170,326 research outputs found
Total synthesis of ulocladol A and analogues alternariol 0-methyl ether and alternariol
No full textUlocladol A is a natural product which has been shown to exhibit tyrosine kinase inhibitory activity against the enzyme Lck. It was isolated from the marine sponge Callyspongia vaginalis in 1999. Prior to the commencement of this project there had been three reported syntheses of ulocladol A, all of which started from intermediates prepared in the synthesis of graphislactones C and D. The routes were relatively long and did not provide much scope for analogous compounds.We proposed it would be possible to prepare ulocladol A via a route which would allow for the synthesis of analogues. Any analogues prepared would be tested against five tyrosine kinases to determine whether any SAR could be elucidated.This report details the use of Suzuki coupling methodology to prepare ulocladol A and eighteen analogues. Several different catalyst systems are reported due to the steric and electronic effects of the substrates used in the Suzuki reaction; also included in the report are the results of the biological testing. Two of the analogues, 2.47 and 2.60, exhibit greater inhibitory activity than ulocladol A and show good activity against four other tyrosine kinases.In addition to the synthesis of ulocladol A and analogues, the report also details the synthesis of alternariol 9-methyl ether and alternariol in the shortest convergent synthesis to dat
Synthetic Human Serum Albumin Sudlow I Binding Site Mimics
No full textHere, we report the design, synthesis, and characterization of molecularly imprinted polymer (MIP) derived mimics of the human serum albumin (HSA) Sudlow I sitethe binding site for the anticoagulant warfarin. MIP design was based upon a combination of experimental (1H NMR) and computational (molecular dynamics) methods. Two MIPs and corresponding nonimprinted reference polymers were synthesized and characterized (scanning electron microscopy; nitrogen sorption; and Fourier transform infrared spectroscopy). MIP−ligand recognition was examined using radioligand binding studies, where the largest number of selective sites was found in a warfarin-imprinted methacrylic acid−ethylene dimethacrylate copolymer (MAA-MIP). The warfarin selectivity of this MIP was confirmed using radioligand displacement and zonal chromatographic studies. A direct comparison of MIP−warfarin binding characteristics with those of the HSA Sudlow I binding site was made, and similarities in site population (per gram polymer or protein) and affinities were observed. The warfarin selectivity of the MIP suggests its potential for use as a recognition element in a MIP-based warfarin sensor and even as a model to aid in understanding and steering blood−plasma protein-regulated transport processes or even for the development of warfarin sensors
Epidemiology of ischaemic stroke subtypes: do differences in epidemiology provide evidence for a distinct lacunar arterial pathology?
No full textBackground Lacunar ischaemic stroke accounts for around one quarter of all
strokes, and is presumed to result from the occlusion of a single perforating artery
supplying the deep subcortical areas of the brain. The underlying arterial pathology
is poorly understood, but is thought to differ from the atherothrombotic processes
that occlude larger intra- and extracranial arteries causing most other ischaemic
stroke subtypes. Progress in understanding the aetiology of lacunar stroke has been
limited by the lack of informative autopsy studies, and the difficulties in studying
small blood vessels using brain imaging. One alternative approach is to compare the
epidemiology of ischaemic stroke subtypes, since differences in the epidemiology
may reflect and inform about different underlying pathologies.
Methods I performed two systematic literature reviews to identify studies presenting
data on (1) the risk factors for, and (2) the outcome of, different ischaemic stroke
subtypes. I extracted relevant data from included studies and performed a series of
meta-analyses comparing risk factor profiles, and risks of death, recurrent stroke and
myocardial infarction (MI) in patients with lacunar versus non-lacunar ischaemic
stroke. To address some of the unanswered questions and controversies surrounding
the causes of ischaemic stroke we set up the Edinburgh Stroke Study (ESS), which I
co-ordinated. We recruited patients with stroke and transient ischaemic attack seen
at our hospital between 2002 and 2005, and followed them for 1-4 years for death,
recurrent stroke and MI. To overcome the methodological limitations of the studies
included in my reviews and of my meta-analyses, I carried out a large collaborative
individual patient data analysis in which I combined data from five stroke registries -
including the ESS - that had used similar robust methodology, and performed a series of analyses comparing the risk factor profiles of patients with lacunar versus nonlacunar
ischaemic stroke. In an updated meta-analysis, I combined this data with
existing published studies that had used an unbiased method of classifying ischaemic
stroke subtypes. Using the ESS data, I compared the risks of recurrent stroke and
MI, and patterns of recurrent stroke subtypes in patients with lacunar versus nonlacunar
stroke.
Results In my systematic review of risk factors I found evidence of classification
bias in many studies, where systematic error was introduced through the use of
classification methods that included risk factors in the definitions of stroke subtypes.
This led to overestimation of some risk factor-stroke subtype associations and, in
particular, to apparently stronger associations between hypertension and diabetes and
lacunar compared with non-lacunar ischaemic stroke. When I included only
unbiased studies, I found a significantly reduced prevalence of atrial fibrillation (AF)
and severe carotid stenosis and a trend towards a reduced prevalence of ischaemic
heart disease (IHD) in lacunar patients. I found a very slight excess of hypertension
among lacunar patients, but no difference in the prevalence of diabetes, or any other
risk factor studied. In my collaborative individual patient data analysis, I confirmed
a significantly lower prevalence of severe carotid stenosis, AF and previous IHD in
patients with lacunar ischaemic stroke, but found no difference in the prevalence of
hypertension, diabetes, or any other risk factor studied, even after adjusting for
confounding factors. These results were largely confirmed in my updated metaanalysis,
although there was a slight excess of hypertension among lacunar compared
with non-lacunar ischaemic strokes. In my systematic review of outcome after
lacunar versus non-lacunar ischaemic stroke, I found a lower risk of death following lacunar compared with non-lacunar stroke which attenuated but persisted long-term;
a higher recurrent stroke risk in non-lacunar patients during the first month only; and
limited data on recurrent stroke subtypes suggesting that ischaemic stroke subtypes
may breed true to type. Data on MI risk were extremely sparse. My analyses of data
from the ESS showed no difference overall in risk of recurrent stroke between
patients with lacunar versus non-lacunar ischaemic stroke, but some evidence for a
lower very early recurrence risk among lacunar patients. There was evidence that
recurrent stroke subtypes breed true, since patients with a lacunar stroke at baseline
were much more likely to have a lacunar than a non-lacunar recurrence. We
identified five times as many MI events following stroke than have been previously
reported in the published literature, and found a non-significantly reduced risk of MI
in patients with lacunar compared with non-lacunar ischaemic stroke.
Conclusions My comparisons of the epidemiology of lacunar versus non-lacunar
ischaemic stroke subtypes revealed differences in the risk factor profiles and risks of
recurrent stroke and myocardial infarction which suggest that a distinct, nonatherothrombotic
arteriopathy underlies many lacunar ischaemic strokes. My
analyses of recurrent stroke subtype patterns suggest that recurrent ischaemic strokes
subtypes tend to breed true, providing further support for a distinct lacunar
arteriopathy. Contrary to widespread belief, hypertension and diabetes do not appear
to be more important in the aetiology of lacunar stroke than in other types of
ischaemic stroke.
These findings support other lines of evidence for a distinct lacunar arteriopathy, and
highlight the need for further research into the aetiology of lacunar ischaemic stroke
Synthetic Human Serum Albumin Sudlow I Binding Site Mimics
No full textHere, we report the design, synthesis, and characterization of molecularly imprinted polymer (MIP) derived mimics of the human serum albumin (HSA) Sudlow I site-the binding site for the anticoagulant warfarin. MIP design was based upon a combination of experimental (H-1 NMR) and computational (molecular dynamics) methods, Two MIPs and corresponding nonimprinted reference polymers were synthesized and characterized (scanning electron microscopy; nitrogen sorption; and Fourier transform infrared spectroscopy). MIP-ligand recognition was examined using radioligand binding studies, where the largest number of selective sites was found in a warfarin-imprinted methacrylic acid ethylene dimethacrylate copolymer (MAA-MIP). The warfarin selectivity of this MIP was confirmed using radioligand displacement and zonal chromatographic studies. A direct comparison of MIP-warfarin binding characteristics with those of the HSA Sudlow I binding site was made, and similarities in site population (per gram polymer or protein) and affinities were observed. The warfarin selectivity of the MIP suggests its potential for use as a recognition element in a MIP-based warfarin sensor and even as a model to aid in understanding and steering blood-plasma protein-regulated transport processes or even for the development of warfarin sensors.</p
Evaluation of Alternatives to Warfarin as Probes For Sudlow Site I of Human Serum Albumin Characterization by High-Performance Affinity Chromatography
No full textWarfarin is often used as a site-specific probe for examining the binding of drugs and other solutes to Sudlow site I of human serum albumin (HSA). However, warfarin has strong binding to HSA and the two chiral forms of warfarin have slightly different binding affinities for this protein. Warfarin also undergoes a slow change in structure when present in common buffers used for binding studies. This report examined the use of four related, achiral compounds (i.e., coumarin, 7-hydroxycoumarin, 7-hydroxy-4-methylcoumarin, and 4-hydroxycoumarin) as possible alternative probes for Sudlow site I in drug binding studies. High-performance affinity chromatography and immobilized HSA columns were used to compare and evaluate the binding properties of these probe candidates. Binding for each of the tested probe candidates to HSA was found to give a good fit to a two-site model. The first group of sites had moderate-to-high affinities for the probe candidates with association equilibrium constants that ranged from 6.4 × 103 M−1 (coumarin) to 5.5 × 104 M−1 (4- hydroxycoumarin) at pH 7.4 and 37°C. The second group of weaker, and probably non-specific, binding regions, had association equilibrium constants that ranged from 3.8 × 101 M−1 (7-hydroxy-4- methylcoumarin) to 7.3 × 102 M−1 (coumarin). Competition experiments based on zonal elution indicated that all of these probe candidates competed with warfarin at their high affinity regions. Warfarin also showed competition with coumarin, 7-hydroxycoumarin and 7-hydroxy-4- methycoumarin for their weak affinity sites but appeared to not bind and or compete for all of the weak sites of 4-hydroxycoumarin. It was found from this group that 4-hydroxycoumarin was the best alternative to warfarin for examining the interactions of drugs at Sudlow site I on HSA. These results also provided information on how the major structural components of warfarin contribute to the binding of this drug at Sudlow site I
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Epidemiology of stroke and its subtypes in Chinese populations
No full textBACKGROUND:
Chinese populations have been reported to have a higher stroke
incidence as well as different stroke epidemiology compared with white populations.
However, reliable comparisons have been precluded by a lack of methodologically
robust studies. I aimed to systematically evaluate the incidence of stroke, the
distribution of its main types/subtypes, and risk factor distributions among stroke
types/subtypes in Chinese, and to compare these with data from white populations.
Methods: I performed a series of systematic reviews and meta-analyses of studies
conducted since 1990 which had data on (1) incidence of stroke, (2) pathological
types of stroke or ischaemic stroke subtypes, and (3) frequency of risk factors among
pathological types of stroke or ischaemic stroke (IS) subtypes in Chinese populations,
and in white populations for comparison. I calculated age-standardized stroke
incidence and the proportions of each pathological type and ischaemic subtype. For
each risk factor, I calculated study-specific and pooled odds ratios (ORs) using a
random effects model for intracerebral haemorrhage (ICH) versus IS, for each IS
subtype versus other subtypes, and for overall IS patients, comparing findings for
Chinese versus Whites.
In addition, I conducted individual patient analyses of data from the National Taiwan
University Hospital (NTUH) Stroke Registry, which consecutively recruited 6675
acute stroke patients from 2006-2011, comparing risk factor profiles among stroke
types and subtypes and using logistic regression to adjust for potential confounding
factors.
RESULTS:
From my systematic reviews, I found a younger onset of stroke, a slightly
higher overall stroke incidence and higher proportion of ICH in Chinese versus white
populations. Although the overall proportion of lacunar infarct appeared higher in
Chinese from hospital-based studies than white populations, confirming the different
distributions of ischaemic subtypes will need further comparable population-based
studies.
In my meta-analyses comparing risk factors for ICH versus IS, in Chinese - but not
Whites – hypertension (HTN) and alcohol intake were significantly more frequent,
while mean age was lower in ICH than IS. In IS, the overall prevalence of
hypertension, diabetes, smoking, and alcohol intake were similar between Chinese
and white IS patients, whereas hypercholesterolaemia, ischaemic heart disease (IHD)
and atrial fibrillation (AF) were less common in Chinese IS patients. As for IS
subtypes, the relative frequencies of risk factors were mostly qualitatively similar
(although different in size) in Chinese and white populations. Compared with other
ischaemic subtypes: large artery atherosclerosis (LAA) strokes were associated with
diabetes; cardioembolic (CE) strokes were associated with AF and IHD; small vessel
disease (SVD) strokes or lacunar strokes were associated with hypertension and
diabetes.
Analyses of NTUH individual patient data showed that HTN and alcohol intake were
independent risk factors for ICH versus IS in a Chinese population in Taiwan,
regardless of age, sex, or other risk factors. The results were consistent with my
previous risk factor meta-analyses for ICH versus IS. In IS analyses, the prevalence
of hypertension, diabetes, AF, and hyperlipidaemia in overall IS patients based in
Taiwan were higher than the pooled results in my risk factor meta-analysis for IS for
all Chinese populations including mainland China. In terms of risk factor
associations with IS subtypes, the findings after controlling for potential confounders
were mostly close to my previous meta-analysis results with the exception of
stronger associations of hypertension and diabetes with SVD (lacunar) strokes.
CONCLUSION:
I have shown a younger onset of stroke, a higher overall stroke
incidence, an around twofold higher proportion of ICH and different distribution of
IS subtypes, as well as some differences in risk factor distributions among
pathological types of stroke and IS subtypes in Chinese compared with white
populations. My results help to inform us of different stroke mechanisms in different
populations, to guide further well-designed research in this area, and to direct better
strategies for stroke prevention in Chinese populations
- …
