11,185 research outputs found
Direct genetic demonstration of Gα13 coupling to the orphan G protein-coupled receptor G2A leading to RhoA-dependent actin rearrangement
G2A is an orphan G protein-coupled receptor (GPCR), expressed predominantly in T and B cells and homologous to a small group of GPCRs of unknown function expressed in lymphoid tissues. G2A is transcriptionally induced in response to diverse stimuli, and its ectopic expression suppresses transformation of B lymphoid precursors by BCR-ABL. G2A induces morphological transformation of NIH 3T3 fibroblasts. Microinjection of constructs encoding G2A into Swiss 3T3 fibroblasts induces actin reorganization into stress fibers that depends on RhoA, but not CDC42 or RAC. G2A elicits RhoA-dependent transcriptional activation of serum response factor. Direct evaluation of RhoA activity demonstrates elevated levels of RhoA-GTP in G2A-expressing cells. Microinjection of embryonic fibroblasts derived from various Galpha knockout mice establishes a requirement for Galpha 13 but not Galpha 12 or Galpha q/11 in G2A-induced actin rearrangement. In conclusion, G2A represents a family of GPCRs expressed in lymphocytes that may link diverse stimuli to cytoskeletal reorganization and transcriptional activation through a pathway involving Galpha 13 and RhoA
On the Performance Prediction of BLAS-based Tensor Contractions
Tensor operations are surging as the computational building blocks for a
variety of scientific simulations and the development of high-performance
kernels for such operations is known to be a challenging task. While for
operations on one- and two-dimensional tensors there exist standardized
interfaces and highly-optimized libraries (BLAS), for higher dimensional
tensors neither standards nor highly-tuned implementations exist yet. In this
paper, we consider contractions between two tensors of arbitrary dimensionality
and take on the challenge of generating high-performance implementations by
resorting to sequences of BLAS kernels. The approach consists in breaking the
contraction down into operations that only involve matrices or vectors. Since
in general there are many alternative ways of decomposing a contraction, we are
able to methodically derive a large family of algorithms. The main contribution
of this paper is a systematic methodology to accurately identify the fastest
algorithms in the bunch, without executing them. The goal is instead
accomplished with the help of a set of cache-aware micro-benchmarks for the
underlying BLAS kernels. The predictions we construct from such benchmarks
allow us to reliably single out the best-performing algorithms in a tiny
fraction of the time taken by the direct execution of the algorithms.Comment: Submitted to PMBS1
BET Bromodomain Inhibition Triggers Apoptosis of NF1-Associated Malignant Peripheral Nerve Sheath Tumors through Bim Induction
SummaryMalignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive sarcomas that develop sporadically or in neurofibromatosis type 1 (NF1) patients. There is no effective treatment for MPNSTs and they are typically fatal. To gain insights into MPNST pathogenesis, we utilized an MPNST mouse model that allowed us to study the evolution of these tumors at the transcriptome level. Strikingly, in MPNSTs we found upregulation of a chromatin regulator, Brd4, and show that BRD4 inhibition profoundly suppresses both growth and tumorigenesis. Our findings reveal roles for BET bromodomains in MPNST development and report a mechanism by which bromodomain inhibition induces apoptosis through induction of proapoptotic Bim, which may represent a paradigm shift in therapy for MPNST patients. Moreover, these findings indicate epigenetic mechanisms underlying the balance of anti- and proapoptotic molecules and that bromodomain inhibition can shift this balance in favor of cancer cell apoptosis
Contributions of inflammation and tumor microenvironment to neurofibroma tumorigenesis
Neurofibromatosis type 1 associates with multiple neoplasms, and the Schwann cell tumor neurofibroma is the most prevalent. A hallmark feature of neurofibroma is mast cell infiltration, which is recruited by chemoattractant stem cell factor (SCF) and has been suggested to sustain neurofibroma tumorigenesis. In the present study, we use new, genetically engineered Scf mice to decipher the contributions of tumor-derived SCF and mast cells to neurofibroma development. We demonstrate that mast cell infiltration is dependent on SCF from tumor Schwann cells. However, removal of mast cells by depleting the main SCF source only slightly affects neurofibroma progression. Other inflammation signatures show that all neurofibromas are associated with high levels of macrophages regardless of Scf status. These findings suggest an active inflammation in neurofibromas and partly explain why mast cell removal alone is not sufficient to relieve tumor burden in this experimental neurofibroma model. Furthermore, we show that plexiform neurofibromas are highly associated with injury-prone spinal nerves that are close to flexible vertebras. In summary, our study details the role of inflammation in neurofibromagenesis. Our data indicate that prevention of inflammation and possibly also nerve injury at the observed tumor locations are therapeutic approaches for neurofibroma prophylaxis and that such treatment should be explored
Spectral Evidence for Emergent Order in BaNaFeAs
We report an angle-resolved photoemission spectroscopy study of the
iron-based superconductor family, BaNaFeAs. This system
harbors the recently discovered double-Q magnetic order appearing in a
reentrant C phase deep within the underdoped regime of the phase diagram
that is otherwise dominated by the coupled nematic phase and collinear
antiferromagnetic order. From a detailed temperature-dependence study, we
identify the electronic response to the nematic phase in an orbital-dependent
band shift that strictly follows the rotational symmetry of the lattice and
disappears when the system restores C symmetry in the low temperature
phase. In addition, we report the observation of a distinct electronic
reconstruction that cannot be explained by the known electronic orders in the
system
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