Spin impurities in diamond can be versatile tools for a wide range of solid-state-based quantum technologies, but finding spin impurities that offer sufficient quality in both photonic and spin ...properties remains a challenge for this pursuit. The silicon-vacancy center has recently attracted much interest because of its spin-accessible optical transitions and the quality of its optical spectrum. Complementing these properties, spin coherence is essential for the suitability of this center as a spin-photon quantum interface. Here, we report all-optical generation of coherent superpositions of spin states in the ground state of a negatively charged silicon-vacancy center using coherent population trapping. Our measurements reveal a characteristic spin coherence time, T2*, exceeding 45 nanoseconds at 4 K. We further investigate the role of phonon-mediated coupling between orbital states as a source of irreversible decoherence. Our results indicate the feasibility of all-optical coherent control of silicon-vacancy spins using ultrafast laser pulses.
Objective
Although migraine is defined by the headache and headache‐associated symptoms, the true beginning of a migraine attack lies in the premonitory phase. To understand the generation of ...attacks, one needs to investigate the phase before headache starts. The premonitory phase of migraine is characterized by a well‐described complex of symptoms. Its duration, however, is not clearly defined, and there are no biomarkers to help define when this phase starts.
Methods
Here, we used functional magnetic resonance imaging (MRI) to elucidate the duration of the premonitory phase in spontaneous human migraine attacks. Because migraine attacks are hardly predictable and thereby the premonitory phase is difficult to catch, we scanned 9 patients daily over a minimum period of 30 days using a well‐established paradigm for functional MRI of trigeminal nociception.
Results
Seven patients were included in the analysis, thus providing cumulative data of 27 spontaneous human migraine attacks including scans before, during, and after migraine pain as well as interictal scans. As a response to painful trigeminal stimulation, activation of the hypothalamus was present within the last 48 hours before headache onset but not earlier.
Interpretation
Using hypothalamic activation as a potential marker for the premonitory phase of migraine in this unique dataset, our data corroborated a duration of 48 hours for the premonitory phase of migraine. We suggest applying this time criterion in future studies when focusing on this phase of the migraine cycle. ANN NEUROL 2020;87:646–651
Enhanced and deregulated expression of N-MYC, a member of the MYC family of transcription factors, drives the development of multiple tumors, including tumors of the nervous and hematologic systems ...and neuroendocrine tumors in other organs. This review summarizes the cell-of-origin, biological features, associated signaling pathways, and current treatment strategies for N-MYC-driven tumors. We also highlight biological differences within specific tumor types that are driven by the different MYC proteins.
N-MYC is a driver of multiple tumor types that are derived through a mechanism that involves direct differentiation within the same lineage (e.g., in the case of neuroblastoma, medulloblastoma, and acute myeloid leukemia) and is often associated with a poor prognosis. Emerging data suggest that N-MYC also drives other tumor types through a mechanism that promotes a lineage switch and that this switch may be exploited for therapeutic purposes.
Resonance fluorescence arises from the interaction of an optical field with a two-level system, and has played a fundamental role in the development of quantum optics and its applications. Despite ...its conceptual simplicity, it entails a wide range of intriguing phenomena, such as the Mollow-triplet emission spectrum, photon antibunching and coherent photon emission. One fundamental aspect of resonance fluorescence--squeezing in the form of reduced quantum fluctuations in the single photon stream from an atom in free space--was predicted more than 30 years ago. However, the requirement to operate in the weak excitation regime, together with the combination of modest oscillator strength of atoms and low collection efficiencies, has continued to necessitate stringent experimental conditions for the observation of squeezing with atoms. Attempts to circumvent these issues had to sacrifice antibunching, owing to either stimulated forward scattering from atomic ensembles or multi-photon transitions inside optical cavities. Here, we use an artificial atom with a large optical dipole enabling 100-fold improvement of the photon detection rate over the natural atom counterpart and reach the necessary conditions for the observation of quadrature squeezing in single resonance-fluorescence photons. By implementing phase-dependent homodyne intensity-correlation detection, we demonstrate that the electric field quadrature variance of resonance fluorescence is three per cent below the fundamental limit set by vacuum fluctuations, while the photon statistics remain antibunched. The presence of squeezing and antibunching simultaneously is a fully non-classical outcome of the wave-particle duality of photons.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Very high risk neuroblastoma is characterised by increased MAPK signalling, and targeting MAPK signalling is a promising therapeutic strategy. We used a deeply characterised panel of neuroblastoma ...cell lines and found that the sensitivity to MEK inhibitors varied drastically between these cell lines. By generating quantitative perturbation data and mathematical modelling, we determined potential resistance mechanisms. We found that negative feedbacks within MAPK signalling and via the IGF receptor mediate re-activation of MAPK signalling upon treatment in resistant cell lines. By using cell-line specific models, we predict that combinations of MEK inhibitors with RAF or IGFR inhibitors can overcome resistance, and tested these predictions experimentally. In addition, phospho-proteomic profiling confirmed the cell-specific feedback effects and synergy of MEK and IGFR targeted treatment. Our study shows that a quantitative understanding of signalling and feedback mechanisms facilitated by models can help to develop and optimise therapeutic strategies. Our findings should be considered for the planning of future clinical trials introducing MEKi in the treatment of neuroblastoma.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Coronal mass ejections (CMEs) strong enough to create electromagnetic effects at latitudes below the auroral oval are frequent events that could soon have substantial impacts on electrical grids. ...Modern society's heavy reliance on these domestic and international networks increases our susceptibility to such a severe space-weather event. Using a new high-resolution model of the global economy, we simulate the economic impact of strong CMEs for three different planetary orientations. We account for the economic impacts within the countries directly affected, as well as the post-disaster economic shock in partner economies linked by international trade. For a 1989 Quebec-like event, the global economic impacts would range from USD 2.4 to 3.4 trillion over a year. Of this total economic shock, about 50% would be felt in countries outside the zone of direct impact, leading to a loss in global Gross Domestic Product (GDP) of 3.9 to 5.6%. The global economic damage is of the same order as wars, extreme financial crisis and estimated for future climate change.
Migraine is a disabling neurological disorder, diagnosis of which is based on clinical criteria. A shortcoming of these criteria is that they do not fully capture the heterogeneity of migraine, ...including the underlying genetic and neurobiological factors. This complexity has generated momentum for biomarker research to improve disease characterisation and identify novel drug targets. In this Series paper, we present the progress that has been made in the search for biomarkers of migraine within genetics, provocation modelling, biochemistry, and neuroimaging research. Additionally, we outline challenges and future directions for each biomarker modality. We also discuss the advances made in combining and integrating data from multiple biomarker modalities. These efforts contribute to developing precision medicine that can be applied to future patients with migraine.
In human neuroblastoma, amplification of the
MYCN gene predicts poor prognosis and resistance to therapy. In a shRNA screen of genes that are highly expressed in
MYCN-amplified tumors, we have ...identified
AURKA as a gene that is required for the growth of
MYCN-amplified neuroblastoma cells but largely dispensable for cells lacking amplified
MYCN. Aurora A has a critical function in regulating turnover of the N-Myc protein. Degradation of N-Myc requires sequential phosphorylation by cyclin B/Cdk1 and Gsk3. N-Myc is therefore degraded during mitosis in response to low levels of PI3-kinase activity. Aurora A interacts with both N-Myc and the SCF
Fbxw7 ubiquitin ligase that ubiquitinates N-Myc and counteracts degradation of N-Myc, thereby uncoupling N-Myc stability from growth factor-dependent signals.
A detailed description is presented of the Extreme Conditions Beamline P02.2 for micro X‐ray diffraction studies of matter at simultaneous high pressure and high/low temperatures at PETRA III, in ...Hamburg, Germany. This includes performance of the X‐ray optics and instrumental resolution as well as an overview of the different sample environments available for high‐pressure studies in the diamond anvil cell. Particularly emphasized are the high‐brilliance and high‐energy X‐ray diffraction capabilities of the beamline in conjunction with the use of fast area detectors to conduct time‐resolved compression studies in the millisecond time regime. Finally, the current capability of the Extreme Conditions Science Infrastructure to support high‐pressure research at the Extreme Conditions Beamline and other PETRA III beamlines is described.
Through negative regulation of gene expression, microRNAs (miRNAs) can function as oncosuppressors in cancers, and can themselves show altered expression in various tumor types. Here, we have ...investigated medulloblastoma tumors (MBs), which arise from an early impairment of developmental processes in the cerebellum, where Notch signaling is involved in many of the cell-fate-determining stages. Notch regulates a subset of MB cells that have stem-cell-like properties and can promote tumor growth. On the basis of this evidence, we hypothesized that miRNAs targeting the Notch pathway can regulate these phenomena, and can be used in anti-cancer therapies.
In a screening of potential targets within Notch signaling, miR-34a was seen to be a regulator of the Notch pathway through its targeting of Notch ligand Delta-like 1 (Dll1). Down-regulation of Dll1 expression by miR-34a negatively regulates cell proliferation, and induces apoptosis and neural differentiation in MB cells. Using an inducible tetracycline on-off model of miR-34a expression, we show that in Daoy MB cells, Dll1 is the first target that is regulated in MB, as compared to the other targets analyzed here: Cyclin D1, cMyc and CDK4. MiR-34a expression negatively affects CD133(+)/CD15(+) tumor-propagating cells, then we assay through reverse-phase proteomic arrays, Akt and Stat3 signaling hypo-phosphorylation. Adenoviruses carrying the precursor miR-34a induce neurogenesis of tumor spheres derived from a genetic animal model of MB (Patch1(+/-) p53(-/-)), thus providing further evidence that the miR-34a/Dll1 axis controls both autonomous and non autonomous signaling of Notch. In vivo, miR-34a overexpression carried by adenoviruses reduces tumor burden in cerebellum xenografts of athymic mice, thus demonstrating an anti-tumorigenic role of miR-34a in vivo.
Despite advances in our understanding of the pathogenesis of MB, one-third of patients with MB remain incurable. Here, we show that stable nucleic-acid-lipid particles carrying mature miR-34a can target Dll1 in vitro and show equal effects to those of adenovirus miR-34a cell infection. Thus, this technology forms the basis for their therapeutic use for the delivery of miR-34a in brain-tumor treatment, with no signs of toxicity described to date in non-human primate trials.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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