Reactive-site mutants of N-TIMP-3 that selectively inhibit ADAMTS-4 and ADAMTS-5: biological and structural implications.

Published versio

Chemokine-induced secretion of gelatinase B in primary human monocytes

Chemokines help control normal leukocyte trafficking as well as their infiltration into tissues during acute and chronic inflammation. Matrix metalloproteinases (MMPs) help support the extravasation and infiltration of leukocytes through limited proteolysis of basement membranes and matrix material. The effect of the chemokines RANTES/CCL5, MCP-1/CCL and SDF-1 /CXCL12 on secretion of the matrix metalloproteinase B and its endogenous inhibitor TIMP-1 was studied. RANTES/CCL5 and SDF-1/CXCL12 were found to induce MMP-9 secretion in primary human monocytes while TIMP-1 secretion was not affected. RANTES/CCL5 effects were mediated through CCR1 because the CCR1 antagonist BX471 was found to effectively block RANTES/CCL5-induced MMP-9 secretion

Double jeopardy-pregnancy and birth during a catastrophic bushfire event followed by a pandemic lockdown, a natural experiment

Background: From November 2019 to January 2020, eastern Australia experienced the worst bushfires in recorded history. Two months later, Sydney and surrounds were placed into lockdown for six weeks due to the COVID-19 pandemic, followed by ongoing restrictions. Many pregnant women at this time were exposed to both the bushfires and COVID-19 restrictions. Objective: To assess the impact of exposure to bushfires and pandemic restrictions on perinatal outcomes. Methods: The study included 60 054 pregnant women who gave birth between November 2017 and December 2020 in South Sydney. Exposure cohorts were based on conception and birthing dates: 1) bushfire late pregnancy, born before lockdown; 2) bushfires in early-mid pregnancy, born during lockdown or soon after; 3) conceived during bushfires, lockdown in second trimester; 4) conceived after bushfires, pregnancy during restrictions. Exposure cohorts were compared with pregnancies in the matching periods in the two years prior. Associations between exposure cohorts and gestational diabetes, preeclampsia, hypertension, stillbirth, mode of birth, birthweight, preterm birth and small for gestational age were assessed using generalised estimating equations, adjusting for covariates. Results: A decrease in low birth weight was observed for cohort 1 (aOR 0.81, 95%CI 0.69, 0.95). Conversely, cohort 2 showed an increase in low birth weight, and increases in prelabour rupture of membranes, and caesarean sections (aOR 1.18, 95%CI 1.03, 1.37; aOR 1.21, 95%CI 1.07, 1.37; aOR 1.10 (1.02, 1.18) respectively). Cohort 3 showed an increase in unplanned caesarean sections and high birth weight babies (aOR 1.15, 95%CI 1.04, 1.27 and aOR 1.16, 95%CI 1.02, 1.31 respectively), and a decrease in gestational diabetes mellitus was observed for both cohorts 3 and 4. Conclusion: Pregnancies exposed to both severe climate events and pandemic disruptions appear to have increased risk of adverse perinatal outcomes beyond only experiencing one event, but further research is needed

Herb-drug interaction: Effect of aqueous extract of Bridelia ferruginea leaves on the pharmacokinetics of metformin

The concurrent use of herbal medicines and orthodox drugs, especially in the treatment and management of chronic ailments, may result in clinically significant herb-drug interactions. Bridelia ferruginea Benth (Euphorbiaceae) is a common medicinal plant with known anti-diabetic properties and has been reported to be taken alongside the orthodox medicine, metformin. The aim of this study was to investigate the effect of aqueous extract of B. ferruginea leaves on the pharmacokinetics of metformin in female Sprague-Dawley rats. Reconstituted freeze dried extract of B. ferruginea leaves (30 mg/kg), and metformin (7 mg/kg) were administered concurrently as a single dose to female Sprague-Dawley rats. Whole blood samples (1 ml) were aseptically withdrawn by tail bleeding at 1, 2, 4, 8, and 24 h after administration of the single dose for pharmacokinetics analyses. Concurrent administration of metformin and B. ferruginea significantly affected (P < 0.05) all the pharmacokinetics parameters of metformin except for the time to attain the maximum concentration (Tmax), which increased but insignificantly. Whereas the area under the curve, maximum whole blood concentration (Cmax) and half-life (T½) of metformin decreased significantly in the presence of B. ferruginea, the elimination rate constant (Kel), clearance (Cl), absorption rate constant (Ka), and volume of distribution (Vd) of metformin increased significantly in the presence of B. ferruginea. Therefore, in clinical practice, patients should be advised on the implication of concurrent administration of metformin and B. ferrruginea

Plankton community composition, organic carbon and thorium-234 particle size distributions, and particle export in the Sargasso Sea

Measurements of plankton community composition (eight planktonic groups), particle size-fractionated (10, 20, 53, 70, and 100-μm Nitex screens) distributions of organic carbon (OC) and 234Th, and particle export of OC and 234Th are reported over a seasonal cycle (2006–2007) from the Bermuda Atlantic Time-Series (BATS) site. Results indicate a convergence of the particle size distributions of OC and 234Th during the winter-spring bloom period (January–March, 2007). The observed convergence of these particle size distributions is directly correlated to the depth-integrated abundance of autotrophic pico-eukaryotes (r = 0.97, P \u3c 0.05) and, to a lesser extent, Synechococcus (r = 0.85, P \u3c 0.14). In addition, there are positive correlations between the sediment trap flux of OC and 234Th at 150 m and the depth-integrated abundance of pico-eukaryotes (r = 0.94, P \u3c 0.06 for OC, and r = 0.98, P \u3c 0.05 for 234Th) and Synechococcus (r = 0.95, P \u3c 0.05 for OC, and r = 0.94, P \u3c 0.06 for 234Th). An implication of these observations and recent modeling studies (Richardson and Jackson, 2007) is that, although small in size, pico-plankton may influence large particle export from the surface waters of the subtropical Atlantic

Current sources of financing power infrastructure in developing countries : principal component analysis approach

Abstract: Infrastructure plays the dominant role in structuring and positioning every nation’s economy and social development. Infrastructure financing is the blue print in achieving infrastructure development in developing and developed countries. This research project determines the current sources of financing infrastructure in developing countries. The study adopted a quantitative research approach with data gathered from the respondents within power infrastructure development in the region. The findings revealed current sources of financing power infrastructure in developing countries to be commercial bank loans, public finance, private finance, power utility fees, public-private partnership, foreign direct investment. These were seen as current sources of financing power infrastructure in developing countries. Having established that no society can develop without adequate investment in the power infrastructure sector, there is a call for adequate investment in the power infrastructure to foster and re-integrate developing countries in the path of economic development and global relevance. If the central government can direct adequate finance and harness the current sources available to develop power infrastructure in their society, it will ultimately lead to enormous economic growth and social development in the region. This research project will contribute to the development of public infrastructure in developing countries, which will directly influence the development of power infrastructure in the region for the purpose of economic relevance and improvement of lives in the society

Exogenously added GPI-anchored tissue inhibitor of matrix metal loproteinase-1 (TIMP-1) displays enhanced and novel biological activities

The family of tissue inhibitors of metalloproteinases (TIMPs) exhibits diverse physiological/biological functions including the inhibition of active matrix metalloproteinases, regulation of proMMP activation, cell growth, and the modulation of angiogenesis. TIMP-1 is a secreted protein that can be detected on the cell surface through its interaction with surface proteins. The diverse biological functions of TIMP-1 are thought to lie, in part, in the kinetics of TIMP-1/MMP/surface protein interactions. Proteins anchored by glycoinositol phospholipids (GPIs), when purified and added to cells in vitro, are incorporated into their surface membranes. A GPI anchor was fused to TIMP-1 to generate a reagent that could be added directly to cell membranes and thus focus defined concentrations of TIMP-1 protein on any cell surface independent of protein-protein interaction. Unlike native TIMP-1, exogenously added GPI-anchored TIMP-1 protein effectively blocked release of MMP-2 and MMP-9 from osteosarcoma cells. TIMP-1-GP1 was a more effective modulator of migration and proliferation than TIMP-1. While control hTIMP-1 protein did not significantly affect migration of primary microvascular endothelial cells at the concentrations tested, the GPI-anchored TIMP-1 protein showed a pronounced suppression of endothelial cell migration in response to bFGF. In addition, TIMP-1-GPI was more effective at inducing microvascular endothelial proliferation. In contrast, fibroblast proliferation was suppressed by the agent. Reagents based on this method should assist in the dissection of the protease cascades and activities involved in TIMP biology. Membrane-fixed TIMP-1 may represent a more effective version of the protein for use in therapeutic expression

What does touch tell us about emotions in touchscreen-based gameplay?

This is the post-print version of the Article. The official published version can be accessed from the link below - Copyright @ 2012 ACM. It is posted here by permission of ACM for your personal use. Not for redistribution.Nowadays, more and more people play games on touch-screen mobile phones. This phenomenon raises a very interesting question: does touch behaviour reflect the player’s emotional state? If possible, this would not only be a valuable evaluation indicator for game designers, but also for real-time personalization of the game experience. Psychology studies on acted touch behaviour show the existence of discriminative affective profiles. In this paper, finger-stroke features during gameplay on an iPod were extracted and their discriminative power analysed. Based on touch-behaviour, machine learning algorithms were used to build systems for automatically discriminating between four emotional states (Excited, Relaxed, Frustrated, Bored), two levels of arousal and two levels of valence. The results were very interesting reaching between 69% and 77% of correct discrimination between the four emotional states. Higher results (~89%) were obtained for discriminating between two levels of arousal and two levels of valence

Blood-brain barrier integrity, intrathecal immunoactivation, and neuronal injury in HIV

OBJECTIVE: Although blood-brain barrier (BBB) impairment has been reported in HIV-infected individuals, characterization of this impairment has not been clearly defined. METHODS: BBB integrity was measured by CSF/plasma albumin ratio in this cross-sectional study of 631 HIV-infected individuals and 71 controls. We also analyzed CSF and blood HIV RNA and neopterin, CSF leukocyte count, and neurofilament light chain protein (NFL) concentrations. The HIV-infected participants included untreated neuroasymptomatic patients, patients with untreated HIV-associated dementia (HAD), and participants on suppressive antiretroviral treatment (ART). RESULTS: The albumin ratio was significantly increased in patients with HAD compared to all other groups. There were no significant differences between untreated neuroasymptomatic participants, treated participants, and controls. BBB integrity, however, correlated significantly with CSF leukocyte count, CSF HIV RNA, serum and CSF neopterin, and age in untreated neuroasymptomatic participants. In a multiple linear regression analysis, age, CSF neopterin, and CSF leukocyte count stood out as independent predictors of albumin ratio. A significant correlation was found between albumin ratio and CSF NFL in untreated neuroasymptomatic patients and in participants on ART. Albumin ratio, age, and CD4 cell count were confirmed as independent predictors of CSF NFL in multivariable analysis. CONCLUSIONS: BBB disruption was mainly found in patients with HAD, where BBB damage correlated with CNS immunoactivation. Albumin ratios also correlated with CSF inflammatory markers and NFL in untreated neuroasymptomatic participants. These findings give support to the association among BBB deterioration, intrathecal immunoactivation, and neuronal injury in untreated neuroasymptomatic HIV-infected individuals