Insight into Actin Organization and Function in Cytokinesis from Analysis of Fission Yeast Mutants

Actin is a key cytoskeletal protein with multiple roles in cellular processes such as polarized growth, cytokinesis, endocytosis, and cell migration. Actin is present in all eukaryotes as highly dynamic filamentous structures, such as linear cables and branched filaments. Detailed investigation of the molecular role of actin in various processes has been hampered due to the multifunctionality of the protein and the lack of alleles defective in specific processes. The actin cytoskeleton of the fission yeast, Schizosaccharomyces pombe, has been extensively characterized and contains structures analogous to those in other cell types. In this study, primarily with the view to uncover actin function in cytokinesis, we generated a large bank of fission yeast actin mutants that affect the organization of distinct actin structures and/or discrete physiological functions of actin. Our screen identified 17 mutants with specific defects in cytokinesis. Some of these cytokinesis mutants helped in dissecting the function of specific actin structures during ring assembly. Further genetic analysis of some of these actin mutants revealed multiple genetic interactions with mutants previously known to affect the actomyosin ring assembly. We also characterize a mutant allele of actin that is suppressed upon overexpression of Cdc8p-tropomyosin, underscoring the utility of this mutant bank. Another 22 mutant alleles, defective in polarized growth and/or other functions of actin obtained from this screen, are also described in this article. This mutant bank should be a valuable resource to study the physiological and biochemical functions of actin.     

4-Bicyclic heteroaryl-piperidine derivatives as potent,orally bioavailable Stearoyl-CoA desaturase-1 (SCD1) inhibitors. Part 1: Urea-based analogs

A new series of urea-based, 4-bicyclic heteroaryl-piperidine derivatives as potent SCD1 inhibitors is described. The structure–activity relationships focused on bicyclic heteroarenes and aminothiazole–urea portions are discussed. A trend of dose-dependent decrease in body weight gain in diet-induced obese (DIO) mice is also demonstrated.     

Design and bio-evaluation of indole derivatives as potent Kv1.5 inhibitors

Atrial fibrillation (AF) is one of the common arrhythmias that threaten human health. Kv1.5 potassium channel is reported as an efficacious and safe target for the treatment of AF. In this paper, we designed and synthesized three series of compounds through modifying the lead compound RH01617 that was screened out by the pharmacophore model we reported earlier. All of the compounds were evaluated by the whole-patch lamp technology and most of them possessed potent inhibitory activities against Kv1.5. Compounds IIIi and IIIl were evaluated for the target selectivity as well as the pharmacodynamic effects in an isolated rat model. Due to the promising pharmacological behavior, compound IIIl deserves further pharmacodynamic and pharmacokinetic evaluations.     

Molecular and pathogenic characterization of new Xanthomonas oryzae pv. oryzae strains from the coastline region of Fangchenggang city in China

Virulence assays and DNA polymorphism analyses were used to characterize 33 Xanthomonas oryzae pv. oryzae (Xoo) strains collected from the coastline region of Fangchenggang city in China. Two new pathogenic races (FXP1 and FXP2), were determined by leaf-clipping inoculation of 12 near-isogenic International Rice-Bacterial Blight (IRBB) rice lines, each containing a single resistance gene. Race FXP1 consisted of twenty-eight strains that were incompatible on IRBB5 and IRBB7, while race FXP2 included five strains that were incompatible on IRBB5 and IRBB7 and moderately virulent on IRBB8 containing the xa8 gene. Restriction fragment length polymorphism (RFLP) analysis revealed that each probe of avrXa10 and IS1112 resolved two haplotypes. In a dendrogram generated from the combined RFLP data, the 33 Xoo strains were resolved into two clusters. There was a weak correlation (r = 0.53) between race and haplotype. All of the rice cultivars planted in the coastline region of Fangchenggang city were susceptible to the representative Xoo strains tested above. However, we found that four rice cultivars used as breeding materials in the laboratory could fully resist infection by the Xoo strains, suggesting that the isolated Xoo strains could be used to detect resistant rice cultivars suitable for planting in the local rice field.     

Gossypol and an HMT G9a inhibitor act in synergy to induce cell death in pancreatic cancer cells

The histone methyltransferase G9a is overexpressed in a variety of cancer types, including pancreatic adenocarcinoma, and promotes tumor invasiveness and metastasis. We recently reported the discovery of BRD4770, a small-molecule inhibitor of G9a that induces senescence in PANC-1 cells. We observed that the cytotoxic effects of BRD4770 were dependent on genetic background, with cell lines lacking functional p53 being relatively resistant to compound treatment. To understand the mechanism of genetic selectivity, we used two complementary screening approaches to identify enhancers of BRD4770. The natural product and putative BH3 mimetic gossypol enhanced the cytotoxicity of BRD4770 in a synergistic manner in p53-mutant PANC-1 cells but not in immortalized non-tumorigenic pancreatic cells. The combination of gossypol and BRD4770 increased LC3-II levels and the autophagosome number in PANC-1 cells, and the compound combination appears to act in a BNIP3 (B-cell lymphoma 2 19-kDa interacting protein)-dependent manner, suggesting that these compounds act together to induce autophagy-related cell death in pancreatic cancer cells.     

Computational investigation on MB<Subscript><Emphasis Type="Italic">n</Emphasis></Subscript> (M = Li-Cs,Be-Ba,Sc-La and Ti; <Emphasis Type="Italic">n</Emphasis> = 28 and 38)

Differing from the weakly antiaromatic B₈₀ buckyball, the medium-sized C ₁–B₂₈ and D _2h –B₃₈, as well as their mono- to tetra-anions, are highly aromatic, as indicated by the negative nucleus-independent chemical shifts (NICSs) at their cage centers. The interior cavities and high aromaticity of the B₂₈ and B₃₈ cages render them very promising hosts to accommodate diverse metal atoms. Accordingly, we carried out systematic density functional theory (DFT) computations on the structures, stabilities and electronic properties of metalloborofullerenes MB _n (M?=?Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba, Sc, Y, La and Ti; n?=?28 and 38). Among them, besides the recently reported M@B₃₈(M?=?Sc, Y and Ti) [Lu et al. (2015) Phys Chem Chem Phys 17:20897–20902], Ti@B₂₈ and M@B₃₈ (M?=?Ca and La) also favor endohedral structures with large binding energies, and are suggested promising targets for experimental applications. Note that Ti@B₂₈ is the first endohedral derivative based on the new B₂₈ fullerene, and La@B₃₈ features the largest metal size inside a B₃₈ cage thus far. These endohedral derivatives, as exemplified by Ca@B₃₈, may exhibit σ and π double aromaticity over the whole cage surface, indicating their considerable stability. In contrast, the other metals prefer to reside at the exterior cage surface, due mainly to the mismatch of their sizes with the boron cages, though the size match is not the only factor to determine their doping form. Furthermore, the infrared absorption spectra and ¹¹B nuclear magnetic resonance spectra of the three new M@B _n complexes were computed to assist future experimental characterization.

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Graphical Abstract Putting more metals into medium-sized boron cages!

     

Evaluation of Liver Ischemia-Reperfusion Injury in Rabbits Using a Nanoscale Ultrasound Contrast Agent Targeting ICAM-1

ObjectiveTo assess the feasibility of ultrasound molecular imaging in the early diagnosis of liver ischemia-reperfusion injury (IRI) using a nanoscale contrast agent targeting anti-intracellular adhesion molecule-1 (anti-ICAM-1).MethodsThe targeted nanobubbles containing anti-ICAM-1 antibody were prepared using the avidin-biotin binding method. Human hepatic sinusoidal endothelial cells (HHSECs) were cultured at the circumstances of hypoxia/reoxygenation (H/R) and low temperature. The rabbit liver IRI model (I/R group) was established using the Pringle’s maneuver. The time-intensity curve of the liver contrast ultrasonographic images was plotted and the peak intensity, time to peak, and time of duration were calculated.ResultsThe size of the targeted nanobubbles were 148.15 ± 39.75 nm and the concentration was 3.6–7.4 × 10⁹/ml, and bound well with the H/R HHSECs. Animal contrast enhanced ultrasound images showed that the peak intensity and time of duration of the targeted nanobubbles were significantly higher than that of common nanobubbles in the I/R group, and the peak intensity and time of duration of the targeted nanobubbles in the I/R group were also significantly higher than that in the SO group.ConclusionThe targeted nanobubbles have small particle size, stable characteristic, and good targeting ability, which can assess hepatic ischemia-reperfusion injury specifically, noninvasively, and quantitatively at the molecular level.     

Hygiene Behaviors Associated with Influenza-Like Illness among Adults in Beijing,China: A Large,Population-Based Survey

The objective of this study was to identify possible hygiene behaviors associated with the incidence of ILI among adults in Beijing. In January 2011, we conducted a multi-stage sampling, cross-sectional survey of adults living in Beijing using self-administered anonymous questionnaires. The main outcome variable was self-reported ILI within the past year. Multivariate logistic regression was used to identify factors associated with self-reported ILI. A total of 13003 participants completed the questionnaires. 6068 (46.7%) of all participants reported ILI during the past year. After adjusting for demographic characteristics, the variables significantly associated with a lower likelihood of reporting ILI were regular physical exercise (OR 0.80; 95% CI 0.74–0.87), optimal hand hygiene (OR 0.87; 95% CI 0.80–0.94), face mask use when going to hospitals (OR 0.87; 95% CI 0.80–0.95), and not sharing of towels and handkerchiefs (OR 0.68; 95% CI 0.63–0.73). These results highlight that personal hygiene behaviors were potential preventive factors against the incidence of ILI among adults in Beijing, and future interventions to improve personal hygiene behaviors are needed in Beijing.