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  • Article
    Castanié A, Mercier JF, Félix S, Maurel A.
    Opt Express. 2014 Dec 01;22(24):29937-53.
    Electromagnetic or acoustic metamaterials can be described in terms of equivalent effective, in general anisotropic, media and several techniques exist to determine the effective permeability and permittivity (or effective mass density and bulk modulus in the context of acoustics). Among these techniques, retrieval methods use the measured reflection and transmission coefficients (or scattering coefficients) for waves incident on a metamaterial slab containing few unit cells. Until now, anisotropic effective slabs have been considered in the literature but they are limited to the case where one of the axes of anisotropy is aligned with the slab interface. We propose an extension to arbitrary orientations of the principal axes of anisotropy and oblique incidence. The retrieval method is illustrated in the electromagnetic case for layered media, and in the acoustic case for array of tilted elliptical particles.
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  • Article
    Zhu Q, Sun X, Ji X, Zhu L, Xu J, Wang C, Zhang C, Xue F, Liu Y.
    Sci Rep. 2016 07 22;6:29937.
    The precise association between metabolic syndrome (MetS) and gallstone disease remains unclear in China. This study aimed to clarify the relationship between MetS and gallstone and evaluate whether counts of metabolic abnormalities had influence on gallstone disease. We fitted gender-specific generalized estimating equation (GEE) regression models with data from a large-scale longitudinal study over 6-year follow-up to elucidate the real association. This study included 18291 participants with 3 times repeated measures at least who were free from a prior history of gallstone disease and cholecystectomy. A total of 873 cases of gallstones occurred during 6-year follow-up. The incidence density of gallstone in the group of subjects with MetS was higher than the group without MetS (10.27 vs 5.79). The GEE analyses confirmed and clarified the association between MetS and gallstone disease in males (RR = 1.33, P = 0.0020), while this association was not significant in females (RR = 1.15, P = 0.4962). With numbers of metabolic syndrome components increasing, the risk of gallstone disease showed corresponding increasing in males. In conclusion, the associations of MetS and gallstone are different in males and in females. And the risk of gallstone disease increases with the number of components of MetS for males but not for females.
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  • Article
    Abdulla A, Zhang Y, Hsu FN, Xiaoli AM, Zhao X, Yang ES, Ji JY, Yang F.
    J Biol Chem. 2014 Oct 24;289(43):29937-47.
    Dysregulation of lipid homeostasis is a common feature of several major human diseases, including type 2 diabetes and cardiovascular disease. However, because of the complex nature of lipid metabolism, the regulatory mechanisms remain poorly defined at the molecular level. As the key transcriptional activators of lipogenic genes, such as fatty acid synthase (FAS), sterol regulatory element-binding proteins (SREBPs) play a pivotal role in stimulating lipid biosynthesis. Several studies have shown that SREBPs are regulated by the NAD(+)-dependent histone deacetylase SIRT1, which forms a complex with the lysine-specific histone demethylase LSD1. Here, we show that LSD1 plays a role in regulating SREBP1-mediated gene expression. Multiple lines of evidence suggest that LSD1 is required for SREBP1-dependent activation of the FAS promoter in mammalian cells. LSD1 knockdown decreases SREBP-1a at the transcription level. Although LSD1 affects nuclear SREBP-1 abundance indirectly through SIRT1, it is also required for SREBP1 binding to the FAS promoter. As a result, LSD1 knockdown decreases triglyceride levels in hepatocytes. Taken together, these results show that LSD1 plays a role in regulating lipogenic gene expression, suggesting LSD1 as a potential target for treating dysregulation of lipid metabolism.
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  • Article
    Cassie H, Duncan EM, Gibb EA, Power A, Young L, Newlands R, Watson MC.
    BMJ Open. 2019 08 15;9(8):e029937.
    OBJECTIVES: Gathering relevant patient information during over-the-counter (OTC) consultations increases the likelihood of safe, effective and person-centred outcomes. The aim of this study was to explore the key determinants to information gathering during consultations for non-prescription medicine requests in community pharmacies in Scotland.
    DESIGN: Semi-structured interviews using the Theoretical Domains Framework (TDF), with community pharmacy teams across Scotland. Interviews explored participants' knowledge of current guidance, skills required to elicit information and barriers and facilitators associated with this behaviour. Theory-based content analysis was undertaken using the TDF as an initial coding framework to identify key determinants and map them to salient domains. Salience was determined by prominence or variation in views. Comparative analysis was undertaken by professional role.
    RESULTS: Thirty interviews were conducted with pharmacists (n=19) and medicine counter assistants (MCAs) (n=11). Eight salient domains were identified: environmental context and resources (privacy), beliefs about consequences (patient safety), skills (communication, decision-making), social influences (patient awareness of pharmacist role), knowledge (awareness and use of standard operating procedures), social professional role and identity (perception of own role), behavioural regulation (training) and intention (to gather information). Similar domains were salient for pharmacists and MCAs; however, different beliefs were associated with different roles. Overarching themes were identified: best practice, health literacy, decision-making and professionalism.
    CONCLUSIONS: Multiple influences and complexities affect the effective management of OTC consultations. While similar factors impact on both pharmacists and MCAs at a patient, professional and environmental level, subtle differences exist in how these influence their management of OTC consultations. This study highlights the importance of tailoring interventions to reflect different roles, functions and responsibilities of community pharmacy personnel.
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  • Article
    Elgarten CW, Thompson JC, Angiolillo A, Chen Z, Conway S, Devidas M, Gupta S, Kairalla JA, McNeer JL, O'Brien MM, Rabin KR, Rau RE, Rheingold SR, Wang C, Wood C, Raetz EA, Loh ML, Alexander S, Miller TP.
    Pediatr Blood Cancer. 2022 11;69(11):e29937.
    Infections cause substantial morbidity for children with acute lymphoblastic leukemia (ALL). Therefore, accurate characterization of infectious adverse events (AEs) reported on clinical trials is imperative to defining, comparing, and managing safety and toxicity. Here, we describe key processes implemented to improve reporting of infectious AEs on two active phase III Children's Oncology Group (COG) ALL trials. Processes include: (a) identifying infections as a targeted toxicity, (b) incorporation of infection-specific case report form questions, and (c) physician review of AEs with real-time data cleaning. Preliminary assessment of these processes suggests improved reporting, as well as opportunities for further improvement.
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  • Article
    Fukunaga R, Yokoyama S.
    J Biol Chem. 2005 Aug 19;280(33):29937-45.
    The editing domain of valyl-tRNA synthetase (ValRS) is known to deacylate, or edit, misformed Thr-tRNA(Val) (post-transfer editing). Here, we determined the 1.7-Angstroms resolution crystal structure of the Thermus thermophilus ValRS editing domain. A comparison of the structure with the previously reported tRNA complex structure revealed conformational changes of the editing domain upon accommodation of the terminal A76; the "GTG loop" moves to expand the pocket, and the side chain of Phe-264 on the GTG loop rotates to interact with the A76 adenine ring. If these conformational changes did not occur, then C75 and A76 of the tRNA would clash with Phe-264. To elucidate the mechanism of the threonine side-chain recognition, we determined the crystal structure of the editing domain bound with [N-(L-threonyl)-sulfamoyl]adenosine at 1.7-Angstroms resolution. The gamma-OH of the threonyl moiety is recognized by the Lys-270, Thr-272, and Asp-279 side chains, which may reject the cognate valyl moiety. Accordingly, ValRS mutants with an Ala substitution for Lys-270 or Asp-279 synthesized significant amounts of Thr-tRNA(Val). The misproduced Thr-tRNA(Val) was hydrolyzed efficiently by the wild-type ValRS, but this post-transfer editing activity was drastically impaired by the Ala substitutions for Lys-270 and Asp-279 and was also decreased by those for Arg-216, Phe-264, and Thr-272. These results indicate that the threonyl moiety and A76 of Thr-tRNA(Val) are recognized by the Lys-270, Thr-272, and Asp-279 side chains and by the Phe-264 side chain, respectively, of the ValRS editing domain.
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  • Article
    Zalewski A, Cecchini EL, Deroo BJ.
    PLoS One. 2012;7(1):e29937.
    Within the ovary, Estrogen Receptor β (ERβ) is localized to the granulosa cells of growing follicles. 17β-estradiol (E2) acting via ERβ augments the actions of follicle stimulating hormone in granulosa cells, leading to granulosa cell differentiation and formation of a preovulatory follicle. Adult ERβ-null females are subfertile and possess ovaries with reduced numbers of growing follicles and corpora lutea. Because the majority of E2 production by granulosa cells occurs once puberty is reached, a role for ERβ in the ovary prior to puberty has not been well examined. We now provide evidence that lack of ERβ disrupts gene expression as early as post-natal day (PND) 13, and in particular, we identify a number of genes of the extracellular matrix (ECM) that are significantly higher in ERβ-null follicles than in wildtype (WT) follicles. Considerable changes occur to the ECM occur during normal folliculogenesis to allow for the dramatic growth, cellular differentiation, and reorganization of the follicle from the primary to preovulatory stage. Using quantitative PCR and immunofluorescence, we now show that several ECM genes are aberrantly overexpressed in ERβ-null follicles. We find that Collagen11a1, a protein highly expressed in cartilage, is significantly higher in ERβ-null follicles than WT follicles as early as PND 13, and this heightened expression continues through PND 23-29 into adulthood. Similarly, Nidogen 2, a highly conserved basement membrane glycoprotein, is elevated in ERβ-null follicles at PND 13 into adulthood, and is elevated specifically in the ERβ-null focimatrix, a basal lamina-like matrix located between granulosa cells. Focimatrix laminin and Collagen IV expression were also higher in ERβ-null ovaries than in WT ovaries at various ages. Our findings suggest two novel observations: a) that ERβ regulates granulosa cell gene expression ovary prior to puberty, and b) that ERβ regulates expression of ECM components in the mouse ovary.
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  • Article
    Liu Q, Levy EJ, Chirico WJ.
    J Biol Chem. 1996 Nov 22;271(47):29937-44.
    Hsp70 molecular chaperones are ATPases that bind to hydrophobic regions of proteins and guide their folding, assembly, and translocation across membranes. The ability of purified Hsp70s to uncoat clathrin-coated vesicles or to stimulate the post-translational translocation of precursor proteins into the endoplasmic reticulum, mitochondria, and the nucleus was previously shown not to be sensitive to the sulfhydryl-modifying reagent N-ethylmaleimide (NEM). During purification of factors required for protein folding in the cytosol, we found that the ATP-agarose binding activity of the yeast Hsp70 Ssa1p in postribosomal supernatants was inhibited by NEM. We also found that completely removing nucleotides from purified Ssa1p rendered its ATP-agarose binding activity, ATPase activity, and post-translational translocation-stimulating activity sensitive to NEM. We modified nucleotide-free Ssa1p with [14C]NEM and then digested it with proteases. Purification and sequencing of the radiolabeled proteolytic fragments revealed that each of Ssa1p's three cysteine residues (Cys-15, Cys-264, and Cys-303) was modified with [14C]NEM. ADP protected each of the cysteine residues from modification and protected Ssa1p from inactivation. The cysteine residues are the reactive centers of three NEM-reactive sites (NRS1-3). A comparison of Ssa1p's NRSs to sequences of other Hsp70s and actin revealed that Cys-15 of NRS1 is highly conserved and that sensitivity to NEM may be a property of many Hsp70s. Based on the three-dimensional structure of Hsc70, the predicted locations of Ssa1p's cysteine residues suggest that NEM may disrupt the conformation of Ssa1p or interfere with its ability to bind nucleotides. Together the results demonstrate that Ssa1p is an NEM-sensitive factor in cytosolic extracts from yeast that stimulates post-translational translocation of proteins into organelles.
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  • Article
    Ma P, Choi DY, Yu Y, Gai X, Yang Z, Debbarma S, Madden S, Luther-Davies B.
    Opt Express. 2013 Dec 02;21(24):29927-37.
    We report the characteristics of low-loss chalcogenide waveguides for sensing in the mid-infrared (MIR). The waveguides consisted of a Ge₁₁.₅As₂₄Se₆₄.₅ rib waveguide core with a 10nm fluoropolymer coating on a Ge₁₁.₅As₂₄S₆₄.₅ bottom cladding and were fabricated by thermal evaporation, photolithography and ICP plasma etching. Over most of the functional group band from 1500 to 4000 cm⁻¹ the losses were < 1 dB/cm with a minimum of 0.3 dB/cm at 2000 cm⁻¹. The basic capabilities of these waveguides for spectroscopy were demonstrated by measuring the absorption spectrum of soluble Prussian blue in Dimethyl Sulphoxide.
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  • Article
    Beran RK, Pyle AM.
    J Biol Chem. 2008 Oct 31;283(44):29929-37.
    Non-structural protein 3 (NS3) is a multifunctional enzyme possessing serine protease, NTPase, and RNA unwinding activities that are required for hepatitis C viral (HCV) replication. HCV non-structural protein 4A (NS4A) binds to the N-terminal NS3 protease domain to stimulate NS3 serine protease activity. In addition, the NS3 protease domain enhances the RNA binding, ATPase, and RNA unwinding activities of the C-terminal NS3 helicase domain (NS3hel). To determine whether NS3hel enhances the NS3 serine protease activity, we purified truncated and full-length NS3-4A complexes and examined their serine protease activities under a variety of salt and pH conditions. Our results indicate that the helicase domain enhances serine protease activity, just as the protease domain enhances helicase activity. Thus, the two enzymatic domains of NS3-4A are highly interdependent. This is the first time that such a complete interdependence has been demonstrated for a multifunctional, single chain enzyme. NS3-4A domain interdependence has important implications for function during the viral lifecycle as well as for the design of inhibitor screens that target the NS3-4A protease.
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  • Article
    Karbowniczek M, Cash T, Cheung M, Robertson GP, Astrinidis A, Henske EP.
    J Biol Chem. 2004 Jul 16;279(29):29930-7.
    Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome with manifestations that can include seizures, mental retardation, autism, and tumors in the brain, retina, kidney, heart, and skin. The products of the TSC1 and TSC2 genes, hamartin and tuberin, respectively, heterodimerize and inhibit the mammalian target of rapamycin (mTOR). We found that tuberin expression increases p42/44 MAPK phosphorylation and B-Raf kinase activity. Short interfering RNA down-regulation of tuberin decreased the p42/44 MAPK phosphorylation and B-Raf activity. Expression of Rheb, the target of the GTPase-activating domain of tuberin, inhibited wild-type B-Raf kinase but not activated forms of B-Raf. The interaction of endogenous Rheb with B-Raf was enhanced by serum and by Ras overexpression. A farnesylation-defective mutant of Rheb co-immunoprecipitated with and inhibited B-Raf but did not activate ribosomal protein S6 kinase, indicating that farnesylation is not required for B-Raf inhibition by Rheb and that B-Raf inhibition and S6 kinase activation are separable activities of Rheb. Consistent with this, inhibition of B-Raf and p42/44 MAPK by Rheb was resistant to rapamycin in contrast to Rheb activation of S6 kinase, which is rapamycin-sensitive. Taken together these data demonstrate that inhibition of B-Raf kinase via Rheb is an mTOR-independent function of tuberin.
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  • Article
    Cho IH, Panzera LC, Chin M, Alpizar SA, Olveda GE, Hill RA, Hoppa MB.
    Proc Natl Acad Sci U S A. 2020 11 24;117(47):29937-29947.
    Analysis of the presynaptic action potential's (APsyn) role in synaptic facilitation in hippocampal pyramidal neurons has been difficult due to size limitations of axons. We overcame these size barriers by combining high-resolution optical recordings of membrane potential, exocytosis, and Ca2+ in cultured hippocampal neurons. These recordings revealed a critical and selective role for Kv1 channel inactivation in synaptic facilitation of excitatory hippocampal neurons. Presynaptic Kv1 channel inactivation was mediated by the Kvβ1 subunit and had a surprisingly rapid onset that was readily apparent even in brief physiological stimulation paradigms including paired-pulse stimulation. Genetic depletion of Kvβ1 blocked all broadening of the APsyn during high-frequency stimulation and eliminated synaptic facilitation without altering the initial probability of vesicle release. Thus, using all quantitative optical measurements of presynaptic physiology, we reveal a critical role for presynaptic Kv channels in synaptic facilitation at presynaptic terminals of the hippocampus upstream of the exocytic machinery.
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  • Article
    Proenza C, Wilkens CM, Beam KG.
    J Biol Chem. 2000 Sep 29;275(39):29935-7.
    A peptide corresponding to residues 681-690 of the II-III loop of the skeletal muscle dihydropyridine receptor alpha(1) subunit (DHPR, alpha(1S)) has been reported to activate the skeletal muscle ryanodine receptor (RyR1) in vitro. Within this region of alpha(1S), a cluster of basic residues, Arg(681)-Lys(685), was previously reported to be indispensable for the activation of RyR1 in microsomal preparations and lipid bilayers. We have used an intact alpha(1S) subunit with scrambled sequence in this region of the II-III loop (alpha(1S)-scr) to test the importance of residues 681-690 and the basic motif for skeletal-type excitation-contraction (EC) coupling and retrograde signaling in vivo. When expressed in dysgenic myotubes (which lack endogenous alpha(1S)), alpha(1S)-scr restored calcium currents that were indistinguishable, in current density and voltage dependence, from those restored by wild-type alpha(1S). The scrambled DHPR also rescued skeletal-type EC coupling, as indicated by electrically evoked contractions in the presence of 0.5 mm Cd(2+) and 0.1 mm La(3+). Furthermore, the release of intracellular Ca(2+), as assayed by the indicator dye, Fluo-3, had similar kinetics and voltage dependence for alpha(1S) and alpha(1S)-scr. These data suggest that residues 681-690 of the alpha(1S) II-III loop are not essential in muscle cells for normal functioning of the DHPR, including skeletal-type EC coupling and retrograde signaling.
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