Effects of Time-Dependent Stimuli in a Competitive Neural Network Model of Perceptual Rivalry

We analyze a competitive neural network model of perceptual rivalry that receives time-varying inputs. Time-dependence of inputs can be discrete or smooth. Spike frequency adaptation provides negative feedback that generates network oscillations when inputs are constant in time. Oscillations that resemble perceptual rivalry involve only one population being “ON” at a time, which represents the dominance of a single percept at a time. As shown in Laing and Chow (J. Comput. Neurosci. 12(1):39–53, 2002), for sufficiently high contrast, one can derive relationships between dominance times and contrast that agree with Levelt’s propositions (Levelt in On binocular rivalry, 1965). Time-dependent stimuli give rise to novel network oscillations where both, one, or neither populations are “ON” at any given time. When a single population receives an interrupted stimulus, the fundamental mode of behavior we find is phase-locking, where the temporally driven population locks its state to the stimulus. Other behaviors are analyzed as bifurcations from this forced oscillation, using fast/slow analysis that exploits the slow timescale of adaptation. When both populations receive time-varying input, we find mixtures of fusion and sole population dominance, and we partition parameter space into particular oscillation types. Finally, when a single population’s input contrast is smoothly varied in time, 1:n mode-locked states arise through period-adding bifurcations beyond phase-locking. Our results provide several testable predictions for future psychophysical experiments on perceptual rivalry.     

Matrilin-3 Induction of IL-1 receptor antagonist Is required for up-regulating collagen II and aggrecan and down-regulating ADAMTS-5 gene expression

Introduction

Deletion or mutation of the gene encoding the cartilage extracellular matrix (ECM) protein matrilin-3 (MATN3) results in the early onset of osteoarthritis (OA), suggesting chondroprotective properties of MATN3. To understand the mechanisms underlying these properties, we determined the effects of MATN3 protein on the expression of several key anabolic and catabolic genes involved in chondrocyte homeostasis, and the dependence of such regulation on the anti-inflammatory cytokine: IL-1 receptor antagonist (IL-1Ra).

Methods

The effects of recombinant human (rh) MATN3 protein were examined in C28/I2 immortalized human chondrocytes, primary human chondrocytes (PHCs), and primary mouse chondrocytes (PMCs). Messenger RNA levels of IL-1Ra, COL2A1, ACAN, MMP-13, and ADAMTS-4 and -5 were determined using real-time RT-PCR. Knocking down IL-1Ra was achieved by siRNA gene silencing. IL-1Ra protein levels were quantified by ELISA and the Bio-Plex Suspension Array System. COL2A1 protein level was quantified using Western blot analysis. Statistic analysis was done using the two-tailed t-test or one-way ANOVA.

Results

rhMATN3 protein induced gene expression of IL-1Ra in C28/I2 cells, PHCs, and PMCs in a dose- and time-dependent manner. Treatment of C28/I2 cells and PHCs with MATN3 protein stimulated gene expression of COL2A1 and ACAN. Conversely, mRNA levels of COL2A1 and ACAN were decreased in MATN3 KO mice. MATN3 protein treatment inhibited IL-1β-induced MMP-13, ADAMTS-4 and ADAMTS-5 in C28/I2 cells and PHCs. Knocking down IL-1Ra abolished the MATN3-mediated stimulation of COL2A1 and ACAN and inhibition of ADAMTS-5, but had no effect on MATN3 inhibition of MMP-13 mRNA.

Conclusion

Our findings point to a novel regulatory role of MATN3 in cartilage homeostasis due to its capacity to induce IL-1Ra, to upregulate gene expression of the major cartilage matrix components, and to downregulate the expression of OA-associated matrix-degrading proteinases in chondrocytes. The chondroprotective properties of endogenous MATN3 depend partly on its induction of IL-1Ra. Our findings raise a possibility to use rhMATN3 protein for anti-inflammatory and chondroprotective therapy.     

Seed dormancy of Cardiospermum halicacabum (Sapindaceae) from three precipitation zones in Sri Lanka

• This study investigated seed germination of Cardiospermum halicacabum, a medicinally important invasive species.
• We compared mass, moisture content (MC), dormancy and dormancy‐breaking treatments and imbibition and germination of scarified and non‐scarified seeds of C. halicacabum from a low‐elevation dry zone (DZ), low‐elevation wet zone (WZ1) and mid‐elevation wet zone (WZ2) in Sri Lanka to test the hypothesis that the percentage of seeds with water‐impermeable seed coats (physical dormancy, PY) decreases with increased precipitation.
• Seed mass was higher in WZ2 than in DZ and WZ1, while seed MC did not vary among the zones. All scarified DZ, WZ1 and WZ2 and non‐scarified DZ and WZ1 seeds imbibed water, but only a few non‐scarified WZ2 seeds did so. When DZ and WZ1 seeds were desiccated, MC and percentage imbibition decreased, showing that these seeds have the ability to develop PY. GA₃ promoted germination of embryos excised from fresh DZ and WZ1 seeds and of scarified WZ2 seeds.
• At maturity, seeds from DZ and WZ1 had only physiological dormancy (PD), while those from WZ2 had combinational dormancy (PY+PD). Thus, our hypothesis was not supported. Since a high percentage of excised embryos developed into normal seedlings; this is a low‐cost method to produce C. halicacabum plants for medicinal and ornamental purposes.

     

A proposed mechanism for physical dormancy break in seeds of Ipomoea lacunosa (Convolvulaceae)

Background and Aims

The water-impermeable seeds of Ipomoea lacunosa undergo sensitivity cycling to dormancy breaking treatment, and slits are formed around bulges adjacent to the micropyle during dormancy break, i.e. the water gap opens. The primary aim of this research was to identify the mechanism of slit formation in seeds of this species.

Methods

Sensitive seeds were incubated at various combinations of relative humidity (RH) and temperature after blocking the hilar area in different places. Increase in seed mass was measured before and after incubation. Scanning electron microscopy (SEM) and staining of insensitive and sensitive seeds were carried out to characterize these states morphologically and anatomically. Water absorption was monitored at 35 and 25 °C at 100 % RH.

Key Results

There was a significant relationship between incubation temperature and RH with percentage seed dormancy break. Sensitive seeds absorbed water vapour, but insensitive seeds did not. Different amounts of water were absorbed by seeds with different blocking treatments. There was a significant relationship between dormancy break and the amount of water absorbed during incubation.

Conclusions

Water vapour seals openings that allow it to escape from seeds and causes pressure to develop below the bulge, thereby causing slits to form. A model for the mechanism of formation of slits (physical dormancy break) is proposed.Key words: Convolvulaceae, Ipomoea lacunosa, dormancy-breaking mechanism, physical dormancy, seeds, sensitivity cycling, water vapour     

Isolation,enzyme-bound structure and antibacterial activity of platencin A1 from Streptomyces platensis

Natural products continue to serve as one of the best sources for discovery of antibacterial agents as exemplified by the recent discoveries of platensimycin and platencin. Chemical modifications as well as discovery of congeners are the main sources for gaining knowledge of structure–activity relationship of natural products. Screening for congeners in the extracts of the fermentation broths of Streptomyces platensis led to the isolation of platencin A₁, a hydroxy congener of platencin. The hydroxylation of the tricyclic enone moiety negatively affected the antibacterial activity and appears to be consistent with the hydrophobic binding pocket of the FabF. Isolation, structure, enzyme-bound structure and activity of platencin A₁ and two other congeners have been described.     

Isolation, structure, and HIV-1-integrase inhibitory activity of structurally diverse fungal metabolites

HIV-1 integrase is a critical enzyme for replication of HIV, and its inhibition is one of the most promising new drug strategies for anti-retroviral therapy, with potentially significant advantages over existing therapies. In this report, a series of HIV-1 inhibitors isolated from the organic extract of fermentations from terrestrial fungi is described. These fungal species, belonging to a variety of genera, were collected from throughout the world following the strict guidelines of Rio Convention on Biodiversity. The polyketide- and terpenoid-derived inhibitors are represented by two naphthoquinones, a biphenyl and two triphenyls, a benzophenone, four aromatics with or without catechol units, a linear aliphatic terpenoid, a diterpenoid, and a sesterterpenoid. These compounds inhibited the coupled and strand-transfer reaction of HIV-1 integrase with an IC₅₀ value of 0.5–120 µM. The bioassay-directed isolation, structure elucidation, and HIV-1 inhibitory activity of these compounds are described.Abbreviations CH ₃ CN Acetonitrile - TFA Trifluoroacetic acid - CD ₃ CN Deuterio acetonitrile - CD ₂ Cl ₂ Deuterio methylene chloride - MEK Methyl ethyl ketone - ZnSe Zinc selenide - UV Ultraviolet - IR Infrared - NMR Nuclear magnetic resonance - COSY Homonuclear H-H correlation spectroscopy - HMQC Heteronuclear multiple-quantum coherence - HMBC Heteronuclear multiple-bond correlation - EIMS Electron-impact mass spectrometry - HREIMS High-resolution electron impact mass spectrometry - ESIMS Electrospray ionization mass spectrometry - HRFABMS High-resolution fast atom bombardment mass spectrometry - MES 2-(N-morpholino)-ethane sulfonic acid     

Identification of diverse microbial metabolites as potent inhibitors of HIV-1 Tat transactivation

HIV-1 Tat is one of six regulatory proteins that are required for viral replication and is an attractive target for the development of new anti-HIV agents. Screening of microbial extracts using a whole cell Tat-dependent transactivation assay, which guided the separation of the active broths, led to the identification of five structurally diverse classes (M(R) range 232-1126) of natural products. These include i) three sesquiterpenoids, namely, sporogen-AO1, petasol, and 6-dehydropetasol, ii) two resorcylic 14-membered lactones, namely monorden and monocillin IV, iii) a ten-membered lactone, iv) a quinoline and quinoxiline bicyclic octadepsipeptides, namely echinomycin and UK-63598, and v) a cyclic heptapeptide, ternatin. These compounds displayed varying degrees of potencies with IC50 values ranging from 0.0002 to 100 microM. The most active compound was the quinoxiline bicyclic octadepsipeptides, UK-63598, which inhibited Tat-dependent transactivation with an IC50 value of 0.2 nM and exhibited a 100-fold therapeutic window with respect to toxicity. In a single-cycle antiviral assay, UK-6358 inhibited viral replication with an IC50 value of 0.5 nM; however, it appeared to be equally toxic at that concentration. Monocillin IV was significantly less active (Tat transactivation inhibitory IC50 of 5 microM) but was not toxic at 100 microM in an equivalent cytotoxicity assay. The compound exhibited antiviral activity with an IC50 value of 6.2 microM in the single-cycle antiviral assay and a sixfold therapeutic window. Details of the isolation, fermentation, and biological activities of these structurally diverse natural products are described.     

Rumen and post-rumen fermentation of spent tea leaf protein and other protein sources studied by the nylon bag method

Spent tea leaf (STL) and seven other protein feeds were subjected to microbial fermentation in nylon bags in the rumen of two fistulated buffalo calves and subsequent acid-pepsin digestion in vitro.The STL showed the lowest protein disappearance rate and rumen solubility at 8 h of fermentation. Polyphenols present in STL appear to offer protection to the protein and reduce rumen fermentation. An over-protection could be responsible for the low solubility of the protein in acid—pepsin solution.The high by-pass ability of STL protein appears to make it a suitable feed for growing calves and milking cows.     

Morphology and anatomy of physical dormancy in Ipomoea lacunosa: identification of the water gap in seeds of Convolvulaceae (Solanales)

BACKGROUND AND AIMS: Convolvulaceae is the most advanced plant family (asterid clade) that produces seeds with physical dormancy (water-impermeable seed coat). There are several different opinions about the nature of the specialized structure ('water gap') in the seed coat through which water initially enters seeds of Convolvulaceae, but none of them has been documented clearly. The primary aim of the study was to identify the water gap in seeds of Ipomoea lacunosa (Convolvulaceae) and to describe its morphology, anatomy and function. METHODS: Light microscopy, scanning electron microscopy, tissue-sectioning, dye-tracking and blocking experiments were used to describe the morphology, anatomy and function of the water gap in seeds of I. lacunosa. KEY RESULTS: Dormancy-breaking treatments caused slits to form around the two bulges on the seed coat adjacent to the hilum, and dye entered the seed only via the disrupted bulges. Bulge anatomy differs from that of the rest of the seed coat. Sclereid cells of the bulges are more compacted and elongated than those in the hilum pad and in the rest of the seed coat away from the bulges. CONCLUSIONS: The transition area between elongated and square-shaped sclereid cells is the place where the water gap opens. Morphology/anatomy of the water gap in Convolvulaceae differs from that of taxa in the other 11 angiosperm plant families that produce seeds with physical dormancy for which it has been described.     

Matrilin-3 Inhibits Chondrocyte Hypertrophy as a Bone Morphogenetic Protein-2 Antagonist

Increased chondrocyte hypertrophy is often associated with cartilage joint degeneration in human osteoarthritis patients. Matrilin-3 knock-out (Matn3 KO) mice exhibit these features. However, the underlying mechanism is unknown. In this study, we sought a molecular explanation for increased chondrocyte hypertrophy in the mice prone to cartilage degeneration. We analyzed the effects of Matn3 on chondrocyte hypertrophy and bone morphogenetic protein (Bmp) signaling by quantifying the hypertrophic marker collagen type X (Col X) gene expression and Smad1 activity in Matn3 KO mice in vivo and in Matn3-overexpressing chondrocytes in vitro. The effect of Matn3 and its specific domains on BMP activity were quantified by Col X promoter activity containing the Bmp-responsive element. Binding of MATN3 with BMP-2 was determined by immunoprecipitation, solid phase binding, and surface plasmon resonance assays. In Matn3 KO mice, Smad1 activity was increased more in growth plate chondrocytes than in wild-type mice. Conversely, Matn3 overexpression in hypertrophic chondrocytes led to inhibition of Bmp-2-stimulated, BMP-responsive element-dependent Col X expression and Smad1 activity. MATN3 bound BMP-2 in a dose-dependent manner. Multiple epidermal growth factor (EGF)-like domains clustered together by the coiled coil of Matn3 is required for Smad1 inhibition. Hence, as a novel BMP-2-binding protein and antagonist in the cartilage extracellular matrix, MATN3 may have the inherent ability to inhibit premature chondrocyte hypertrophy by suppressing BMP-2/Smad1 activity.