75 research outputs found
One-dimensional Rydberg Gas in a Magnetoelectric Trap
We study the quantum properties of Rydberg atoms in a magnetic
Ioffe-Pritchard trap which is superimposed by a homogeneous electric field.
Trapped Rydberg atoms can be created in long-lived electronic states exhibiting
a permanent electric dipole moment of several hundred Debye. The resulting
dipole-dipole interaction in conjunction with the radial confinement is
demonstrated to give rise to an effectively one-dimensional ultracold Rydberg
gas with a macroscopic interparticle distance. We derive analytical expressions
for the electric dipole moment and the critical linear density of Rydberg
atoms.Comment: 4 pages, 2 figure
LGMD-1C: Role of Caveolin-3 in Neuromuscular Junction Structure and Function
Caveolin-3 is a muscle specific scaffolding protein with both structural and signaling roles. Lack of caveolin-3 expression has been implicated in limb-girdle muscular dystrophy, along with distal myopathy and rippling muscle disease. These diseases are characterized by progressive muscle weakness and muscle wasting. Nicotinic acetylcholine receptor (nAChR) clustering and localization are important for efficient nerve to muscle contractile signal transmission. It is hypothesized that muscle weakness could originate through disrupted nAChR clustering, disrupting the efficiency of signaling from the motorneuron to the muscle. While the molecular mechanisms involved in nAChR clustering remain to be fully defined, we hypothesize caveolin-3 is important for nAChR clustering and overall neuromuscular junction function.Caveolin-3 and the nAChR co-localize and associate evidenced by immunofluorescence and immunoprecipitation. These results were replicated in differentiated wildtype myotubes treated with the nAChR clustering agent, neural agrin. In differentiated caveolin-3 null myotubes, agrin treatment yields a 60% reduction in nAChR clusters as compared to agrin treated wildtype myotubes. Agrin induces nAChR clustering, through activation of muscle specific kinase (MuSK) and downstream through Rac-1 activation. In differentiated wildtype myotubes, Rac-1 activation peaks at 1 hour of agrin treatment, while in differentiated caveolin-3 null myotubes there is dramatically reduced Rac-1 activation upon agrin treatment. Immunoprecipitation of MuSK shows that caveolin-3 and MuSK association peaks at 1 hour of agrin treatment in wildtype cells. This corresponds to the peak of MuSK phosphorylation which also occurs at 1 hour. Agrin induced MuSK phosphorylation was decreased more significantly than the overall decrease in MuSK expression in the caveolin-3 null cells as compared to the wildtype results. These results indicate a role for caveolin-3 in efficient nAChR clustering.Electromyography studies in anesthetized mice indicated lengthened latencies of the muscle action potential in the caveolin-3 null mice as compared to wildtype mice. There were also decreased overall electromyography (EMG) amplitude and EMG area under the curve in caveolin-3 null mice. Comparison of contractile strength in wildtype and caveolin-3 null animals indicated tetanic contractions to be less stable in the caveolin-3 null animals, though there was late potentiation in actual contractile strength.Lack of caveolin-3 affects the neuromuscular junction formation and transmission without affecting overall contractile strength. This research opens a novel view, that correct neuromuscular junction formation and neuromuscular transmission is important in the development of muscular dystrophies
Interaction-induced stabilization of circular Rydberg atoms
We discuss a candidate solution for the controlled trapping and manipulation
of two individual Rydberg atoms by means of a magnetic Ioffe-Pritchard trap
that is superimposed by a constant electric field. In such a trap Rydberg atoms
experience a permanent electric dipole moment that can be of the order of
several hundred Debye. The interplay of electric dipolar repulsion and three
dimensional magnetic confinement leads to a well controllable equilibrium
configuration with tunable trap frequency and atomic distance. We thoroughly
investigate the trapping potentials and analyze the interaction-induced
stabilization of two such trapped Rydberg atoms. Possible limitations and
collapse scenarios are discussed.Comment: 18 pages, 5 figure
Gendered endings: Narratives of male and female suicides in the South African Lowveld
This is the author's accepted manuscript. The final publication is available at Springer via http://dx.doi.org/10.1007/s11013-012-9258-y. Copyright @ Springer Science+Business Media, LLC 2012.Durkheim’s classical theory of suicide rates being a negative index of social solidarity downplays the salience of gendered concerns in suicide. But gendered inequalities have had a negative impact: worldwide significantly more men than women perpetrate fatal suicides. Drawing on narratives of 52 fatal suicides in Bushbuckridge, South Africa, this article suggests that Bourdieu’s concepts of ‘symbolic violence’ and ‘masculine domination’ provide a more appropriate framework for understanding this paradox. I show that the thwarting of investments in dominant masculine positions have been the major precursor to suicides by men. Men tended to take their own lives as a means of escape. By contrast, women perpetrated suicide to protest against the miserable consequences of being dominated by men. However, contra the assumption of Bourdieu’s concept of ‘habitus’, the narrators of suicide stories did reflect critically upon gender constructs
FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted
[EN] Background & Aims: Cholangiocarcinoma (CCA) is a neoplasia of
the biliary tract driven by genetic, epigenetic and transcriptional
mechanisms. Herein, we investigated the role of the transcription
factor FOSL1, as well as its downstream transcriptional effectors,
in the development and progression of CCA.
Methods: FOSL1 was investigated in human CCA clinical samples.
Genetic inhibition of FOSL1 in human and mouse CCA cell
lines was performed in in vitro and in vivo models using
constitutive and inducible short-hairpin RNAs. Conditional
FOSL1 ablation was done using a genetically engineered mouse
(GEM) model of CCA (mutant KRAS and Trp53 knockout). Followup
RNA and chromatin immunoprecipitation (ChIP) sequencing
analyses were carried out and downstream targets were validated
using genetic and pharmacological inhibition.
Results: An inter-species analysis of FOSL1 in CCA was conducted.
First, FOSL1 was found to be highly upregulated in human
and mouse CCA, and associated with poor patient survival.
Pharmacological inhibition of different signalling pathways in
CCA cells converged on the regulation of FOSL1 expression.
Functional experiments showed that FOSL1 is required for cell
proliferation and cell cycle progression in vitro, and for tumour
growth and tumour maintenance in both orthotopic and subcutaneous
xenograft models. Likewise, FOSL1 genetic abrogation
in a GEM model of CCA extended mouse survival by decreasing
the oncogenic potential of transformed cholangiocytes. RNA and
ChIP sequencing studies identified direct and indirect transcriptional
effectors such as HMGCS1 and AURKA, whose genetic
and pharmacological inhibition phenocopied FOSL1 loss.
Conclusions: Our data illustrate the functional and clinical
relevance of FOSL1 in CCA and unveil potential targets amenable
to pharmacological inhibition that could enable the implementation
of novel therapeutic strategies.
Lay summary: Understanding the molecular mechanisms
involved in cholangiocarcinoma (bile duct cancer) development
and progression stands as a critical step for the development of
novel therapies. Through an inter-species approach, this study
provides evidence of the clinical and functional role of the
transcription factor FOSL1 in cholangiocarcinoma. Moreover, we
report that downstream effectors of FOSL1 are susceptible to
pharmacological inhibition, thus providing new opportunities
for therapeutic intervention.A.V. was supported by ADA of the University of Navarra, Spain,
O.E. by FSE; MINECO; FJCI-2017-34233, Spain, R.E. by a donation
from Mauge Burgos de la Iglesia’s family, Spain, and P. Olaizola by
the Basque Government (PRE_2016_1_0269), Basque Country,
Spain. M.J.P. was funded by ISCIII [FIS PI14; 00399, PI17; 00022]
cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER),
Spain; Spanish Ministry of Economy and Competitiveness
(MINECO: “Ramón y Cajal” Program RYC-2015-17755), Spain.
M.A.A was funded by La Caixa Foundation, HEPACARE project,
Spain, ISCIII FIS PI16/01126 cofinanced by “Fondo Europeo de
Desarrollo Regional” (FEDER), Spain, and “Fundación Científica de
la Asociación Española Contra el Cáncer’’ (AECC Scientific Foundation)
Rare Cancers 2017, Spain. J.M.B. was funded by the
Spanish Carlos III Health Institute (ISCIII) (FIS PI15; 01132, PI18;
01075 and Miguel Servet Program CON14; 00129 and CPII19;
00008), Spain, co-financed by “Fondo Europeo de Desarrollo
Regional” (FEDER), Spain; “Euskadi RIS3” (2019222054) and
BIOEF (Basque Foundation for Innovation and Health Research:
EiTB Maratoia BIO15; CA; 016; BD), Basque Country, Spain;
“Fundación Científica de la Asociación Española Contra el Cáncer”
(AECC Scientific Foundation) Rare Cancers 2017, Spain. S.V. was
supported by FEDER; MINECO (SAF2017-89944-R), Spain, by the
Government of Navarra-Health Research Department (58; 2018),
Navarra, Spain, by La Caixa and Caja Navarra Foundation-CIMA
agreement, Spain. None of the funding sources were involved
in the decision to submit the article for publication. This article is
based upon work from COST Action CA18122 European Cholangiocarcinoma
Network, supported by COST (European Cooperation
in Science and Technology). COST (European Cooperation in Science and Technology) is a funding agency for research and
innovation networks (www.cost.eu)
Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease that is refractory to medical intervention. Notch pathway antagonism has been shown to prevent pancreatic preneoplasia progression in mouse models, but potential benefits in the setting of an established PDA tumor have not been established. We demonstrate that the gamma secretase inhibitor MRK003 effectively inhibits intratumoral Notch signaling in the KPC mouse model of advanced PDA. Although MRK003 monotherapy fails to extend the lifespan of KPC mice, the combination of MRK003 with the chemotherapeutic gemcitabine prolongs survival. Combination treatment kills tumor endothelial cells and synergistically promotes widespread hypoxic necrosis. These results indicate that the paucivascular nature of PDA can be exploited as a therapeutic vulnerability, and the dual targeting of the tumor endothelium and neoplastic cells by gamma secretase inhibition constitutes a rationale for clinical translation
FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted
Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention
A Functional Proteomic Method for Biomarker Discovery
The sequencing of the human genome holds out the hope for personalized medicine, but it is clear that analysis of DNA or RNA content alone is not sufficient to understand most disease processes. Proteomic strategies that allow unbiased identification of proteins and their post-transcriptional and -translation modifications are an essential complement to genomic strategies. However, the enormity of the proteome and limitations in proteomic methods make it difficult to determine the targets that are particularly relevant to human disease. Methods are therefore needed that allow rational identification of targets based on function and relevance to disease. Screening methodologies such as phage display, SELEX, and small-molecule combinatorial chemistry have been widely used to discover specific ligands for cells or tissues of interest, such as tumors. Those ligands can be used in turn as affinity probes to identify their cognate molecular targets when they are not known in advance. Here we report an easy, robust and generally applicable approach in which phage particles bearing cell- or tissue-specific peptides serve directly as the affinity probes for their molecular targets. For proof of principle, the method successfully identified molecular binding partners, three of them novel, for 15 peptides specific for pancreatic cancer
Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma
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