Catalytic Asymmetric Synthesis of Bicycloprolines by a 1,3-Dipolar Cycloaddition/Intramolecular Alkylation Strategy

This document is the Accepted Manuscript version of a Published Work that appeared in final form inJournal of Organic Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/acs.joc.6b01100 to Published Work, see http://pubs.acs.org/page/policy/articlesonrequest/index.htmlThe diastereoselective one-pot synthesis of hexahydrocyclopenta [b] pyrrole derivatives (bicycloprolines) has been achieved by base-mediated reactions of (E)-tert-butyl 6-bromo-2-hexenoate with α-imino esters. The catalytic asymmetric version of this process has been efficiently achieved using the CuI/(R)-DTBM-Segphos complex as a catalyst following a two-step 1,3-dipolar cycloaddition/intramolecular alkylation sequence.Financial support of this work by the Ministerio de Economía y Competitividad and Fondo Europeo de Desarrollo Regional (MINECO CTQ2012-35790 and MINECO/FEDER CTQ2015-66954-P) are gratefully acknowledged. M.G.-E. and A.P.-E. thank the MICINN for predoctoral fellowship

La relación médico-paciente en el tratamiento de la diabetes tipo 1. Un estudio cualitativo

ObjetivosConocer las experiencias y las expectativas de pacientes con diabetes tipo 1 (DM1) y sus familiares sobre la relación que establecen con sus médicos y su influencia en la forma de afrontar la enfermedad y el tratamiento.DiseñoDiseño cualitativo a través de grupos focales realizado en 2001.EmplazamientoDistintos centros sanitarios de Granada y Sevilla.ParticipantesPacientes con DM1, familiars y/o cuidadores.MétodoMuestreo teórico con representación de los perfiles más característicos. Procedimiento de análisis cualitativo: asignación de códigos al texto, triangulación e interpretación de resultados.ResultadosLa relación médico-paciente influye decisivamente en la vivencia emocional de la enfermedad y en la manera en que los pacientes asumen el control. Los pacientes entrevistados aseguran que la relación con sus médicos está centrada en los signos y los síntomas de la enfermedad, y que el aspecto emocional se deja de lado. Es frecuente que los profesionales basen su comunicación en la reprimenda y en la amenaza. Los tratamientos se imponen más que se consensúan, y las posibilidades de participación en las decisiones clínicas son escasas. En consecuencia, los pacientes desarrollan estrategias para tomar sus propias decisiones sobre el tratamiento adaptándolo a su vida.ConclusionesDesean un modelo de relación con sus médicos en el que les escuchen, empaticen con su situación, comprendan los problemas que enfrentan para seguir el tratamiento, les transmitan ánimos y adapten sus recomendaciones a las circunstancias vitales y emocionales de cada paciente. Se prefiere a los profesionales que combinan la competencia técnica (incluida la dimensión relacional) con la humanidad y la amabilidad, y que asumen su corresponsabilidad en el éxito del tratamiento.ObjectivesTo know the experiences and expectations of diabetes mellitus type 1 (DM1) patients and their relatives as regards the relationships established with doctors, and the impact of such relationships on their strategies to cope with the disease and treatment.DesignQualitative design based on focus groups conducted in 2001.LocationSeveral health care centres in Granada and Seville, Spain.ParticipantsDM1 patients and their relatives and/or carers.MethodTheory-based sampling including the most representative profiles. Qualitative analysis procedure: text coding, triangulation and interpretation of results.ResultsDoctor/patient relationship highly influences the emotional experience of disease and the way patients gain control over it. Interviewed patients said that the relationship with doctors is focused on disease signs and symptoms, leaving emotional aspects aside. Very often, provider communication is built on recrimination and threat. Treatment is imposed rather than agreed, with scarce opportunities for participating in clinical decisions. Patients develop strategies to take their own decisions and adapting treatment to their daily life.ConclusionsPatients value a relationship model whereby providers listen and empathise with their situation, understand their difficulties in treatment compliance, encourage them, and adapt recommendations to the personal and emotional circumstances of each patient. They prefer doctors combining professional competence-including relational skills-with humanity and kindness, as well as being capable of assuming their co-responsibility in treatment success

MAGIC detection of GRB 201216C at z = 1.1

H. Abe et al.Gamma-ray bursts (GRBs) are explosive transient events occurring at cosmological distances, releasing a large amount of energy as electromagnetic radiation over several energy bands. We report the detection of the long GRB 201216C by the MAGIC telescopes. The source is located at z = 1.1 and thus it is the farthest one detected at very high energies. The emission above 70 GeV of GRB 201216C is modelled together with multiwavelength data within a synchrotron and synchrotron self-Compton (SSC) scenario. We find that SSC can explain the broad-band data well from the optical to the very-high-energy band. For the late-time radio data, a different component is needed to account for the observed emission. Differently from previous GRBs detected in the very-high-energy range, the model for GRB 201216C strongly favours a wind-like medium. The model parameters have values similar to those found in past studies of the afterglows of GRBs detected up to GeV energies.The financial support of the German BMBF, MPG, and HGF; the Italian INFN and INAF; the Swiss National Fund SNF; the grants PID2019-104114RB-C31, PID2019-104114RB-C32, PID2019-104114RB-C33, PID2019-105510GB-C31, PID2019-107847RB-C41, PID2019-107847RB-C42, PID2019-107847RB-C44, PID2019-107988GB-C22, PID2020-118491GB-I00 funded by the Spanish MCIN/AEI/ 10.13039/501100011033; the Indian Department of Atomic Energy; the Japanese ICRR, the University of Tokyo, JSPS, and MEXT; the Bulgarian Ministry of Education and Science, National RI Roadmap Project DO1-400/18.12.2020 and the Academy of Finland grant number 320045 is gratefully acknowledged. This work was also been supported by Centros de Excelencia ‘Severo Ochoa’ y Unidades ‘María de Maeztu’ programme of the Spanish MCIN/AEI/ 10.13039/501100011033 (SEV-2016-0588, CEX2019-000920-S, CEX2019-000918-M, CEX2021-001131-S, MDM-2015-0509-18-2) and by the CERCA institution of the Generalitat de Catalunya; by the Croatian Science Foundation (HrZZ) Project IP-2016-06-9782 and the University of Rijeka Project uniri-prirod-18-48; by the Deutsche Forschungsgemeinschaft (SFB1491 and SFB876); the Polish Ministry Of Education and Science grant number 2021/WK/08; and by the Brazilian MCTIC, CNPq, and FAPERJ. This work was supported by JSPS KAKENHI grant number JP21K20368. LN acknowledges partial support from the INAF Mini-grant ‘Shock acceleration in Gamma Ray Bursts’.With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX2019-000918-M).With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX2019-000920-S).With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX2021-001131-S).Peer reviewe

Performance and first measurements of the MAGIC stellar intensity interferometer

In recent years, a new generation of optical intensity interferometers has emerged, leveraging the existing infrastructure of Imaging Atmospheric Cherenkov Telescopes (IACTs). The MAGIC telescopes host the MAGIC-SII system (Stellar Intensity Interferometer), implemented to investigate the feasibility and potential of this technique on IACTs. After the first successful measurements in 2019, the system was upgraded and now features a real-time, dead-time-free, 4-channel, GPU-based correlator. These hardware modifications allow seamless transitions between MAGIC’s standard very-high-energy gamma-ray observations and optical interferometry measurements within seconds. We establish the feasibility and potential of employing IACTs as competitive optical Intensity Interferometers with minimal hardware adjustments. The measurement of a total of 22 stellar diameters are reported, 9 corresponding to reference stars with previous comparable measurements, and 13 with no prior measurements. A prospective implementation involving telescopes from the forthcoming Cherenkov Telescope Array Observatory’s Northern hemisphere array, such as the first prototype of its Large-Sized Telescopes, LST-1, is technically viable. This integration would significantly enhance the sensitivity of the current system and broaden the UV-plane coverage. This advancement would enable the system to achieve competitive sensitivity with the current generation of long-baseline optical interferometers over blue wavelengths

MAGIC detection of GRB 201216C at z = 1.1

Gamma-ray bursts (GRBs) are explosive transient events occurring at cosmological distances, releasing a large amount of energy as electromagnetic radiation over several energy bands. We report the detection of the long GRB 201216C by the MAGIC telescopes. The source is located at z = 1.1 and thus it is the farthest one detected at very high energies. The emission above 70 GeV of GRB 201216C is modelled together with multiwavelength data within a synchrotron and synchrotron self-Compton (SSC) scenario. We find that SSC can explain the broad-band data well from the optical to the very-high-energy band. For the late-time radio data, a different component is needed to account for the observed emission. Differently from previous GRBs detected in the very-high-energy range, the model for GRB 201216C strongly favours a wind-like medium. The model parameters have values similar to those found in past studies of the afterglows of GRBs detected up to GeV energies

Constraints on axion-like particles with the Perseus Galaxy Cluster with MAGIC

Axion-like particles (ALPs) are pseudo-Nambu-Goldstone bosons that emerge in various theories beyond the standard model. These particles can interact with high-energy photons in external magnetic fields, influencing the observed gamma-ray spectrum. This study analyzes 41.3 hrs of observational data from the Perseus Galaxy Cluster collected with the MAGIC telescopes. We focused on the spectra the radio galaxy in the center of the cluster: NGC 1275. By modeling the magnetic field surrounding this target, we searched for spectral indications of ALP presence. Despite finding no statistical evidence of ALP signatures, we were able to exclude ALP models in the sub-micro electronvolt range. Our analysis improved upon previous work by calculating the full likelihood and statistical coverage for all considered models across the parameter space. Consequently, we achieved the most stringent limits to date for ALP masses around 50 neV, with cross sections down to $g_{a\gamma} = 3 \times 10^{-12}$ GeV$^{-1}$.Comment: 25 pages, 10 figures, accepted for publication in Physics of the Dark Univers

Multimessenger Characterization of Markarian 501 during Historically Low X-Ray and γ-Ray Activity

We study the broadband emission of Mrk 501 using multiwavelength observations from 2017 to 2020 performed with a multitude of instruments, involving, among others, MAGIC, Fermi's Large Area Telescope (LAT), NuSTAR, Swift, GASP-WEBT, and the Owens Valley Radio Observatory. Mrk 501 showed an extremely low broadband activity, which may help to unravel its baseline emission. Nonetheless, significant flux variations are detected at all wave bands, with the highest occurring at X-rays and very-high-energy (VHE) 3-rays. A significant correlation (>3σ) between X-rays and VHE 3-rays is measured, supporting leptonic scenarios to explain the variable parts of the emission, also during low activity. This is further supported when we extend our data from 2008 to 2020, and identify, for the first time, significant correlations between the Swift X-Ray Telescope and Fermi-LAT. We additionally find correlations between high-energy 3-rays and radio, with the radio lagging by more than 100 days, placing the 3-ray emission zone upstream of the radio-bright regions in the jet. Furthermore, Mrk 501 showed a historically low activity in X-rays and VHE 3-rays from mid-2017 to mid-2019 with a stable VHE flux (>0.2 TeV) of 5% the emission of the Crab Nebula. The broadband spectral energy distribution (SED) of this 2 yr long low state, the potential baseline emission of Mrk 501, can be characterized with one-zone leptonic models, and with (lepto)-hadronic models fulfilling neutrino flux constraints from IceCube. We explore the time evolution of the SED toward the low state, revealing that the stable baseline emission may be ascribed to a standing shock, and the variable emission to an additional expanding or traveling shock. © 2023. The Author(s). Published by the American Astronomical Society

MAGIC observations provide compelling evidence of hadronic multi-TeV emission from the putative PeVatron SNR G106.3+2.7

Context. Certain types of supernova remnants (SNRs) in our Galaxy are assumed to be PeVatrons, capable of accelerating cosmic rays (CRs) to ∼ PeV energies. However, conclusive observational evidence for this has not yet been found. The SNR G106.3+2.7, detected at 1- 100 TeV energies by different γ-ray facilities, is one of the most promising PeVatron candidates. This SNR has a cometary shape, which can be divided into a head and a tail region with different physical conditions. However, in which region the 100 TeV emission is produced has not yet been identified because of the limited position accuracy and/or angular resolution of existing observational data. Additionally, it remains unclear as to whether the origin of the γ-ray emission is leptonic or hadronic. Aims. With the better angular resolution provided by new MAGIC data compared to earlier γ-ray datasets, we aim to reveal the acceleration site of PeV particles and the emission mechanism by resolving the SNR G106.3+2.7 with 0.1 resolution at TeV energies. Methods. We observed the SNR G106.3+2.7 using the MAGIC telescopes for 121.7 h in total - after quality cuts - between May 2017 and August 2019. The analysis energy threshold is ∼0.2 TeV, and the angular resolution is 0.07-0.1. We examined the γ-ray spectra of different parts of the emission, whilst benefitting from the unprecedented statistics and angular resolution at these energies provided by our new data. We also used measurements at other wavelengths such as radio, X-rays, GeV γ-rays, and 10 TeV γ-rays to model the emission mechanism precisely. Results. We detect extended γ-ray emission spatially coincident with the radio continuum emission at the head and tail of SNR G106.3+2.7. The fact that we detect a significant γ-ray emission with energies above 6.0 TeV from only the tail region suggests that the emissions above 10 TeV detected with air shower experiments (Milagro, HAWC, Tibet ASγ and LHAASO) are emitted only from the SNR tail. Under this assumption, the multi-wavelength spectrum of the head region can be explained with either hadronic or leptonic models, while the leptonic model for the tail region is in contradiction with the emission above 10 TeV and X-rays. In contrast, the hadronic model could reproduce the observed spectrum at the tail by assuming a proton spectrum with a cutoff energy of ∼1 PeV for that region. Such high-energy emission in this middle-aged SNR (4-10 kyr) can be explained by considering a scenario where protons escaping from the SNR in the past interact with surrounding dense gases at present. Conclusions. The γ-ray emission region detected with the MAGIC telescopes in the SNR G106.3+2.7 is extended and spatially coincident with the radio continuum morphology. The multi-wavelength spectrum of the emission from the tail region suggests proton acceleration up to ∼PeV, while the emission mechanism of the head region could either be hadronic or leptonic

MAGIC observations provide compelling evidence of the hadronic multi-TeV emission from the putative PeVatron SNR G106.3+2.7

The SNR G106.3+2.7, detected at 1--100 TeV energies by different $\gamma$-ray facilities, is one of the most promising PeVatron candidates. This SNR has a cometary shape which can be divided into a head and a tail region with different physical conditions. However, it is not identified in which region the 100 TeV emission is produced due to the limited position accuracy and/or angular resolution of existing observational data. Additionally, it remains unclear whether the origin of the $\gamma$-ray emission is leptonic or hadronic. With the better angular resolution provided by these new MAGIC data compared to earlier $\gamma$-ray datasets, we aim to reveal the acceleration site of PeV particles and the emission mechanism by resolving the SNR G106.3+2.7 with 0.1$^\circ$ resolution at TeV energies. We detected extended $\gamma$-ray emission spatially coincident with the radio continuum emission at the head and tail of SNR G106.3+2.7. The fact that we detected a significant $\gamma$-ray emission with energies above 6.0 TeV from the tail region only suggests that the emissions above 10 TeV, detected with air shower experiments (Milagro, HAWC, Tibet AS$\gamma$ and LHAASO), are emitted only from the SNR tail. Under this assumption, the multi-wavelength spectrum of the head region can be explained with either hadronic or leptonic models, while the leptonic model for the tail region is in contradiction with the emission above 10 TeV and X-rays. In contrast, the hadronic model could reproduce the observed spectrum at the tail by assuming a proton spectrum with a cutoff energy of $\sim 1$ PeV for the tail region. Such a high energy emission in this middle-aged SNR (4--10 kyr) can be explained by considering the scenario that protons escaping from the SNR in the past interact with surrounding dense gases at present.Comment: 13 pages, 7 figures, Accepted for publication in A&