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11.
Martin FL Kelly JG Llabjani V Martin-Hirsch PL Patel II Trevisan J Fullwood NJ Walsh MJ 《Nature protocols》2010,5(11):1748-1760
Infrared (IR) spectroscopy of intact cells results in a fingerprint of their biochemistry in the form of an IR spectrum; this has given rise to the new field of biospectroscopy. This protocol describes sample preparation (a tissue section or cytology specimen), the application of IR spectroscopy tools, and computational analysis. Experimental considerations include optimization of specimen preparation, objective acquisition of a sufficient number of spectra, linking of the derived spectra with tissue architecture or cell type, and computational analysis. The preparation of multiple specimens (up to 50) takes 8 h; the interrogation of a tissue section can take up to 6 h (~100 spectra); and cytology analysis (n = 50, 10 spectra per specimen) takes 14 h. IR spectroscopy generates complex data sets and analyses are best when initially based on a multivariate approach (principal component analysis with or without linear discriminant analysis). This results in the identification of class clustering as well as class-specific chemical entities. 相似文献
12.
Influence of surface shape on DNA binding of bimetallo helicates 总被引:1,自引:0,他引:1
Peberdy JC Malina J Khalid S Hannon MJ Rodger A 《Journal of inorganic biochemistry》2007,101(11-12):1937-1945
In order to probe the DNA-helicate interactions responsible for the DNA binding and remarkable changes of the DNA secondary structure induced by a tetracationic bi-metallo helicate [Fe(2)(L(1))(3)](4+) (L(1)=C(25)H(20)N(4)), we have designed and synthesised derivatives with hydrophobic methyl groups at different positions on the ligand backbone. Two dimetallo helicates [Fe(2)(L(i))(3)](4+) were prepared using ligands L(3) and L(5) with the methyl substituent on, respectively, the 3 and 5 positions of the pyridyl ring thus producing a wider or slightly longer tetracationic DNA binder. UV/visible absorbance, circular and linear dichroism spectroscopies have been used to characterize the interactions of the cylinders with DNA with the aim of investigating any sequence preference or selectivity upon binding. Competitive binding studies using fluorescent dyes Hoechst 33258 (a minor groove binder), ethidium bromide (an intercalator) and a major groove binding cation (cobalt (III) hexammine) which induces the B-->Z transition have been employed to determine the binding geometries of the enantiomers of two methylated helicates (L(3) and L(5)) to DNA and compare with the data obtained previously for the unmethylated analogue (L(1)). The results demonstrate that the racemic mixtures and the resolved enantiomers of all helicates bind to DNA inducing structural changes. The overall conclusion from the effect of adding these groups to the surface of the parent helicate is that increasing the width (L(3)) reduces the DNA binding strength, the bending and coiling effect and the groove selectivity of the enantiomers compared with the parent compound. There is limited evidence to suggest a slight GC sequence preference. Lengthening the helicate (L(5)) results in DNA interactions similar to those of the parent compounds, with an increased preference of the P enantiomer for the minor groove indicating an enhancement of mode selectivity. 相似文献
13.
An integrative approach combining ion mobility mass spectrometry,X-ray crystallography,and nuclear magnetic resonance spectroscopy to study the conformational dynamics of α1-antitrypsin upon ligand binding
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Mun Peak Nyon Tanya Prentice Jemma Day John Kirkpatrick Ganesh N Sivalingam Geraldine Levy Imran Haq James A Irving David A Lomas John Christodoulou Bibek Gooptu Konstantinos Thalassinos 《Protein science : a publication of the Protein Society》2015,24(8):1301-1312
Native mass spectrometry (MS) methods permit the study of multiple protein species within solution equilibria, whereas ion mobility (IM)-MS can report on conformational behavior of specific states. We used IM-MS to study a conformationally labile protein (α1-antitrypsin) that undergoes pathological polymerization in the context of point mutations. The folded, native state of the Z-variant remains highly polymerogenic in physiological conditions despite only minor thermodynamic destabilization relative to the wild-type variant. Various data implicate kinetic instability (conformational lability within a native state ensemble) as the basis of Z α1-antitrypsin polymerogenicity. We show the ability of IM-MS to track such disease-relevant conformational behavior in detail by studying the effects of peptide binding on α1-antitrypsin conformation and dynamics. IM-MS is, therefore, an ideal platform for the screening of compounds that result in therapeutically beneficial kinetic stabilization of native α1-antitrypsin. Our findings are confirmed with high-resolution X-ray crystallographic and nuclear magnetic resonance spectroscopic studies of the same event, which together dissect structural changes from dynamic effects caused by peptide binding at a residue-specific level. IM-MS methods, therefore, have great potential for further study of biologically relevant thermodynamic and kinetic instability of proteins and provide rapid and multidimensional characterization of ligand interactions of therapeutic interest.PDB Code(s): 4PYW 相似文献
14.
A palaeoecological investigation into the role of fire and human activity in the development of montane grasslands in East Africa 总被引:1,自引:0,他引:1
Human activity has been widely implicated in the origin and expansion of montane grasslands in East Africa, yet little palaeoecological
evidence exists to test whether these grasslands are natural or secondary. Pollen and charcoal data derived from two Holocene
records in the Eastern Arc mountains of Tanzania are used as a case study to investigate the supposed secondary nature of
montane grasslands in Africa. Fossil pollen data are used to detect vegetation change, and charcoal analysis is used to reconstruct
fire history. The pollen data are characterised by stable proportions of local taxa suggesting permanence of grasslands throughout
the past ~13,000 years. Recent increases in fire adapted taxa such as Morella point towards the development of a grassland/forest patch mosaic possibly associated with burning. However, robust evidence
of human activity is absent from the records, which may be attributed to the late human occupation of the mountains. The records
indicate long-term persistence of grasslands which, coupled with a lack of evidence of human activity, suggests that these
grasslands are not secondary. These data support the hypothesis that grasslands are an ancient and primary component of montane
vegetation in Africa, but that they experienced some expansion during the late Holocene as a result of changing fire regime. 相似文献
15.
Large-scale candidate gene analysis of HDL particle features 总被引:1,自引:0,他引:1
Kaess BM Tomaszewski M Braund PS Stark K Rafelt S Fischer M Hardwick R Nelson CP Debiec R Huber F Kremer W Kalbitzer HR Rose LM Chasman DI Hopewell J Clarke R Burton PR Tobin MD Hengstenberg C Samani NJ 《PloS one》2011,6(1):e14529
Background
HDL cholesterol (HDL-C) is an established marker of cardiovascular risk with significant genetic determination. However, HDL particles are not homogenous, and refined HDL phenotyping may improve insight into regulation of HDL metabolism. We therefore assessed HDL particles by NMR spectroscopy and conducted a large-scale candidate gene association analysis.Methodology/Principal Findings
We measured plasma HDL-C and determined mean HDL particle size and particle number by NMR spectroscopy in 2024 individuals from 512 British Caucasian families. Genotypes were 49,094 SNPs in >2,100 cardiometabolic candidate genes/loci as represented on the HumanCVD BeadChip version 2. False discovery rates (FDR) were calculated to account for multiple testing. Analyses on classical HDL-C revealed significant associations (FDR<0.05) only for CETP (cholesteryl ester transfer protein; lead SNP rs3764261: p = 5.6*10−15) and SGCD (sarcoglycan delta; rs6877118: p = 8.6*10−6). In contrast, analysis with HDL mean particle size yielded additional associations in LIPC (hepatic lipase; rs261332: p = 6.1*10−9), PLTP (phospholipid transfer protein, rs4810479: p = 1.7*10−8) and FBLN5 (fibulin-5; rs2246416: p = 6.2*10−6). The associations of SGCD and Fibulin-5 with HDL particle size could not be replicated in PROCARDIS (n = 3,078) and/or the Women''s Genome Health Study (n = 23,170).Conclusions
We show that refined HDL phenotyping by NMR spectroscopy can detect known genes of HDL metabolism better than analyses on HDL-C. 相似文献16.
Lefman J Zhang P Hirai T Weis RM Juliani J Bliss D Kessel M Bos E Peters PJ Subramaniam S 《Journal of bacteriology》2004,186(15):5052-5061
Electron tomography is a powerful method for determining the three-dimensional structures of large macromolecular assemblies, such as cells, organelles, and multiprotein complexes, when crystallographic averaging methods are not applicable. Here we used electron tomographic imaging to determine the molecular architecture of Escherichia coli cells engineered to overproduce the bacterial chemotaxis receptor Tsr. Tomograms constructed from fixed, cryosectioned cells revealed that overproduction of Tsr led to formation of an extended internal membrane network composed of stacks and extended tubular structures. We present an interpretation of the tomogram in terms of the packing arrangement of Tsr using constraints derived from previous X-ray and electron-crystallographic studies of receptor clusters. Our results imply that the interaction between the cytoplasmic ends of Tsr is likely to stabilize the presence of the membrane networks in cells overproducing Tsr. We propose that membrane invaginations that are potentially capable of supporting axial interactions between receptor clusters in apposing membranes could also be present in wild-type E. coli and that such receptor aggregates could play an important role in signal transduction during bacterial chemotaxis. 相似文献
17.
Marek Stibal Jemma L. Wadham Grzegorz P. Lis Jon Telling Richard D. Pancost Ashley Dubnick Martin J. Sharp Emily C. Lawson Catriona E. H. Butler Fariha Hasan Martyn Tranter Alexandre M. Anesio 《Global Change Biology》2012,18(11):3332-3345
Subglacial environments are largely anoxic, contain organic carbon (OC) overridden by glacier ice during periods of advance, and harbour active microbial communities. This creates favourable conditions for OC degradation via methanogenesis. It has been hypothesized that OC beneath ice sheets is converted to methane (CH4) and may be released to the atmosphere during retreat. However, there are limited data available to support this contention. Here, we present new data on the abundance, diversity and activity of methanogenic archaea and the amount and character of OC in subglacial sediments from Arctic and Antarctic glacial systems based on different substrate types. We employed long‐term laboratory incubations to quantify the CH4 production potential in different subglacial settings. Significant numbers of methanogens (up to 7 × 104 cells g?1) were detected in the samples and clones of Methanomicrobiales and Methanosarcinales were identified in clone libraries. Long lag periods (up to >200 days) were observed before significant CH4 concentrations were measured. We report order of magnitude differences in rates of CH4 production (101–105 fmol g?1 d?1) in different subglacial sediments, reflecting contrasts in the origin of the sediment and the OC character. Hence, we predict that contrasting rates of CH4 production are likely to occur beneath glaciers and ice sheets that overran different types of substrate. We subsequently estimated the potential for CH4 production beneath the Laurentide/Inuitian/Cordilleran and Fennoscandian Ice Sheets during a typical 85 ka Quaternary glacial/interglacial cycle. CH4 production from lacustrine‐derived OC is likely to be an order of magnitude higher (~6.3–27 Pg C) than that from overridden soils (~0.55–0.68 Pg C), possibly due to a difference in lability between lacustrine and soil OC. While representing a fraction of the entire OC pool (~418–610 Pg C), this finding highlights the importance of considering the character of different OC pools when calculating subglacial CH4 production. 相似文献
18.
Jemma Evans Natalie J. Hannan Cassandra Hincks Luk J. F. Rombauts Lois A. Salamonsen 《PloS one》2012,7(12)
Background
Synchronous development of the endometrium (to achieve a receptive state) and of the embryo is essential for successful implantation and ongoing pregnancy. Endometrial receptivity exists only for a finite time in a menstrual cycle and the endometrium is refractory to embryo implantation outside of this window. Administration of hormones to stimulate multifollicular development within the ovary, integral to the majority of assisted reproduction (ART) protocols, dramatically alters the hormonal milieu to which the endometrium is exposed versus normal menstrual cycles. Endometrial maturation may be profoundly affected by this altered endocrine environment.Aim
Compare endometrial histology in fertile women, fertile women undergoing hormonal stimulation for oocyte donation and infertile women undergoing fresh embryo transfers in an ART cycle with further comparisons between women who did or did not become pregnant. Examine the presence of leukocytes and markers of endometrial maturation.Methods
Endometrial histology was examined by hematoxylin and eosin staining with a semi quantitative scoring method developed to compare histological appearance of tissues. The presence of leukocytes and developmental markers was examined by immunohistochemistry and scored.Results
Endometrial histology was dramatically altered upon stimulation for ART. However, those women who became pregnant presented with significantly less alterations in histological endometrial maturation. Numbers and activation status of leukocyte populations were also altered within the endometria stimulated for ART, with neutrophils undergoing degranulation, usually observed only pre-menstrually.Conclusion
We propose that such developmental changes render the endometrium hostile to the embryo and that modifications to ART protocols should be considered to take account of the requirement for endometrial receptivity and hence increase pregnancy rates. 相似文献19.
Stibal M Hasan F Wadham JL Sharp MJ Anesio AM 《Extremophiles : life under extreme conditions》2012,16(2):255-265
Microbial ecosystems beneath glaciers and ice sheets are thought to play an active role in regional and global carbon cycling.
Subglacial sediments are assumed to be largely anoxic, and thus various pathways of organic carbon metabolism may occur here.
We examine the abundance and diversity of prokaryotes in sediment beneath two glaciers (Lower Wright Glacier in Antarctica
and Russell Glacier in Greenland) with different glaciation histories and thus with different organic carbon substrates. The
total microbial abundance in the Lower Wright Glacier sediment, originating from young lacustrine sediment, was an order of
magnitude higher (~8 × 106 cells per gram of wet sediment) than in Russell Glacier sediment (~9 × 105 cells g−1) that is of Holocene-aged soil origin. 4% of the microbes from the Russell Glacier sediment and 0.04–0.35% from Lower Wright
Glacier were culturable at 10°C. The Lower Wright Glacier subglacial community was dominated by Proteobacteria, followed by
Firmicutes. The Russell Glacier library was much less diverse and also dominated by Proteobacteria. Low numbers and diversity
of both Euryarchaeota and Crenarchaeota were found in both sediments. The identified clones were related to bacteria with
both aerobic and anaerobic metabolisms, indicating the presence of both oxic and anoxic conditions in the sediments. 相似文献
20.