Greener and sustainable approach for the synthesis of commercially important epoxide building blocks using polymer-supported Mo(VI) complexes as catalysts

The growing concern for the environment, increasingly stringent standards for the release of chemicals into the environment and economic competitiveness have prompted extensive efforts to improve chemical synthesis and manufacturing methods as well as development of new synthetic methodologies that minimise or completely eliminate pollutants. As a consequence, more and more attention has been focused on the use of safer chemicals through proper design of clean processes and products. Epoxides are key raw materials or intermediates in organic synthesis, particularly for the functionalisation of substrates and production of a wide variety of chemicals such as pharmaceuticals, plastics, paints, perfumes, food additives and adhesives. The conventional methods for the industrial production of epoxides employ either stoichiometric peracids or chlorohydrin as an oxygen source. However, both methods have serious environmental impact as the former produces an equivalent amount of acid waste, whilst the later yields chlorinated by-products and calcium chloride waste. Hence, a greener and efficient route for catalytic epoxidation that could improve manufacturing efficiency by reducing operational cost and minimising waste products is highly desired. In this chapter, a greener alkene epoxidation process using molybdenum (Mo) based heterogeneous catalyst and tert-butyl hydroperoxide (TBHP) as an oxidant has been presented. A polystyrene 2-(aminomethyl)pyridine supported molybdenum(VI) complex, i.e. Ps.AMP.Mo and a polybenzimidazole supported Mo(VI) complex, i.e. PBI.Mo have been successfully prepared and characterised. The catalytic activities of the polymer supported Mo(VI) complexes have been evaluated for epoxidation of 1-hexene and 4-vinyl-1-cyclohexene (4-VCH) in a batch reactor. Experiments have been carried out to study the effect of reaction temperature, feed molar ratio of alkene to TBHP and catalyst loading on the yield of epoxide for optimisation of reaction conditions in a batch reactor. The long term stability of the polymer supported Mo(VI) catalysts have been evaluated by recycling the catalysts several times in batch experiments using conditions that form the basis for continuous epoxidation studies. The extent of Mo leaching from each polymer supported catalyst has been investigated by isolating any residue from reaction supernatant studies after removal of heterogeneous catalyst and using the residue as potential catalyst for epoxidation. The efficiency of Ps.AMP.Mo catalyst has been assessed for continuous epoxidation of 1-hexene and 4-vinyl-1-cyclohexne with TBHP as an oxidant using a FlowSyn reactor by studying the effect of reaction temperature, feed molar ratio of alkene to TBHP and feed flow rate on the conversion of TBHP and the yield of epoxide. The catalysts were found to be active and selective for batch and continuous epoxidation of alkenes using TBHP as an oxidant. The continuous epoxidation in a FlowSyn reactor has shown considerable time savings, high reproducibility and selectivity along with remarkable improvement in catalyst stability compared to the reactions carried out in a batch reactor

Distributed Synthesis in Continuous Time

We introduce a formalism modelling communication of distributed agents strictly in continuous-time. Within this framework, we study the problem of synthesising local strategies for individual agents such that a specified set of goal states is reached, or reached with at least a given probability. The flow of time is modelled explicitly based on continuous-time randomness, with two natural implications: First, the non-determinism stemming from interleaving disappears. Second, when we restrict to a subclass of non-urgent models, the quantitative value problem for two players can be solved in EXPTIME. Indeed, the explicit continuous time enables players to communicate their states by delaying synchronisation (which is unrestricted for non-urgent models). In general, the problems are undecidable already for two players in the quantitative case and three players in the qualitative case. The qualitative undecidability is shown by a reduction to decentralized POMDPs for which we provide the strongest (and rather surprising) undecidability result so far

Upregulation of the cell-cycle regulator RGC-32 in Epstein-Barr virus-immortalized cells

Epstein-Barr virus (EBV) is implicated in the pathogenesis of multiple human tumours of lymphoid and epithelial origin. The virus infects and immortalizes B cells establishing a persistent latent infection characterized by varying patterns of EBV latent gene expression (latency 0, I, II and III). The CDK1 activator, Response Gene to Complement-32 (RGC-32, C13ORF15), is overexpressed in colon, breast and ovarian cancer tissues and we have detected selective high-level RGC-32 protein expression in EBV-immortalized latency III cells. Significantly, we show that overexpression of RGC-32 in B cells is sufficient to disrupt G2 cell-cycle arrest consistent with activation of CDK1, implicating RGC-32 in the EBV transformation process. Surprisingly, RGC-32 mRNA is expressed at high levels in latency I Burkitt's lymphoma (BL) cells and in some EBV-negative BL cell-lines, although RGC-32 protein expression is not detectable. We show that RGC-32 mRNA expression is elevated in latency I cells due to transcriptional activation by high levels of the differentially expressed RUNX1c transcription factor. We found that proteosomal degradation or blocked cytoplasmic export of the RGC-32 message were not responsible for the lack of RGC-32 protein expression in latency I cells. Significantly, analysis of the ribosomal association of the RGC-32 mRNA in latency I and latency III cells revealed that RGC-32 transcripts were associated with multiple ribosomes in both cell-types implicating post-initiation translational repression mechanisms in the block to RGC-32 protein production in latency I cells. In summary, our results are the first to demonstrate RGC-32 protein upregulation in cells transformed by a human tumour virus and to identify post-initiation translational mechanisms as an expression control point for this key cell-cycle regulator

Pulmonary histoplasmosis presenting as chronic productive cough, fever, and massive unilateral consolidation in a 15-year-old immune-competent boy: a case report

Severe histoplasmosis is known to be among the AIDS-defining opportunistic infections affecting patients with very low CD4 cell counts in histoplasmosis-endemic areas. Histoplasma capsulatum var. duboisii is common in West and Central Africa, where it occurs in both HIV/AIDS and non-HIV patients. Few cases of life-threatening histoplasmosis in immune-competent individuals have been reported worldwide. We describe a case of pulmonary histoplasmosis diagnosed on the basis of autopsy and histological investigations. A 15-year old East African immune-competent boy with a history of smear-positive tuberculosis and a two-year history of rock cutting presented to our hospital with chronic productive cough, fever, and massive unilateral consolidation. At the time of presentation to our hospital, this patient was empirically treated for recurrent tuberculosis without success, and he died on the seventh day after admission. The autopsy revealed a huge granulomatous lesion with caseation, but no acid-fast bacilli were detected on several Ziehl-Neelsen stains. However, periodic acid-Schiff staining was positive, and the histological examination revealed features suggestive of Histoplasma yeast cells. Severe pulmonary histoplasmosis should be considered in evaluating immune-competent patients with risk factors for the disease who present with pulmonary symptoms mimicking tuberculosis

Reduction in podocyte density as a pathologic feature in early diabetic nephropathy in rodents: Prevention by lipoic acid treatment

BACKGROUND: A reduction in the number of podocytes and podocyte density has been documented in the kidneys of patients with diabetes mellitus. Additional studies have shown that podocyte injury and loss occurs in both diabetic animals and humans. However, most studies in animals have examined relatively long-term changes in podocyte number and density and have not examined effects early after initiation of diabetes. We hypothesized that streptozotocin diabetes in rats and mice would result in an early reduction in podocyte density and that this reduction would be prevented by antioxidants. METHODS: The number of podocytes per glomerular section and the podocyte density in glomeruli from rats and mice with streptozotocin (STZ)-diabetes mellitus was determined at several time points based on detection of the glomerular podocyte specific antigens, WT-1 and GLEPP1. The effect of insulin administration or treatment with the antioxidant, α-lipoic acid, on podocyte number was assessed. RESULTS: Experimental diabetes resulted in a rapid decline in apparent podocyte number and podocyte density. A significant reduction in podocytes/glomerular cross-section was found in STZ diabetes in rats at 2 weeks (14%), 6 weeks (18%) and 8 weeks (34%) following STZ injection. Similar declines in apparent podocyte number were found in STZ diabetes in C57BL/6 mice at 2 weeks, but not at 3 days after injection. Treatment with α-lipoic acid substantially prevented podocyte loss in diabetic rats but treatment with insulin had only a modest effect. CONCLUSION: STZ diabetes results in reduction in apparent podocyte number and in podocyte density within 2 weeks after onset of hyperglycemia. Prevention of these effects with antioxidant therapy suggests that this early reduction in podocyte density is due in part to increased levels of reactive oxygen species as well as hyperglycemia

Biphasic toxicodynamic features of some antimicrobial agents on microbial growth: a dynamic mathematical model and its implications on hormesis

<p>Abstract</p> <p>Background</p> <p>In the present work, we describe a group of anomalous dose-response (DR) profiles and develop a dynamic model that is able to explain them. Responses were obtained from conventional assays of three antimicrobial agents (nisin, pediocin and phenol) against two microorganisms (<it>Carnobacterium piscicola </it>and <it>Leuconostoc mesenteroides</it>).</p> <p>Results</p> <p>Some of these anomalous profiles show biphasic trends which are usually attributed to hormetic responses. But they can also be explained as the result of the time-course of the response from a microbial population with a bimodal distribution of sensitivity to an effector, and there is evidence suggesting this last origin. In light of interest in the hormetic phenomenology and the possibility of confusing it with other phenomena, especially in the bioassay of complex materials we try to define some criteria which allow us to distinguish between <it>sensu stricto </it>hormesis and biphasic responses due to other causes. Finally, we discuss some problems concerning the metric of the dose in connection with the exposure time, and we make a cautionary suggestion about the use of bacteriocins as antimicrobial agents.</p> <p>Conclusions</p> <p>The mathematical model proposed, which combines the basis of DR theory with microbial growth kinetics, can generate and explain all types of anomalous experimental profiles. These profiles could also be described in a simpler way by means of bisigmoidal equations. Such equations could be successfully used in a microbiology and toxicology context to discriminate between hormesis and other biphasic phenomena.</p

Neuro-immune signatures in chronic low back pain subtypes

We recently showed that patients with different chronic pain conditions (such as chronic low back pain, fibromyalgia, migraine, and Gulf War Illness) demonstrated elevated brain and/or spinal cord levels of the glial marker 18 kDa translocator protein, which suggests that neuroinflammation might be a pervasive phenomenon observable across multiple etiologically heterogeneous pain disorders. Interestingly, the spatial distribution of this neuroinflammatory signal appears to exhibit a degree of disease specificity (e.g. with respect to the involvement of the primary somatosensory cortex), suggesting that different pain conditions may exhibit distinct “neuroinflammatory signatures”. To further explore this hypothesis, we tested whether neuroinflammatory signal can characterize putative etiological subtypes of chronic low back pain patients based on clinical presentation. Specifically, we explored neuroinflammation in patients whose chronic low back pain either did or did not radiate to the leg (i.e. “radicular” vs. “axial” back pain). Fifty-four chronic low back pain patients, twenty-six with axial back pain (43.7 ± 16.6 y.o. [mean±SD]) and twenty-eight with radicular back pain (48.3 ± 13.2 y.o.), underwent PET/MRI with [11C]PBR28, a second-generation radioligand for the 18 kDa translocator protein. [11C]PBR28 signal was quantified using standardized uptake values ratio (validated against volume of distribution ratio; n = 23). Functional MRI data were collected simultaneously to the [11C]PBR28 data 1) to functionally localize the primary somatosensory cortex back and leg subregions and 2) to perform functional connectivity analyses (in order to investigate possible neurophysiological correlations of the neuroinflammatory signal). PET and functional MRI measures were compared across groups, cross-correlated with one another and with the severity of “fibromyalgianess” (i.e. the degree of pain centralization, or “nociplastic pain”). Furthermore, statistical mediation models were employed to explore possible causal relationships between these three variables. For the primary somatosensory cortex representation of back/leg, [11C]PBR28 PET signal and functional connectivity to the thalamus were: 1) higher in radicular compared to axial back pain patients, 2) positively correlated with each other and 3) positively correlated with fibromyalgianess scores, across groups. Finally, 4) fibromyalgianess mediated the association between [11C]PBR28 PET signal and primary somatosensory cortex-thalamus connectivity across groups. Our findings support the existence of “neuroinflammatory signatures” that are accompanied by neurophysiological changes, and correlate with clinical presentation (in particular, with the degree of nociplastic pain) in chronic pain patients. These signatures may contribute to the subtyping of distinct pain syndromes and also provide information about inter-individual variability in neuro-immune brain signals, within diagnostic groups, that could eventually serve as targets for mechanism-based precision medicine approaches

The Hubble Constant

I review the current state of determinations of the Hubble constant, which gives the length scale of the Universe by relating the expansion velocity of objects to their distance. There are two broad categories of measurements. The first uses individual astrophysical objects which have some property that allows their intrinsic luminosity or size to be determined, or allows the determination of their distance by geometric means. The second category comprises the use of all-sky cosmic microwave background, or correlations between large samples of galaxies, to determine information about the geometry of the Universe and hence the Hubble constant, typically in a combination with other cosmological parameters. Many, but not all, object-based measurements give $H_0$ values of around 72-74km/s/Mpc , with typical errors of 2-3km/s/Mpc. This is in mild discrepancy with CMB-based measurements, in particular those from the Planck satellite, which give values of 67-68km/s/Mpc and typical errors of 1-2km/s/Mpc. The size of the remaining systematics indicate that accuracy rather than precision is the remaining problem in a good determination of the Hubble constant. Whether a discrepancy exists, and whether new physics is needed to resolve it, depends on details of the systematics of the object-based methods, and also on the assumptions about other cosmological parameters and which datasets are combined in the case of the all-sky methods.Comment: Extensively revised and updated since the 2007 version: accepted by Living Reviews in Relativity as a major (2014) update of LRR 10, 4, 200

Foxp3 and IL-10 Expression Correlates with Parasite Burden in Lesional Tissues of Post Kala Azar Dermal Leishmaniasis (PKDL) Patients

Post kala azar dermal leishamniasis (PKDL), an unusual dermatosis develops in 5–15% of apparently cured visceral leishmaniasis cases in India and in about 60% of cases in Sudan. PKDL cases assume importance since they constitute a major human reservoir for the parasite. Inadequate treatment of VL, genetics, nutrition and immunological mechanisms that allow renewed multiplication of latent parasites or reinfection predispose to PKDL. Immunopathogenesis of PKDL is poorly understood. IL-10 is widely accepted as an immuno-suppressive cytokine and produced by diverse cell populations including, B cells, macrophages and CD4+ T cells. Natural T regulatory (nTreg) cells are subpopulation of CD4+ T cells that inhibit the response of other T cells. In this study we reported the accumulation of nTreg cells in lesion tissues of PKDL patients. Further correlation of Treg markers and IL-10 with parasite load in lesion tissues suggested a role of IL-10 and Treg in parasite establishment or persistence. Further studies are warranted to explore antigen specific IL-10 source in lesion tissues and unravel the concerted induction or accumulation of Treg in PKDL