441 research outputs found
The protease inhibitor JO146 demonstrates a critical role for CtHtrA for Chlamydia trachomatis reversion from penicillin persistence
The Chlamydia trachomatis serine protease HtrA (CtHtrA) has recently been demonstrated to be essential during the replicative phase of the chlamydial developmental cycle. A chemical inhibition strategy (serine protease inhibitor JO146) was used to demonstrate this essential role and it was found that the chlamydial inclusions diminish in size and are lost from the cell after CtHtrA inhibition without formation of viable elementary bodies. The inhibitor (JO146) was used in this study to investigate the role of CtHtrA for penicillin persistence and heat stress conditions for Chlamydia trachomatis. JO146 addition during penicillin persistence resulted in only minor reductions (~1 log) in the final viable infectious yield after persistent Chlamydia were reverted from persistence. However, JO146 treatment during the reversion and recovery from penicillin persistence was completely lethal for Chlamydia trachomatis. JO146 was completely lethal when added either during heat stress conditions, or during the recovery from heat stress conditions. These data together indicate that CtHtrA has essential roles during some stress environments (heat shock), recovery from stress environments (heat shock and penicillin persistence), as well as the previously characterized essential role during the replicative phase of the chlamydial developmental cycle. Thus, CtHtrA is an essential protease with both replicative phase and stress condition functions for Chlamydia trachomatis. © 2013 Ong, Marsh, Lawrence, Allan, Timms and Huston
Manually operated scratch tester for characterization of mechanical properties of thin films
Author name used in this publication: Chung Wo OngAuthor name used in this publication: Woon Ming Lau2004-2005 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe
In vitro susceptibility of recent Chlamydia trachomatis clinical isolates to the CtHtrA inhibitor JO146
© 2015 Institut Pasteur. The present study aimed to establish if a previously identified Chlamydia trachomatis HtrA (CtHtrA) inhibitor, JO146, is effective against currently circulating clinical isolates to validate if CtHtrA is a clinically relevant target for future therapeutic development. Inhibition of CtHtrA during the middle of the chlamydial replicative cycle until the completion of the cycle resulted in loss of infectious progeny for six unique clinical isolates representing different serovars. This supports the potential for CtHtrA to be a clinically relevant target for development of new therapeutics and suggests the importance of further investigation of JO146 as a lead compound
Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNFα, NFκB, p38 and caspase 8 dependent pathways
Tuberculosis (TB) of the central nervous system (CNS) is a deadly disease characterized by extensive tissue destruction, driven by molecules such as Matrix Metalloproteinase-2 (MMP-2) which targets CNS-specific substrates. In a simplified cellular model of CNS TB, we demonstrated that conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb), but not direct infection, unexpectedly down-regulates constitutive microglial MMP-2 gene expression and secretion by 72.8% at 24 hours, sustained up to 96 hours (P < 0.01), dependent upon TNF-α. In human CNS TB brain biopsies but not controls the p38 pathway was activated in microglia/macrophages. Inhibition of the p38 MAP kinase pathway resulted in a 228% increase in MMP-2 secretion (P < 0.01). In contrast ERK MAP kinase inhibition further decreased MMP-2 secretion by 76.6% (P < 0.05). Inhibition of the NFκB pathway resulted in 301% higher MMP-2 secretion than CoMTb alone (P < 0.01). Caspase 8 restored MMP-2 secretion to basal levels. However, this caspase-dependent regulation of MMP-2 was independent of p38 and NFκB pathways; p38 phosphorylation was increased and p50/p65 NFκB nuclear trafficking unaffected by caspase 8 inhibition. In summary, suppression of microglial MMP-2 secretion by M.tb-infected monocyte-dependent networks paradoxically involves the pro-inflammatory mediators TNF-α, p38 MAP kinase and NFκB in addition to a novel caspase 8-dependent pathway
X-ray photoemission spectroscopy of nonmetallic materials : electronic structures of boron and BᵪOᵧ
Author name used in this publication: H. Huang2003-2004 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe
Large enhancement of the thermopower in NaCoO at high Na doping
Research on the oxide perovskites has uncovered electronic properties that
are strikingly enhanced compared with those in conventional metals. Examples
are the high critical temperatures of the cuprate superconductors and the
colossal magnetoresistance in the manganites. The conducting layered cobaltate
displays several interesting electronic phases as is varied
including water-induced superconductivity and an insulating state that is
destroyed by field. Initial measurements showed that, in the as-grown
composition, displays moderately large thermopower and
conductivity . However, the prospects for thermoelectric cooling
applications faded when the figure of merit was found to be small at this
composition (0.60.7). Here we report that, in the poorly-explored
high-doping region 0.75, undergoes an even steeper enhancement. At the
critical doping 0.85, (at 80 K) reaches values 40 times
larger than in the as-grown crystals. We discuss prospects for low-temperature
thermoelectric applications.Comment: 6 pages, 7 figure
Randomised controlled single-blind study of conventional versus depot mydriatic drug delivery prior to cataract surgery
BACKGROUND: A prerequisite for safe cataract surgery is an adequately dilated pupil. The authors conducted a trial to assess the efficacy (in terms of pupil diameter) of a depot method of pre-operative pupil dilatation, as compared with repeated instillations of drops (which is time-consuming for the nursing staff and uncomfortable for the patient). METHODS: A prospective randomised masked trial was conducted comprising 130 patients with no significant ocular history undergoing elective clear corneal phacoemulsification. 65 patients had mydriatic drops (Tropicamide 1%, Phenylephrine 2.5%, Diclofenac sodium 0.1%) instilled prior to surgery, 65 had a wick soaked in the same drop mixture placed in the inferior fornix. Horizontal pupil diameters were recorded on a millimetre scale immediately prior to surgery. RESULTS: There was no significant difference in pupil size between the two groups (p = 0.255, Student's t-test). CONCLUSION: There was no significant difference between the mydriasis obtained with the depot system compared with conventional drop application. Use of a depot mydriatic delivery system appears to be a safe and efficient method of drug delivery. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Register ISRCTN7804776
Endocytic reawakening of motility in jammed epithelia
Dynamics of epithelial monolayers has recently been interpreted in terms of a jamming or rigidity transition. How cells control such phase transitions is, however, unknown. Here we show that RAB5A, a key endocytic protein, is sufficient to induce large-scale, coordinated motility over tens of cells, and ballistic motion in otherwise kinetically arrested monolayers. This is linked to increased traction forces and to the extension of cell protrusions, which align with local velocity. Molecularly, impairing endocytosis, macropinocytosis or increasing fluid efflux abrogates RAB5A-induced collective motility. A simple model based on mechanical junctional tension and an active cell reorientation mechanism for the velocity of self-propelled cells identifies regimes of monolayer dynamics that explain endocytic reawakening of locomotion in terms of a combination of large-scale directed migration and local unjamming. These changes in multicellular dynamics enable collectives to migrate under physical constraints and may be exploited by tumours for interstitial dissemination
Mixed Emotional Experience Is Associated with and Precedes Improvements in Psychological Well-Being
BACKGROUND: The relationships between positive and negative emotional experience and physical and psychological well-being have been well-documented. The present study examines the prospective positive relationship between concurrent positive and negative emotional experience and psychological well-being in the context of psychotherapy. METHODS: 47 adults undergoing psychotherapy completed measures of psychological well-being and wrote private narratives that were coded by trained raters for emotional content. RESULTS: The specific concurrent experience of happiness and sadness was associated with improvements in psychological well-being above and beyond the impact of the passage of time, personality traits, or the independent effects of happiness and sadness. Changes in mixed emotional experience preceded improvements in well-being. CONCLUSIONS: Experiencing happiness alongside sadness in psychotherapy may be a harbinger of improvement in psychological well-being
A survey of oral health in a Sudanese population
10.1186/1472-6831-12-5BMC Oral Health121
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