodelling. This extends to bone where its role, however, remains largely unresolved. In this study, we have used Micro-CT to assess bone mass and architecture, histological and histochemical evaluation to characterise the skeletal phenotype of Timp-3 KO mice and have complemented this by also examining similar indices in mice harbouring a Timp-3 transgene driven via a Col-2a-driven promoter to specifically target overexpression to chondrocytes. Our data show that Timp-3 deficiency compromises tibial bone mass and structure in both cortical and trabecular compartments, with corresponding increases in osteoclasts. Transgenic overexpression also generates defects in tibial structure predominantly in the cortical bone along the entire shaft without significant increases in osteoclasts. These alterations in cortical mass significantly compromise predicted tibial load-bearing resistance to torsion in both genotypes. Neither Timp-3 KO nor transgenic mouse growth plates are significantly affected. The impact of Timp-3 deficiency and of transgenic overexpression extends to produce modification in craniofacial bones of both endochondral and intramembranous origins. These data indicate that the levels of Timp-3 are crucial in the attainment of functionally-appropriate bone mass and architecture and that this arises from chondrogenic and osteogenic lineages

LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target

Effective treatments and animal models for the most prevalent neurodegenerative form of blindness in elderly people, called age-related macular degeneration (AMD), are lacking. Genome-wide association studies have identified lipid metabolism and inflammation as AMD-associated pathogenic pathways. Given liver X receptors (LXRs), encoded by the nuclear receptor subfamily 1 group H members 2 and 3 (NR1H3 and NR1H2), are master regulators of these pathways, herein we investigated the role of LXR in human and mouse eyes as a function of age and disease and tested the therapeutic potential of targeting LXR. We identified immunopositive LXR fragments in human extracellular early dry AMD lesions and a decrease in LXR expression within the retinal pigment epithelium (RPE) as a function of age. Aged mice lacking LXR presented with isoform-dependent ocular pathologies. Specifically, loss of the Nr1h3 isoform resulted in pathobiologies aligned with AMD, supported by compromised visual function, accumulation of native and oxidized lipids in the outer retina, and upregulation of ocular inflammatory cytokines, while absence of Nr1h2 was associated with ocular lipoidal degeneration. LXR activation not only ameliorated lipid accumulation and oxidant-induced injury in RPE cells but also decreased ocular inflammatory markers and lipid deposition in a mouse model, thereby providing translational support for pursuing LXR-active pharmaceuticals as potential therapies for dry AMD

Interleukin-10 Overexpression Promotes Fas-Ligand-Dependent Chronic Macrophage-Mediated Demyelinating Polyneuropathy

BACKGROUND:Demyelinating polyneuropathy is a debilitating, poorly understood disease that can exist in acute (Guillain-Barré syndrome) or chronic forms. Interleukin-10 (IL-10), although traditionally considered an anti-inflammatory cytokine, has also been implicated in promoting abnormal angiogenesis in the eye and in the pathobiology of autoimmune diseases such as lupus and encephalomyelitis. PRINCIPAL FINDINGS:Overexpression of IL-10 in a transgenic mouse model leads to macrophage-mediated demyelinating polyneuropathy. IL-10 upregulates ICAM-1 within neural tissues, promoting massive macrophage influx, inflammation-induced demyelination, and subsequent loss of neural tissue resulting in muscle weakness and paralysis. The primary insult is to perineural myelin followed by secondary axonal loss. Infiltrating macrophages within the peripheral nerves demonstrate a highly pro-inflammatory signature. Macrophages are central players in the pathophysiology, as in vivo depletion of macrophages using clodronate liposomes reverses the phenotype, including progressive nerve loss and paralysis. Macrophage-mediate demyelination is dependent on Fas-ligand (FasL)-mediated Schwann cell death. SIGNIFICANCE:These findings mimic the human disease chronic idiopathic demyelinating polyneuropathy (CIDP) and may also promote further understanding of the pathobiology of related conditions such as acute idiopathic demyelinating polyneuropathy (AIDP) or Guillain-Barré syndrome

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling, in inflammation and in vascular biology. The human family includes 19 members that can be sub-grouped on the basis of their known substrates, namely the aggrecanases or proteoglycanases (ADAMTS1, 4, 5, 8, 9, 15 and 20), the procollagen N-propeptidases (ADAMTS2, 3 and 14), the cartilage oligomeric matrix protein-cleaving enzymes (ADAMTS7 and 12), the von-Willebrand Factor proteinase (ADAMTS13) and a group of orphan enzymes (ADAMTS6, 10, 16, 17, 18 and 19). Control of the structure and function of the extracellular matrix (ECM) is a central theme of the biology of the ADAMTS, as exemplified by the actions of the procollagen-N-propeptidases in collagen fibril assembly and of the aggrecanases in the cleavage or modification of ECM proteoglycans. Defects in certain family members give rise to inherited genetic disorders, while the aberrant expression or function of others is associated with arthritis, cancer and cardiovascular disease. In particular, ADAMTS4 and 5 have emerged as therapeutic targets in arthritis. Multiple ADAMTSs from different sub-groupings exert either positive or negative effects on tumorigenesis and metastasis, with both metalloproteinase-dependent and -independent actions known to occur. The basic ADAMTS structure comprises a metalloproteinase catalytic domain and a carboxy-terminal ancillary domain, the latter determining substrate specificity and the localization of the protease and its interaction partners; ancillary domains probably also have independent biological functions. Focusing primarily on the aggrecanases and proteoglycanases, this review provides a perspective on the evolution of the ADAMTS family, their links with developmental and disease mechanisms, and key questions for the future

Mononuclear cells modulate the activity of pancreatic stellate cells which in turn promote fibrosis and inflammation in chronic pancreatitis

Background: Interactions between mononuclear cells and activated pancreatic myofibroblasts (pancreatic stellate cells; PSC) may contribute to inflammation and fibrosis in chronic pancreatitis (CP). Methods: Markers of fibrosis and inflammation were concomitantly analysed by immunohistochemistry in chronic pancreatitis tissues. In vitro, PSC were stimulated with TNFalpha and LPS. Primary human blood mononuclear cells (PBMC) and PSC were cocultured, followed by analysis of cytokines and extracellular matrix (ECM) proteins. PBMC were derived from healthy donors and CP and septic shock patients. Results: In areas of mononuclear cell infiltration in chronic pancreatitis tissues, there was decreased immunoreactivity for collagen1 and fibronectin, in contrast to areas with sparse mononuclear cells, although PSC were detectable in both areas. LPS and TNFalpha induced collagen1 and fibronectin levels as well as the matrix degradation enzyme MMP-1. Coculture experiments with PSC and PBMC revealed increased fibronectin secretion induced by PBMC. In addition, donor and CP PBMC significantly induced an increase in IL-6, MCP-1 and TGFbeta levels under coculture conditions. Determination of the source of cytokines and ECM proteins by mRNA expression analysis confirmed PSC as major contributors of ECM production. The increase in cytokine expression was PBMC- and also PSC-derived. Conclusion: Mononuclear cells modulate the activity of pancreatic stellate cells, which may in turn promote fibrosis and inflammation

Regularity of critical invariant circles of the standard nontwist map

We study critical invariant circles of several noble rotation numbers at the edge of break-up for an area-preserving map of the cylinder, which violates the twist condition.These circles admit essentially unique parametrizations by rotational coordinates. We present a high accuracy computation of about 107 Fourier coefficients. This allows us to compute the regularity of the conjugating maps and to show that, to the extent of numerical precision, it only depends on the tail of the continued fraction expansion.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49075/2/non5_3_013.pd