4,511 research outputs found
Intestinal stem cells lacking the Math1 tumour suppressor are refractory to Notch inhibitors
Intestinal cells are constantly produced from a stem cell reservoir that gives rise to proliferating transient amplifying cells, which subsequently differentiate into one of the four principal cell types. Signalling pathways, including the Notch signalling pathway, coordinate these differentiation processes and their deregulation may cause cancer. Pharmacological inhibition through Îł-secretase inhibitors or genetic inactivation of the Notch signalling pathway results in the complete loss of proliferating crypt progenitors due to their conversion into post-mitotic goblet cells. The basic helixâloopâhelix transcription factor Math1 is essential for intestinal secretory cell differentiation. Because of the critical roles of both Math1 and Notch signalling in intestinal homeostasis and neoplastic transformation, we sought to determine the genetic hierarchy regulating the differentiation of intestinal stem cells into secretory cells. In this paper, we demonstrate that the conversion of intestinal stem cells into goblet cells upon inhibition of the Notch signalling pathway requires Math1
UK experience of liver transplantation for erythropoietic protoporphyria
Erythropoietic protoporphyria (EPP) is characterised by excess production of free protoporphyrin from the bone marrow, most commonly due to deficiency of the enzyme ferrochelatase. Excess protoporphyrin gives rise to the cutaneous photosensitivity characteristic of the disease, and in a minority of patients leads to end-stage liver disease necessitating liver transplantation (LT). There is limited information regarding the timing, impact and long-term outcome of LT in such patients, thus we aimed to identify the indications and outcomes of all transplants performed for EPP in the UK using data from the UK Transplant Registry. Between 1987 and 2009, five patients underwent LT for EPP liver disease. Median follow-up was 60 months, and there were two deaths at 44 and 95 months from causes unrelated to liver disease. The remaining recipients are alive at 22.4 years, 61 months and 55 months after transplant. A high rate of postoperative biliary stricturing requiring multiple biliary interventions was observed. Recurrent EPP-liver disease occurred in 4/5 (80%) of patients but graft failure has not been observed. Given the role of biliary obstruction in inducing EPP-mediated liver damage, we suggest that consideration should be given for construction of a Roux loop at the time of transplant. Thus we demonstrate that although EPP liver transplant recipients have a good long-term survival, comparable to patients undergoing LT for other indications, biliary complications and disease recurrence are almost universal, and bone marrow transplantation should be considered where possible
Delta1 Expression, Cell Cycle Exit, and Commitment to a Specific Secretory Fate Coincide within a Few Hours in the Mouse Intestinal Stem Cell System
The stem cells of the small intestine are multipotent: they give rise, via transit-amplifying cell divisions, to large numbers of columnar absorptive cells mixed with much smaller numbers of three different classes of secretory cells - mucus-secreting goblet cells, hormone-secreting enteroendocrine cells, and bactericide-secreting Paneth cells. Notch signaling is known to control commitment to a secretory fate, but why are the secretory cells such a small fraction of the population, and how does the diversity of secretory cell types arise? Using the mouse as our model organism, we find that secretory cells, and only secretory cells, pass through a phase of strong expression of the Notch ligand Delta1 (Dll1). Onset of this Dll1 expression coincides with a block to further cell division and is followed in much less than a cell cycle time by expression of Neurog3 â a marker of enteroendocrine fate â or Gfi1 â a marker of goblet or Paneth cell fate. By conditional knock-out of Dll1, we confirm that Delta-Notch signaling controls secretory commitment through lateral inhibition. We infer that cells stop dividing as they become committed to a secretory fate, while their neighbors continue dividing, explaining the final excess of absorptive over secretory cells. Our data rule out schemes in which cells first become committed to be secretory, and then diversify through subsequent cell divisions. A simple mathematical model shows how, instead, Notch signaling may simultaneously govern the commitment to be secretory and the choice between alternative modes of secretory differentiation
Star Clusters
This review concentrates almost entirely on globular star clusters. It
emphasises the increasing realisation that few of the traditional problems of
star cluster astronomy can be studied in isolation: the influence of the Galaxy
affects dynamical evolution deep in the core, and the spectrum of stellar
masses; in turn the evolution of the core determines the highest stellar
densities, and the rate of encounters. In this way external tidal effects
indirectly influence the formation and evolution of blue stragglers, binary
pulsars, X-ray sources, etc. More controversially, the stellar density appears
to influence the relative distribution of normal stars. In the opposite sense,
the evolution of individual stars governs much of the early dynamics of a
globular cluster, and the existence of large numbers of primordial binary stars
has changed important details of our picture of the dynamical evolution. New
computational tools which will become available in the next few years will help
dynamical theorists to address these questions.Comment: 10 pages, 3 figures, Te
Binary and Millisecond Pulsars at the New Millennium
We review the properties and applications of binary and millisecond pulsars.
Our knowledge of these exciting objects has greatly increased in recent years,
mainly due to successful surveys which have brought the known pulsar population
to over 1300. There are now 56 binary and millisecond pulsars in the Galactic
disk and a further 47 in globular clusters. This review is concerned primarily
with the results and spin-offs from these surveys which are of particular
interest to the relativity community.Comment: 59 pages, 26 figures, 5 tables. Accepted for publication in Living
Reviews in Relativity (http://www.livingreviews.org
Liver-Targeting of Interferon-Alpha with Tissue-Specific Domain Antibodies
PMCID: PMC3581439This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Static stretching of the hamstring muscle for injury prevention in football codes: a systematic review
Purpose: Hamstring injuries are common among football players. There is still disagreement regarding prevention. The aim of this review is to determine whether static stretching reduces hamstring injuries in football codes.
Methods: A systematic literature search was conducted on the online databases PubMed, PEDro, Cochrane, Web of Science, Bisp and Clinical Trial register. Study results were presented descriptively and the quality of the studies assessed were based on Cochraneâs ârisk of biasâ tool.
Results: The review identified 35 studies, including four analysis studies. These studies show deficiencies in the quality of study designs.
Conclusion: The study protocols are varied in terms of the length of intervention and follow-up. No RCT studies are available, however, RCT studies should be conducted in the near future
Analysis of the potential of cancer cell lines to release tissue factor-containing microvesicles: correlation with tissue factor and PAR2 expression
BackgroundDespite the association of cancer-derived circulating tissue factor (TF)-containing microvesicles and hypercoagulable state, correlations with the incidence of thrombosis remain unclear.MethodsIn this study the upregulation of TF release upon activation of various cancer cell lines, and the correlation with TF and PAR2 expression and/or activity was examined. Microvesicle release was induced by PAR2 activation in seventeen cell lines and released microvesicle density, microvesicle-associated TF activity, and phoshpatidylserine-mediated activity were measured. The time-course for TF release was monitored over 90 min in each cell line. In addition, TF mRNA expression, cellular TF protein and cell-surface TF activities were quantified. Moreover, the relative expression of PAR2 mRNA and cellular protein were analysed. Any correlations between the above parameters were examined by determining the Pearsonâs correlation coefficients.ResultsTF release as microvesicles peaked between 30â60 min post-activation in the majority of cell lines tested. The magnitude of the maximal TF release positively correlated with TF mRNA (câ=â0.717; p
An increased estimate of the merger rate of double neutron stars from observations of a highly relativistic system
The merger of close binary systems containing two neutron stars should
produce a burst of gravitational waves, as predicted by the theory of general
relativity. A reliable estimate of the double-neutron-star merger rate in the
Galaxy is crucial in order to predict whether current gravity wave detectors
will be successful in detecting such bursts. Present estimates of this rate are
rather low, because we know of only a few double-neutron-star binaries with
merger times less than the age of the Universe. Here we report the discovery of
a 22-ms pulsar, PSR J0737-3039, which is a member of a highly relativistic
double-neutron-star binary with an orbital period of 2.4 hours. This system
will merge in about 85 Myr, a time much shorter than for any other known
neutron-star binary. Together with the relatively low radio luminosity of PSR
J0737-3039, this timescale implies an order-of-magnitude increase in the
predicted merger rate for double-neutron-star systems in our Galaxy (and in the
rest of the Universe).Comment: 6 pages, 2 figure
Governance of Sexual Functioning by General vs. Special Psychological Mechanisms Remains an Empirical Issue
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