242 research outputs found
A Multidimensional Diversity-Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles
Synthetic macrocycles are an attractive area in drug discovery. However, their use has been hindered by a lack of versatile platforms for the generation of structurally (and thus shape) diverse macrocycle libraries. Herein, we describe a new concept in library synthesis, termed multidimensional diversity-oriented synthesis, and its application towards macrocycles. This enabled the step-efficient generation of a library of 45 novel, structurally diverse, and highly-functionalized macrocycles based around a broad range of scaffolds and incorporating a wide variety of biologically relevant structural motifs. The synthesis strategy exploited the diverse reactivity of aza-ylides and imines, and featured eight different macrocyclization methods, two of which were novel. Computational analyses reveal a broad coverage of molecular shape space by the library and provides insight into how the various diversity-generating steps of the synthesis strategy impact on molecular shape.The research leading to these results has received funding from the European Research Council under the European UnionÏs Seventh Framework Programme (FP7/2007–2013)/ ERC grant agreement no. [279337/DOS]. The authors also thank AstraZeneca, the EPSRC, the BBSRC, the MRC and the Wellcome Trust for funding. F.N. and D.L.K. thank the Gates Cambridge. F.N. also thanks Trinity College for a Krishnan-Ang Studentship. D.W. thanks the DFG for a postdoctoral fellowship (WI 4198/1-1). S.B. thanks the Herchel Smith Fund. The authors thank Dr John Davies for X-ray crystallography and Dr Andrew Bond for refinement (both from the University of Cambridge)
Regulation of the cd38 promoter in human airway smooth muscle cells by TNF-α and dexamethasone
<p>Abstract</p> <p>Background</p> <p>CD38 is expressed in human airway smooth muscle (HASM) cells, regulates intracellular calcium, and its expression is augmented by tumor necrosis factor alpha (TNF-α). CD38 has a role in airway hyperresponsiveness, a hallmark of asthma, since deficient mice develop attenuated airway hyperresponsiveness compared to wild-type mice following intranasal challenges with cytokines such as IL-13 and TNF-α. Regulation of CD38 expression in HASM cells involves the transcription factor NF-κB, and glucocorticoids inhibit this expression through NF-κB-dependent and -independent mechanisms. In this study, we determined whether the transcriptional regulation of CD38 expression in HASM cells involves response elements within the promoter region of this gene.</p> <p>Methods</p> <p>We cloned a putative 3 kb promoter fragment of the human <it>cd38 </it>gene into pGL3 basic vector in front of a luciferase reporter gene. Sequence analysis of the putative <it>cd38 </it>promoter region revealed one NF-κB and several AP-1 and glucocorticoid response element (GRE) motifs. HASM cells were transfected with the 3 kb promoter, a 1.8 kb truncated promoter that lacks the NF-κB and some of the AP-1 sites, or the promoter with mutations of the NF-κB and/or AP-1 sites. Using the electrophoretic mobility shift assays, we determined the binding of nuclear proteins to oligonucleotides encoding the putative <it>cd38 </it>NF-κB, AP-1, and GRE sites, and the specificity of this binding was confirmed by gel supershift analysis with appropriate antibodies.</p> <p>Results</p> <p>TNF-α induced a two-fold activation of the 3 kb promoter following its transfection into HASM cells. In cells transfected with the 1.8 kb promoter or promoter constructs lacking NF-κB and/or AP-1 sites or in the presence of dexamethasone, there was no induction in the presence of TNF-α. The binding of nuclear proteins to oligonucleotides encoding the putative <it>cd38 </it>NF-κB site and some of the six AP-1 sites was increased by TNF-α, and to some of the putative <it>cd38 </it>GREs by dexamethasone.</p> <p>Conclusion</p> <p>The EMSA results and the cd38 promoter-reporter assays confirm the functional role of NF-κB, AP-1 and GREs in the cd38 promoter in the transcriptional regulation of CD38.</p
An Integrated Approach for Finding Overlooked Genes in Shigella
Background: The completion of numerous genome sequences introduced an era of whole-genome study. However, many genes are missed during genome annotation, including small RNAs (sRNAs) and small open reading frames (sORFs). In order to improve genome annotation, we aimed to identify novel sRNAs and sORFs in Shigella, the principal etiologic agents of bacillary dysentery. Methodology/Principal Findings: We identified 64 sRNAs in Shigella, which were experimentally validated in other bacteria based on sequence conservation. We employed computer-based and tiling array-based methods to search for sRNAs, followed by RT-PCR and northern blots, to identify nine sRNAs in Shigella flexneri strain 301 (Sf301) and 256 regions containing possible sRNA genes. We found 29 candidate sORFs using bioinformatic prediction, array hybridization and RT-PCR verification. We experimentally validated 557 (57.9%) DOOR operon predictions in the chromosomes of Sf301 and 46 (76.7%) in virulence plasmid.We found 40 additional co-expressed gene pairs that were not predicted by DOOR. Conclusions/Significance: We provide an updated and comprehensive annotation of the Shigella genome. Our study increased the expected numbers of sORFs and sRNAs, which will impact on future functional genomics and proteomics studies. Our method can be used for large scale reannotation of sRNAs and sORFs in any microbe with a known genom
Human embryonic stem cell cultivation: historical perspective and evolution of xeno-free culture systems
Experimental studies of e + e -→ some charmless processes containing K S0 at √s = 3.773 and 3.65 GeV
We measure the observed cross sections for the charmless processes e + e -→K S0 K - K - K + π ++ c.c., K S0 K - π + η+c.c., K S0 K - π + π + π - η+c.c., K S0 K - K - K + π + η+c.c., K S0 K - K - K + π + π 0+c.c., K S0 K - ρ ++c.c. and K S0 K - π + ρ 0+c.c. We also extract upper limits on the branching fractions for ψ(3770) decays into these final states at 90% C.L. Analyzed data samples correspond to 17.3 pb-1 and 6.5 pb-1 integrated luminosities registered, respectively, at √s = 3.773 and 3.65 GeV, with the BES-II detector at the BEPC collider. © 2009 Springer-Verlag / Società Italiana di Fisica.published_or_final_versionSpringer Open Choice, 21 Feb 201
Search for ψ(3770)→ charmless final states involving η or π0 mesons
We search for ψ(3770) → π+π-η, K+K-η, pp̄η, ρ0π+π-η, K+K-π+π-η, pp̄π+π-η, pp̄K+K-η and pp̄K+K- π0 using data samples of 17.3 and 6.5 pb-1 integrated luminosities recorded at the center-of-mass energies of 3.773 and 3.65 GeV, respectively, by the BES-II detector operating at the BEPC collider. We obtain cross section measurements at both energies and upper limits on ψ(3770) decay branching fractions to the final states studied. © © Springer-Verlag / Società Italiana di Fisica 2010.published_or_final_versionSpringer Open Choice, 21 Feb 201
Prevalence and trend of hepatitis C virus infection among blood donors in Chinese mainland: a systematic review and meta-analysis
<p>Abstract</p> <p>Background</p> <p>Blood transfusion is one of the most common transmission pathways of hepatitis C virus (HCV). This paper aims to provide a comprehensive and reliable tabulation of available data on the epidemiological characteristics and risk factors for HCV infection among blood donors in Chinese mainland, so as to help make prevention strategies and guide further research.</p> <p>Methods</p> <p>A systematic review was constructed based on the computerized literature database. Infection rates and 95% confidence intervals (95% CI) were calculated using the approximate normal distribution model. Odds ratios and 95% CI were calculated by fixed or random effects models. Data manipulation and statistical analyses were performed using STATA 10.0 and ArcGIS 9.3 was used for map construction.</p> <p>Results</p> <p>Two hundred and sixty-five studies met our inclusion criteria. The pooled prevalence of HCV infection among blood donors in Chinese mainland was 8.68% (95% CI: 8.01%-9.39%), and the epidemic was severer in North and Central China, especially in Henan and Hebei. While a significant lower rate was found in Yunnan. Notably, before 1998 the pooled prevalence of HCV infection was 12.87% (95%CI: 11.25%-14.56%) among blood donors, but decreased to 1.71% (95%CI: 1.43%-1.99%) after 1998. No significant difference was found in HCV infection rates between male and female blood donors, or among different blood type donors. The prevalence of HCV infection was found to increase with age. During 1994-1995, the prevalence rate reached the highest with a percentage of 15.78% (95%CI: 12.21%-19.75%), and showed a decreasing trend in the following years. A significant difference was found among groups with different blood donation types, Plasma donors had a relatively higher prevalence than whole blood donors of HCV infection (33.95% <it>vs </it>7.9%).</p> <p>Conclusions</p> <p>The prevalence of HCV infection has rapidly decreased since 1998 and kept a low level in recent years, but some provinces showed relatively higher prevalence than the general population. It is urgent to make efficient measures to prevent HCV secondary transmission and control chronic progress, and the key to reduce the HCV incidence among blood donors is to encourage true voluntary blood donors, strictly implement blood donation law, and avoid cross-infection.</p
SPARC: a matricellular regulator of tumorigenesis
Although many clinical studies have found a correlation of SPARC expression with malignant progression and patient survival, the mechanisms for SPARC function in tumorigenesis and metastasis remain elusive. The activity of SPARC is context- and cell-type-dependent, which is highlighted by the fact that SPARC has shown seemingly contradictory effects on tumor progression in both clinical correlative studies and in animal models. The capacity of SPARC to dictate tumorigenic phenotype has been attributed to its effects on the bioavailability and signaling of integrins and growth factors/chemokines. These molecular pathways contribute to many physiological events affecting malignant progression, including extracellular matrix remodeling, angiogenesis, immune modulation and metastasis. Given that SPARC is credited with such varied activities, this review presents a comprehensive account of the divergent effects of SPARC in human cancers and mouse models, as well as a description of the potential mechanisms by which SPARC mediates these effects. We aim to provide insight into how a matricellular protein such as SPARC might generate paradoxical, yet relevant, tumor outcomes in order to unify an apparently incongruent collection of scientific literature
Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases
The production of peroxide and superoxide is an inevitable consequence of
aerobic metabolism, and while these particular "reactive oxygen species" (ROSs)
can exhibit a number of biological effects, they are not of themselves
excessively reactive and thus they are not especially damaging at physiological
concentrations. However, their reactions with poorly liganded iron species can
lead to the catalytic production of the very reactive and dangerous hydroxyl
radical, which is exceptionally damaging, and a major cause of chronic
inflammation. We review the considerable and wide-ranging evidence for the
involvement of this combination of (su)peroxide and poorly liganded iron in a
large number of physiological and indeed pathological processes and
inflammatory disorders, especially those involving the progressive degradation
of cellular and organismal performance. These diseases share a great many
similarities and thus might be considered to have a common cause (i.e.
iron-catalysed free radical and especially hydroxyl radical generation). The
studies reviewed include those focused on a series of cardiovascular, metabolic
and neurological diseases, where iron can be found at the sites of plaques and
lesions, as well as studies showing the significance of iron to aging and
longevity. The effective chelation of iron by natural or synthetic ligands is
thus of major physiological (and potentially therapeutic) importance. As
systems properties, we need to recognise that physiological observables have
multiple molecular causes, and studying them in isolation leads to inconsistent
patterns of apparent causality when it is the simultaneous combination of
multiple factors that is responsible. This explains, for instance, the
decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference
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