Formation and Structural Analysis of Novel Dibornyl Ethers

One- and two-dimensional NMR spectroscopy has been used to establish the regio- and stereochemistry of novel dibornyl ethers, obtained by acid-catalysed condensation of camphor-derived a-hydroxybornanones South African Journal of Chemistry Vol.55 2002: 111-11

Use of Cooking Fuels and Cataract in a Population-Based Study: The India Eye Disease Study.

BACKGROUND: Biomass cooking fuels are commonly used in Indian households, especially by the poorest socioeconomic groups. Cataract is highly prevalent in India and the major cause of vision loss. The evidence on biomass fuels and cataract is limited. OBJECTIVES: To examine the association of biomass cooking fuels with cataract and type of cataract. METHODS: We conducted a population-based study in north and south India using randomly sampled clusters to identify people ≥ 60 years old. Participants were interviewed and asked about cooking fuel use, socioeconomic and lifestyle factors and attended hospital for digital lens imaging (graded using the Lens Opacity Classification System III), anthropometry, and blood collection. Years of use of biomass fuels were estimated and transformed to a standardized normal distribution. RESULTS: Of the 7,518 people sampled, 94% were interviewed and 83% of these attended the hospital. Sex modified the association between years of biomass fuel use and cataract; the adjusted odds ratio (OR) for a 1-SD increase in years of biomass fuel use and nuclear cataract was 1.04 (95% CI: 0.88, 1.23) for men and 1.28 (95% CI: 1.10, 1.48) for women, p interaction = 0.07. Kerosene use was low (10%). Among women, kerosene use was associated with nuclear (OR = 1.76, 95% CI: 1.04, 2.97) and posterior subcapsular cataract (OR = 1.71, 95% CI: 1.10, 2.64). There was no association among men. CONCLUSIONS: Our results provide robust evidence for the association of biomass fuels with cataract for women but not for men. Our finding for kerosene and cataract among women is novel and requires confirmation in other studies. Citation: Ravilla TD, Gupta S, Ravindran RD, Vashist P, Krishnan T, Maraini G, Chakravarthy U, Fletcher AE. 2016. Use of cooking fuels and cataract in a population-based study: the India Eye Disease Study. Environ Health Perspect 124:1857-1862; http://dx.doi.org/10.1289/EHP193

The Custodial Randall-Sundrum Model: From Precision Tests to Higgs Physics

We reexamine the Randall-Sundrum (RS) model with enlarged gauge symmetry SU(2)_L x SU(2)_R x U(1)_X x P_LR in the presence of a brane-localized Higgs sector. In contrast to the existing literature, we perform the Kaluza-Klein (KK) decomposition within the mass basis, which avoids the truncation of the KK towers. Expanding the low-energy spectrum as well as the gauge couplings in powers of the Higgs vacuum expectation value, we obtain analytic formulas which allow for a deep understanding of the model-specific protection mechanisms of the T parameter and the left-handed Z-boson couplings. In particular, in the latter case we explain which contributions escape protection and identify them with the irreducible sources of P_LR symmetry breaking. We furthermore show explicitly that no protection mechanism is present in the charged-current sector confirming existing model-independent findings. The main focus of the phenomenological part of our work is a detailed discussion of Higgs-boson couplings and their impact on physics at the CERN Large Hadron Collider. For the first time, a complete one-loop calculation of all relevant Higgs-boson production and decay channels is presented, incorporating the effects stemming from the extended electroweak gauge-boson and fermion sectors.Comment: 74 pages, 13 figures, 3 tables. v2: Matches version published in JHE

Anaphase-promoting complex/cyclosome protein Cdc27 is a target for curcumin-induced cell cycle arrest and apoptosis

<p>Abstract</p> <p>Background</p> <p>Curcumin (diferuloylmethane), the yellow pigment in the Asian spice turmeric, is a hydrophobic polyphenol from the rhizome of <it>Curcuma longa</it>. Because of its chemopreventive and chemotherapeutic potential with no discernable side effects, it has become one of the major natural agents being developed for cancer therapy. Accumulating evidence suggests that curcumin induces cell death through activation of apoptotic pathways and inhibition of cell growth and proliferation. The mitotic checkpoint, or spindle assembly checkpoint (SAC), is the major cell cycle control mechanism to delay the onset of anaphase during mitosis. One of the key regulators of the SAC is the anaphase promoting complex/cyclosome (APC/C) which ubiquitinates cyclin B and securin and targets them for proteolysis. Because APC/C not only ensures cell cycle arrest upon spindle disruption but also promotes cell death in response to prolonged mitotic arrest, it has become an attractive drug target in cancer therapy.</p> <p>Methods</p> <p>Cell cycle profiles were determined in control and curcumin-treated medulloblastoma and various other cancer cell lines. Pull-down assays were used to confirm curcumin binding. APC/C activity was determined using an <it>in vitro </it>APC activity assay.</p> <p>Results</p> <p>We identified Cdc27/APC3, a component of the APC/C, as a novel molecular target of curcumin and showed that curcumin binds to and crosslinks Cdc27 to affect APC/C function. We further provide evidence that curcumin preferably induces apoptosis in cells expressing phosphorylated Cdc27 usually found in highly proliferating cells.</p> <p>Conclusions</p> <p>We report that curcumin directly targets the SAC to induce apoptosis preferably in cells with high levels of phosphorylated Cdc27. Our studies provide a possible molecular mechanism why curcumin induces apoptosis preferentially in cancer cells and suggest that phosphorylation of Cdc27 could be used as a biomarker to predict the therapeutic response of cancer cells to curcumin.</p

Greedy optimal control for elliptic problems and its application to turnpike problems

This is a post-peer-review, pre-copyedit version of an article published in Numerische Mathematik. The final authenticated version is available online at: https://doi.org/10.1007/s00211-018-1005-zWe adapt and apply greedy methods to approximate in an efficient way the optimal controls for parameterized elliptic control problems. Our results yield an optimal approximation procedure that, in particular, performs better than simply sampling the parameter-space to compute controls for each parameter value. The same method can be adapted for parabolic control problems, but this leads to greedy selections of the realizations of the parameters that depend on the initial datum under consideration. The turnpike property (which ensures that parabolic optimal control problems behave nearly in a static manner when the control horizon is long enough) allows using the elliptic greedy choice of the parameters in the parabolic setting too. We present various numerical experiments and an extensive discussion of the efficiency of our methodology for parabolic control and indicate a number of open problems arising when analyzing the convergence of the proposed algorithmsThis project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No. 694126-DyCon). Part of this research was done while the second author visited DeustoTech and Univesity of Deusto with the support of the DyCon project. The second author was also partially supported by Croatian Science Foundation under ConDyS Project, IP-2016-06-2468. The work of the third author was partially supported by the Grants MTM2014-52347, MTM2017-92996 of MINECO (Spain) and ICON of the French AN

Working conditions, self-perceived stress, anxiety, depression and quality of life: A structural equation modelling approach

<p>Abstract</p> <p>Background</p> <p>The relationships between working conditions [job demand, job control and social support]; stress, anxiety, and depression; and perceived quality of life factors [physical health, psychological wellbeing, social relationships and environmental conditions] were assessed using a sample of 698 male automotive assembly workers in Malaysia.</p> <p>Methods</p> <p>The validated Malay version of the Job Content Questionnaire (JCQ), Depression Anxiety Stress Scales (DASS) and the World Health Organization Quality of Life-Brief (WHOQOL-BREF) were used. A structural equation modelling (SEM) analysis was applied to test the structural relationships of the model using AMOS version 6.0, with the maximum likelihood ratio as the method of estimation.</p> <p>Results</p> <p>The results of the SEM supported the hypothesized structural model (<it>χ</it>²= 22.801, <it>df </it>= 19, <it>p </it>= 0.246). The final model shows that social support (JCQ) was directly related to all 4 factors of the WHOQOL-BREF and inversely related to depression and stress (DASS). Job demand (JCQ) was directly related to stress (DASS) and inversely related to the environmental conditions (WHOQOL-BREF). Job control (JCQ) was directly related to social relationships (WHOQOL-BREF). Stress (DASS) was directly related to anxiety and depression (DASS) and inversely related to physical health, environment conditions and social relationships (WHOQOL-BREF). Anxiety (DASS) was directly related to depression (DASS) and inversely related to physical health (WHOQOL-BREF). Depression (DASS) was inversely related to the psychological wellbeing (WHOQOL-BREF). Finally, stress, anxiety and depression (DASS) mediate the relationships between job demand and social support (JCQ) to the 4 factors of WHOQOL-BREF.</p> <p>Conclusion</p> <p>These findings suggest that higher social support increases the self-reported quality of life of these workers. Higher job control increases the social relationships, whilst higher job demand increases the self-perceived stress and decreases the self-perceived quality of life related to environmental factors. The mediating role of depression, anxiety and stress on the relationship between working conditions and perceived quality of life in automotive workers should be taken into account in managing stress amongst these workers.</p

The novel curcumin analog FLLL32 decreases STAT3 DNA binding activity and expression, and induces apoptosis in osteosarcoma cell lines

<p>Abstract</p> <p>Background</p> <p>Curcumin is a naturally occurring phenolic compound shown to have a wide variety of antitumor activities; however, it does not attain sufficient blood levels to do so when ingested. Using structure-based design, a novel compound, FLLL32, was generated from curcumin. FLLL32 possesses superior biochemical properties and more specifically targets STAT3, a transcription factor important in tumor cell survival, proliferation, metastasis, and chemotherapy resistance. In our previous work, we found that several canine and human osteosarcoma (OSA) cell lines, but not normal osteoblasts, exhibit constitutive phosphorylation of STAT3. Compared to curcumin, we hypothesized that FLLL32 would be more efficient at inhibiting STAT3 function in OSA cells and that this would result in enhanced downregulation of STAT3 transcriptional targets and subsequent death of OSA cells.</p> <p>Methods</p> <p>Human and canine OSA cells were treated with vehicle, curcumin, or FLLL32 and the effects on proliferation (CyQUANT^®), apoptosis (SensoLyte^®Homogeneous AMC Caspase- 3/7 Assay kit, western blotting), STAT3 DNA binding (EMSA), and vascular endothelial growth factor (VEGF), survivin, and matrix metalloproteinase-2 (MMP2) expression (RT-PCR, western blotting) were measured. STAT3 expression was measured by RT-PCR, qRT- PCR, and western blotting.</p> <p>Results</p> <p>Our data showed that FLLL32 decreased STAT3 DNA binding by EMSA. FLLL32 promoted loss of cell proliferation at lower concentrations than curcumin leading to caspase-3- dependent apoptosis, as evidenced by PARP cleavage and increased caspase 3/7 activity; this could be inhibited by treatment with the pan-caspase inhibitor Z-VAD-FMK. Treatment of OSA cells with FLLL32 decreased expression of survivin, VEGF, and MMP2 at both mRNA and protein levels with concurrent decreases in phosphorylated and total STAT3; this loss of total STAT3 occurred, in part, via the ubiquitin-proteasome pathway.</p> <p>Conclusions</p> <p>These data demonstrate that the novel curcumin analog FLLL32 has biologic activity against OSA cell lines through inhibition of STAT3 function and expression. Future work with FLLL32 will define the therapeutic potential of this compound <it>in vivo</it>.</p

Systemic Biomarkers of Neutrophilic Inflammation, Tissue Injury and Repair in COPD Patients with Differing Levels of Disease Severity

The identification and validation of biomarkers to support the assessment of novel therapeutics for COPD continues to be an important area of research. The aim of the current study was to identify systemic protein biomarkers correlated with measures of COPD severity, as well as specific protein signatures associated with comorbidities such as metabolic syndrome. 142 protein analytes were measured in serum of 140 patients with stable COPD, 15 smokers without COPD and 30 non-smoking controls. Seven analytes (sRAGE, EN-RAGE, NGAL, Fibrinogen, MPO, TGF-α and HB-EGF) showed significant differences between severe/very severe COPD, mild/moderate COPD, smoking and non-smoking control groups. Within the COPD subjects, univariate and multivariate analyses identified analytes significantly associated with FEV1, FEV1/FVC and DLCO. Most notably, a set of 5 analytes (HB-EGF, Fibrinogen, MCP-4, sRAGE and Sortilin) predicted 21% of the variability in DLCO values. To determine common functions/pathways, analytes were clustered in a correlation network by similarity of expression profile. While analytes related to neutrophil function (EN-RAGE, NGAL, MPO) grouped together to form a cluster associated with FEV1 related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-α) formed another cluster associated with both DLCO and FEV1 related parameters. Associations of Fibrinogen with DLCO and MPO with FEV1/FVC were stronger in patients without metabolic syndrome (r  =  −0.52, p  = 0.005 and r  =  −0.61, p  = 0.023, respectively) compared to patients with coexisting metabolic syndrome (r  =  −0.25, p  = 0.47 and r  =  −0.15, p  = 0.96, respectively), and may be driving overall associations in the general cohort. In summary, our study has identified known and novel serum protein biomarkers and has demonstrated specific associations with COPD disease severity, FEV1, FEV1/FVC and DLCO. These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD

The unfolded protein response in immunity and inflammation.

The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses.This work was supported by the Netherlands Organization for Scientific Research Rubicon grant 825.13.012 (J.G.); US National Institutes of Health (NIH) grants DK044319, DK051362, DK053056 and DK088199, and the Harvard Digestive Diseases Center (HDDC) grant DK034854 (R.S.B.); National Institutes of Health grants DK042394, DK088227, DK103183 and CA128814 (R.J.K.); and European Research Council (ERC) Starting Grant 260961, ERC Consolidator Grant 648889, and the Wellcome Trust Investigator award 106260/Z/14/Z (A.K.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nri.2016.6