432 research outputs found
Local dynamics of topological magnetic defects in the itinerant helimagnet FeGe
Chiral magnetic interactions induce complex spin textures including helical
and conical spin waves, as well as particle-like objects such as magnetic
skyrmions and merons. These spin textures are the basis for innovative device
paradigms and give rise to exotic topological phenomena, thus being of interest
for both applied and fundamental sciences. Present key questions address the
dynamics of the spin system and emergent topological defects. Here we analyze
the micromagnetic dynamics in the helimagnetic phase of FeGe. By combining
magnetic force microscopy, single-spin magnetometry, and
Landau-Lifschitz-Gilbert simulations we show that the nanoscale dynamics are
governed by the depinning and subsequent motion of magnetic edge dislocations.
The motion of these topologically stable objects triggers perturbations that
can propagate over mesoscopic length scales. The observation of stochastic
instabilities in the micromagnetic structure provides new insight to the
spatio-temporal dynamics of itinerant helimagnets and topological defects, and
discloses novel challenges regarding their technological usage
A 0535+26 in the August/September 2005 outburst observed by RXTE and INTEGRAL
In this Letter we present results from INTEGRAL and RXTE observations of the
spectral and timing behavior of the High Mass X-ray Binary A 0535+26 during its
August/September 2005 normal (type I) outburst with an average flux
F(5-100keV)~400mCrab. The search for cyclotron resonance scattering features
(fundamental and harmonic) is one major focus of the paper. Our analysis is
based on data from INTEGRAL and RXTE Target of Opportunity Observations
performed during the outburst. The pulse period is determined. X-ray pulse
profiles in different energy ranges are analyzed. The broad band INTEGRAL and
RXTE pulse phase averaged X-ray spectra are studied. The evolution of the
fundamental cyclotron line at different luminosities is analyzed. The pulse
period P is measured to be 103.39315(5)s at MJD 53614.5137. Two absorption
features are detected in the phase averaged spectra at E_1~45keV and
E_2~100keV. These can be interpreted as the fundamental cyclotron resonance
scattering feature and its first harmonic and therefore the magnetic field can
be estimated to be B~4x10^12G.Comment: 4 pages, 5 figures, accepted for publication in A&A Letter
Drosophila Activated Cdc42 Kinase Has an Anti-Apoptotic Function
Activated Cdc42 kinases (Acks) are evolutionarily conserved non-receptor tyrosine kinases. Activating somatic mutations and increased ACK1 protein levels have been found in many types of human cancers and correlate with a poor prognosis. ACK1 is activated by epidermal growth factor (EGF) receptor signaling and functions to regulate EGF receptor turnover. ACK1 has additionally been found to propagate downstream signals through the phosphorylation of cancer relevant substrates. Using Drosophila as a model organism, we have determined that Drosophila Ack possesses potent anti-apoptotic activity that is dependent on Ack kinase activity and is further activated by EGF receptor/Ras signaling. Ack anti-apoptotic signaling does not function through enhancement of EGF stimulated MAP kinase signaling, suggesting that it must function through phosphorylation of some unknown effector. We isolated several putative Drosophila Ack interacting proteins, many being orthologs of previously identified human ACK1 interacting proteins. Two of these interacting proteins, Drk and yorkie, were found to influence Ack signaling. Drk is the Drosophila homolog of GRB2, which is required to couple ACK1 binding to receptor tyrosine kinases. Drk knockdown blocks Ack survival activity, suggesting that Ack localization is important for its pro-survival activity. Yorkie is a transcriptional co-activator that is downstream of the Salvador-Hippo-Warts pathway and promotes transcription of proliferative and anti-apoptotic genes. We find that yorkie and Ack synergistically interact to produce tissue overgrowth and that yorkie loss of function interferes with Ack anti-apoptotic signaling. Our results demonstrate how increased Ack signaling could contribute to cancer when coupled to proliferative signals
The autophagy protein Ambra1 regulates gene expression by supporting novel transcriptional complexes
Ambra1 is considered an autophagy and trafficking protein with roles in neurogenesis and cancer cell invasion. Here, we report that Ambra1 also localizes to the nucleus of cancer cells, where it has a novel nuclear scaffolding function that controls gene expression. Using biochemical fractionation and proteomics, we found that Ambra1 binds to multiple classes of proteins in the nucleus, including nuclear pore proteins, adaptor proteins such as FAK and Akap8, chromatin-modifying proteins, and transcriptional regulators like Brg1 and Atf2. We identified biologically important genes, such as Angpt1, Tgfb2, Tgfb3, Itga8, and Itgb7, whose transcription is regulated by Ambra1-scaffolded complexes, likely by altering histone modifications and Atf2 activity. Therefore, in addition to its recognized roles in autophagy and trafficking, Ambra1 scaffolds protein complexes at chromatin, regulating transcriptional signaling in the nucleus. This novel function for Ambra1, and the specific genes impacted, may help to explain the wider role of Ambra1 in cancer cell biology
Transcriptomic analysis of cutaneous squamous cell carcinoma reveals a multi-gene prognostic signature associated with metastasis.
BackgroundMetastasis of cutaneous squamous cell carcinoma (cSCC) is uncommon. Current staging methods are reported to have sub-optimal performances in metastasis prediction. Accurate identification of patients with tumours at high risk of metastasis would have a significant impact on management.ObjectiveTo develop a robust and validated gene expression profile (GEP) signature for predicting primary cSCC metastatic risk using an unbiased whole transcriptome discovery-driven approach.MethodsArchival formalin-fixed paraffin-embedded primary cSCC with perilesional normal tissue from 237 immunocompetent patients (151 non-metastasising and 86 metastasising) were collected retrospectively from four centres. TempO-seq was used to probe the whole transcriptome and machine learning algorithms were applied to derive predictive signatures, with a 3:1 split for training and testing datasets.ResultsA 20-gene prognostic model was developed and validated, with an accuracy of 86.0%, sensitivity of 85.7%, specificity of 86.1%, and positive predictive value of 78.3% in the testing set, providing more stable, accurate prediction than pathological staging systems. A linear predictor was also developed, significantly correlating with metastatic risk.LimitationsThis was a retrospective 4-centre study and larger prospective multicentre studies are now required.ConclusionThe 20-gene signature prediction is accurate, with the potential to be incorporated into clinical workflows for cSCC
Transcriptomic analysis of cutaneous squamous cell carcinoma reveals a multi-gene prognostic signature associated with metastasis.
BACKGROUND: Metastasis of cutaneous squamous cell carcinoma (cSCC) is uncommon. Current staging methods are reported to have sub-optimal performances in metastasis prediction. Accurate identification of patients with tumours at high risk of metastasis would have a significant impact on management. OBJECTIVE: To develop a robust and validated gene expression profile (GEP) signature for predicting primary cSCC metastatic risk using an unbiased whole transcriptome discovery-driven approach. METHODS: Archival formalin-fixed paraffin-embedded primary cSCC with perilesional normal tissue from 237 immunocompetent patients (151 non-metastasising and 86 metastasising) were collected retrospectively from four centres. TempO-seq was used to probe the whole transcriptome and machine learning algorithms were applied to derive predictive signatures, with a 3:1 split for training and testing datasets. RESULTS: A 20-gene prognostic model was developed and validated, with an accuracy of 86.0%, sensitivity of 85.7%, specificity of 86.1%, and positive predictive value of 78.3% in the testing set, providing more stable, accurate prediction than pathological staging systems. A linear predictor was also developed, significantly correlating with metastatic risk. LIMITATIONS: This was a retrospective 4-centre study and larger prospective multicentre studies are now required. CONCLUSION: The 20-gene signature prediction is accurate, with the potential to be incorporated into clinical workflows for cSCC
Resonant Spin Excitation in an Overdoped High Temperature Superconductor
An inelastic neutron scattering study of overdoped Bi_2Sr_2CaCu_2O_{8+\delta}
$ (T_c = 83 K) has revealed a resonant spin excitation in the superconducting
state. The mode energy is E_res=38 meV, significantly lower than in optimally
doped Bi_2Sr_2CaCu_2O_{8+\delta} (T_c = 91 K, E_ res =43 meV). This
observation, which indicates a constant ratio E_res /k_B T_c \sim 5.4, helps
resolve a long-standing controversy about the origin of the resonant spin
excitation in high-temperature superconductors.Comment: final version: PRL 86, 1610 (2001
Future business and the role of purchasing and supply management: Opportunities for âbusiness-not-as-usualâ PSM research
The raison d'ĂȘtre for this article is simple: traditional ways of researching, theorizing, and practicing purchasing and supply management (PSM) are no longer sufficient to âmeet the momentâ. Scholars need to advance a âbusiness-not-as-usualâ footing approach to their work, if they are to make a meaningful contribution to addressing the current and future emergencies, as highlighted by recent extreme weather and the COVID-19 pandemic. Yet, what can this, or should this, mean for a field rooted in traditional business thinking? This article builds on the Journal of Purchasing and Supply Management's (JPSM) 25th Anniversary Special Issue editorial (2019); members of the JPSM's editorial team advance their unique perspectives on what âbusiness-not-as-usualâ means for PSM. Specifically, we advocate both thinking much more widely, in scope and ambition, than we currently do, and simultaneously building our ability to comprehend supply chains in a more nuanced and granular way. We explore whether the bias toward positivist work has omitted potentially interesting findings, and viewpoints. This leads to a call to re-think how we approach our work: should the key criteria always be to focus on theory development or testing? Should academics âthink biggerâ? Turning to specific research themes, illustrations of how our current thinking can be challenged or broadened by addressing the circular economy, and role of purchasing and innovation. Specifically, the focus on the PSM function as an intrapreneur within the larger organization, and the role of innovation and technology in PSM work. Taken together, we hope the ideas and arguments presented here will inform and inspire ambitious and novel approaches to PSM research with significant and enduring impact on the transformation of business
A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability
43 p.-5 fig.Despite the approval of several multikinase inhibitors that target SRC and the overwhelming evidence of the role of SRC in the progression and resistance mechanisms of many solid malignancies, inhibition of its kinase activity has thus far failed to improve patient outcomes. Here we report the small molecule eCF506 locks SRC in its native inactive conformation, thereby inhibiting both enzymatic and scaffolding functions that prevent phosphorylation and complex formation with its partner FAK. This unprecedented mechanism of action resulted in highly potent and selective pathway inhibition, in culture and in vivo. Treatment with eCF506 resulted in increased antitumor efficacy and tolerability in syngeneic murine cancer models, demonstrating significant therapeutic advantages over existing SRC/ABL inhibitors. Therefore, this novel mode of inhibiting SRC could lead to improved treatment of SRC-associated disorders.C.T. thanks the CMVM of the University of Edinburgh (Principal's scholarship). D.L.
acknowledges support from the Spanish Ministry of Science, Innovation and Universities for the Spanish State Research Agency Retos Grant RTI2018-099318-B-I00, cofunded by the European Regional Development Fund (FEDER). E.R.W., J.C.D. and K.G.M. are funded by CRUK. J.R.L.O. acknowledges support from the Molecular Interactions Facility funds at the CIB-CSIC. T.V. is funded by H2020-MSCA-IF-2016-749299. RCM thanks the support from the Vice Rectorate for Research of the University of Granada. X.-F.L. and B.-Z.Q. are funded by a CRUK Career Development Fellowship (C49791/A17367). B.-Z.Q. also acknowledges support from an ERC Starting Grant (716379). C.S, M.C.F. and V.G.B are funded by CRUK Programme Grant C157/A15703. N.O.C. and A.U.B are grateful to the CMVM of the University of Edinburgh and Wellcome Trust for financial support (ISSF3).Peer reviewe
Selfâpollination in island and mainland populations of the introduced hummingbirdâpollinated plant, Nicotiana glauca (Solanaceae)
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142032/1/ajb20672.pd
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