133 research outputs found
Genetic structure of sigmodontine rodents (Cricetidae) along an altitudinal gradient of the Atlantic Rain Forest in southern Brazil
The population genetic structure of two sympatric species of sigmodontine rodents (Oligoryzomys nigripes and Euryoryzomys russatus) was examined for mitochondrial DNA (mtDNA) sequence haplotypes of the control region. Samples were taken from three localities in the Atlantic Rain Forest in southern Brazil, along an altitudinal gradient with different types of habitat. In both species there was no genetic structure throughout their distribution, although levels of genetic variability and gene flow were high
Expression profile of genes regulated by activity of the Na-H exchanger NHE1
BACKGROUND: In mammalian cells changes in intracellular pH (pH(i)), which are predominantly controlled by activity of plasma membrane ion exchangers, regulate a diverse range of normal and pathological cellular processes. How changes in pH(i )affect distinct cellular processes has primarily been determined by evaluating protein activities and we know little about how pH(i )regulates gene expression. RESULTS: A global profile of genes regulated in mammalian fibroblasts by decreased pH(i )induced by impaired activity of the plasma membrane Na-H exchanger NHE1 was characterized by using cDNA microarrays. Analysis of selected genes by quantitative RT-PCR, TaqMan, and immunoblot analyses confirmed results obtained from cDNA arrays. Consistent with established roles of pH(i )and NHE1 activity in cell proliferation and oncogenic transformation, grouping regulated genes into functional categories and biological pathways indicated a predominant number of genes with altered expression were associated with growth factor signaling, oncogenesis, and cell cycle progression. CONCLUSION: A comprehensive analysis of genes selectively regulated by pH(i )provides insight on candidate targets that might mediate established effects of pH(i )on a number of normal and pathological cell functions
Acidic Extracellular pH Promotes Activation of Integrin αvÎČ3
Acidic extracellular pH is characteristic of the cell microenvironment in several important physiological and pathological contexts. Although it is well established that acidic extracellular pH can have profound effects on processes such as cell adhesion and migration, the underlying molecular mechanisms are largely unknown. Integrin receptors physically connect cells to the extracellular matrix, and are thus likely to modulate cell responses to extracellular conditions. Here, we examine the role of acidic extracellular pH in regulating activation of integrin [alpha]v[beta]3. Through computational molecular dynamics simulations, we find that acidic extracellular pH promotes opening of the [alpha]v[beta]3 headpiece, indicating that acidic pH can thereby facilitate integrin activation. This prediction is consistent with our flow cytometry and atomic force microscope-mediated force spectroscopy assays of integrin [alpha]v[beta]3 on live cells, which both demonstrate that acidic pH promotes activation at the intact cell surface. Finally, quantification of cell morphology and migration measurements shows that acidic extracellular pH affects cell behavior in a manner that is consistent with increased integrin activation. Taken together, these computational and experimental results suggest a new and complementary mechanism of integrin activation regulation, with associated implications for cell adhesion and migration in regions of altered pH that are relevant to wound healing and cancer.National Institute of Biomedical Imaging and Bioengineering (U.S.) (Award Number T32EB006348)Massachusetts Institute of Technology (Collamore-Rogers Fellowship)National Institutes of Health (U.S.) (NIH Cell Migration Consortium Grant U54-GM069668)National Science Foundation (U.S.) (CAREER Award)Singapore-MIT Alliance for Research and Technology (BioSystem and Micromechanics (BioSyM) Interdisciplinary Research Group
Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1ÎČ, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1ÎČ innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.
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
Updated measurements of exclusive J/Ï and Ï(2S) production cross-sections in pp collisions at âs = 7 TeV
The differential cross-section as a function of rapidity has been measured for the exclusive production of J/Ï and Ï(2S) mesons in protonâproton collisions at âs = 7 TeV, using data collected by the LHCb experiment, corresponding to an integrated luminosity of 930 pbâ1. The cross-sections times branching fractions to two muons having pseudorapidities between 2.0 and 4.5 are measured to be where the first uncertainty is statistical and the second is systematic. The measurements agree with next-to-leading order QCD predictions as well as with models that include saturation effects
Search for CP violation in Îb0âpKâ and Îb0âpÏâ decays
A search for CP violation in Îb0âpKâ and Îb0âpÏâ decays is presented using a sample of pp collisions collected with the LHCb detector and corresponding to an integrated luminosity of 3.0fbâ1. The CP -violating asymmetries are measured to be ACPpKâ=â0.020±0.013±0.019 and ACPpÏâ=â0.035±0.017±0.020, and their difference ACPpKââACPpÏâ=0.014±0.022±0.010, where the first uncertainties are statistical and the second systematic. These are the most precise measurements of such asymmetries to date
Search for dark photons produced in 13 TeV collisions
Searches are performed for both promptlike and long-lived dark photons,
A
0
, produced in proton-proton
collisions at a center-of-mass energy of 13 TeV, using
A
0
â
Ό
ĂŸ
Ό
â
decays and a data sample corresponding
to an integrated luminosity of
1
.
6
fb
â
1
collected with the LHCb detector. The promptlike
A
0
search covers
the mass range from near the dimuon threshold up to 70 GeV, while the long-lived
A
0
search is restricted to
the low-mass region
214
<m
Ă°
A
0
Ă
<
350
MeV. No evidence for a signal is found, and 90% confidence
level exclusion limits are placed on the
Îł
â
A
0
kinetic-mixing strength. The constraints placed on promptlike
dark photons are the most stringent to date for the mass range
10
.
6
<m
Ă°
A
0
Ă
<
70
GeV, and are
comparable to the best existing limits for
m
Ă°
A
0
Ă
<
0
.
5
GeV. The search for long-lived dark photons is the
first to achieve sensitivity using a displaced-vertex signature
Studies of beauty baryon decays to D0phâ and Î+châ final states
Decays of beauty baryons to the D0phâ and Î+châ final states (where h indicates a pion or a kaon) are studied using a data sample of pp collisions, corresponding to an integrated luminosity of 1.0ââfbâ1, collected by the LHCb detector. The Cabibbo-suppressed decays Î0bâD0pKâ and Î0bâÎ+cKâ are observed, and their branching fractions are measured with respect to the decays Î0bâD0pÏâ and Î0bâÎ+cÏâ. In addition, the first observation is reported of the decay of the neutral beauty-strange baryon Î0b to the D0pKâ final state, and a measurement of the Î0b mass is performed. Evidence of the Î0bâÎ+cKâ decay is also reported
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