Overexpression of alpha-synuclein at non-toxic levels increases dopaminergic cell death induced by copper exposure via modulation of protein degradation pathways

Gene multiplications or point mutations in alpha (α)-synuclein are associated with familial and sporadic Parkinson’s disease (PD). An increase in copper (Cu) levels has been reported in the cerebrospinal fluid and blood of PD patients, while occupational exposure to Cu has been suggested to augment the risk to develop PD. We aimed to elucidate the mechanisms by which α-synuclein and Cu regulate dopaminergic cell death. Short-term overexpression of WT or A53T α-synuclein had no toxic effect in human dopaminergic cells and primary midbrain cultures, but it exerted a synergistic effect on Cu-induced cell death. Cell death induced by Cu was potentiated by overexpression of the Cu transporter protein 1 (Ctr1) and depletion of intracellular glutathione (GSH) indicating that the toxic effects of Cu are linked to alterations in its intracellular homeostasis. Using the redox sensor roGFP, we demonstrated that Cu-induced oxidative stress was primarily localized in the cytosol and not in the mitochondria. However, α-synuclein overexpression had no effect on Cu-induced oxidative stress. WT or A53T α-synuclein overexpression exacerbated Cu toxicity in dopaminergic cells and yeast in the absence of α-synuclein aggregation. Cu increased autophagic flux and protein ubiquitination. Impairment of autophagy by overexpression of a dominant negative Atg5 form or inhibition of the ubiquitin/proteasome system (UPS) with MG132 enhanced Cu-induced cell death. However, only inhibition of the UPS stimulated the synergistic toxic effects of Cu and α-synuclein overexpression. Our results demonstrate that α-synuclein stimulates Cu toxicity in dopaminergic cells independent from its aggregation via modulation of protein degradation pathways

Indicaciones y utilidad de la inmunoglobulina por vía intravenosa en el manejo de polimiositis refractaria. Reporte de caso y revisión de la literatura

Las miopatías inflamatorias corresponden a un grupo heterogéneo de enfermedades adquiridas que comprometen el sistema muscular. Tienen en común la presencia de debilidad como síntoma predominante asociado a inflamación muscular. La polimiositis (PM) es una entidad subaguda que afecta principalmente adultos y compromete estructuras musculares proximales. En este artículo se presenta el caso de un paciente de 19 años de edad con diagnóstico confirmado de PM por clínica (compromiso muscular proximal, disfagia), por los resultados de las pruebas bioquímicas (elevación sérica de la creatina kinasa o CK), por estudio de la ultraestructura por microscopia óptica de alta resolución y por los resultados de la resonancia magnética nuclear (RMN) de músculo, quien fue refractario al manejo inicial con corticoesteroides, azatioprina y ciclofosfamida. Con la administración de inmunoglobulina por vía intravenosa se observa una respuesta clínica favorable con aumento progresivo de la fuerza muscular. A pesar de que los esteroides constituyen el tratamiento de elección, en los casos refractarios se usan los agentes inmunosupresores, y la recomendación para su utilización depende de la experiencia médica o conocimiento empírico y de los resultados de los estudios de análisis de seguridad y eficacia. La inmunoglobulina por vía IV es ampliamente usada en el tratamiento de varias enfermedades autoinmunes y su eficacia radica en el efecto inmunomodulador. Sin embargo, es necesario realizar estudios clínicos controlados adicionales, que evalúen su eficacia y seguridad en pacientes con PM

Miopatía por cuerpos de inclusión. Caso clínico y revisión de la literatura

La miositis por cuerpos de inclusión (MCI) es una patología poco común que se presenta en individuos mayores de 50 años y con mayor frecuencia en hombres; sin embargo, los síntomas pueden empezar 20 años antes de su diagnóstico. Hasta un 30% de los casos de miopatías inflamatorias pueden ser de MCI y su prevalencia varía en los diferentes países y grupos étnicos. Clínicamente se manifiesta como debilidad lentamente progresiva proximal y distal. En este artículo se presenta un caso de una paciente de 78 años con antecedentes previos de diabetes mellitus tipo 2, hipertensión arterial, e hipotiroidismo, con cuadro de 18 meses de evolución consistente en debilidad de miembros inferiores, incapacidad para subir y bajar escaleras, limitación en la marcha, acompañado de disestesias. Se realizó la medición de la creatin quinasa (CK) y su valor inicial fue 7820, la electromiografía y neuroconducciones mostraron polineuropatia axonal motora en las cuatro extremidades y miopatía inflamatoria. Se trató con glucorticoides a dosis de 1 mg/kg y después de seis meses de tratamiento no se observó mejoría. Se decide tomar biopsia muscular que mostró miopatía por cuerpos de inclusión, lo que explicó la falla terapéutica inicial. Este caso es interesante desde el punto de vista clínico, ya que no es frecuente la elevación de la CK en los niveles que presentó la paciente y por las múltiples comorbilidades asociadas

The Metacognitive Strategies of College Students in Emilio Aguinaldo College-Cavite, Philippines

In educational psychology, metacognition is regarded as a pivotal component of successful learning, involving awareness and control over one's cognitive processes. This paper investigates the metacognitive strategies employed by college students at Emilio Aguinaldo College - Cavite, Philippines, with a focus on how these strategies contribute to their academic and personal growth. The study pursued a mixed-methods research design, integrating a survey adapted from renowned Filipino scholars to ascertain the metacognitive approaches of 25 Teacher Education majors during the Academic Year 2021-2022. The findings illuminate that the predominant strategy among students is self-motivation, despite encountering distractions that impede their task performance. Interestingly, it also uncovers the resilience of these students in navigating educational challenges amid the pandemic, harnessing metacognition to enhance learning and fortify their future teaching vocations. However, the study's scope is confined to examining metacognitive strategy improvement, relying solely on the self-assessed metacognitive levels of the participants. This research contributes original insights into the metacognitive strategies within the unique context of Philippine higher education, centering on a select group of Education majors and their self-regulatory learning techniques

Cytokine inflammation state in non-alcoholic steatohepatitis surpasses that of chronic hepatits C and alcoholic liver disease

Increased serum levels of cytokines were reported in persistent inflammatory conditions such as non-alcoholic steatohepatitis (NASH), chronic hepatitis C (CHC) and alcoholic liver disease (ALD). The aim of this study was to compare cytokines IL-6, TNF-α, VEGF, EG-VEGF, BB-PDGF and ICAM-1 levels in these patients. Ninety patients seen in two Mexican outpatient clinics (Liver Unit, UANL and HIPAM and UNAM) were included: NASH (30), CHC (30) and ALD (30). Serum cytokines IL-6, TNF-α, VEGF, EG-VEGF, BB-PDGF and ICAM-1 were measured by ELISA. A statistically significant difference was found in 5/6 mediators studied in NASH patients vs. CHC and ALD. Regarding ICAM-1 (5.482±613 vs. 2.145±1011 vs. 1.830±1224 pg/mL; P<0.05; respectively), IL-6 (2.430±1506 vs. 726±735 vs. 516±603 pg/mL; P<0.05, respectively), TNF-α (3686±1409 vs. 677±747 vs. 437±70 pg/mL; P<0.05; respectively), VEFG (2.267±486 vs. 421±557 vs. 554±619 pg/mL; P<0.05; respectively) and EG-VEGF (2.146±1914 vs. 1.225±1388 vs. 799±1046 pg/mL; P<0.05; respectively). VEGF positively correlated with TNF-α(r+0.51 and P=0.004) in NASH and negatively in CHC (r-0.44 and P=0.01). The only positive correlation for BB-PDGF was with EG-VEGF levels (r=+0.41 and P=0.02). IL-6 exhibited a positive correlation vs. ICAM-1 in ALD (r+0.42 and P=0.02). We demonstrated a significant increase in pro-inflammatory cytokines (TNF-α, IL-6, VEGF and EG-VEGF) and ICAM-1 in patients with NASH. Correlations showed differential cytokine and adhesion molecule patterns on the basis of the liver disease etiology. These abnormalities in cytokine profile can influence the pathophysiology of liver injury

Discovery of a low-mass companion inside the debris ring surrounding the F5V star HD 206893

Aims: Uncovering the ingredients and the architecture of planetary systems is a very active field of research that has fuelled many new theories on giant planet formation, migration, composition, and interaction with the circumstellar environment. We aim at discovering and studying new such systems, to further expand our knowledge of how low-mass companions form and evolve. Methods: We obtained high-contrast H-band images of the circumstellar environment of the F5V star HD 206893, known to host a debris disc never detected in scattered light. These observations are part of the SPHERE High Angular Resolution Debris Disc Survey (SHARDDS) using the InfraRed Dual-band Imager and Spectrograph (IRDIS) installed on VLT/SPHERE. Results: We report the detection of a source with a contrast of 3.6 × 10[SUP]-5[/SUP] in the H-band, orbiting at a projected separation of 270 milliarcsec or 10 au, corresponding to a mass in the range 24 to 73 M[SUB]Jup[/SUB] for an age of the system in the range 0.2 to 2 Gyr. The detection was confirmed ten months later with VLT/NaCo, ruling out a background object with no proper motion. A faint extended emission compatible with the disc scattered light signal is also observed. Conclusions: The detection of a low-mass companion inside a massive debris disc makes this system an analog of other young planetary systems such as β Pictoris, HR 8799 or HD 95086 and requires now further characterisation of both components to understand their interactions.Peer reviewe

Crystal Structure of a Complex of DNA with One AT-Hook of HMGA1

We present here for the first time the crystal structure of an AT-hook domain. We show the structure of an AT-hook of the ubiquitous nuclear protein HMGA1, combined with the oligonucleotide d(CGAATTAATTCG)2, which has two potential AATT interacting groups. Interaction with only one of them is found. The structure presents analogies and significant differences with previous NMR studies: the AT-hook forms hydrogen bonds between main-chain NH groups and thymines in the minor groove, DNA is bent and the minor groove is widened

SARS-CoV-2 breakthrough infections among vaccinated individuals with rheumatic disease : Results from the COVID-19 Global Rheumatology Alliance provider registry

Funding Information: members of the COVID-19 Global Rheumatology Alliance and do not necessarily represent the views of the American College of Rheumatology (ACR), EULAR, the UK National Health Service (NHS), the National Institute for Health Research (NIHR), the UK Department of Health or any other organisation. Competing interests KLH reports she has received non-personal speaker’s fees from AbbVie and grant income from BMS, UCB and Pfizer, all unrelated to this manuscript; KLH is supported by the NIHR Manchester Biomedical Research Centre. LG reports personal consultant fees from AbbVie, Amgen, BMS, Biogen, Celgene, Gilead, Janssen, Lilly, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis and UCB, and grants from Amgen, Lilly, Janssen, Pfizer, Sandoz, Sanofi and Galapagos, all unrelated to this manuscript. AS reports research grants from a consortium of 14 companies (among them AbbVie, BMS, Celltrion, Fresenius Funding Information: Kabi, Gilead/Galapagos, Lilly, Mylan/Viatris, Hexal, MSD, Pfizer, Roche, Samsung, Sanofi-Aventis and UCB) supporting the German RABBIT register and personal fees from lectures for AbbVie, MSD, Roche, BMS, Lilly and Pfizer, all unrelated to this manuscript. LC has not received fees or personal grants from any laboratory, but her institute works by contract for laboratories among other institutions, such as AbbVie Spain, Eisai, Gebro Pharma, Merck Sharp & Dohme España, Novartis Farmaceutica, Pfizer, Roche Farma, Sanofi-Aventis, Astellas Pharma, Actelion Pharmaceuticals España, Grünenthal and UCB Pharma. EF-M reports personal consultant fees from Boehringer Ingelheim Portugal and that LPCDR received support for specific activities: grants from AbbVie, Novartis, Janssen-Cilag, Lilly Portugal, Sanofi, Grünenthal, MSD, Celgene, Medac, Pharmakern and GAfPA; grants and non-financial support from Pfizer; and non-financial support from Grünenthal, outside the submitted work. IB reports personal consultant fees from AbbVie, Novartis, Pfizer and Janssen, all unrelated to this manuscript. JZ reports speaker fees from AbbVie, Novartis and Janssen/Johnson & Johnson, all unrelated to this manuscript. GR-C reports personal consultant fees from Eli Lilly and Novartis, all unrelated to this manuscript. JS is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers: R01 AR077607, P30 AR070253 and P30 AR072577), and the R Bruce and Joan M Mickey Research Scholar Fund. JS has received research support from Amgen and Bristol Myers Squibb and performed consultancy for Bristol Myers Squibb, Gilead, Inova, Janssen and Optum, unrelated to this work. LW receives speaker’s bureau fees from Aurinia Pharma, unrelated to this manuscript. SB reports no competing interests related to this work. He reports non-branded consulting fees for AbbVie, Horizon and Novartis (all <$10 000). MGM has no competing interests related to this work. She serves as a patient consultant for BMS, BI JNJ and Aurinia (all <$10 000). RG reports no competing interests related to this work. Outside of this work she reports personal and/or speaking fees from AbbVie, Janssen, Novartis, Pfizer and Cornerstones and travel assistance from Pfizer (all <$10 000). JH reports no competing interests related to this work. He is supported by grants from the Rheumatology Research Foundation and has salary support from the Childhood Arthritis and Rheumatology Research Alliance. He has performed consulting for Novartis, Sobi and Biogen, all unrelated to this work (<$10 000). ESi reports non-financial support from Canadian Arthritis Patient Alliance, outside the submitted work. PS reports personal fees from the American College of Rheumatology/Wiley Publishing, outside the submitted work. ZW reports grant support from Bristol Myers Squibb and Principia/Sanofi and performed consultancy for Viela Bio and MedPace, outside the submitted work. His work is supported by grants from the National Institutes of Health. PMM has received consulting/speaker’s fees from AbbVie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this study. PMM is supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC). PCR reports no competing interests related to this work. Outside of this work PCR reports personal fees from AbbVie, Atom Bioscience, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Kukdong, Novartis, UCB, Roche and Pfizer; meeting attendance support from BMS, Pfizer and UCB; and grant funding from Janssen, Novartis, Pfizer and UCB Pharma (all <$10 000). JY reports no competing interests related to this work. Her work is supported by grants from the National Institutes of Health (K24 AR074534 and P30 AR070155). Outside of this work, she has received research grants or performed consulting for Gilead, BMS Foundation, Pfizer, Aurinia and AstraZeneca. Funding Information: Twitter Jean Liew @rheum_cat, Loreto Carmona @carmona_loreto, Pedro M Machado @pedrommcmachado and Philip C Robinson @philipcrobinson Contributors All authors contributed to the study design, data collection, interpretation of results and review/approval of the final submitted manuscript. JL and MG are guarantors for this manuscript. Funding MG reports grants from the National Institutes of Health, NIAMS, outside the submitted work. KLH is supported by the NIHR Manchester Biomedical Research Centre. JS is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers: R01 AR077607, P30 AR070253 and P30 AR072577), and the R Bruce and Joan M Mickey Research Scholar Fund. JH is supported by grants from the Rheumatology Research Foundation. ZW is supported by grants from the National Institutes of Health. PMM is supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC). JY is supported by grants from the National Institutes of Health (K24 AR074534 and P30 AR070155). Publisher Copyright: ©Objective. While COVID-19 vaccination prevents severe infections, poor immunogenicity in immunocompromised people threatens vaccine effectiveness. We analysed the clinical characteristics of patients with rheumatic disease who developed breakthrough COVID-19 after vaccination against SARS-CoV-2.  Methods. We included people partially or fully vaccinated against SARS-CoV-2 who developed COVID-19 between 5 January and 30 September 2021 and were reported to the Global Rheumatology Alliance registry. Breakthrough infections were defined as occurring ≥14 days after completion of the vaccination series, specifically 14 days after the second dose in a two-dose series or 14 days after a single-dose vaccine. We analysed patients' demographic and clinical characteristics and COVID-19 symptoms and outcomes. Results SARS-CoV-2 infection was reported in 197 partially or fully vaccinated people with rheumatic disease (mean age 54 years, 77% female, 56% white). The majority (n=140/197, 71%) received messenger RNA vaccines. Among the fully vaccinated (n=87), infection occurred a mean of 112 (±60) days after the second vaccine dose. Among those fully vaccinated and hospitalised (n=22, age range 36-83 years), nine had used B cell-depleting therapy (BCDT), with six as monotherapy, at the time of vaccination. Three were on mycophenolate. The majority (n=14/22, 64%) were not taking systemic glucocorticoids. Eight patients had pre-existing lung disease and five patients died. Conclusion. More than half of fully vaccinated individuals with breakthrough infections requiring hospitalisation were on BCDT or mycophenolate. Further risk mitigation strategies are likely needed to protect this selected high-risk population.publishersversionPeer reviewe