مجال
التميز
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تميز دراسي وبحثي + جائزة تفوقية
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البحوث المنشورة
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البحث (1):
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عنوان البحث:
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Information
Transfer via Gonadotropin-Releasing Hormone Receptors to ERK and NFAT:
Sensing GnRH and Sensing Dynamics
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رابط إلى البحث:
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Click here
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تاريخ النشر:
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27 February
2017
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موجز عن البحث:
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Information
theoretic approaches can be used to quantify information transfer via cell
signaling networks. In this study, we do so for gonadotropin-releasing
hormone (GnRH) activation of extracellular signal-regulated kinase (ERK) and
nuclear factor of activated T cells (NFAT) in large numbers of individual
fixed LβT2 and HeLa cells. Information transfer, measured by mutual
information between GnRH and ERK or NFAT, was <1 bit (despite 3-bit system
inputs). It was increased by sensing both ERK and NFAT, but the increase was
<50%. In live cells, information transfer via GnRH receptors to NFAT was
also <1 bit and was increased by consideration of response trajectory, but
the increase was <10%. GnRH secretion is pulsatile, so we explored
information gained by sensing a second pulse, developing a model of GnRH
signaling to NFAT with variability introduced by allowing effectors to
fluctuate. Simulations revealed that when cell–cell variability reflects
rapidly fluctuating effector levels, additional information is gained by
sensing two GnRH pulses, but where it is due to slowly fluctuating effectors,
responses in one pulse are predictive of those in another, so little
information is gained from sensing both. Wet laboratory experiments revealed
that the latter scenario holds true for GnRH signaling; within the timescale
of our experiments (1 to 2 hours), cell–cell variability in the NFAT pathway
remains relatively constant, so trajectories are reproducible from pulse to
pulse. Accordingly, joint sensing, sensing of response trajectories, and
sensing of repeated pulses can all increase information transfer via GnRH
receptors, but in each case the increase is small.
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البحث (2):
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عنوان البحث:
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Gonadotropin-releasing hormone signaling: An
information theoretic approach
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رابط إلى البحث:
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Click
here
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تاريخ النشر:
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29 July
2017
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موجز عن البحث:
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Gonadotropin-releasing
hormone (GnRH) is a peptide hormone that mediates central control of
reproduction, acting via G-protein coupled receptors that are primarily Gq
coupled and mediate GnRH effects on the synthesis and secretion of
luteinizing hormone and follicle-stimulating hormone. A great deal is known
about the GnRH receptor signaling network but GnRH is secreted in short
pulses and much less is known about how gonadotropes decode this pulsatile
signal. Similarly, single cell measures reveal considerable cell-cell
heterogeneity in responses to GnRH but the impact of this variability on
signaling is largely unknown. Ordinary differential equation-based
mathematical models have been used to explore the decoding of pulse dynamics
and information theory-derived statistical measures are increasingly used to
address the influence of cell-cell variability on the amount of information
transferred by signaling pathways. Here, we describe both approaches for GnRH
signaling, with emphasis on novel insights gained from the information
theoretic approach and on the fundamental question of why GnRH is secreted in
pulses.
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البحث (3):
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عنوان البحث:
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Exploring Dynamics and Noise in
Gonadotropin-Releasing Hormone (GnRH) Signaling
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رابط إلى البحث:
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Click
here
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تاريخ النشر:
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13 November
2018
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موجز عن البحث:
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Gonadotropin-releasing
hormone (GnRH) acts via G-protein coupled receptors on pituitary
gonadotropes. These are Gq-coupled receptors that mediate acute effects of
GnRH on the exocytotic secretion of luteinizing hormone (LH) and
follicle-stimulating hormone (FSH), as well as the chronic regulation of
their synthesis. FSH and LH control steroidogenesis and gametogenesis in the
gonads so GnRH mediates control of reproduction by the central nervous
system. GnRH is secreted in short pulses and the effects of GnRH on its
target cells are dependent on the dynamics of these pulses. Here we provide a
brief overview of the signaling network activated by GnRH with emphasis on
the use of high content imaging for their examination. We also describe
computational approaches that we have used to simulate GnRH signaling in
order to explore dynamics, noise, and information transfer in this system.
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البحث (4):
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عنوان البحث:
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Role of the posterodorsal medial amygdala in
predator odour stress‐induced puberty delay in female rats
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رابط إلى البحث:
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Click here
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تاريخ النشر:
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09 April
2019
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موجز عن البحث:
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Puberty
onset is influenced by various factors, including psychosocial stress. The
present study investigated cat‐odour stress on puberty onset and oestrous
cyclicity in rats. Female weanling rats were exposed to either soiled cat
litter or fresh unused litter for 10 consecutive days. Following vaginal
opening (VO), rats were smeared for 14 days to determine oestrous cyclicity.
Anxiety‐like behaviour was assessed using standard
anxiety tests. Brains were collected to determine corticotrophin‐releasing
factor (CRF), CRF receptor 1 (CRF‐R1) and CRF receptor 2 (CRF‐R2)
mRNA in the paraventricular nucleus (PVN), as well as the central nucleus of
the amygdala (CEA) and the medial nucleus of the amygdala (MEA). Cat odour
delayed VO and first oestrus, disrupted oestrous cycles and caused anxiogenic
responses. Cat odour elicited increased CRF mRNA expression in the PVN but
not in the CeA. CRF‐R1 and CRF‐R2 mRNA
levels in the PVN and CeA were unaffected by cat odour; however, CRF‐R1
mRNA levels were decreased in the MeA. The role of CRF signalling in the MeA,
particularly its posterodorsal subnucleus (MePD), with respect to pubertal
timing was directly examined by unilateral intra‐MePD
administration of CRF (0.2 nmol day‐1 for 14 days) via an osmotic
mini‐pump from postnatal day 24 and was shown to
delay VO and first oestrus. These data suggest that CRF signalling in the
MePD may be associated with predator odour‐induced
puberty delay.
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المؤتمرات العلمية:
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المؤتمر (1):
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عنوان المؤتمر:
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The
annual meeting of the British Society for Neuroendocrinology
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تاريخ الإنعقاد:
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10 – 12
September 2017
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مكان
الإنعقاد:
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Nottingham, UK
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طبيعة المشاركة:
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Oral presentation
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عنوان المشاركة:
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Measuring
information transfer via gonadotrophin-releasing hormone receptors
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ملخص المشاركة:
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Gonadotropin-releasing
hormone (GnRH) acts via G-protein coupled receptors on pituitary gonadotrophs,
causing a (largely) PKC-mediated activation of ERK, and a Ca2+-mediated
activation of Nuclear Factor of Activated T-cells (NFAT), both of which
mediate GnRH effects on gonadotropin expression. We monitor their activation
by high content imaging (fluorescence staining for ppERK and nuclear
translocation of an NFAT1c-EFP reporter) in LbT2 gonadotroph cells. We also
express Egr1-zsGREEN and/or NFAT-RE-asRED reporters as transcriptional
readouts for ERK and NFAT activation, respectively. Single cell measures reveal
high cell-to-cell variability, and information theoretical approaches can be
used to explore its influence on information transfer. Here we use Mutual
Information (MI) between GnRH and our single cell experimental readouts
(I(response; GnRH)) as measures of information transfer via GnRH receptors.
An MI of 1Bit means that the system can unambiguously distinguish two
(identically distributed) inputs and we routinely provide a 3Bit input (i.e.,
8=23 GnRH concentrations). However, the MI between GnRH and these readouts
was always <1Bit. Joint sensing of ERK and NFAT increased MI but the
effect was small and joint MI values were also <1. Information transfer
could be increased by sensing response trajectory and when we tracked
NFAT1c-EFP in individual cells I(NFAT-nuclear fraction; GnRH) values were
maximal (~0.45Bit) at ~30min and slightly higher values (~0.65Bit) were
obtained by consideration of trajectories. Thus, LbT2 cells appear to be
unreliable sensors of GnRH concentration because most available information
is lost through signalling and, although information transfer was increased
by joint sensing and trajectory sensing, the increases seen were small.
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المؤتمر (2):
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عنوان المؤتمر:
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Europhysiology 2018
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تاريخ الإنعقاد:
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14 – 16
September 2018
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مكان
الإنعقاد:
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London, UK
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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Quantification
of information transfer via gonadotrophin-releasing hormone receptors (GnRHR)
reveals a marked loss of information through signalling
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ملخص المشاركة:
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Gonadotropin-releasing
hormone (GnRH) is a hypothalamic neuropeptide that acts via GnRHR on the
pituitary gonadotrope. It is secreted in pulses and acts via GnRHR to
activate ERK and Nuclear Factor of Activated T-cells (NFAT). Both of which
mediate GnRH effects on the synthesis of reproductive hormones. Using
automated fluorescence microscopy, effects of GnRH on cell signalling in
individual cells can be quantified revealing marked cell-cell heterogeneity.
Information theoretic approaches, which consider cell-cell heterogeneity and
its impact on information transfer, can be used to quantify information
transfer via cell signalling pathways. Here we use the mutual information
(MI) between GnRH concentration and measured responses (I(response; GnRH)) as
a measure of information transfer via GnRHR. MI is measured in Bits, with an
MI of 1 Bit indicating a system that can unambiguously distinguish between
two inputs. Initially, we did this in fixed LbT2 cells (gonadotrope-derived
cells). The cells were stimulated with various concentrations of GnRH
(0-10-6M) before staining for ppERK (immunohistochemistry), and in some
experiments, cells were infected with recombinant adenovirus for expression
of NFAT- EFP. As Ca2+ causes NFAT to translocate to the nucleus, the nuclear
fraction (NF) provides a readout for elevation of the cytoplasmic Ca2+
concentration ([Ca2+]i) by GnRH. Our data, therefore, suggest that most
information from the environment is lost through signalling. The I(ppERK;
GnRH) and I(NFAT-NF; GnRH) values were always <1Bit despite 3Bit input.
Joint sensing of ppERK and NFAT-NF increased slightly MI values [1,2],
suggesting that, by ignoring response dynamics, information transfer is
underestimated. Therefore, using live cell measurements and MI calculations
taking response trajectory into account, NFAT-EFP translocation was tracked
in response to a single pulse of GnRH. The I(NFAT-NF; GnRH) values were ~0.5
Bit at 30 min and remained elevated for 60 min. Taking response trajectories
into account increased MI values to ~0.65 Bit. We also tracked NFAT-EFP
translocation responses in cells receiving two pulses of GnRH and found that
the information gain from the second pulse was small. Similar experiments
were performed using Fluo-4 measurements of [Ca2+]i. The I(Ca2+; GnRH) values
were ~0.8 Bit, 24sec after stimulation, reducing to ~0.66 Bit after 2 min.
These values were increased to 1Bit by consideration of trajectories. Thus,
LbT2 cells are unreliable sensors of GnRH concentration because a
considerable amount of information is lost through signalling. Although joint
sensing, trajectory sensing and sensing repeated pulses increased information
transfer, this was typically <20% suggesting that most information is lost
early in the GnRH signalling cascade, prior to Ca2+ mobilization.
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المؤتمر (3):
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عنوان المؤتمر:
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Society for Endocrinology BES 2018
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تاريخ الإنعقاد:
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19 – 21
November 2018
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مكان
الإنعقاد:
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Scotland, UK
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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Measuring
information transfer via gonadotrophin-releasing hormone receptors (GnRHR)
shows a remarkable loss of information through signalling
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ملخص المشاركة:
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Gonadotropin-releasing
hormone (GnRH) is a hypothalamic neuropeptide that acts via GnRHR on the
pituitary gonadotrope. It is secreted in pulses and acts via GnRHR to
activate ERK and Nuclear Factor of Activated T-cells (NFAT), mediating GnRH
effects on gonadotropin expression. We monitor their activation by high
content imaging (fluorescence staining for ppERK and nuclear translocation of
an NFAT1c-EFP reporter) in fixed LbT2
gonadotroph cells. Single cell measures reveal high cell-cell heterogeneity,
and information theoretical approaches can be used to explore its influence
on information transfer. Here we use Mutual information (MI) between GnRH
concentration and measured responses (I(response; GnRH)) to measure (in Bits)
information transfer via GnRHR. One bit of information can resolve two
different signal values. However, the MI values were always <1Bit despite
3Bit input. Joint sensing of ERK and NFAT increased MI values, but the increase
was modest, suggesting that, by ignoring response dynamics, information
transfer is underestimated. Therefore, using live cell measurements and MI
calculations taking response trajectory into account, NFAT-EFP translocation
was tracked in response to a single pulse of GnRH. The I(NFAT-NF; GnRH) was
0.4Bit at 30min and increased to 0.54 Bit by consideration of trajectories.
We also tracked NFAT-EFP translocation responses in cells receiving two
pulses of GnRH and found that the information gained from the second pulse
was little. Similar experiments were performed using Fluo-4 measurements of
[Ca2+]i. The I(Ca2+; GnRH) was 0.8Bit,
24sec after stimulation, and increased to 1Bit by sensing trajectories. Thus,
LbT2 cells are
unreliable sensors of GnRH concentration because a considerable amount of
information is lost through signalling. Although joint sensing, trajectory
sensing and sensing repeated pulses increased information transfer, this was
typically <20% suggesting that most information is lost early in the GnRH
signalling cascade, prior to Ca2+ mobilisation.
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جوائز التكريم:
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الجائزة (1):
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مسمى الجائزة:
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Best
Poster Prize Presentation
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الجهة المانحة:
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University of Bristol
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تاريخ الجائزة:
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11 April
2018
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مجال التكريم:
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Best poster presentation at the Showcase
and Network Day hosted by the Bristol Neuroscience Research Network at the
University of Bristol.
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