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- Alvarez, Mariano J., et al.
(författare)
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A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:7, s. 979-989
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Tidskriftsartikel (refereegranskat)abstract
- We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.
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- Anchordoqui, Luis A., et al.
(författare)
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The Forward Physics Facility : Sites, experiments, and physics potential
- 2022
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Ingår i: Physics reports. - : Elsevier. - 0370-1573 .- 1873-6270. ; 968, s. 1-50
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Tidskriftsartikel (refereegranskat)abstract
- The Forward Physics Facility (FPF) is a proposal to create a cavern with the space and infrastructure to support a suite of far-forward experiments at the Large Hadron Collider during the High Luminosity era. Located along the beam collision axis and shielded from the interaction point by at least 100 m of concrete and rock, the FPF will house experiments that will detect particles outside the acceptance of the existing large LHC experiments and will observe rare and exotic processes in an extremely low-background environment. In this work, we summarize the current status of plans for the FPF, including recent progress in civil engineering in identifying promising sites for the FPF and the experiments currently envisioned to realize the FPF's physics potential. We then review the many Standard Model and new physics topics that will be advanced by the FPF, including searches for long-lived particles, probes of dark matter and dark sectors, high-statistics studies of TeV neutrinos of all three flavors, aspects of perturbative and non-perturbative QCD, and high-energy astroparticle physics.
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- Arca Sedda, Manuel, et al.
(författare)
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The missing link in gravitational-wave astronomy A summary of discoveries waiting in the decihertz range
- 2021
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Ingår i: Experimental astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 51, s. 1427-1440
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Tidskriftsartikel (refereegranskat)abstract
- Since 2015 the gravitational-wave observations of LIGO and Virgo have transformed our understanding of compact-object binaries. In the years to come, ground-based gravitational-wave observatories such as LIGO, Virgo, and their successors will increase in sensitivity, discovering thousands of stellar-mass binaries. In the 2030s, the space-based LISA will provide gravitational-wave observations of massive black holes binaries. Between the similar to 10-10(3) Hz band of ground-based observatories and the similar to 10(-4)-10(- 1) Hz band of LISA lies the uncharted decihertz gravitational-wave band. We propose a Decihertz Observatory to study this frequency range, and to complement observations made by other detectors. Decihertz observatories are well suited to observation of intermediate-mass (similar to 10(2)-10(4)M(circle dot)) black holes; they will be able to detect stellar-mass binaries days to years before they merge, providing early warning of nearby binary neutron star mergers and measurements of the eccentricity of binary black holes, and they will enable new tests of general relativity and the Standard Model of particle physics. Here we summarise how a Decihertz Observatory could provide unique insights into how black holes form and evolve across cosmic time, improve prospects for both multimessenger astronomy and multiband gravitational-wave astronomy, and enable new probes of gravity, particle physics and cosmology.
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- Karan, Kunal, et al.
(författare)
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Implications of future climate change on crop and irrigation water requirements in a semi-arid river basin using CMIP6 GCMs
- 2022
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Ingår i: Journal of Arid Land. - : Springer Science and Business Media LLC. - 1674-6767 .- 2194-7783. ; 14:11, s. 1234-1257
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Tidskriftsartikel (refereegranskat)abstract
- Agriculture faces risks due to increasing stress from climate change, particularly in semi-arid regions. Lack of understanding of crop water requirement (CWR) and irrigation water requirement (IWR) in a changing climate may result in crop failure and socioeconomic problems that can become detrimental to agriculture-based economies in emerging nations worldwide. Previous research in CWR and IWR has largely focused on large river basins and scenarios from the Coupled Model Intercomparison Project Phase 3 (CMIP3) and Coupled Model Intercomparison Project Phase 5 (CMIP5) to account for the impacts of climate change on crops. Smaller basins, however, are more susceptible to regional climate change, with more significant impacts on crops. This study estimates CWRs and IWRs for five crops (sugarcane, wheat, cotton, sorghum, and soybean) in the Pravara River Basin (area of 6537 km2) of India using outputs from the most recent Coupled Model Intercomparison Project Phase 6 (CMIP6) General Circulation Models (GCMs) under Shared Socio-economic Pathway (SSP)245 and SSP585 scenarios. An increase in mean annual rainfall is projected under both scenarios in the 2050s and 2080s using ten selected CMIP6 GCMs. CWRs for all crops may decline in almost all of the CMIP6 GCMs in the 2050s and 2080s (with the exceptions of ACCESS-CM-2 and ACCESS-ESM-1.5) under SSP245 and SSP585 scenarios. The availability of increasing soil moisture in the root zone due to increasing rainfall and a decrease in the projected maximum temperature may be responsible for this decline in CWR. Similarly, except for soybean and cotton, the projected IWRs for all other three crops under SSP245 and SSP585 scenarios show a decrease or a small increase in the 2050s and 2080s in most CMIP6 GCMs. These findings are important for agricultural researchers and water resource managers to implement long-term crop planning techniques and to reduce the negative impacts of climate change and associated rainfall variability to avert crop failure and agricultural losses.
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- Schewkunow, Vitali, et al.
(författare)
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Thermodynamic evidence of non-muscle myosin II-lipid-membrane interaction.
- 2008
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 366:2, s. 500-5
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Tidskriftsartikel (refereegranskat)abstract
- A unique feature of protein networks in living cells is that they can generate their own force. Proteins such as non-muscle myosin II are an integral part of the cytoskeleton and have the capacity to convert the energy of ATP hydrolysis into directional movement. Non-muscle myosin II can move actin filaments against each other, and depending on the orientation of the filaments and the way in which they are linked together, it can produce contraction, bending, extension, and stiffening. Our measurements with differential scanning calorimetry showed that non-muscle myosin II inserts into negatively charged phospholipid membranes. Using lipid vesicles made of DMPG/DMPC at a molar ratio of 1:1 at 10mg/ml in the presence of different non-muscle myosin II concentrations showed a variation of the main phase transition of the lipid vesicle at around 23 degrees C. With increasing concentrations of non-muscle myosin II the thermotropic properties of the lipid vesicle changed, which is indicative of protein-lipid interaction/insertion. We hypothesize that myosin tail binds to acidic phospholipids through an electrostatic interaction using the basic side groups of positive residues; the flexible, amphipathic helix then may partially penetrate into the bilayer to form an anchor. Using the stopped-flow method, we determined the binding affinity of non-muscle myosin II when anchored to lipid vesicles with actin, which was similar to a pure actin-non-muscle myosin II system. Insertion of myosin tail into the hydrophobic region of lipid membranes, a model known as the lever arm mechanism, might explain how its interaction with actin generates cellular movement.
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- Sedda, Manuel Arca, et al.
(författare)
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The missing link in gravitational-wave astronomy : discoveries waiting in the decihertz range
- 2020
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Ingår i: Classical and quantum gravity. - : IOP Publishing. - 0264-9381 .- 1361-6382. ; 37:21
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Tidskriftsartikel (refereegranskat)abstract
- The gravitational-wave astronomical revolution began in 2015 with LIGO's observation of the coalescence of two stellar-mass black holes. Over the coming decades, ground-based detectors like laser interferometer gravitational-wave observatory (LIGO), Virgo and KAGRA will extend their reach, discovering thousands of stellar-mass binaries. In the 2030s, the space-basedlaser interferometer space antenna(LISA) will enable gravitational-wave observations of the massive black holes in galactic centres. Between ground-based observatories and LISA lies the unexplored dHz gravitational-wave frequency band. Here, we show the potential of adecihertz observatory(DO) which could cover this band, and complement discoveries made by other gravitational-wave observatories. The dHz range is uniquely suited to observation of intermediate-mass (similar to 10(2)-10(4)M(circle dot)) black holes, which may form the missing link between stellar-mass and massive black holes, offering an opportunity to measure their properties. DOs will be able to detect stellar-mass binaries days to years before they merge and are observed by ground-based detectors, providing early warning of nearby binary neutron star mergers, and enabling measurements of the eccentricity of binary black holes, providing revealing insights into their formation. Observing dHz gravitational-waves also opens the possibility of testing fundamental physics in a new laboratory, permitting unique tests of general relativity (GR) and the standard model of particle physics. Overall, a DO would answer outstanding questions about how black holes form and evolve across cosmic time, open new avenues for multimessenger astronomy, and advance our understanding of gravitation, particle physics and cosmology.
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