| 11. |
- Peterziel, H, et al.
(author)
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Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM
- 2022
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In: NPJ precision oncology. - : Springer Science and Business Media LLC. - 2397-768X. ; 6:1, s. 94-
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Journal article (peer-reviewed)abstract
- The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75–78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.
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| 12. |
- Corsi, Alessandra, et al.
(author)
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A Search for Relativistic Ejecta in a Sample of ZTF Broad-lined Type Ic Supernovae
- 2023
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In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 953:2
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Journal article (peer-reviewed)abstract
- The dividing line between gamma-ray bursts (GRBs) and ordinary stripped-envelope core-collapse supernovae (SNe) is yet to be fully understood. Observationally mapping the variety of ejecta outcomes (ultrarelativistic, mildly relativistic, or nonrelativistic) in SNe of Type Ic with broad lines (Ic-BL) can provide a key test to stellar explosion models. However, this requires large samples of the rare SN Ic-BL events with follow-up observations in the radio, where fast ejecta can be probed largely free of geometry and viewing angle effects. Here, we present the results of a radio (and X-ray) follow-up campaign of 16 SNe Ic-BL detected by the Zwicky Transient Facility (ZTF). Our radio campaign resulted in four counterpart detections and 12 deep upper limits. None of the events in our sample is as relativistic as SN 1998bw and we constrain the fraction of SN 1998bw-like explosions to <19% (3σ Gaussian equivalent), a factor of ≈2 smaller than previously established. We exclude relativistic ejecta with radio luminosity densities in between ≈5 × 1027 erg s−1 Hz−1 and ≈1029 erg s−1 Hz−1 at t ≳ 20 days since explosion for ≈60% of the events in our sample. This shows that SNe Ic-BL similar to the GRB-associated SNe 1998bw, 2003lw, and 2010bh, or to the relativistic SNe 2009bb and iPTF17cw, are rare. Our results also exclude an association of the SNe Ic-BL in our sample with largely off-axis GRBs with energies E ≳ 1050 erg. The parameter space of SN 2006aj-like events (faint and fast-peaking radio emission) is, on the other hand, left largely unconstrained, and systematically exploring it represents a promising line of future research.
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| 13. |
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| 14. |
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| 15. |
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| 16. |
- Malik, Yashpal S., et al.
(author)
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SARS-CoV-2 Spike Protein Extrapolation for COVID Diagnosis and Vaccine Development
- 2021
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In: Frontiers in Molecular Biosciences. - : Frontiers Media S.A.. - 2296-889X. ; 8
-
Research review (peer-reviewed)abstract
- Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) led to coronavirus disease 2019 (COVID-19) pandemic affecting nearly 71.2 million humans in more than 191 countries, with more than 1.6 million mortalities as of 12 December, 2020. The spike glycoprotein (S-protein), anchored onto the virus envelope, is the trimer of S-protein comprised of S1 and S2 domains which interacts with host cell receptors and facilitates virus-cell membrane fusion. The S1 domain comprises of a receptor binding domain (RBD) possessing an N-terminal domain and two subdomains (SD1 and SD2). Certain regions of S-protein of SARS-CoV-2 such as S2 domain and fragment of the RBD remain conserved despite the high selection pressure. These conserved regions of the S-protein are extrapolated as the potential target for developing molecular diagnostic techniques. Further, the S-protein acts as an antigenic target for different serological assay platforms for the diagnosis of COVID-19. Virus-specific IgM and IgG antibodies can be used to detect viral proteins in ELISA and lateral flow immunoassays. The S-protein of SARS-CoV-2 has very high sequence similarity to SARS-CoV-1, and the monoclonal antibodies (mAbs) against SARS-CoV-1 cross-react with S-protein of SARS-CoV-2 and neutralize its activity. Furthermore, in vitro studies have demonstrated that polyclonal antibodies targeted against the RBD of S-protein of SARS-CoV-1 can neutralize SARS-CoV-2 thus inhibiting its infectivity in permissive cell lines. Research on coronaviral S-proteins paves the way for the development of vaccines that may prevent SARS-CoV-2 infection and alleviate the current global coronavirus pandemic. However, specific neutralizing mAbs against SARS-CoV-2 are in clinical development. Therefore, neutralizing antibodies targeting SARS-CoV-2 S-protein are promising specific antiviral therapeutics for pre-and post-exposure prophylaxis and treatment of SARS-CoV-2 infection. We hereby review the approaches taken by researchers across the world to use spike gene and S-glycoprotein for the development of effective diagnostics, vaccines and therapeutics against SARA-CoV-2 infection the COVID-19 pandemic.
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| 17. |
- Schulz, S., et al.
(author)
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Classical and cubic Rashba effect in the presence of in-plane 4f magnetism at the iridium silicide surface of the antiferromagnet GdIr2Si2
- 2021
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In: Physical Review B. - 2469-9950. ; 103:3
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Journal article (peer-reviewed)abstract
- We present a combined experimental and theoretical study of the two-dimensional electron states at the iridium-silicide surface of the antiferromagnet GdIr2Si2 above and below the Néel temperature. Using angle-resolved photoemission spectroscopy (ARPES) we find a significant spin-orbit splitting of the surface states in the paramagnetic phase. By means of ab initio density-functional-theory (DFT) calculations we establish that the surface electron states that reside in the projected band gap around the M¯ point exhibit very different spin structures which are governed by the conventional and the cubic Rashba effect. The latter is reflected in a triple spin winding, i.e., the surface electron spin reveals three complete rotations upon moving once around the constant energy contours. Below the Néel temperature, our ARPES measurements show an intricate photoemission intensity picture characteristic of a complex magnetic domain structure. The orientation of the domains, however, can be clarified from a comparative analysis of the ARPES data and their DFT modeling. To characterize a single magnetic domain picture, we resort to the calculations and scrutinize the interplay of the Rashba spin-orbit coupling field with the in-plane exchange field, provided by the ferromagnetically ordered 4f moments of the near-surface Gd layer.
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| 18. |
- Vuorinen, V., et al.
(author)
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Modelling aerosol transport and virus exposure with numerical simulations in relation to SARS-CoV-2 transmission by inhalation indoors
- 2020
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In: Safety Science. - : Elsevier BV. - 0925-7535. ; 130
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Journal article (peer-reviewed)abstract
- We provide research findings on the physics of aerosol and droplet dispersion relevant to the hypothesized aerosol transmission of SARS-CoV-2 during the current pandemic. We utilize physics-based modeling at different levels of complexity, along with previous literature on coronaviruses, to investigate the possibility of airborne transmission. The previous literature, our 0D-3D simulations by various physics-based models, and theoretical calculations, indicate that the typical size range of speech and cough originated droplets (d⩽20μm) allows lingering in the air for O(1h) so that they could be inhaled. Consistent with the previous literature, numerical evidence on the rapid drying process of even large droplets, up to sizes O(100μm), into droplet nuclei/aerosols is provided. Based on the literature and the public media sources, we provide evidence that the individuals, who have been tested positive on COVID-19, could have been exposed to aerosols/droplet nuclei by inhaling them in significant numbers e.g. O(100). By 3D scale-resolving computational fluid dynamics (CFD) simulations, we give various examples on the transport and dilution of aerosols (d⩽20μm) over distances O(10m) in generic environments. We study susceptible and infected individuals in generic public places by Monte-Carlo modelling. The developed model takes into account the locally varying aerosol concentration levels which the susceptible accumulate via inhalation. The introduced concept, ’exposure time’ to virus containing aerosols is proposed to complement the traditional ’safety distance’ thinking. We show that the exposure time to inhale O(100) aerosols could range from O(1s) to O(1min) or even to O(1h) depending on the situation. The Monte-Carlo simulations, along with the theory, provide clear quantitative insight to the exposure time in different public indoor environments.
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| 19. |
- Adamo, Christin S., et al.
(author)
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EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis
- 2022
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 109:12, s. 2230-2252
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Journal article (peer-reviewed)abstract
- EMILIN1 (elastin-microfibril-interface-located-protein-1) is a structural component of the elastic fiber network and localizes to the interface between the fibrillin microfibril scaffold and the elastin core. How EMILIN1 contributes to connective tissue integrity is not fully understood. Here, we report bi-allelic EMILIN1 loss-of-function variants causative for an entity combining cutis laxa, arterial tortuosity, aneurysm formation, and bone fragility, resembling autosomal-recessive cutis laxa type 1B, due to EFEMP2 (FBLN4) deficiency. In both humans and mice, absence of EMILIN1 impairs EFEMP2 extracellular matrix deposition and LOX activity resulting in impaired elastogenesis, reduced collagen crosslinking, and aberrant growth factor signaling. Collagen fiber ultrastructure and histopathology in EMILIN1- or EFEMP2-deficient skin and aorta corroborate these findings and murine Emilin1-/- femora show abnormal trabecular bone formation and strength. Altogether, EMILIN1 connects elastic fiber network with collagen fibril formation, relevant for both bone and vascular tissue homeostasis.
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| 20. |
- Balasubramanian, A. R., et al.
(author)
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Reachability in Continuous Pushdown VASS
- 2024
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In: Proceedings of the ACM on Programming Languages. - : Association for Computing Machinery (ACM). - 2475-1421. ; 8:POPL
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Journal article (peer-reviewed)abstract
- Pushdown Vector Addition Systems with States (PVASS) consist of finitely many control states, a pushdown stack, and a set of counters that can be incremented and decremented, but not tested for zero. Whether the reachability problem is decidable for PVASS is a long-standing open problem.We consider continuous PVASS, which are PVASS with a continuous semantics. This means, the counter values are rational numbers and whenever a vector is added to the current counter values, this vector is first scaled with an arbitrarily chosen rational factor between zero and one.We show that reachability in continuous PVASS is NEXPTIME-complete. Our result is unusually robust: Reachability can be decided in NEXPTIME even if all numbers are specified in binary. On the other hand, NEXPTIME-hardness already holds for coverability, in fixed dimension, for bounded stack, and even if all numbers are specified in unary.
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