Homochirality and the need of energy

The mechanisms for explaining how a stable asymmetric chemical system can be formed from a symmetric chemical system, in the absence of any asymmetric influence other than statistical fluctuations, have been developed during the last decades, focusing on the non-linear kinetic aspects. Besides the absolute necessity of self-amplification processes, the importance of energetic aspects is often underestimated. Going down to the most fundamental aspects, the distinction between a single object -- that can be intrinsically asymmetric -- and a collection of objects -- whose racemic state is the more stable one -- must be emphasized. A system of strongly interacting objects can be described as one single object retaining its individuality and a single asymmetry; weakly or non-interacting objects keep their own individuality, and are prone to racemize towards the equilibrium state. In the presence of energy fluxes, systems can be maintained in an asymmetric non-equilibrium steady-state. Such dynamical systems can retain their asymmetry for times longer than their racemization time.Comment: 8 pages, 7 figures, submitted to Origins of Life and Evolution of Biosphere

Relevance similarity: an alternative means to monitor information retrieval systems

BACKGROUND: Relevance assessment is a major problem in the evaluation of information retrieval systems. The work presented here introduces a new parameter, "Relevance Similarity", for the measurement of the variation of relevance assessment. In a situation where individual assessment can be compared with a gold standard, this parameter is used to study the effect of such variation on the performance of a medical information retrieval system. In such a setting, Relevance Similarity is the ratio of assessors who rank a given document same as the gold standard over the total number of assessors in the group. METHODS: The study was carried out on a collection of Critically Appraised Topics (CATs). Twelve volunteers were divided into two groups of people according to their domain knowledge. They assessed the relevance of retrieved topics obtained by querying a meta-search engine with ten keywords related to medical science. Their assessments were compared to the gold standard assessment, and Relevance Similarities were calculated as the ratio of positive concordance with the gold standard for each topic. RESULTS: The similarity comparison among groups showed that a higher degree of agreements exists among evaluators with more subject knowledge. The performance of the retrieval system was not significantly different as a result of the variations in relevance assessment in this particular query set. CONCLUSION: In assessment situations where evaluators can be compared to a gold standard, Relevance Similarity provides an alternative evaluation technique to the commonly used kappa scores, which may give paradoxically low scores in highly biased situations such as document repositories containing large quantities of relevant data

A Common Model for Cytokine Receptor Activation: Combined Scissor-Like Rotation and Self-Rotation of Receptor Dimer Induced by Class I Cytokine

The precise mechanism by which the binding of a class I cytokine to the extracellular domain of its corresponding receptor transmits a signal through the cell membrane remains unclear. Receptor activation involves a cytokine-receptor complex with a 1∶2 stoichiometry. Previously we used our transient-complex theory to calculate the rate constant of the initial cytokine-receptor binding to form a 1∶1 complex. Here we computed the binding pathway leading to the 1∶2 activation complex. Three cytokine systems (growth hormone, erythropoietin, and prolactin) were studied, and the focus was on the binding of the extracellular domain of the second receptor molecule after forming the 1∶1 complex. According to the transient-complex theory, translational and rotation diffusion of the binding entities bring them together to form a transient complex, which has near-native relative separation and orientation but not the short-range specific native interactions. Subsequently conformational rearrangement leads to the formation of the native complex. We found that the changes in relative orientations between the two receptor molecules from the transient complex to the 1∶2 native complex are similar for the three cytokine-receptor systems. We thus propose a common model for receptor activation by class I cytokines, involving combined scissor-like rotation and self-rotation of the two receptor molecules. Both types of rotations seem essential: the scissor-like rotation separates the intracellular domains of the two receptor molecules to make room for the associated Janus kinase molecules, while the self-rotation allows them to orient properly for transphosphorylation. This activation model explains a host of experimental observations. The transient-complex based approach presented here may provide a strategy for designing antagonists and prove useful for elucidating activation mechanisms of other receptors

Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma

Multiple myeloma (MM), an incurable plasma cell malignancy, requires localisation within the bone marrow. This microenvironment facilitates crucial interactions between the cancer cells and stromal cell types that permit the tumour to survival and proliferate. There is increasing evidence that the bone marrow mesenchymal stem cell (BMMSC) is stably altered in patients with MM – a phenotype also postulated to exist in patients with monoclonal gammopathy of undetermined significance (MGUS) a benign condition that precedes MM. In this study, we describe a mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by BMMSCs in patients with MGUS and MM directly alters malignant plasma cell phenotype. We identify PADI2 as one of the most highly upregulated transcripts in BMMSCs from both MGUS and MM patients, and that through its enzymatic deimination of histone H3 arginine 26, PADI2 activity directly induces the upregulation of interleukin-6 (IL-6) expression. This leads to the acquisition of resistance to the chemotherapeutic agent, bortezomib, by malignant plasma cells. We therefore describe a novel mechanism by which BMMSC dysfunction in patients with MGUS and MM directly leads to pro-malignancy signalling through the citrullination of histone H3R26

How patients understand depression associated with chronic physical disease - A systematic review

Background: Clinicians are encouraged to screen people with chronic physical illness for depression. Screening alone may not improve outcomes, especially if the process is incompatible with patient beliefs. The aim of this research is to understand peoples beliefs about depression, particularly in the presence of chronic physical disease. Methods: A mixed method systematic review involving a thematic analysis of qualitative studies and quantitative studies of beliefs held by people with current depressive symptoms. MEDLINE, EMBASE, PSYCHINFO, CINAHL, BIOSIS, Web of Science, The Cochrane Library, UKCRN portfolio, National Research Register Archive, Clinicaltrials.gov and OpenSIGLE were searched from database inception to 31st December 2010. A narrative synthesis of qualitative and quantitative data, based initially upon illness representations and extended to include other themes not compatible with that framework. Results: A range of clinically relevant beliefs was identified from 65 studies including the difficulty in labeling depression, complex causal factors instead of the biological model, the roles of different treatments and negative views about the consequences of depression. We found other important themes less related to ideas about illness: the existence of a self-sustaining depression spiral; depression as an existential state; the ambiguous status of suicidal thinking; and the role of stigma and blame in depression. Conclusions: Approaches to detection of depression in physical illness need to be receptive to the range of beliefs held by patients. Patient beliefs have implications for engagement with depression screening

Mitochondrial Associated Ubiquitin Fold Modifier-1 Mediated Protein Conjugation in Leishmania donovani

In this report, we demonstrate the existence of the ubiquitin fold modifier-1 (Ufm1) and its conjugation pathway in trypanosomatid parasite Leishmania donovani. LdUfm1 is activated by E1-like enzyme LdUba5. LdUfc1 (E2) specifically interacted with LdUfm1 and LdUba5 to conjugate LdUfm1 to proteinaceous targets. Mass spectrometry analysis revealed that LdUfm1 is conjugated to Leishmania protein targets that are associated with mitochondria. Immunofluorescence experiments showed that Leishmania Ufm1, Uba5 and Ufc1 are associated with the mitochondria. The demonstration that all the components of this system as well as the substrates are associated with mitochondrion suggests it may have physiological roles not yet described in any other organism. Overexpression of a non-conjugatable form of LdUfm1 and an active site mutant of LdUba5 resulted in reduced survival of Leishmania in the macrophage. Since mitochondrial activities are developmentally regulated in the life cycle of trypanosomatids, Ufm1 mediated modifications of mitochondrial proteins may be important in such regulation. Thus, Ufm1 conjugation pathway in Leishmania could be explored as a potential drug target in the control of Leishmaniasis

Columnar and Equiaxed Solidification of Al-7 wt.% Si Alloys in Reduced Gravity in the Framework of the CETSOL Project

International audienceDuring casting, often a dendritic microstructure is formed, resulting in a columnar or an equiaxed grain structure, or leading to a transition from columnar to equiaxed growth (CET). The detailed knowledge of the critical parameters for the CET is important because the microstructure affects materials properties. To provide unique data for testing of fundamental theories of grain and microstructure formation, solidification experiments in microgravity environment were performed within the European Space Agency Microgravity Application Promotion (ESA MAP) project Columnar-to-Equiaxed Transition in SOLidification Processing (CETSOL). Reduced gravity allows for purely diffusive solidification conditions, i.e., suppressing melt flow and sedimentation and floatation effects. On-board the International Space Station, Al-7 wt.% Si alloys with and without grain refiners were solidified in different temperature gradients and with different cooling conditions. Detailed analysis of the microstructure and the grain structure showed purely columnar growth for nonrefined alloys. The CET was detected only for refined alloys, either as a sharp CET in the case of a sudden increase in the solidification velocity or as a progressive CET in the case of a continuous decrease of the temperature gradient. The present experimental data were used for numerical modeling of the CET with three different approaches: (1) a front tracking model using an equiaxed growth model, (2) a three-dimensional (3D) cellular automaton–finite element model, and (3) a 3D dendrite needle network method. Each model allows for predicting the columnar dendrite tip undercooling and the growth rate with respect to time. Furthermore, the positions of CET and the spatial extent of the CET, being sharp or progressive, are in reasonably good quantitative agreement with experimental measurements

The fire toxicity of polyurethane foams [Review]

Polyurethane is widely used, with its two major applications, soft furnishings and insulation, having low thermal inertia, and hence enhanced flammability. In addition to their flammability, polyurethanes form carbon monoxide, hydrogen cyanide and other toxic products on decomposition and combustion. The chemistry of polyurethane foams and their thermal decomposition are discussed in order to assess the relationship between the chemical and physical composition of the foam and the toxic products generated during their decomposition. The toxic product generation during flaming combustion of polyurethane foams is reviewed, in order to relate the yields of toxic products and the overall fire toxicity to the fire conditions. The methods of assessment of fire toxicity are outlined in order to understand how the fire toxicity of polyurethane foams may be quantified. In particular, the ventilation condition has a critical effect on the yield of the two major asphyxiants, carbon monoxide and hydrogen cyanid

Protein Kinase Cδ Stimulates Proteasome-Dependent Degradation of C/EBPα during Apoptosis Induction of Leukemic Cells

BACKGROUND:The precise regulation and maintenance of balance between cell proliferation, differentiation and death in metazoan are critical for tissue homeostasis. CCAAT/enhancer-binding protein alpha (C/EBPalpha) has been implicated as a key regulator of differentiation and proliferation in various cell types. Here we investigated the potential dynamic change and role of C/EBPalpha protein during apoptosis induction. METHODOLOGY/PRINCIPAL FINDINGS:Upon onset of apoptosis induced by various kinds of inducers such as NSC606985, etoposide and others, C/EBPalpha expression presented a profound down-regulation in leukemic cell lines and primary cells via induction of protein degradation and inhibition of transcription, as assessed respectively by cycloheximide inhibition test, real-time quantitative RT-PCR and luciferase reporter assay. Applying chemical inhibition, forced expression of dominant negative mutant and catalytic fragment (CF) of protein kinase Cdelta (PKCdelta), which was proteolytically activated during apoptosis induction tested, we showed that the active PKCdelta protein contributed to the increased degradation of C/EBPalpha protein. Three specific proteasome inhibitors antagonized C/EBPalpha degradation during apoptosis induction. More importantly, ectopic expression of PKCdelta-CF stimulated the ubiquitination of C/EBPalpha protein, while the chemical inhibition of PKCdelta action significantly inhibited the enhanced ubiquitination of C/EBPalpha protein under NSC606985 treatment. Additionally, silencing of C/EBPalpha expression by small interfering RNAs enhanced, while inducible expression of C/EBPalpha inhibited NSC606985/etoposide-induced apoptosis in leukemic cells. CONCLUSIONS/SIGNIFICANCE:These observations indicate that the activation of PKCdelta upon apoptosis results in the increased proteasome-dependent degradation of C/EBPalpha, which partially contributes to PKCdelta-mediated apoptosis

Triptolide Inhibits the Proliferation of Prostate Cancer Cells and Down-Regulates SUMO-Specific Protease 1 Expression

Recently, traditional Chinese medicine and medicinal herbs have attracted more attentions worldwide for its anti-tumor efficacy. Celastrol and Triptolide, two active components extracted from the Chinese herb Tripterygium wilfordii Hook F (known as Lei Gong Teng or Thunder of God Vine), have shown anti-tumor effects. Celastrol was identified as a natural 26 s proteasome inhibitor which promotes cell apoptosis and inhibits tumor growth. The effect and mechanism of Triptolide on prostate cancer (PCa) is not well studied. Here we demonstrated that Triptolide, more potent than Celastrol, inhibited cell growth and induced cell death in LNCaP and PC-3 cell lines. Triptolide also significantly inhibited the xenografted PC-3 tumor growth in nude mice. Moreover, Triptolide induced PCa cell apoptosis through caspases activation and PARP cleavage. Unbalance between SUMOylation and deSUMOylation was reported to play an important role in PCa progression. SUMO-specific protease 1 (SENP1) was thought to be a potential marker and therapeutical target of PCa. Importantly, we observed that Triptolide down-regulated SENP1 expression in both mRNA and protein levels in dose-dependent and time-dependent manners, resulting in an enhanced cellular SUMOylation in PCa cells. Meanwhile, Triptolide decreased AR and c-Jun expression at similar manners, and suppressed AR and c-Jun transcription activity. Furthermore, knockdown or ectopic SENP1, c-Jun and AR expression in PCa cells inhibited the Triptolide anti-PCa effects. Taken together, our data suggest that Triptolide is a natural compound with potential therapeutic value for PCa. Its anti-tumor activity may be attributed to mechanisms involving down-regulation of SENP1 that restores SUMOylation and deSUMOyaltion balance and negative regulation of AR and c-Jun expression that inhibits the AR and c-Jun mediated transcription in PCa