943 research outputs found
Molecular regulation of the PAIâ1 gene by hypoxia: contributions of Egrâ1, HIFâ1 α, and C/EBPα
Hypoxia, as occurs during tissue ischemia, tips the natural anticoagulant/procoagulant balance of the endovascular wall to favor activation of coagulation. Plasminogen activator inhibitorâ1 (PAIâ1) is an important factor suppressing fibrinolysis under conditions of low oxygen tension. We previously reported that hypoxia induced PAIâ1 mRNA and antigen expression in murine macrophages secondary to increased de novo transcription as well as increased mRNA stability. We now show in RAW264.7 murine macrophages that the transcription factors early growth response geneâ1 (Egrâ1), hypoxiaâinducible factorâ1α (HIFâ1α), and CCAAT/enhancer binding protein α (C/EBPα) are quickly activated in hypoxia and are responsible for transcription and expression of PAIâ1. Murine PAIâ1 promoter constructs, including Egr, HIFâ1α, and/or C/EBPα binding sites, were transfected into RAW 264.7 murine macrophages. To identify the relative importance of each of these putative hypoxiaâresponsive elements, cells were exposed to normobaric hypoxia, and transcriptional activity was recorded. At 16 h of hypoxic exposure, murine PAIâ1 promoter deletion constructs that included Egr, HIFâ1α, and/or C/EBPα binding sites demonstrated increased tranâscriptional activity. Mutation of each of these three murine PAIâ1 promoter sites (or a combination of them) resulted in a marked reduction in hypoxia sensitivity as detected by transcriptional analysis. Functional data obtained using 32Pâlabeled Egr, HIFâ1 α response element (HRE), and C/EBPα oligonucleotides revealed induction of DNA binding activity in nuclear extracts from hypoxic RAW cells, with supershift analysis confirming activation of Egrâ1, HIFâ1 α, or C/EBPα. ChIP analysis confirmed the authenticity of these interactions as each of these transcription factors binds to chromatin under hypoxic conditions. Further, the induction of PAIâ1 by Egrâ1, HIFâ1 α, or C/EBPα was replicated in primary peritoneal macrophages. These data suggest that although HIFâ1 α appears to dominate the PAIâ1 transcriptional response in hypâoxia, Egrâ1 and C/EBPα greatly augment this response and can do so independent of HIFâ1α or each other. These studies are relevant to ischemic upâregulation of the PAIâ1 gene and consequent accrual of microâvascular thrombus under ischemic conditions.âLiao, H., Hyman, M. C., Lawrence, D. A., Pinsky, D. J. Molecular regulation of the PAIâ1 gene by hypoxia: contributions of Egrâ1, HIFâ1α, and C/EBPα. FASEB J. 21, 935â949 (2007)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154298/1/fsb2fj066285com.pd
Cell proliferation and differentiation kinetics during spermatogenesis in Hydra carnea
Spermatogenesis inHydra carnea was investigated. The cell proliferation and differentiation kinetics of intermediates in the spermatogenesis pathway were determined, using quantitative determinations of cell abundance, pulse and continuous labelling with3H-thymidine and nuclear DNA measurements. Testes develop in the ectoderm of male hydra as a result of interstitial cell proliferation. Gonial stem cells and proliferating spermatogonia have cell cycles of 28 h and 22 h, respectively. Stem cells undergo four, five or six cell divisions prior to meiosis which includes a premeiotic S+G2 phase of 20 h followed by a long meiotic prophase (22 h).
Spermatid differentiation requires 12â29 h. When they first appear, testes contain only proliferating spermatogonia; meiotic and postmeiotic cells appear after 2 and 3 days, respectively and release of mature sperm begins after 4 days. Mature testes produce about 27,000 sperm per day over a period of 4â6 days: about 220 gonial stem cells per testis are required to support this level of sperm differentiation. Further results indicate that somatic (e.g. nematocyte) differentiation does not occur in testes although it continues normally in ectodermal tissue outside testes. Our results support the hypothesis that spermatogenesis is controlled locally in regions of the ectoderm where testes develop
Dynamics and Transport in Random Antiferromagnetic Spin Chains
We present the first results on the low-frequency dynamical and transport
properties of random antiferromagnetic spin chains at low temperature (). We
obtain the momentum and frequency dependent dynamic structure factor in the
Random Singlet (RS) phases of both spin-1/2 and spin-1 chains, as well as in
the Random Dimer phase of spin-1/2 chains. We also show that the RS phases are
unusual `spin-metals' with divergent low-frequency conductivity at T=0, and
follow the spin conductivity through `metal-insulator' transitions tuned by the
strength of dimerization or Ising anisotropy in the spin-1/2 case, and by the
strength of disorder in the spin-1 case.Comment: 4 pages (two-column format). Presentation substantially revised to
accomodate new result
Effect of a Physician Uncertainty Reduction Intervention on Blood Pressure in Uncontrolled Hypertensives-A Cluster Randomized Trial
BACKGROUND: Clinical inertia, provider failure to appropriately intensify treatment, is a major contributor to uncontrolled blood pressure (BP). Some clinical inertia may result from physician uncertainty over the patientâs usual BP, adherence, or value of continuing efforts to control BP through lifestyle changes.
OBJECTIVE: To test the hypothesis that providing physicians with uncertainty reduction tools, including 24-h ambulatory BP monitoring, electronic bottle cap monitoring, and lifestyle assessment and counseling, will lead to improved BP control.
DESIGN: Cluster randomized trial with five intervention clinics (IC) and five usual care clinics (UCC).
SETTING: Six public and 4 private primary care clinics.
PARTICIPANTS: A total of 665 patients (63 percent African American) with uncontrolled hypertension (BP â„140 mmHg/90 mmHg or â„130/80 mmHg if diabetic).
INTERVENTIONS: An order form for uncertainty reduction tools was placed in the IC participantsâ charts before each visit and results fed back to the provider.
OUTCOME MEASURES: Percent with controlled BP at last visit. Secondary outcome was BP changes from baseline.
RESULTS: Median follow-up time was 24 months. IC physicians intensified treatment in 81% of IC patients compared to 67% in UCC (p\u3c0.001); 35.0% of IC patients and 31.9% of UCC patients achieved control at the last recorded visit (p\u3e0.05). Multi-level mixed effects longitudinal regression modeling of SBP and DBP indicated a significant, non-linear slope difference favoring IC (p time Ă group interaction=0.048 for SBP and p=0.001 for DBP). The model-predicted difference attributable to intervention was â2.8 mmHg for both SBP and DBP by month 24, and â6.5 mmHg for both SBP and DBP by month 36.
CONCLUSIONS: The uncertainty reduction intervention did not achieve the pre-specified dichotomous outcome, but led to lower measured BP in IC patients
MicroRNA profiling reveals marker of motor neuron disease in ALS models
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by the loss of motor neurons (MNs) in the brain and spinal cord, leading to fatally debilitating weakness. Because this disease predominantly affects MNs, we aimed to characterize the distinct expression profile of that cell type to elucidate underlying disease mechanisms and to identify novel targets that inform on MN health during ALS disease time course. microRNAs (miRNAs) are short, noncoding RNAs that can shape the expression profile of a cell and thus often exhibit cell-type-enriched expression. To determine MN-enriched miRNA expression, we used Cre recombinase-dependent miRNA tagging and affinity purification in mice. By defining thein vivomiRNA expression of MNs, all neurons, astrocytes, and microglia, we then focused on MN-enriched miRNAs via a comparative analysis and found that they may functionally distinguish MNs postnatally from other spinal neurons. Characterizing the levels of the MN-enriched miRNAs in CSF harvested from ALS models of MN disease demonstrated that one miRNA (miR-218) tracked with MN loss and was responsive to an ALS therapy in rodent models. Therefore, we have used cellular expression profiling tools to define the distinct miRNA expression of MNs, which is likely to enrich future studies of MN disease. This approach enabled the development of a novel, drug-responsive marker of MN disease in ALS rodents.SIGNIFICANCE STATEMENTAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons (MNs) in the brain and spinal cord are selectively lost. To develop tools to aid in our understanding of the distinct expression profiles of MNs and, ultimately, to monitor MN disease progression, we identified small regulatory microRNAs (miRNAs) that were highly enriched or exclusive in MNs. The signal for one of these MN-enriched miRNAs is detectable in spinal tap biofluid from an ALS rat model, where its levels change as disease progresses, suggesting that it may be a clinically useful marker of disease status. Furthermore, rats treated with ALS therapy have restored expression of this MN RNA marker, making it an MN-specific and drug-responsive marker for ALS rodents.</jats:p
Variable Radio Sources in the Galactic Plane
Using three epochs of VLA observations of the Galactic Plane in the first
quadrant taken ~15 years apart, we have conducted a search for a population of
variable Galactic radio emitters in the flux density range 1-100 mJy at 6 cm.
We find 39 variable sources in a total survey area of 23.2 sq deg. Correcting
for various selection effects and for the extragalactic variable population of
active galactic nuclei, we conclude there are ~1.6 Galactic sources per sq deg
which vary by more than 50% on a time scale of years (or shorter). We show that
these sources are much more highly variable than extragalactic objects; more
than 50% show variability by a factor >2 compared to <10% for extragalactic
objects in the same flux density range. We also show that the fraction of
variable sources increases toward the Galactic center (another indication that
this is a Galactic population), and that the spectral indices of many of these
sources are flat or inverted. A small number of the variables are coincident
with mid-IR sources and two are coincident with X-ray emitters, but most have
no known counterparts at other wavelengths. Intriguingly, one lies at the
center of a supernova remnant, while another appears to be a very compact
planetary nebula; several are likely to represent activity associated with star
formation regions. We discuss the possible source classes which could
contribute to the variable cohort and followup observations which could clarify
the nature of these sources.Comment: 11 pages, 7 figures; to be published in the Astronomical Journal;
data available on MAGPIS website at http://third.ucllnl.org/gps
Griffiths effects and quantum critical points in dirty superconductors without spin-rotation invariance: One-dimensional examples
We introduce a strong-disorder renormalization group (RG) approach suitable
for investigating the quasiparticle excitations of disordered superconductors
in which the quasiparticle spin is not conserved. We analyze one-dimensional
models with this RG and with elementary transfer matrix methods. We find that
such models with broken spin rotation invariance {\it generically} lie in one
of two topologically distinct localized phases. Close enough to the critical
point separating the two phases, the system has a power-law divergent
low-energy density of states (with a non-universal continuously varying
power-law) in either phase, due to quantum Griffiths singularities. This
critical point belongs to the same infinite-disorder universality class as the
one dimensional particle-hole symmetric Anderson localization problem, while
the Griffiths phases in the vicinity of the transition are controlled by lines
of strong (but not infinite) disorder fixed points terminating in the critical
point.Comment: 14 pages (two-column PRB format), 9 eps figure
Dynamics and transport in random quantum systems governed by strong-randomness fixed points
We present results on the low-frequency dynamical and transport properties of
random quantum systems whose low temperature (), low-energy behavior is
controlled by strong disorder fixed points. We obtain the momentum and
frequency dependent dynamic structure factor in the Random Singlet (RS) phases
of both spin-1/2 and spin-1 random antiferromagnetic chains, as well as in the
Random Dimer (RD) and Ising Antiferromagnetic (IAF) phases of spin-1/2 random
antiferromagnetic chains. We show that the RS phases are unusual `spin metals'
with divergent low-frequency spin conductivity at T=0, and we also follow the
conductivity through novel `metal-insulator' transitions tuned by the strength
of dimerization or Ising anisotropy in the spin-1/2 case, and by the strength
of disorder in the spin-1 case. We work out the average spin and energy
autocorrelations in the one-dimensional random transverse field Ising model in
the vicinity of its quantum critical point. All of the above calculations are
valid in the frequency dominated regime \omega \agt T, and rely on previously
available renormalization group schemes that describe these systems in terms of
the properties of certain strong-disorder fixed point theories. In addition, we
obtain some information about the behavior of the dynamic structure factor and
dynamical conductivity in the opposite `hydrodynamic' regime for
the special case of spin-1/2 chains close to the planar limit (the quantum x-y
model) by analyzing the corresponding quantities in an equivalent model of
spinless fermions with weak repulsive interactions and particle-hole symmetric
disorder.Comment: Long version (with many additional results) of Phys. Rev. Lett. {\bf
84}, 3434 (2000) (available as cond-mat/9904290); two-column format, 33 pages
and 8 figure
Infliximab Does Not Promote the Presence of Collagenolytic Bacteria in a Mouse Model of Colorectal Anastomosis
BACKGROUND: Previous work from our group has suggested a pivotal role for collagenolytic bacteria in the development of anastomotic complications. Tumor necrosis factor antagonists are a mainstay of treatment for patients with inflammatory bowel disease. The reported impact of these agents on key surgical outcomes such as anastomotic leak has been inconsistent. The objective of this study is to assess the impact of infliximab on the anastomotic microbiome in a mouse model of colon resection. DESIGN: BALB/c mice underwent colon resection with primary anastomosis. Mice were randomly assigned to receive either an intraperitoneal dose of saline (control) or 10 mg/kg of infliximab for 8 weeks prior to surgery. On postoperative day 7, the animals were sacrificed. Anastomotic tissues were analyzed by histology with TUNNEL staining as a marker of epithelial apoptosis. In order to assess compositional and functional changes of the local microbiome, anastomotic tissues were further analyzed by 16S rRNA V4 region sequencing and for the presence of collagenolytic strains that may impair anastomotic healing. The main outcome measures were microbiome community structure and the presence of collagenolytic bacteria. RESULTS: Infliximab-treated mice demonstrated an increase in epithelial apoptosis, consistent with the expected drug effect. Although infliximab modified the perianastomotic microbiome, no increase in the presence of collagenolytic bacteria was observed. CONCLUSIONS: Infliximab did not promote the emergence of collagenolytic bacteria or demonstrably impair anastomotic healing in a mouse model of colon resection and anastomosis
Variable and Transient Radio Sources in the FIRST Survey
A comprehensive search for variable and transient radio sources has been
conducted using ~55,000 snapshot images of the FIRST survey. We present an
analysis leading to the discovery of 1,627 variable and transient objects down
to mJy levels over a wide range of timescales (few minutes to years).
Variations observed range from 20% to a factor of 25. Multi-wavelength matching
for counterparts reveals the diverse classes of objects exhibiting variability,
ranging from nearby stars and pulsars to galaxies and distant quasars.
Interestingly, more than half of the objects in the sample have either no
classified counterparts or no corresponding sources at any other wavelength and
require multi-wavelength follow-up observations. We discuss these classes of
variables and speculate on the identity of objects that lack multi-wavelength
counterparts.Comment: 63 pages, 18 encapsulated postscript figures (19 if individual
subfigures are counted), 3 tables. LaTeX style file fltpage.sty used.
Submitted, accepted and "in press" for publication in the Astrophysical
Journal. Full electronic version of table 1 (tab1.txt) has been uploaded and
can be obtained after extracting the zipped source fil
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