317 research outputs found
Leptin signalling in pancreatic islets and clonal insulin-secreting cells
Leptin is a cytokine secreted from adipose tissue at a
rate commensurate with the size of the body's fat
stores. In addition to its anorectic and thermogenic
central actions, leptin is known to act on peripheral
tissues, including the pancreatic ß-cell where it
inhibits insulin secretion and reduces insulin
transcript levels. However, the role of leptin
signalling through its full-length receptor, OB-Rb,
in the ß-cell remains unclear. In the present study,
we show that leptin activates a signal transducer and
activator of transcription (STAT)3 signalling mechanism
in pancreatic islets and in a rat model of the
pancreatic ß-cell, RINm5F. Leptin induced DNA
binding to a STAT consensus oligonucleotide and
resulted in transcriptional activation from STAT
reporter constructs in a manner consistent with
STAT3 activation. Western blot analysis confirmed
activation of STAT3 in RINm5F and isolated rat
islets. Conditions that mimic increased metabolic
activity resulted in attenuation of leptin-mediated
STAT DNA binding but had no significant eVect
on STAT3 tyrosine phosphorylation in RINm5F
cells. In addition, leptin activated the mitogen
activated protein (MAP) kinase pathway in
RINm5F cells. The present study provides a
framework for OB-Rb signalling mechanisms in the
programming of the ß-cell by leptin and suggests
that increased metabolic activity may modulate this
function
Statistical Mechanics of 2+1 Gravity From Riemann Zeta Function and Alexander Polynomial:Exact Results
In the recent publication (Journal of Geometry and Physics,33(2000)23-102) we
demonstrated that dynamics of 2+1 gravity can be described in terms of train
tracks. Train tracks were introduced by Thurston in connection with description
of dynamics of surface automorphisms. In this work we provide an example of
utilization of general formalism developed earlier. The complete exact solution
of the model problem describing equilibrium dynamics of train tracks on the
punctured torus is obtained. Being guided by similarities between the dynamics
of 2d liquid crystals and 2+1 gravity the partition function for gravity is
mapped into that for the Farey spin chain. The Farey spin chain partition
function, fortunately, is known exactly and has been thoroughly investigated
recently. Accordingly, the transition between the pseudo-Anosov and the
periodic dynamic regime (in Thurston's terminology) in the case of gravity is
being reinterpreted in terms of phase transitions in the Farey spin chain whose
partition function is just a ratio of two Riemann zeta functions. The mapping
into the spin chain is facilitated by recognition of a special role of the
Alexander polynomial for knots/links in study of dynamics of self
homeomorphisms of surfaces. At the end of paper, using some facts from the
theory of arithmetic hyperbolic 3-manifolds (initiated by Bianchi in 1892), we
develop systematic extension of the obtained results to noncompact Riemannian
surfaces of higher genus. Some of the obtained results are also useful for 3+1
gravity. In particular, using the theorem of Margulis, we provide new reasons
for the black hole existence in the Universe: black holes make our Universe
arithmetic. That is the discrete Lie groups of motion are arithmetic.Comment: 69 pages,11 figures. Journal of Geometry and Physics (in press
Diagnostic value of exome and whole genome sequencing in craniosynostosis
Background Craniosynostosis, the premature fusion of one or more cranial sutures, occurs in ~1 in 2250 births, either in isolation or as part of a syndrome. Mutations in at least 57 genes have been associated with craniosynostosis, but only a minority of these are included in routine laboratory genetic testing. Methods We used exome or whole genome sequencing to seek a genetic cause in a cohort of 40 subjects with craniosynostosis, selected by clinical or molecular geneticists as being high-priority cases, and in whom prior clinically driven genetic testing had been negative. Results We identified likely associated mutations in 15 patients (37.5%), involving 14 different genes. All genes were mutated in single families, except for IL11RA (two families). We classified the other positive diagnoses as follows: commonly mutated craniosynostosis genes with atypical presentation (EFNB1, TWIST1); other core craniosynostosis genes (CDC45, MSX2, ZIC1); genes for which mutations are only rarely associated with craniosynostosis (FBN1, HUWE1, KRAS, STAT3); and known disease genes for which a causal relationship with craniosynostosis is currently unknown (AHDC1, NTRK2). In two further families, likely novel disease genes are currently undergoing functional validation. In 5 of the 15 positive cases, the (previously unanticipated) molecular diagnosis had immediate, actionable consequences for either genetic or medical management (mutations in EFNB1, FBN1, KRAS, NTRK2, STAT3). Conclusions This substantial genetic heterogeneity, and the multiple actionable mutations identified, emphasises the benefits of exome/whole genome sequencing to identify causal mutations in craniosynostosis cases for which routine clinical testing has yielded negative results
An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics
For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types
Search for charginos in e+e- interactions at sqrt(s) = 189 GeV
An update of the searches for charginos and gravitinos is presented, based on
a data sample corresponding to the 158 pb^{-1} recorded by the DELPHI detector
in 1998, at a centre-of-mass energy of 189 GeV. No evidence for a signal was
found. The lower mass limits are 4-5 GeV/c^2 higher than those obtained at a
centre-of-mass energy of 183 GeV. The (\mu,M_2) MSSM domain excluded by
combining the chargino searches with neutralino searches at the Z resonance
implies a limit on the mass of the lightest neutralino which, for a heavy
sneutrino, is constrained to be above 31.0 GeV/c^2 for tan(beta) \geq 1.Comment: 22 pages, 8 figure
Hadronization properties of b quarks compared to light quarks in e+e- -> q qbar from 183 to 200 GeV
The DELPHI detector at LEP has collected 54 pb^{-1} of data at a
centre-of-mass energy around 183 GeV during 1997, 158 pb^{-1} around 189 GeV
during 1998, and 187 pb^{-1} between 192 and 200 GeV during 1999. These data
were used to measure the average charged particle multiplicity in e+e- -> b
bbar events, _{bb}, and the difference delta_{bl} between _{bb} and the
multiplicity, _{ll}, in generic light quark (u,d,s) events: delta_{bl}(183
GeV) = 4.55 +/- 1.31 (stat) +/- 0.73 (syst) delta_{bl}(189 GeV) = 4.43 +/- 0.85
(stat) +/- 0.61 (syst) delta_{bl}(200 GeV) = 3.39 +/- 0.89 (stat) +/- 1.01
(syst). This result is consistent with QCD predictions, while it is
inconsistent with calculations assuming that the multiplicity accompanying the
decay of a heavy quark is independent of the mass of the quark itself.Comment: 13 pages, 2 figure
Looking forward through the past: identification of 50 priority research questions in palaeoecology
1. Priority question exercises are becoming an increasingly common tool to frame future agendas in conservation and ecological science. They are an effective way to identify research foci that advance the field and that also have high policy and conservation relevance. 2. To date, there has been no coherent synthesis of key questions and priority research areas for palaeoecology, which combines biological, geochemical and molecular techniques in order to reconstruct past ecological and environmental systems on time-scales from decades to millions of years. 3. We adapted a well-established methodology to identify 50 priority research questions in palaeoecology. Using a set of criteria designed to identify realistic and achievable research goals, we selected questions from a pool submitted by the international palaeoecology research community and relevant policy practitioners. 4. The integration of online participation, both before and during the workshop, increased international engagement in question selection. 5. The questions selected are structured around six themes: human–environment interactions in the Anthropocene; biodiversity, conservation and novel ecosystems; biodiversity over long time-scales; ecosystem processes and biogeochemical cycling; comparing, combining and synthesizing information from multiple records; and new developments in palaeoecology. 6. Future opportunities in palaeoecology are related to improved incorporation of uncertainty into reconstructions, an enhanced understanding of ecological and evolutionary dynamics and processes and the continued application of long-term data for better-informed landscape management
The parent?infant dyad and the construction of the subjective self
Developmental psychology and psychopathology has in the past been more concerned with the quality of self-representation than with the development of the subjective agency which underpins our experience of feeling, thought and action, a key function of mentalisation. This review begins by contrasting a Cartesian view of pre-wired introspective subjectivity with a constructionist model based on the assumption of an innate contingency detector which orients the infant towards aspects of the social world that react congruently and in a specifically cued informative manner that expresses and facilitates the assimilation of cultural knowledge. Research on the neural mechanisms associated with mentalisation and social influences on its development are reviewed. It is suggested that the infant focuses on the attachment figure as a source of reliable information about the world. The construction of the sense of a subjective self is then an aspect of acquiring knowledge about the world through the caregiver's pedagogical communicative displays which in this context focuses on the child's thoughts and feelings. We argue that a number of possible mechanisms, including complementary activation of attachment and mentalisation, the disruptive effect of maltreatment on parent-child communication, the biobehavioural overlap of cues for learning and cues for attachment, may have a role in ensuring that the quality of relationship with the caregiver influences the development of the child's experience of thoughts and feelings
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