956 research outputs found
miR-132/212 knockout mice reveal roles for these miRNAs in regulating cortical synaptic transmission and plasticity
miR-132 and miR-212 are two closely related miRNAs encoded in the same intron of a small non-coding gene, which have been suggested to play roles in both immune and neuronal function. We describe here the generation and initial characterisation of a miR-132/212 double knockout mouse. These mice were viable and fertile with no overt adverse phenotype. Analysis of innate immune responses, including TLR-induced cytokine production and IFNβ induction in response to viral infection of primary fibroblasts did not reveal any phenotype in the knockouts. In contrast, the loss of miR-132 and miR-212, while not overtly affecting neuronal morphology, did affect synaptic function. In both hippocampal and neocortical slices miR-132/212 knockout reduced basal synaptic transmission, without affecting paired-pulse facilitation. Hippocampal long-term potentiation (LTP) induced by tetanic stimulation was not affected by miR-132/212 deletion, whilst theta burst LTP was enhanced. In contrast, neocortical theta burst-induced LTP was inhibited by loss of miR-132/212. Together these results indicate that miR-132 and/or miR-212 play a significant role in synaptic function, possibly by regulating the number of postsynaptic AMPA receptors under basal conditions and during activity-dependent synaptic plasticity
I-CARE, a European Prospective Cohort Study Assessing Safety and Effectiveness of Biologics in Inflammatory Bowel Disease
Background and aims: There is a need to evaluate the benefit-risk ratio of current therapies in inflammatory bowel disease (IBD) patients to provide the best quality of care. The primary objective of I-CARE (IBD Cancer and serious infections in Europe) was to assess prospectively safety concerns in IBD, with specific focus on the risk of cancer/lymphoma and serious infections in patients treated with anti-tumor necrosis factor and other biologic monotherapy as well as in combination with immunomodulators.. Methods: I-CARE was designed as a European prospective longitudinal observational multicenter cohort study to include patients with a diagnosis of Crohn's disease, ulcerative colitis, or IBD unclassified established at least 3 months prior to enrollment. Results: A total of 10,206 patients were enrolled between March 2016 and April 2019, including 6169 (60.4%) patients with Crohn's disease, 3853 (37.8%) with ulcerative colitis, and 184 (1.8%) with a diagnosis of IBD unclassified. Thirty-two percent of patients were receiving azathioprine/thiopurines, 4.6% 6-mercaptopurine, and 3.2% methotrexate at study entry. At inclusion, 47.3% of patients were treated with an anti-tumor necrosis factor agent, 8.8% with vedolizumab, and 3.4% with ustekinumab. Roughly one-quarter of patients (26.8%) underwent prior IBD-related surgery. Sixty-six percent of patients had been previously treated with systemic steroids. Three percent of patients had a medical history of cancer prior to inclusion and 1.1% had a history of colonic, esophageal, or uterine cervix high-grade dysplasia.. Conclusions: I-CARE is an ongoing investigator-initiated observational European prospective cohort study that will provide unique information on the long-term benefits and risks of biological therapies in IBD patients
Proteomes and Signalling Pathways of Antler Stem Cells
As the only known example of complete organ regeneration in mammals, deer antler in the growing or velvet phase is of major interest in developmental biology. This regeneration event initiates from self-renewing antler stem cells that exhibit pluripotency. At present, it remains unclear how the activation and quiescence of antler stem cells are regulated. Therefore, in the present study proteins that were differentially expressed between the antler stem cells and somatic cells (facial periosteum) were identified by a gel-based proteomic technique, and analysed using Ingenuity Pathway Analysis software. Several molecular pathways (PI3K/Akt, ERK/MAPK, p38 MAPK, etc.) were found to be activated during proliferation. Also expressed were the transcription factors POU5F1, SOX2, NANOG and MYC, which are key markers of embryonic stem cells. Expression of these proteins was confirmed in both cultured cells and fresh tissues by Western blot analysis. Therefore, the molecular pathways and transcription factors identified in the current study are common to embryonic and adult stem cells. However, expression of embryonic stem cell transcription factors would suggest that antler stem cells are, potentially, an intermediary stem cell type between embryonic and the more specialized tissue-specific stem cells like those residing in muscle, fat or from a hematopoietic origin. The retention of this embryonic, pluripotent lineage may be of fundamental importance for the subsequent regenerative capacity of antlers
A phase II study of cell cycle inhibitor UCN-01 in patients with metastatic melanoma: a California Cancer Consortium trial
Background Genetic abnormalities in cell cycle control are common in malignant melanoma. UCN-01 (7-hydroxystaurosporine) is an investigational agent that exhibits antitumor activity by perturbing the cancer cell cycle. A patient with advanced melanoma experienced a partial response in a phase I trial of single agent UCN-01. We sought to determine the activity of UCN-01 against refractory metastatic melanoma in a phase II study. Patients and methods Patients with advanced melanoma received UCN-01 at 90 mg/m2 over 3 h on cycle 1, reduced to 45 mg/m2 over 3 h for subsequent cycles, every 21 days. Primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A two-stage (17â+â16), single arm phase II design was employed. A true response rate of âĽ20% (i.e., at least one responder in the first stage, or at least four responders overall) was to be considered promising for further development of UCN-01 in this setting. Results Seventeen patients were accrued in the first stage. One patient was inevaluable for response. Four (24%) patients had stable disease, and 12 (71%) had disease progression. As there were no responders in the first stage, the study was closed to further accrual. Median PFS was 1.3 months (95% CI, 1.2â3.0) while median OS was 7.3 months (95% CI, 3.4â18.4). One-year and two year OS rates were 41% and 12%, respectively. A median of two cycles were delivered (range, 1â18). Grade 3 treatment-related toxicities include hyperglycemia (Nâ=â2), fatigue (Nâ=â1), and diarrhea (Nâ=â1). One patient experienced grade 4 creatinine elevation and grade 4 anemia possibly due to UCN-01. No dose modification was required as these patients had disease progression. Conclusion Although well tolerated, UCN-01 as a single agent did not have sufficient clinical activity to warrant further study in refractory melanoma
Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS.
Many mutations confer one or more toxic function(s) on copper/zinc superoxide dismutase 1 (SOD1) that impair motor neuron viability and cause familial amyotrophic lateral sclerosis (FALS). Using a conformation-specific antibody that detects misfolded SOD1 (C4F6), we found that oxidized wild-type SOD1 and mutant SOD1 share a conformational epitope that is not present in normal wild-type SOD1. In a subset of human sporadic ALS (SALS) cases, motor neurons in the lumbosacral spinal cord were markedly C4F6 immunoreactive, indicating that an aberrant wild-type SOD1 species was present. Recombinant, oxidized wild-type SOD1 and wild-type SOD1 immunopurified from SALS tissues inhibited kinesin-based fast axonal transport in a manner similar to that of FALS-linked mutant SOD1. Our findings suggest that wild-type SOD1 can be pathogenic in SALS and identify an SOD1-dependent pathogenic mechanism common to FALS and SALS
Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV
The performance of muon reconstruction, identification, and triggering in CMS
has been studied using 40 inverse picobarns of data collected in pp collisions
at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection
criteria covering a wide range of physics analysis needs have been examined.
For all considered selections, the efficiency to reconstruct and identify a
muon with a transverse momentum pT larger than a few GeV is above 95% over the
whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4,
while the probability to misidentify a hadron as a muon is well below 1%. The
efficiency to trigger on single muons with pT above a few GeV is higher than
90% over the full eta range, and typically substantially better. The overall
momentum scale is measured to a precision of 0.2% with muons from Z decays. The
transverse momentum resolution varies from 1% to 6% depending on pseudorapidity
for muons with pT below 100 GeV and, using cosmic rays, it is shown to be
better than 10% in the central region up to pT = 1 TeV. Observed distributions
of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO
Effective Rheology of Bubbles Moving in a Capillary Tube
We calculate the average volumetric flux versus pressure drop of bubbles
moving in a single capillary tube with varying diameter, finding a square-root
relation from mapping the flow equations onto that of a driven overdamped
pendulum. The calculation is based on a derivation of the equation of motion of
a bubble train from considering the capillary forces and the entropy production
associated with the viscous flow. We also calculate the configurational
probability of the positions of the bubbles.Comment: 4 pages, 1 figur
Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV
The performance of muon reconstruction, identification, and triggering in CMS
has been studied using 40 inverse picobarns of data collected in pp collisions
at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection
criteria covering a wide range of physics analysis needs have been examined.
For all considered selections, the efficiency to reconstruct and identify a
muon with a transverse momentum pT larger than a few GeV is above 95% over the
whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4,
while the probability to misidentify a hadron as a muon is well below 1%. The
efficiency to trigger on single muons with pT above a few GeV is higher than
90% over the full eta range, and typically substantially better. The overall
momentum scale is measured to a precision of 0.2% with muons from Z decays. The
transverse momentum resolution varies from 1% to 6% depending on pseudorapidity
for muons with pT below 100 GeV and, using cosmic rays, it is shown to be
better than 10% in the central region up to pT = 1 TeV. Observed distributions
of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO
X-ray emission from the Sombrero galaxy: discrete sources
We present a study of discrete X-ray sources in and around the
bulge-dominated, massive Sa galaxy, Sombrero (M104), based on new and archival
Chandra observations with a total exposure of ~200 ks. With a detection limit
of L_X = 1E37 erg/s and a field of view covering a galactocentric radius of ~30
kpc (11.5 arcminute), 383 sources are detected. Cross-correlation with Spitler
et al.'s catalogue of Sombrero globular clusters (GCs) identified from HST/ACS
observations reveals 41 X-rays sources in GCs, presumably low-mass X-ray
binaries (LMXBs). We quantify the differential luminosity functions (LFs) for
both the detected GC and field LMXBs, whose power-low indices (~1.1 for the
GC-LF and ~1.6 for field-LF) are consistent with previous studies for
elliptical galaxies. With precise sky positions of the GCs without a detected
X-ray source, we further quantify, through a fluctuation analysis, the GC LF at
fainter luminosities down to 1E35 erg/s. The derived index rules out a
faint-end slope flatter than 1.1 at a 2 sigma significance, contrary to recent
findings in several elliptical galaxies and the bulge of M31. On the other
hand, the 2-6 keV unresolved emission places a tight constraint on the field
LF, implying a flattened index of ~1.0 below 1E37 erg/s. We also detect 101
sources in the halo of Sombrero. The presence of these sources cannot be
interpreted as galactic LMXBs whose spatial distribution empirically follows
the starlight. Their number is also higher than the expected number of cosmic
AGNs (52+/-11 [1 sigma]) whose surface density is constrained by deep X-ray
surveys. We suggest that either the cosmic X-ray background is unusually high
in the direction of Sombrero, or a distinct population of X-ray sources is
present in the halo of Sombrero.Comment: 11 figures, 5 tables, ApJ in pres
Azimuthal anisotropy of charged particles at high transverse momenta in PbPb collisions at sqrt(s[NN]) = 2.76 TeV
The azimuthal anisotropy of charged particles in PbPb collisions at
nucleon-nucleon center-of-mass energy of 2.76 TeV is measured with the CMS
detector at the LHC over an extended transverse momentum (pt) range up to
approximately 60 GeV. The data cover both the low-pt region associated with
hydrodynamic flow phenomena and the high-pt region where the anisotropies may
reflect the path-length dependence of parton energy loss in the created medium.
The anisotropy parameter (v2) of the particles is extracted by correlating
charged tracks with respect to the event-plane reconstructed by using the
energy deposited in forward-angle calorimeters. For the six bins of collision
centrality studied, spanning the range of 0-60% most-central events, the
observed v2 values are found to first increase with pt, reaching a maximum
around pt = 3 GeV, and then to gradually decrease to almost zero, with the
decline persisting up to at least pt = 40 GeV over the full centrality range
measured.Comment: Replaced with published version. Added journal reference and DO
- âŚ