Egg-based influenza split virus vaccine with monoglycosylation induces cross-strain protection against influenza virus infections.

Each year influenza virus infections cause hundreds of thousands of deaths worldwide and a significant level of morbidity with major economic burden. At the present time, vaccination with inactivated virus vaccine produced from embryonated chicken eggs is the most prevalent method to prevent the infections. However, current influenza vaccines are only effective against closely matched circulating strains and must be updated and administered yearly. Therefore, generating a vaccine that can provide broad protection is greatly needed for influenza vaccine development. We have previously shown that vaccination of the major surface glycoprotein hemagglutinin (HA) of influenza virus with a single N-acetylglucosamine at each of the N-glycosylation sites [monoglycosylated HA (HAmg)] can elicit better cross-protection compared with the fully glycosylated HA (HAfg). In the current study, we produced monoglycosylated inactivated split H1N1 virus vaccine from chicken eggs by the N-glycosylation process inhibitor kifunensine and the endoglycosidase Endo H, and intramuscularly immunized mice to examine its efficacy. Compared with vaccination of the traditional influenza vaccine with complex glycosylations from eggs, the monoglycosylated split virus vaccine provided better cross-strain protection against a lethal dose of virus challenge in mice. The enhanced antibody responses induced by the monoglycosylated vaccine immunization include higher neutralization activity, higher hemagglutination inhibition, and more HA stem selectivity, as well as, interestingly, higher antibody-dependent cellular cytotoxicity. This study provides a simple and practical procedure to enhance the cross-strain protection of influenza vaccine by removing the outer part of glycans from the virus surface through modifications of the current egg-based process.

Screening and Identification of the Main Metabolites of Schisantherin a In Vivo and In Vitro by Using UHPLC-Q-TOF-MS/MS.

Schisantherin A is an active ingredient originating from Schisandra chinensis (Turcz.) which has hepatoprotective and anti-oxidation activities. In this study, in vitro metabolisms investigated on rat liver microsomes (RLMs) and in vivo metabolisms explored on male Sprague Dawley rats of Schisantherin A were tested, respectively. The metabolites of Schisantherin A were identified using ultra-high-performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS). Based on the method, 60 metabolites were successfully identified and structurally characterized including 48 phase-I and 12 phase-II metabolites. Among the metabolites, 45 metabolites were reported for the first time. Moreover, 56 and eight metabolites were detected in urine and bile and 19 metabolites were identified in rats' plasma. It demonstrated that hepatic and extra-hepatic metabolic pathways were both involved in Schisantherin A biotransformation in rats. Five in vitro metabolites were structurally characterized for the first time. The results indicated that the metabolic pathways mainly include oxidation, reduction, methylation, and conjugation with glucuronide, taurine, glucose, and glutathione groups. This study provides a practical strategy for rapidly screening and identifying metabolites, and the results provide basic data for future pharmacological and toxicology studies of Schisantherin A and other lignin ingredients.

Design, Synthesis and Antibacterial Evaluation of 1-[(1R,2S)-2-Fluorocyclopropyl]ciprofloxacin-1,2,4-triazole-5(4H)-thione Hybrids.

A new class of 1-[(1R,2S)-2-fluorocyclopropyl]ciprofloxacin (CPFX)-1,2,4-triazole-5(4H)-thione hybrids 6a - 6o was designed, synthesized and evaluated for their in vitro antibacterial activities against a panel of clinically important drug-sensitive and drug-resistant Gram-positive and Gram-negative pathogens. Our results revealed that all hybrids 6a - 6o had great potency against the tested strains, especially Gram-negative pathogens. The synthesized hybrids were more potent than the parent 1-[(1R,2S)-2-fluorocyclopropyl]CPFX (1) and comparable to CPFX and levofloxacin against the majority of the tested pathogens, worth to be further investigated.

Synthesis and In Vitro Antimycobacterial and Antibacterial Activity of 8-OMe Ciprofloxacin-Hydrozone/Azole Hybrids.

A series of novel 8-OMe ciprofloxacin (CPFX)-hydrazone/azole hybrids were designed, synthesized, and evaluated for their in vitro biological activities. Our results reveal that all of the hydrozone-containing hybrids (except for 7) show potency against Mycobacterium tuberculosis (MTB) H37Rv (minimum inhibitory concentration (MIC): <0.5 µM), which is better than the parent drug CPFX, and comparable to moxifloxacin and isoniazid, some of the tested Gram-positive strains (MIC: 0.06-4 µg/mL), and most Gram-negative strains (MIC: ≤0.03-4 µg/mL).

The synthesis and antistaphylococcal activity of dehydroabietic acid derivatives: Modifications at C-12.

A series of 12-oxime and O-oxime ether derivatives of dehydroabietic acid were synthesized and investigated for the antibacterial activity against Staphylococcus aureus Newman strain and five multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108, and NRS-271). The aromatic oximate derivative 11a showed the highest activity with MIC of 0.39-0.78µg/mL against S. aureus Newman. Of note, compounds 10b, 11 and 14 showed the most potent antibacterial activity against five multidrug-resistant S. aureus with MIC values of 1.25-3.13µg/mL. These results offered useful information for further strategic optimization in search of the antibacterial candidates against infection of multidrug-resistant Gram-positive bacteria.

Role of ATG8 and autophagy in programmed nuclear degradation in Tetrahymena thermophila.

Autophagy is an evolutionarily conserved mechanism for the degradation of cellular components, but its role in enucleation during differentiation has not been established. Tetrahymena thermophila is a unicellular eukaryote with two functionally distinct nuclei, the somatic (macro-) and the germ line (micro-) nuclei. These nuclei are produced during sexual reproduction (conjugation), which involves differentiation and selective degradation of several specific nuclei. To examine the role of autophagy in nuclear degradation, we studied the function of two ATG8 genes in Tetrahymena. Through fluorescent protein tagging, we found that both proteins are targeted to degrading nuclei at specific stages, with some enrichment on the nuclear periphery, suggesting the formation of autophagosomes surrounding these nuclei. In addition, ATG8 knockout mutant cells showed a pronounced delay in nuclear degradation without apparently preventing the completion of other developmental events. This evidence provided direct support for a critical role for autophagy in programmed nuclear degradation. The results also showed differential roles for two ATG8 genes, with ATG8-65 playing a more significant role in starvation than ATG8-2, although both are important in nuclear degradation.

A trimethylsulfonium salt with a novel polymeric cadmate anion.

The title salt, catena-poly[trimethylsulfonium [µ2-chlorido-di-µ2-thiocyanato-cadmate(II)]] {(C3H9S)[CdCl(NCS)2]}n, consists of trimethylsulfonium cations sandwiched between layers of a two-dimensional polyanion. The Cd(II) centre displays a distorted octahedral environment coordinated by two bridging Cl atoms, two thiocyanate N atoms and two thiocyanate S atoms. The thiocyanate groups adopt the µ-1,3-coordination mode and bridge the Cd(II) centres into a one-dimensional zigzag chain extended along the [110] direction. The Cd(II) centres of the zigzag chains are crosslinked by bridging Cl atoms, forming a two-dimensional polyanion. The two-dimensional anions are linked to layers of trimethylsulfonium cations by weak intermolecular C-H···Cl hydrogen bonds, forming the three-dimensional structure.

A tetranuclear cadmium(II) complex based on the 2-(quinolin-8-yloxy)acetonitrile ligand.

The hydrothermal reaction of 2-(quinolin-8-yloxy)acetonitrile and Cd(ClO(4))(2) yielded the noncentrosymmetric coordination complex tetrakis[µ-2-(quinolin-8-yloxy)acetato]tetrakis[µ-2-(quinolin-8-yloxy)acetonitrile]tetracadmium tetrakis(perchlorate) dihydrate, [Cd(4)(C(11)H(8)NO(3))(4)(C(11)H(8)N(2)O)(4)](ClO(4))(4)·2H(2)O. The local coordination environment around the Cd(II) cation can be best described as a capped octahedron defined by two N atoms and five O atoms from three ligands. The Cd(II) cations are linked by the ligands with Cd-O-Cd and Cd-O-C-C-O-Cd bridges, forming tetranuclear units, there being two independent tertranuclear units in the structure. The fourfold rotoinversion centre sits at the centre of each Cd(4) core. The two perchlorate anions in the asymmetric unit are linked by the water molecule through O-H...O hydrogen bonds.

Bis{tris[(1H-benzimidazol-3-ium-2-yl)methyl]amine} tetraaquaocta-µ2-chlorido-octachloridopentacadmate(II) monohydrate.

The title compound, (C24H24N7)2[Cd5Cl16(H2O)4]·H2O, contains a [Cd5Cl16(H2O)4]6⁻ anion, two triply protonated tris[(1H-benzimidazol-3-ium-2-yl)methyl]amine cations and one solvent water molecule. The structure of the anion is a novel chloride-bridged pentanuclear cluster. The five unique CdII centres have quite different coordination environments. Two of the central hexacoordinated CdII cations have a CdOCl5 chromophore, in which each CdII cation is ligated by four bridging chloride ligands, one terminal chloride ligand and one water molecule, adopting a distorted octahedral environment. The third central CdII cation is octahedrally coordinated by four bridging chloride ligands and two water molecules. Finally, the two terminal CdII cations are pentacoordinated by two bridging and three terminal chloride ligands and adopt a trigonal-bipyramidal geometry. A three-dimensional supramolecular network is formed through intra- and intermolecular O-H∙∙∙O, O-H∙∙∙Cl, N-H∙∙∙Cl and N-H∙∙∙O hydrogen bonds and π-π interactions between the cations and anions.

A Prognostic Signature for Colon Adenocarcinoma Patients Based on m6A-Related lncRNAs.

N6-methyladenosine (m6A) modification is a common epigenetic modification. It is reported that lncRNA can be regulated by m6A modification. Previous studies have shown that lncRNAs associated with m6A regulation (m6A-lncRNAs) serve as ideal prognostic biomarkers. However, whether lncRNAs are involved in m6A modification in colon adenocarcinoma (COAD) needs further exploration. The objective of this study was to construct an m6A-lncRNAs-based signature for patients with COAD. We obtained the RNA sequencing data and clinical information from The Cancer Genome Atlas (TCGA). Pearson correlation analysis was employed to recognize lncRNAs associated with m6A regulation (m6A-lncRNAs). 24 prognostic m6A-lncRNAs was identified by univariate Cox regression analysis. Gene set enrichment analysis (GSAE) was used to investigate the potential cellular pathways and biological processes. We have also explored the relationship between immune infiltrate levels and m6A-lncRNAs. Then, a predictive signature based on the expression of 13 m6A-lncRNAs was constructed by the Lasso regression algorithm, including UBA6-AS1, AC139149.1, U91328.1, AC138207.5, AC025171.4, AC008760.1, ITGB1-DT, AP001619.1, AL391422.4, AC104532.2, ZEB1-AS1, AC156455.1, and AC104819.3. ROC curves and K M survival curves have shown that the risk score has a well-predictive ability. We also set up a quantitative nomogram on the basis of risk score and prognosis-related clinical characteristics. In summary, we have identified some m6A-lncRNAs that correlated with prognosis and tumor immune microenvironment in COAD. In addition, a potential alternative signature based on the expression of m6A-lncRNAs was provided for the management of COAD patients.

Synthesis, antimycobacterial and antibacterial activity of ciprofloxacin derivatives containing a N-substituted benzyl moiety.

We report herein the design and synthesis of a series of novel ciprofloxacin (CPFX) derivatives with remarkable improvement in lipophilicity by introducing a substituted benzyl moiety to the N atom on the C-7 piperazine ring of CPFX. Antimycobacterial and antibacterial activity of the newly synthesized compounds was evaluated. Results reveal that compound 4f has good in vitro activity against all of the tested Gram-positive strains including MRSA and MRSE (MICs: 0.06-32 µg/mL) which is two to eightfold more potent than or comparable to the parent drug CPFX (MICs: 0.25-128 µg/mL), Gram-negative bacteria P. aeruginosa (MICs: 0.5-4 µg/mL) and M. tuberculosis H37Rv ATCC 27294 (MIC: 1 µg/mL).

3-Methyl-anilinium hydrogen phthalate.

The asymmetric unit of the title salt, C(7)H(10)N(+)·C(8)H(5)O(4) (-), consists of two 3-methyl-phenyl-ammonium cations and two hydrogen phthalate anions. There are strong intra-molecular O-H⋯O hydrogen bonds in the virtually planar (r.m.s. deviations = 0.054 Å) phthalate anions. In the crystal, the cations and anions are connected via an extensive sytem of N-H⋯O hydrogen bonds into a corrugated layer extended parallel to (001).

Tris(hy-droxy-meth-yl)methanaminium trifluoro-acetate.

In the crystal structure of the title salt, C(4)H(12)NO(3) (+)·C(2)F(3)O(2) (-), N-H⋯O and O-H⋯O hydrogen bonds link the ions, forming a complex three-dimensional network.

2-Trifluoro-methyl-1H-benzimidazol-3-ium nitrate.

Ihe title salt, C(8)H(6)F(3)N(2) (+)·NO(3) (-), the F atoms of the triflouromethyl group are disordered over two sets of sites in a 0.58 (2):0.42 (2) ratio. In the crystal, N-H⋯O hydrogen bonds link the cations and anions into chains running parallel to the b axis. There is π-π stacking between symmetry-related benzene rings with a centroid-centroid distance of 3.949 (3) Å. The crystal studied was a non-merohedral twin, with a 19% minor component.

2-Trifluoro-methyl-1H-benzimidazol-3-ium tetra-fluoro-borate-2-trifluoro-methyl-1H-benzimidazole-water (1/1/1).

The asymmetric unit of the title compound, C(8)H(6)F(3)N(2) (+)·BF(4) (-)·C(8)H(5)F(3)N(2)·H(2)O, consists of two 2-trifluoro-methyl-benzimidazole mol-ecules, each of which is protonated on a 50% basis, one tetra-fluoro-borate anion and a water mol-ecule. The two 2-trifluoromethylbenzimidazole mol-ecules thus exist as half-neutral half-cation entities. They are linked by N-H⋯N hydrogen bonds involving the half-occupancy hydrogens in each mol-ecule. The F atoms of one of the trifluoro-methyl groups are disordered over two sets of sites [in a 0.518 (14):0.482 (14) ratio], as are the F atoms of the tetra-fluoroborate anion [0.507 (14):0.493 (14) ratio]. The water mol-ecule is linked to one of the 2-trifluoro-methyl-benzimidazole mol-ecules via an N-H⋯O hydrogen bond.

Tetra-kis(4-meth-oxy-anilinium) hexa-chloridobismuthate(III) chloride monohydrate.

In the crystal of the title compound, (C(7)H(10)NO)(4)[BiCl(6)]Cl·H(2)O, the Bi(III) cation is located on an inversion center and coordinated by six Cl(-) anions in a slightly distorted octa-hedral geometry; the uncoordinated Cl(-) anion and lattice water mol-ecule are located on a twofold rotation axis. Two independent 4-meth-oxy-anilinium cations are linked to the Bi complex, the uncoordinated Cl(-) anion and lattice water mol-ecule via N-H⋯Cl and N-H⋯O hydrogen bonds.

Bis(3-methyl-anilinium) hexa-chlorido-stannate(IV) dihydrate.

In the title compound, (C(7)H(10)N)(2)[SnCl(6)]·2H(2)O, the Sn(IV) atom lies on a site with symmetry 2/m. One of the Cl atoms lies on a mirror plane and the 3-methyl-anilinium cation is also situated on a mirror plane. The water mol-ecule is located on a twofold rotation axis. The H atoms of the methyl and ammonium groups and the solvent water mol-ecule are disordered by symmetry. In the crystal, N-H⋯Cl, O-H⋯Cl and N-H⋯O hydrogen bonds connect the organic cations, the inorganic octahedrally shaped anions and the water mol-ecules.

1-Acetyl-oxymethyl-1,3,5,7-tetra-aza-adamantan-1-ium hexa-fluoro-phosphate.

In the crystal structure of the title salt, C(9)H(17)N(4)O(2) (+)·PF(6) (-), the cations and anions are linked by weak C-H⋯F inter-actions while C-H⋯O inter-actions also occur between the cations.

5-Nitro-2-trifluoro-methyl-1H-benzimidazole monohydrate.

In the crystal structure of the title compound, C(8)H(4)F(3)N(3)O(2)·H(2)O, the main mol-ecule and the water mol-ecule are linked by an N-H⋯O hydrogen bond. O-H⋯N, O-H⋯O and C-H⋯O hydrogen bonds further link the mol-ecules into sheets.

2-Trifluoro-methyl-1H-benzimidazole.

The asymmetric unit of the title compound, C(8)H(5)F(3)N(2), consists of two half-mol-ecules, one lies on a mirror plane and the other is generated by twofold rotation symmetry, with the axis running through the trifluoro-methyl C atom and the attached benzimidazole C atom. The two 2-trifluoro-methyl-1H-benzimidazole mol-ecules are connected by N-H⋯N hydrogen bonds involving the disordered NH H atoms into chains running parallel to the c axis. One of the trifluoro-methyl groups is disordered over two orientations of equal occupancy.