Julichrome Monomers from Marine Gastropod Mollusk‐Associated Streptomyces and Stereochemical Revision of Julichromes Q3 ⋅ 5 and Q3 ⋅ 3

Two julichrome monomers, julichromes Q₁₁ ( 1 ) and Q₁₂ ( 2 ), along with five known julichromes (Q₁₀, Q_{3 ? 5}, Q_{3 ? 3}, Q_{6 ? 6}, Q₆, 3 – 7 ) and four known anthraquinones (chrysophanol, 4‐acetylchrysophanol, islandicin, huanglongmycin A, 8 – 11 ), were isolated from the marine gastropod mollusk Batillaria zonalis‐associated Streptomyces sampsonii SCSIO 054. This is the first report of julichromes isolated from a marine source. Extensive dissection of 1D and 2D NMR datasets combined with X‐ray crystallography enabled rigorous elucidation of the previously reported configurations of julichrome Q_{3 ? 5} ( 4 ) and related julichrome Q_{3 ? 3} ( 5 ); both of the configuration at C(9) needs to be revised. In addition, julichrome Q₁₂ ( 2 ) was found to display antibacterial activity against Micrococcus luteus and Bacillus subtilis with MICs of 2.0 and 8.0 μg mL^?1; four compounds ( 1 , 3 , 6 , 7 ) also showed inhibitory activities against an array of methicillin‐resistant Staphylococcus aureus, S. aureus and S. simulans AKA1 with MIC values ranging from 8 to 64 μg mL^?1.     

Cation–π, amino–π, π–π, and H‐bond interactions stabilize antigen–antibody interfaces

The identification of immunogenic regions on the surface of antigens, which are able to stimulate an immune response, is a major challenge for the design of new vaccines. Computational immunology aims at predicting such regions—in particular B‐cell epitopes—but is far from being reliably applicable on a large scale. To gain understanding into the factors that contribute to the antigen–antibody affinity and specificity, we perform a detailed analysis of the amino acid composition and secondary structure of antigen and antibody surfaces, and of the interactions that stabilize the complexes, in comparison with the composition and interactions observed in other heterodimeric protein interfaces. We make a distinction between linear and conformational B‐cell epitopes, according to whether they consist of successive residues along the polypeptide chain or not. The antigen–antibody interfaces were shown to differ from other protein–protein interfaces by their smaller size, their secondary structure with less helices and more loops, and the interactions that stabilize them: more H‐bond, cation–π, amino–π, and π–π interactions, and less hydrophobic packing; linear and conformational epitopes can clearly be distinguished. Often, chains of successive interactions, called cation/amino–π and π–π chains, are formed. The amino acid composition differs significantly between the interfaces: antigen–antibody interfaces are less aliphatic and more charged, polar and aromatic than other heterodimeric protein interfaces. Moreover, paratopes and epitopes—albeit to a lesser extent—have amino acid compositions that are distinct from general protein surfaces. This specificity holds promise for improving B‐cell epitope prediction. Proteins 2014; 82:1734–1746. © 2014 Wiley Periodicals, Inc.     

Contributions of the σW, σM and σX regulons to the lantibiotic resistome of Bacillus subtilis

In Bacillus subtilis, the extracytoplasmic function (ECF) σ factors σ^M, σ^W and σ^X all contribute to resistance against lantibiotics. Nisin, a model lantibiotic, has a dual mode of action: it inhibits cell wall synthesis by binding lipid II, and this complex also forms pores in the cytoplasmic membrane. These activities can be separated in a nisin hinge‐region variant (N20P M21P) that binds lipid II, but no longer permeabilizes membranes. The major contribution of σ^M to nisin resistance is expression of ltaSa, encoding a stress‐activated lipoteichoic acid synthase, and σ^X functions primarily by activation of the dlt operon controlling d ‐alanylation of teichoic acids. Together, σ^M and σ^X regulate cell envelope structure to decrease access of nisin to its lipid II target. In contrast, σ^W is principally involved in protection against membrane permeabilization as it provides little protection against the nisin hinge region variant. σ^W contributes to nisin resistance by regulation of a signal peptide peptidase (SppA), phage shock proteins (PspA and YvlC, a PspC homologue) and tellurite resistance related proteins (YceGHI). These defensive mechanisms are also effective against other lantibiotics such as mersacidin, gallidermin and subtilin and comprise an important subset of the intrinsic antibiotic resistome of B. subtilis.     

Evidence of π‐stacking interactions in the self‐assembly of hIAPP22‐29

The role aromatic amino acids play in the formation of amyloid is a subject of controversy. In an effort to clarify the contribution of aromaticity to the self‐assembly of human islet amyloid polypeptide (hIAPP)_22‐29, peptide analogs containing electron donating groups (EDGs) or electron withdrawing groups (EWGs) as substituents on the aromatic ring of Phe‐23 at the para position have been synthesized and characterized using turbidity measurements in conjunction with Raman and fluorescence spectroscopy. Results indicate the incorporation of EDGs on the aromatic ring of Phe‐23 virtually abolish the ability of hIAPP_22‐29 to form amyloid. Peptides containing EWGs were still capable of forming aggregates. These aggregates were found to be rich in β‐sheet secondary structure. Transmission electron microscopy images of the aggregates confirm the presence of amyloid fibrils. The observed difference in amyloidogenic propensity between peptides containing EDGs and those with EWGs appears not to be based on differences in peptide hydrophobicity. Fluorescence and Raman spectroscopic investigations reveal that the environment surrounding the aromatic ring becomes more hydrophobic and ordered upon aggregation. Furthermore, Raman measurements of peptide analogs containing EWGs, conclusively demonstrate a distinct downshift in the ? C?C? ring mode (ca. 1600 cm^?1) upon aggregation that has previously been shown to be indicative of π‐stacking. While previous work has demonstrated that π‐stacking is not an absolute requirement for fibrillization, our findings indicate that Phe‐23 also contributes to fibril formation through π‐stacking interactions and that it is not only the hydrophobic nature of this residue that is relevant in the self‐assembly of hIAPP_22‐29. © Proteins 2013. © 2012 Wiley Periodicals, Inc.     

Spectral‐converting study of Ba9–3(m+n)/2ErmYbnY2Si6O24 (m = 0.005 – 0.2, n = 0 – 0.3) orthosilicate phosphors

Optical materials composed of Ba_9–3(m+n)/2Er_mYb_nY₂Si₆O₂₄ (m = 0.005–0.2, n = 0–0.3) were prepared using a solid‐state reaction. The X‐ray diffraction patterns of the obtained phosphors were examined to index the peak positions. The photoluminescence (PL) excitation and emission spectra of the Er³⁺‐activated phosphors and the critical emission quenching as a function of Er³⁺ content in the Ba_9–3m/2Er_mY₂Si₆O₂₄ structure were monitored. The spectral conversion properties of Er³⁺ and Er³⁺–Yb³⁺ ions doped in Ba₉Y₂Si₆O₂₄ phosphors were elucidated under diode‐laser irradiation at 980 nm. Up‐conversion emission spectra and the dependence of the emission intensity on pump power for the Ba_8.55Er_0.1Yb_0.2Y₂Si₆O₂₄ phosphor were investigated. The desired up‐conversion of the emitted light, which passed through the green, yellow, orange and red regions of the spectrum, was achieved through the use of appropriate Er³⁺ and/or Yb³⁺ concentrations in the host structure and 980 nm excitation light. The up‐conversion mechanism in the phosphors is described by an energy‐level schematic. Copyright © 2015 John Wiley & Sons, Ltd.     

Tunable photoluminescence properties of Sr1‐yCayMoO4:Sm3+ phosphors (0 ≤ y < 1)

A series of Sr_1‐x‐yCa_yMoO₄:xSm³⁺ (0 ≤ x ≤ 7 mol% and 0 ≤ y < 1) phosphors was synthesized by a conventional solid‐state reaction method in air, and their structural and spectroscopic properties were investigated. The optimal doping concentration of Sm³⁺ in SrMoO₄:Sm³⁺ phosphor is 5 mol%. Under excitation with 275 nm, in Sr_1‐x‐yCa_yMoO₄:xSm³⁺ (0 ≤ x ≤ 7 mol% and 0 ≤ y < 1) phosphors, the emission band of the host was found to overlap with the excitation bands peaking at ~500 nm of Sm³⁺ ion, and the energy transfer from MoO₄^2? group to Sm³⁺ ion can also be observed. The International Commission on Illumination (CIE) chromaticity coordinates of Sr_0.95‐yCa_yMoO₄:0.05Sm³⁺ phosphors with excitation 275 nm varied systematically from an orange (0.4961, 0.3761) (y = 0) to a white color (0.33, 0.3442) (y = 0.95) with increasing calcium oxide (CaO) concentration. However, Sr_0.95‐yCa_yMoO₄:0.05Sm³⁺ phosphors with excitation at 404 nm only showed red emission and the energy transfer between MoO₄^2? group to Sm³⁺ ion was not observed. The complex mechanisms of luminescence and energy transfer are discussed by energy level diagrams of MoO₄^2? group and Sm³⁺ ion. Copyright © 2015 John Wiley & Sons, Ltd.     

Energy transfer in M5(PO4)3 F:Eu2+,Ce3+ (M = Ca and Ba) phosphors

M₅(PO₄)₃ F:Eu²⁺ (M = Ca and Ba) co‐doped with Ce³⁺ phosphors were successfully prepared by the combustion synthesis method. The introduction of co‐dopant (Ce³⁺) into the host enhanced the luminescent intensity of the M₅(PO₄)₃ F:Eu²⁺ (M = Ca and Ba) efficiently. Previously, we have reported the synthesis and photoluminescence properties of same phosphors. The aim of this article is to report energy transfer mechanism between Ce³⁺?Eu²⁺ ions in M₅(PO₄)₃ F:Eu²⁺ (M = Ca and Ba) phosphors, where Ce³⁺ ions act as sensitizers and Eu²⁺ ions act as activators. The M₅(PO₄)₃ F:Eu²⁺ (M = Ca and Ba) co‐doped with Ce³⁺ phosphor exhibits great potential for use in white ultraviolet (UV) light‐emitting diode applications to serve as a single‐phased phosphor that can be pumped with near‐UV or UV light‐emitting diodes. Copyright © 2013 John Wiley & Sons, Ltd.     

Immunomodulatory Activity of 3β,6β‐Dihydroxyolean‐12‐en‐27‐oic Acid in Tumor‐Bearing Mice

3β,6β‐Dihydroxyolean‐12‐en‐27‐oic acid ( 1 ) is a pentacyclic triterpenoid isolated from the rhizomes of Astilbe chinensis. To evaluate the in vivo antitumor potential and to elucidate its immunological mechanisms, effect of 1 on the growth of mouse‐transplantable tumors, and the immune response in naive and tumor‐bearing mice were investigated. The mice inoculated with mouse tumor cell lines were orally treated with 1 at the doses of 40, 60, and 80 mg/kg for 10 days. The effects of 1 on the growth of mouse‐transplantable S180 sarcoma and H22 hepatoma, splenocyte proliferation, cytotoxic T lymphocyte (CTL) activity, natural killer (NK) cell activity, and production of interleukin‐2 (IL‐2) from splenocytes in S180‐bearing mice were measured. Furthermore, the effect of 1 on 2,4‐dinitrofluorobenzene (DNFB)‐induced delayed‐type hypersensitivity (DTH) reactions and the sheep red blood cell (SRBC)‐induced antibody response in naive mice were also studied. Compound 1 could not only significantly inhibit the growth of mouse transplantable S180 sarcoma and H22 hepatoma, increase splenocytes proliferation, CTL and NK cell activity, and the level of IL‐2 secreted by splenocytes in tumor‐bearing mice, but also remarkably promote the DTH reaction and enhance anti‐SRBC antibody titers in naive mice. These results suggested that 1 could improve both cellular and humoral immune response, and could act as antitumor agent with immunomodulatory activity.     

The proofreading 3′→5′ exonuclease activity of DNA polymerases: a kinetic barrier to translesion DNA synthesis

The 3′→5′ exonuclease activity intrinsic to several DNA polymerases plays a primary role in genetic stability; it acts as a first line of defense in correcting DNA polymerase errors. A mismatched basepair at the primer terminus is the preferred substrate for the exonuclease activity over a correct basepair. The efficiency of the exonuclease as a proofreading activity for mispairs containing a DNA lesion varies, however, being dependent upon both the DNA polymerase/exonuclease and the type of DNA lesion. The exonuclease activities intrinsic to the T4 polymerase (family B) and DNA polymerase γ (family A) proofread DNA mispairs opposite endogenous DNA lesions, including alkylation, oxidation, and abasic adducts. However, the exonuclease of the Klenow polymerase cannot discriminate between correct and incorrect bases opposite alkylation and oxidative lesions. DNA damage alters the dynamics of the intramolecular partitioning of DNA substrates between the 3′→5′ exonuclease and polymerase activities. Enzymatic idling at lesions occurs when an exonuclease activity efficiently removes the same base that is preferentially incorporated by the DNA polymerase activity. Thus, the exonuclease activity can also act as a kinetic barrier to translesion synthesis (TLS) by preventing the stable incorporation of bases opposite DNA lesions. Understanding the downstream consequences of exonuclease activity at DNA lesions is necessary for elucidating the mechanisms of translesion synthesis and damage-induced cytotoxicity.     

Energy transfer between Ce3+ → Gd3+ or Tb3+ in KNaSO4 microphosphor

KNaSO₄ microphosphor doped with Ce,Gd and Ce,Tb and prepared by a wet chemical method was studied using X‐ray diffraction (XRD), scanning electron microscopy (SEM) and photoluminescence (PL) characterization. KNaSO₄ has a 5‐µm particle size detected by SEM. KNaSO₄:Ce³⁺,Tb³⁺ showed blue and green emission (at 494 nm, 557 nm, 590 nm) of Tb³⁺ due to ⁵D₄ → ⁷F_J (J = 4, 5, 6) transitions. KNaSO₄:Ce³⁺,Gd³⁺ showed luminescence in the ultraviolet (UV) light region at 314 nm for an excitation at 271 nm wavelength. It was observed that efficient energy transfer took place from Ce³⁺ → Gd³⁺ and Ce³⁺ → Tb³⁺ sublattices indicating that Ce³⁺ could effectively sensitize Gd³⁺ or Tb³⁺ (green emission). Ce³⁺ emission weakened and Gd³⁺ or Tb³⁺ enhanced the emission significantly in KNaSO₄. This paper discusses the development and understanding of photoluminescence and the effect of Tb³⁺ and Gd³⁺ on KNaSO₄:Ce³⁺. Copyright © 2015 John Wiley & Sons, Ltd.     

The β‐sheet breakers and π‐stacking

Fibrillation of β‐amyloid is recognized as a key process leading to the development of Alzheimer's disease. Small peptides called β‐sheet breakers were found to inhibit the process of β‐amyloid fibrillation and to dissolve amyloid fibrils in vitro, in vivo, and in cell culture studies [1,2]. The mechanism by which peptide inhibition takes place remains elusive and a detailed model needs to be established. Here, we present new insights into the possible role of consecutive Phe residues, present in the structure of β‐sheet breakers, supported by the results obtained by means of MD simulations. We performed a 30‐ns MD of two β‐sheet breakers: iAβ5 (LPFFD) and iAβ6 (LPFFFD) which have two and three consecutive Phe residues, respectively. We have found that Phe rings in these peptides tend to form stacked conformations. For one of the peptides – iAβ6 – the calculated electrostatic contribution to free energy of one of the conformers with three rings stacked (c2) is significantly lower than that corresponding to the unstacked one (c1), two rings stacked (c0) and second conformer with three rings stacked (c3). This may favor the interaction of the c2 conformer with the target on amyloid fibril. We hypothesize that the mechanism of inhibition of amyloidogenesis by β‐sheet breaker involves competition among π‐stacked Phe residues of the inhibitor and π‐stacking within the β‐amyloid fibril. iAβ6 may be a promising candidate for a lead compound of amyloidogenesis inhibitors. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.     

Beyond basins: φ,ψ preferences of a residue depend heavily on the φ,ψ values of its neighbors

The Ramachandran plot distributions of nonglycine residues from experimentally determined structures are routinely described as grouping into one of six major basins: β, P_II, α, α_L, ξ and γ'. Recent work describing the most common conformations adopted by pairs of residues in folded proteins [i.e., (φ,ψ)₂‐motifs] showed that commonly described major basins are not true single thermodynamic basins, but are composed of distinct subregions that are associated with various conformations of either the preceding or following neighbor residue. Here, as documentation of the extent to which the conformational preferences of a central residue are influenced by the conformations of its two neighbors, we present a set of φ,ψ‐plots that are delimited simultaneously by the φ,ψ‐angles of its neighboring residues on both sides. The level of influence seen here is typically greater than the influence associated with considering the identities of neighboring residues, implying that the use of this heretofore untapped information can improve the accuracy of structure prediction algorithms and low resolution protein structure refinement.     

Photoluminescence properties of LiTi2 − xEux(PO4)3 phosphor

A solid‐state reaction route‐based LiTi_{2 ? x}Eu_x(PO₄)₃ was phosphor synthesized for the first time to evaluate its luminescence performance by excitation, emission and lifetime (τ) measurements. The LiTi_{2 ? x}Eu_x(PO₄)₃ phosphor was excited at λ_exci. = 397 nm to give an intense orange–red (597 nm) emission attributed to the ⁵D₀ → ⁷F₁ magnetic dipole (ΔJ = ±1) transition and red (616 nm) emission (⁵D₀ → ⁷F₂), which is an electric dipole (ΔJ = ±2) transition of the Eu³⁺ ion. Beside this, excitation and emission spectra of host LiTi₂(PO₄)₃ powder were also reported. The effect of Eu³⁺ concentration on luminescence characteristics was explained from emission and lifetime profiles. Concentration quenching in the LiTi_{2 ? x}Eu_x(PO₄)₃ phosphor was studied from the Dexter's model. Dipole–quadrupole interaction is found to be responsible for energy transfer among Eu³⁺ ions in the host lattice. The LiTi_{2 ? x}Eu_x(PO₄)₃ phosphor displayed a reddish‐orange colour realized from a CIE chromaticity diagram. We therefore suggest that this new phosphor could be used as an optical material of technological importance in the field of display devices. Copyright © 2016 John Wiley & Sons, Ltd.     

Synthesis and Antiproliferative Activities of Novel Substituted 5‐Anilino‐α‐Glucofuranose Derivatives

In order to find novel antitumor candidate agents with high efficiency and low toxicity, 14 novel substituted 5‐anilino‐α‐glucofuranose derivatives have been designed, synthesized and evaluated for antiproliferative activities in vitro. Their structures were characterized by NMR (¹H and ¹³C) and HR‐MS, and configuration (R/S) at C(5) was identified by two‐dimensional ¹H,¹H‐NOESY‐NMR spectrum. Their antiproliferative activities against human tumor cells were investigated by MTT assay. The results demonstrated that most of the synthesized compounds had antiproliferative effects comparable to the reference drugs gefitinib and lapatinib. In particular, (5R)‐5‐O‐(3‐chloro‐4‐{[5‐(4‐fluorophenyl)thiophen‐2‐yl]methyl}anilino)‐5‐deoxy‐1,2‐O‐(1‐methylethylidene)‐α‐glucofuranose ( 9da ) showed the most potent antiproliferative effects against SW480, A431 and A549 cells, with IC₅₀ values of 8.57, 5.15 and 15.24 μm , respectively. This work suggested 5‐anilino‐α‐glucofuranose as an antitumor core structure that may open a new way to develop more potent anti‐cancer agents.     

π–π Stacking mediated drug–drug interactions in human CYP2E1

Because of having many low molecular mass substrates, CYP2E1 is of particular interests to the pharmaceutical industry. Many evidences showed that this enzyme can adopt multiple substrates to significantly reduce the oxidation rate of the substrates. The detailed mechanism for this observation is still unclear. In the current study, we employed GPU‐accelerated molecular dynamics simulations to study the multiple‐binding mode of human CYP2E1, with an aim of offering a mechanistic explanation for the unexplained multiple‐substrate binding. Our results showed that Thr303 and Phe478 were key factors for the substrate recognition and multiple‐substrate binding. The former can form a significant hydrogen bond to recognize and position the substrate in the productive binding orientation in the active site. The latter acted as a mediator for the substrate communications via π–π stacking interactions. In the multiple‐binding mode, the aforementioned π–π stacking interactions formed by the aromatic rings of both substrates and Phe478 drove the first substrate far away from the catalytic center, orienting in an additional binding position and going against the substrate metabolism. All these findings could give atomic insights into the detailed mechanism for the multiple‐substrate binding in human CYP2E1, providing useful information for the drug metabolism mechanism and personalized use of clinical drugs. Proteins 2013; © 2012 Wiley Periodicals, Inc.