574 research outputs found
Eigenvector Centrality Distribution for Characterization of Protein Allosteric Pathways
Determining the principal energy pathways for allosteric communication in
biomolecules, that occur as a result of thermal motion, remains challenging due
to the intrinsic complexity of the systems involved. Graph theory provides an
approach for making sense of such complexity, where allosteric proteins can be
represented as networks of amino acids. In this work, we establish the
eigenvector centrality metric in terms of the mutual information, as a mean of
elucidating the allosteric mechanism that regulates the enzymatic activity of
proteins. Moreover, we propose a strategy to characterize the range of the
physical interactions that underlie the allosteric process. In particular, the
well known enzyme, imidazol glycerol phosphate synthase (IGPS), is utilized to
test the proposed methodology. The eigenvector centrality measurement
successfully describes the allosteric pathways of IGPS, and allows to pinpoint
key amino acids in terms of their relevance in the momentum transfer process.
The resulting insight can be utilized for refining the control of IGPS
activity, widening the scope for its engineering. Furthermore, we propose a new
centrality metric quantifying the relevance of the surroundings of each
residue. In addition, the proposed technique is validated against experimental
solution NMR measurements yielding fully consistent results. Overall, the
methodologies proposed in the present work constitute a powerful and cost
effective strategy to gain insight on the allosteric mechanism of proteins
Sex-Specific Alterations in NOS Regulation of Vascular Function in Aorta and Mesenteric Arteries from Spontaneously Hypertensive Rats Compared to Wistar Kyoto Rats
The present study tested the hypothesis that spontaneously hypertensive rats (SHR) have impaired nitric oxide synthase (NOS)-mediated regulation of vascular function versus Wistar-Kyoto rats (WKY). Aorta and small mesenteric arteries were studied from male and female SHR (M SHR and F SHR) and WKY (M WKY and F WKY). Phenylephrine (PE)-induced vasoconstriction was greater in aorta of M SHR versus all others (P \u3c 0.05); there were neither sex nor strain differences in PE contraction in mesenteric arteries. The NOS inhibitor l-Nitro-Arginine Methyl Ester (l-NAME) increased PE-induced vasoconstriction in all rats, although the increase was the least in male SHR (P \u3c 0.05), revealing a blunted vasoconstrictor buffering capacity of NOS. l-NAME increased sensitivity to PE-induced constriction only in mesenteric arteries of SHR, although, the maximal percent increase in contraction was comparable among groups. ACh-induced relaxation was also less in aorta from M SHR versus all others (P \u3c 0.05). ACh relaxation was comparable among groups in mesenteric arteries, although SHR exhibited a greater NOS component to ACh-induced relaxation than WKY. To gain mechanistic insight into sex and strain differences in vascular function, NOS activity and NOS3 protein expression were measured. Aortic NOS activity was comparable between groups and M SHR had greater NOS3 expression than M WKY. In contrast, although vascular function was largely maintained in mesenteric arteries of SHR, NOS activity was less in SHR versus WKY. In conclusion, M SHR exhibit a decrease in NOS regulation of vascular function compared to F SHR and WKY, although this is not mediated by decreases in NOS activity and/or expression
Bleeding jejunal varices and portal thrombosis in a splenectomized patient with hereditary spherocytosis
Bleeding from varices located in the small bowel is a
very uncommon finding; nonetheless, such events accompany
with a high mortality rate (1– 4). Moreover,
early diagnosis of jejunal or ileal varices cannot usually
be accomplished with standard diagnostic tools
(ie, esophagogastroduodenoscopy, colonoscopy).
Most reports in the literature relate to subjects with
liver cirrhosis, often with hepatocarcinoma; in unusual
anatomical situations, varices may develop beyond
the ligament of Treitz in adjunct to the far more
common location in the esophageal and gastric wall.
Thrombosis of the portal vein is a common feature in
such conditions. Portal thrombosis has also been described
in association with overt or latent myeloproliferative
diseases (5); its occurrence in nonneoplastic
hematological conditions in subjects with normal liver
function is quite uncommon.
This report describes the observation of jejunal
varices, with repeated episodes of “melena of unknown
origin,” some of which quite severe, as their
clinical presentation in a patient with portal thrombosis
and with otherwise absolutely normal liver function,
who had undergone splenectomy for hereditary
spherocytosis in early adolescence
Automation of RNA-based biomarker extraction from dried blood spots for the detection of blood doping.
Aim: Transcriptomic biomarkers originating from reticulocytes measured in dried blood spots (DBSs) may be reliable indicators of blood doping. Methods/results: Here, we examined changes in the expression levels of the erythropoiesis-related ALAS2, CA1 and SLC4A1 genes in DBS samples from elite athletes and volunteers of clinical study with recombinant erythropoietin dose. Conclusion: By comparing the mean intraday coefficients of variation for ALAS2L, ALASLC, CA1 and SLC4A1 between manual and automated RNA extractions, an average improvement was observed, whereas the assessment of interday variability provided comparable results for both manual and automated approaches. Our results confirmed that RNA biomarkers on DBS support are efficient to detect blood doping
Total Degree Formula for the Generic Offset to a Parametric Surface
We provide a resultant-based formula for the total degree w.r.t. the spatial
variables of the generic offset to a parametric surface. The parametrization of
the surface is not assumed to be proper.Comment: Preprint of an article to be published at the International Journal
of Algebra and Computation, World Scientific Publishing,
DOI:10.1142/S021819671100680
Age-associated alterations in cholesterol homeostasis: evidence from a cross-sectional study in a Northern Italy population.
BACKGROUND:
The modifications of cholesterol metabolism associated with aging are ill-defined. The objective of this study was to define age-associated alterations of the different metabolic pathways controlling cholesterol homeostasis by analyzing circulating sterols.
METHODS:
We analyzed serum samples collected from 201 adult (75 male, 126 female) subjects within the epidemiological MICOL study (Multicentrica Italiana Colelitiasi). The age range was 38-79 years; 103 had evidence of gallstones. The concentrations of the different sterols, recognized as markers of the main pathways of cholesterol homeostasis, were analyzed by gas chromatography-mass spectrometry, including lathosterol (synthesis), campesterol and sitosterol (absorption), and 7α-hydroxy-4-cholesten-3-one (degradation to bile acids).
RESULTS:
A significant direct correlation was detected between age and cholesterol levels (r =0.34, P<0.01). The lathosterol/cholesterol ratio was lower in older age quartiles (P<0.05 by analysis of variance), with an inverse correlation between the lathosterol/cholesterol ratio and age (r=-0.32, P<0.01). Such correlation was particularly evident in females. The campesterol/cholesterol and sitosterol/cholesterol ratios were inversely correlated with aging in control, but not in gallstone patients. The levels of 7α-hydroxy-4-cholesten-3-one were not correlated with age.
CONCLUSION:
These data show a reduction of cholesterol synthesis with aging which is associated with increased circulating cholesterol levels. The finding might be related to a reduced metabolic need for cholesterol in advancing age, leading to a downregulation of the main mechanisms of cholesterol intake in the liver. A different age-related behavior was observed in gallstone-free versus gallstone patients regarding cholesterol absorption. The possible implications in terms of the pharmacological management of hypercholesterolemia in the elderly remain to be defined
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