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71.
The increasing incidence of hospital acquired infections caused by antibiotic resistant pathogens has led to an increase in morbidity and mortality, finding alternative antibiotics unaffected by resistance mechanisms is fundamentally important for treating this problem. Naturally occurring proteins usually carry short peptide fragments that exhibit noticeable biological activity against a wide variety of microorganisms such as bacteria, fungi and protozoa. Traditional discovery of such antimicrobially active fragments (i.e. antimicrobial peptides, AMPs) from protein repertoire is either random or led by chance. Here, we report the use of a rational protocol that combines in silico prediction and in vitro assay to identify potential AMPs with high activity and low toxicity from the entire human genome. In the procedure, a three-step inference strategy is first proposed to perform genome-wide analysis to infer AMPs in a high-throughput manner. By employing this strategy we are able to screen more than one million peptide candidates generated from various human proteins, from which we identify four highly promising samples, and subsequently their antibacterial activity on five strains as well as cytotoxicity on human myoblasts are tested experimentally. As a consequence, two high-activity, low-toxicity peptides are discovered, which could be used as the structural basis to further develop new antibiotics. In addition, from 1491 known AMPs we also derive a quantitative measure called antibacterial propensity index (API) for 20 naturally occurring amino acids, which shows a significant allometric correlation with the theoretical minimal inhibitory concentration of putative peptides against Gram-positive and Gram-negative bacteria. This study may provide a proof-of-concept paradigm for the genome-wide discovery of novel antimicrobial peptides by using a combination of in silico and in vitro analyses. 相似文献
72.
Matteo Nadai Giovanna Sattin Giorgio Palù Manlio Palumbo Sara N. Richter 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
G-quadruplexes are polymorphic non-canonical nucleic acid conformations involved both in physiological and pathological processes. Given the high degree of folding heterogeneity and comparable conformational stabilities, different G-quadruplex forms can occur simultaneously, hence rendering the use of basic instrumental methods for structure determination, like X-ray diffraction or NMR, hardly useful. Footprinting techniques represent valuable and relatively rapid alternative to characterize DNA folding. The natural diterpenoid clerocidin is an alkylating agent that specifically reacts at single-stranded DNA regions, with different mechanisms depending on the exposed nucleotide.Methods
Clerocidin was used to footprint G-quadruplex structures formed by telomeric and oncogene promoter sequences (c-myc, bcl-2, c-kit2), and by the thrombin binding aptamer.Results
The easy modulability of CL reactivity towards DNA bases permitted to discriminate fully and partially protected sites, highlights stretched portions of the G-quadruplex conformation, and discriminate among topologies adopted by one sequence in different environmental conditions. Importantly, CL displayed the unique property to allow detection of G-quadruplex folding within a duplex context.Conclusions
CL is a finely performing new tool to unveil G-quadruplex arrangements in DNA sequences under genomically relevant conditions.General significance
Nucleic acid G-quadruplex structures are an emerging research field because of the recent indication of their involvement in a series of key biological functions, in particular in regulation of proliferation-associated gene expression. The use of clerocidin as footprinting agent to identify G-quadruplex structures under genomically relevant conditions may allow detection of new G-quadruplex-based regulatory regions. 相似文献73.
Abstract A total of 1599 stoats were collected from 14 study areas (including all 10 National Parks) from 1972 to 1976. Samples were larger in summer, and contained more females. Young stoats are born in September-October, and females reach adult weight by the following March, though males not until after August. There was significant geographic variation in the body size of adult stoats sampled: males from lowland podocarp/broadleaved forests averaged 3% smaller than males from upland beech forests in skull length, and 4% smaller in head-and-body length. This pattern was repeated, less clearly, in females and in young (approximately 2–5 months old). In contrast with stoats in Britain, assumed to be still the same size as the colonising stock introduced into New Zealand in 1884 and subsequently, males from lowland podocarp forests were unchanged or possibly smaller, and males from upland beech forests were larger; females were larger in all habitats. In males, the extent of geographic variation is almost as great in New Zealand as in the whole of continental Europe. Possible explanations of this pattern are discussed. 相似文献
74.
Kousaku Ohkawa Ayako Nishida Reiko Honma Yoshihiko Matsui Keiji Nagaya Akira Yuasa 《Biofouling》2013,29(4):337-350
Attachment of the freshwater mussel, Limnoperna fortunei, was tested using non‐treated surfaces, viz. glass, nylon, rubber, silicone and Teflon, together with glass surfaces modified with nine kinds of silane coupling agents. Among the surfaces tested, the mussel avoided attaching to Teflon, silicone, and glass modified with 3‐bromopropyltrimethoxysilane or 3,3,3‐(trifluo‐ropropyl)‐trimethoxysilane. With respect to the relationship between the percentage attachment and the surface free energy (sfe) of the substrates, it was found that attachment was considerably reduced on the substrates which exhibited relatively low sfe, as above. The mean number of secreted byssuses per attaching mussel also decreased with decreasing substrate sfe. Furthermore, when the sfe was divided into the dispersion and polar components, the percentage mussel attachment was related to the polar component. These results suggest that effective antifouling towards L. fortunei is achieved on substrates with a low sfe polar component. 相似文献
75.
《Chronobiology international》2013,30(3):285-311
The circadian pacemaker and sleep homeostasis play pivotal roles in vigilance state control. It has been hypothesized that age-related changes in the human circadian pacemaker, as well as sleep homeostatic mechanisms, contribute to the hallmarks of age-related changes in sleep, that is, earlier wake time and reduced sleep consolidation. Assessments of circadian parameters in healthy young (~20–30 years old) and older people (~65–75 years old)—in the absence of the confounding effects of sleep, changes in posture, and light exposure—have demonstrated that an earlier wake time in older people is accompanied by about a 1h advance of the rhythms of core body temperature and melatonin. In addition, older people wake up at an earlier circadian phase of the body temperature and plasma melatonin rhythm. The amplitude of the endogenous circadian component of the core body temperature rhythm assessed during constant routine and forced desynchrony protocols is reduced by 20–30% in older people. Recent assessments of the intrinsic period of the human circadian pacemaker in the absence of the confounding effects of light revealed no age-related reduction of this parameter in both sighted and blind individuals. Wake maintenance and sleep initiation are not markedly affected by age except that sleep latencies are longer in older people when sleep initiation is attempted in the early morning. In contrast, major age-related reductions in the consolidation and duration of sleep occur at all circadian phases. Sleep of older people is particularly disrupted when scheduled on the rising limb of the temperature rhythm, indicating that the sleep of older people is more susceptible to arousal signals genernpated by the circadian pacemaker. Sleep-homeostatic mechanisms, as assayed by the sleep-deprivation–induced increase of EEG slow-wave activity (SWA), are operative in older people, although during both baseline sleep and recovery sleep SWA in older people remains at lower levels. The internal circadian phase advance of awakening, as well as the age-related reduction in sleep consolidation, appears related to an age-related reduction in the promotion of sleep by the circadian pacemaker during the biological night in combination with a reduced homeostatic pressure for sleep. Early morning light exposure associated with this advance of awakening in older people could reinforce the advanced circadian phase. Quantification of the interaction between sleep homeostasis and circadian rhythmicity contributes to understanding age-related changes in sleep timing and quality. (Chronobiology International, 17(3), 285–311, 2000) 相似文献
76.
Sudipta Hazra Subhalakshmi Ghosh Madhushree Das Sarma Smriti Sharma Mousumi Das Prakash Saudagar Vijay Kumar Prajapati Vikash Kumar Dubey Shyam Sundar Banasri Hazra 《Experimental parasitology》2013
World health organization has called for academic research and development of new chemotherapeutic strategies to overcome the emerging resistance and side effects exhibited by the drugs currently used against leishmaniasis. Diospyrin, a bis-naphthoquinone isolated from Diospyros montana Roxb., and its semi-synthetic derivatives, were reported for inhibitory activity against protozoan parasites including Leishmania. Presently, we have investigated the antileishmanial effect of a di-epoxide derivative of diospyrin (D17), both in vitro and in vivo. Further, the safety profile of D17 was established by testing its toxicity against normal macrophage cells (IC50 ∼ 20.7 μM), and also against normal BALB/c mice in vivo. The compound showed enhanced activity (IC50 ∼ 7.2 μM) as compared to diospyrin (IC50 ∼ 12.6 μM) against Leishmania donovani promastigotes. Again, D17 was tested on L. donovani BHU1216 isolated from a sodium stibogluconate-unresponsive patient, and exhibited selective inhibition of the intracellular amastigotes (IC50 ∼ 0.18 μM). Also, treatment of infected BALB/c mice with D17 at 2 mg/kg/day reduced the hepatic parasite load by about 38%. Subsequently, computational docking studies were undertaken on selected enzymes of trypanothione metabolism, viz. trypanothione reductase (TryR) and ornithine decarboxylase (ODC), followed by the enzyme kinetics, where D17 demonstrated non-competitive inhibition of the L. donovani ODC, but could not inhibit TryR. 相似文献
77.
Pahangensin A and B,two new antibacterial diterpenes from the rhizomes of Alpinia pahangensis Ridley
Yasodha Sivasothy Halijah Ibrahim Audra Shaleena Paliany Siti Aisyah Alias Khalijah Awang 《Bioorganic & medicinal chemistry letters》2013,23(23):6280-6285
The rhizomes of Alpinia pahangensis Ridley yielded a new bis-labdanic diterpene for which the name pahangensin A (1) was proposed along with a new labdane diterpene, pahangensin B (2). Their structures were elucidated by spectroscopic methods including, 1D and 2D NMR techniques and LCMS-IT-TOF analysis. Pahangensin A (1) was found to be an antibacterial agent against Staphylococcus aureus, Bacillus cereus and Bacillus subtilis with MIC values less than 100 μg/mL, respectively. Pahangensin B (2) exhibited antibacterial activity (MIC <100 μg/mL) against B. cereus. 相似文献
78.
79.
Yoshihiro Kato Motoji Kawasaki Tomohiro Nigo Shunya Nakamura Akira Fusano Yasuhiro Teranishi Mari N. Ito Takaaki Sumiyoshi 《Bioorganic & medicinal chemistry》2013,21(18):5851-5854
A series of 2,3-disubstituted pyridines were synthesized and evaluated for their PDE4 inhibitory activity. We successfully modified undesirable cyano group of initial lead compound 2 to 4-pyridyl group with improvement of in vitro efficacy and optimized the position of nitrogen atoms in pyridine moiety and alkylene linker. The most potent compound showed significant efficacy in animal models of asthma and inflammation. 相似文献
80.
Takashi Matsumoto Daisuke Yoshida Shigenobu Mizusaki Hideo Tomita Koichi Koshimizu 《Bioscience, biotechnology, and biochemistry》2013,77(4):861-864
The mutagenic activities of quinoline, isoquinoline, phenanthridine, benzo(f)quinoline, benzo(h)quinoline and their α-amino derivatives were compared in relation to the effect of structural changes using the Salmonella typhimurium test system. All mutagenic compounds tested require the liver microsomal fraction for their mutagenic activity. Phenanthridine, two benzoquinolines and quinoline were mutagenic. α-Amination of two benzoquinolines and quinoline resulted to increase their mutagenic activity intensively. Addition of a benzene ring to the benzene moiety of 2-aminoquinoline, so that two carbon atoms are shared, affected distinctly the increase in the mutagenic activity. The co-existence of benzoquinoline series with 2-aminobenzo(f)quinoline showed the clear synergistic action. 相似文献