253 research outputs found
Non-Enzymatic Decomposition of Collagen Fibers by a Biglycan Antibody and a Plausible Mechanism for Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory and destructive joint disorder that affects tens of millions of people worldwide. Normal healthy joints maintain a balance between the synthesis of extracellular matrix (ECM) molecules and the proteolytic degradation of damaged ones. In the case of RA, this balance is shifted toward matrix destruction due to increased production of cleavage enzymes and the presence of (autoimmune) immunoglobulins resulting from an inflammation induced immune response. Herein we demonstrate that a polyclonal antibody against the proteoglycan biglycan (BG) causes tissue destruction that may be analogous to that of RA affected tissues. The effect of the antibody is more potent than harsh chemical and/or enzymatic treatments designed to mimic arthritis-like fibril de-polymerization. In RA cases, the immune response to inflammation causes synovial fibroblasts, monocytes and macrophages to produce cytokines and secrete matrix remodeling enzymes, whereas B cells are stimulated to produce immunoglobulins. The specific antigen that causes the RA immune response has not yet been identified, although possible candidates have been proposed, including collagen types I and II, and proteoglycans (PG's) such as biglycan. We speculate that the initiation of RA associated tissue destruction in vivo may involve a similar non-enzymatic decomposition of collagen fibrils via the immunoglobulins themselves that we observe here ex vivo
Control of Vertebrate Skeletal Mineralization by Polyphosphates
BACKGROUND:Skeletons are formed in a wide variety of shapes, sizes, and compositions of organic and mineral components. Many invertebrate skeletons are constructed from carbonate or silicate minerals, whereas vertebrate skeletons are instead composed of a calcium phosphate mineral known as apatite. No one yet knows why the dynamic vertebrate skeleton, which is continually rebuilt, repaired, and resorbed during growth and normal remodeling, is composed of apatite. Nor is the control of bone and calcifying cartilage mineralization well understood, though it is thought to be associated with phosphate-cleaving proteins. Researchers have assumed that skeletal mineralization is also associated with non-crystalline, calcium- and phosphate-containing electron-dense granules that have been detected in vertebrate skeletal tissue prepared under non-aqueous conditions. Again, however, the role of these granules remains poorly understood. Here, we review bone and growth plate mineralization before showing that polymers of phosphate ions (polyphosphates: (PO(3)(-))(n)) are co-located with mineralizing cartilage and resorbing bone. We propose that the electron-dense granules contain polyphosphates, and explain how these polyphosphates may play an important role in apatite biomineralization. PRINCIPAL FINDINGS/METHODOLOGY:The enzymatic formation (condensation) and destruction (hydrolytic degradation) of polyphosphates offers a simple mechanism for enzymatic control of phosphate accumulation and the relative saturation of apatite. Under circumstances in which apatite mineral formation is undesirable, such as within cartilage tissue or during bone resorption, the production of polyphosphates reduces the free orthophosphate (PO(4)(3-)) concentration while permitting the accumulation of a high total PO(4)(3-) concentration. Sequestering calcium into amorphous calcium polyphosphate complexes can reduce the concentration of free calcium. The resulting reduction of both free PO(4)(3-) and free calcium lowers the relative apatite saturation, preventing formation of apatite crystals. Identified in situ within resorbing bone and mineralizing cartilage by the fluorescent reporter DAPI (4',6-diamidino-2-phenylindole), polyphosphate formation prevents apatite crystal precipitation while accumulating high local concentrations of total calcium and phosphate. When mineralization is required, tissue non-specific alkaline phosphatase, an enzyme associated with skeletal and cartilage mineralization, cleaves orthophosphates from polyphosphates. The hydrolytic degradation of polyphosphates in the calcium-polyphosphate complex increases orthophosphate and calcium concentrations and thereby favors apatite mineral formation. The correlation of alkaline phosphatase with this process may be explained by the destruction of polyphosphates in calcifying cartilage and areas of bone formation. CONCLUSIONS/SIGNIFICANCE:We hypothesize that polyphosphate formation and hydrolytic degradation constitute a simple mechanism for phosphate accumulation and enzymatic control of biological apatite saturation. This enzymatic control of calcified tissue mineralization may have permitted the development of a phosphate-based, mineralized endoskeleton that can be continually remodeled
Origin of magnetoelectric behavior in BiFeO
The magnetoelectric behavior of BiFeO has been explored on the basis of
accurate density functional calculations. The structural, electronic, magnetic,
and ferroelectric properties of BiFeO are predicted correctly without
including strong correlation effect in the calculation. Moreover, the
experimentally-observed elongation of cubic perovskite-like lattice along the
[111] direction is correctly reproduced. At high pressure we predicted a
pressure-induced structural transition and the total energy calculations at
expanded lattice show two lower energy ferroelectric phases, closer in energy
to the ground state phase. Band-structure calculations show that BiFeO will
be an insulator in A- and G-type antiferromagnetic phases and a metal in other
magnetic configurations. Chemical bonding in BiFeO has been analyzed using
various tools and electron localization function analysis shows that
stereochemically active lone-pair electrons at the Bi sites are responsible for
displacements of the Bi atoms from the centro-symmetric to the
noncentrosymmetric structure and hence the ferroelectricity. A large
ferroelectric polarization (88.7 C/cm) is predicted in accordance
with recent experimental findings. The net polarization is found to mainly (
98%) originate from Bi atoms. Moreover the large scatter in experimentally
reported polarization values is due to the large anisotropy in the spontaneous
polarization.Comment: 19 pages, 12 figures, 4 table
Chiral and herringbone symmetry breaking in water-surface monolayers
We report the observation from monolayers of eicosanoic acid in the L′2 phase of three distinct out-of-plane first-order diffraction peaks, indicating molecular tilt in a nonsymmetry direction and hence the absence of mirror symmetry. At lower pressures the molecules tilt in the direction of their nearest neighbors. In this region we find a structural transition, which we tentatively identify as the rotator-herringbone transition L2d−L2h
Magnetism, FeS colloids, and Origins of Life
A number of features of living systems: reversible interactions and weak
bonds underlying motor-dynamics; gel-sol transitions; cellular connected
fractal organization; asymmetry in interactions and organization; quantum
coherent phenomena; to name some, can have a natural accounting via
interactions, which we therefore seek to incorporate by expanding the horizons
of `chemistry-only' approaches to the origins of life. It is suggested that the
magnetic 'face' of the minerals from the inorganic world, recognized to have
played a pivotal role in initiating Life, may throw light on some of these
issues. A magnetic environment in the form of rocks in the Hadean Ocean could
have enabled the accretion and therefore an ordered confinement of
super-paramagnetic colloids within a structured phase. A moderate H-field can
help magnetic nano-particles to not only overcome thermal fluctuations but also
harness them. Such controlled dynamics brings in the possibility of accessing
quantum effects, which together with frustrations in magnetic ordering and
hysteresis (a natural mechanism for a primitive memory) could throw light on
the birth of biological information which, as Abel argues, requires a
combination of order and complexity. This scenario gains strength from
observations of scale-free framboidal forms of the greigite mineral, with a
magnetic basis of assembly. And greigite's metabolic potential plays a key role
in the mound scenario of Russell and coworkers-an expansion of which is
suggested for including magnetism.Comment: 42 pages, 5 figures, to be published in A.R. Memorial volume, Ed
Krishnaswami Alladi, Springer 201
Electrical Impedance of Acupuncture Meridians: The Relevance of Subcutaneous Collagenous Bands
Background: The scientific basis for acupuncture meridians is unknown. Past studies have suggested that acupuncture meridians are physiologically characterized by low electrical impedance and anatomically associated with connective tissue planes. We are interested in seeing whether acupuncture meridians are associated with lower electrical impedance and whether ultrasound-derived measures – specifically echogenic collagenous bands- can account for these impedance differences. Methods/Results: In 28 healthy subjects, we assessed electrical impedance of skin and underlying subcutaneous connective tissue using a four needle-electrode approach. The impedances were obtained at 10 kHz and 100 kHz frequencies and at three body sites- upper arm (Large Intestine meridian), thigh (Liver), and lower leg (Bladder). Meridian locations were determined by acupuncturists. Ultrasound images were obtained to characterize the anatomical features at each measured site. We found significantly reduced electrical impedance at the Large Intestine meridian compared to adjacent control for both frequencies. No significant decrease in impedance was found at the Liver or Bladder meridian. Greater subcutaneous echogenic densities were significantly associated with reduced impedances in both within-site (meridian vs. adjacent control) and between-site (arm vs. thigh vs. lower leg) analyses. This relationship remained significant in multivariabl
Tensor Decomposition Reveals Concurrent Evolutionary Convergences and Divergences and Correlations with Structural Motifs in Ribosomal RNA
Evolutionary relationships among organisms are commonly described by using a
hierarchy derived from comparisons of ribosomal RNA (rRNA) sequences. We propose that
even on the level of a single rRNA molecule, an organism's evolution is composed
of multiple pathways due to concurrent forces that act independently upon different
rRNA degrees of freedom. Relationships among organisms are then compositions of
coexisting pathway-dependent similarities and dissimilarities, which cannot be
described by a single hierarchy. We computationally test this hypothesis in
comparative analyses of 16S and 23S rRNA sequence alignments by using a tensor
decomposition, i.e., a framework for modeling composite data. Each alignment is
encoded in a cuboid, i.e., a third-order tensor, where nucleotides, positions and
organisms, each represent a degree of freedom. A tensor mode-1 higher-order singular
value decomposition (HOSVD) is formulated such that it separates each cuboid into
combinations of patterns of nucleotide frequency variation across organisms and
positions, i.e., “eigenpositions” and corresponding nucleotide-specific
segments of “eigenorganisms,” respectively, independent of a-priori
knowledge of the taxonomic groups or rRNA structures. We find, in support of our
hypothesis that, first, the significant eigenpositions reveal multiple similarities
and dissimilarities among the taxonomic groups. Second, the corresponding
eigenorganisms identify insertions or deletions of nucleotides exclusively conserved
within the corresponding groups, that map out entire substructures and are enriched
in adenosines, unpaired in the rRNA secondary structure, that participate in tertiary
structure interactions. This demonstrates that structural motifs involved in rRNA
folding and function are evolutionary degrees of freedom. Third, two previously
unknown coexisting subgenic relationships between Microsporidia and Archaea are
revealed in both the 16S and 23S rRNA alignments, a convergence and a divergence,
conferred by insertions and deletions of these motifs, which cannot be described by a
single hierarchy. This shows that mode-1 HOSVD modeling of rRNA alignments might be
used to computationally predict evolutionary mechanisms
Rapid Evolution of Enormous, Multichromosomal Genomes in Flowering Plant Mitochondria with Exceptionally High Mutation Rates
A pair of species within the genus Silene have evolved the largest known mitochondrial genomes, coinciding with extreme changes in mutation rate, recombination activity, and genome structure
Speech, truth and liberty: Bentham to John Stuart Mill
Bentham’s Utilitarianism transforms earlier free speech doctrine in the service of the pursuit of truth and the control of government, preserving the distinction between statements of opinion and of fact and awarding the latter a lesser degree of protection. The work of James Mill and the early writings of John Stuart Mill retain this distinction, but their accounts are weighed down by the problems of a direct Utilitarian approach, in their consequentialist balancing of different values against each other, and in their dependence on a majoritarian epistemology and their commitment to a naive progressive optimism. Mill goes on in On Liberty to address and resolve these problems on the basis of a new justification for free speech as free deliberative thought. I argue that, contrary to most interpretations, his new justification leaves untouched the basic distinction between absolutely protected expressions of opinion and only functionally and contingently protected assertions of fact, leaving room for restrictions on factual statements, especially when untrue
Dibutyltin Disrupts Glucocorticoid Receptor Function and Impairs Glucocorticoid-Induced Suppression of Cytokine Production
BACKGROUND: Organotins are highly toxic and widely distributed environmental chemicals. Dibutyltin (DBT) is used as stabilizer in the production of polyvinyl chloride plastics, and it is also the major metabolite formed from tributyltin (TBT) in vivo. DBT is immunotoxic, however, the responsible targets remain to be defined. Due to the importance of glucocorticoids in immune-modulation, we investigated whether DBT could interfere with glucocorticoid receptor (GR) function. METHODOLOGY: We used HEK-293 cells transiently transfected with human GR as well as rat H4IIE hepatoma cells and native human macrophages and human THP-1 macrophages expressing endogenous receptor to study organotin effects on GR function. Docking of organotins was used to investigate the binding mechanism. PRINCIPAL FINDINGS: We found that nanomolar concentrations of DBT, but not other organotins tested, inhibit ligand binding to GR and its transcriptional activity. Docking analysis indicated that DBT inhibits GR activation allosterically by inserting into a site close to the steroid-binding pocket, which disrupts a key interaction between the A-ring of the glucocorticoid and the GR. DBT inhibited glucocorticoid-induced expression of phosphoenolpyruvate carboxykinase (PEPCK) and tyrosine-aminotransferase (TAT) and abolished the glucocorticoid-mediated transrepression of TNF-alpha-induced NF-kappaB activity. Moreover, DBT abrogated the glucocorticoid-mediated suppression of interleukin-6 (IL-6) and TNF-alpha production in lipopolysaccharide (LPS)-stimulated native human macrophages and human THP-1 macrophages. CONCLUSIONS: DBT inhibits ligand binding to GR and subsequent activation of the receptor. By blocking GR activation, DBT may disturb metabolic functions and modulation of the immune system, providing an explanation for some of the toxic effects of this organotin
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