The regulated expression of chimeric tyrosine hydroxylase–insulin transcripts during early development

Biological complexity does not appear to be simply correlated with gene number but rather other mechanisms contribute to the morphological and functional diversity across phyla. Such mechanisms regulate different transcriptional, translational and post-translational processes and include the recently identified transcription induced chimerism (TIC). We have found two novel chimeric transcripts in the chick and quail that result from the fusion of tyrosine hydroxylase (TH) and insulin into a single mature transcript. The th and insulin genes are located in tandem and they are generally transcribed independently. However, it appears that two chimeric transcripts containing exons from both the genes can also be produced in a regulated manner. The TH–INS1 and TH–INS2 chimeras differ in their insulin gene content, and they encode two novel isoforms of the TH protein with markedly reduced functionality when compared with the canonical TH. In addition, the TH–INS1 chimeric mRNA generates a small amount of insulin. We propose that TIC is an additional mechanism that can be employed to further regulate TH and insulin expression according to the specific needs of developing vertebrates

Muerte neural temprana: un proceso inadvertido en el desarrollo del sistema nervioso.

15 p.-7 fig.[EN]During the development of the vertebrate nervous system, multiple physiological processes are involved in the generation of its complex cytoarchitecture and functionality. Among them, programmed cell death has been recognized as a key process that affects connecting neurons. By contrast, there is limited information available regarding the cell death that affects neuroepithelial cells, and recently born neurons and glia, hindering the comprehensive understanding of neural development. We have demonstrated that exquisitely regulated PCD occurs during early stages of neural development such as neurulation and neurogenesis. We have characterized how survival signals from proteins like proinsulin/insulin, c-Raf, and HSC70 counteract caspase-dependent apoptosis, which affects neuroepithelial cells proliferation and the generation of retinal ganglion cells. Furthermore, the characterization of these physiological signals during retinal neurogenesis has the potential to provide new therapeutic tools to attenuate retinal neurodegeneration.[ES]Durante el desarrollo del sistema nervioso de vertebrados, múltiples procesos fisiológicos participan en la generación de su compleja arquitectura celular y funcionalidad. Entre ellos, la muerte celular programada que afecta a neuronas de conexión está reconocido como un proceso fundamental. Por otro lado, hay escasa información disponible acerca de la muerte celular que afecta a células neuroepiteliales y a neuronas y glía recién nacidas, lo que impide que tengamos una noción completa sobre el desarrollo neural. Los estudios de nuestro laboratorio han demostrado que la muerte celular programada se encuentra finamente regulada y ocurre en etapas tan tempranas del desarrollo como la neurulación o la neurogénesis. Hemos caracterizado el papel que moléculas de supervivencia, como la proinsulina/insulina, c-Raf o HSC70, desempeñan bloqueando la apoptosis dependiente de caspasas, proceso que afecta a células neuroepiteliales proliferativas, así como a la generación de las células ganglionares de la retina. Es más, la caracterización de estas señales fisiológicas originadas durante la neurogénesis de la retina nos ha proporcionado una nueva herramienta terapéutica potencial para el tratamiento y atenuación de las neurodegeneraciones retinianas.Research in the laboratory is funded by grants-in-aid from the Spanish Ministerio de Educación y Ciencia (SAF2007-66175-C02-01 to EJdlR, BFU2007-61055/BMC to FdP, and BFU2006-00508 to PB).Peer reviewe

Ghrelin Facilitates GLUT2-, SGLT1- and SGLT2-mediated Intestinal Glucose Transport in Goldfish (Carassius auratus)

Glucose homeostasis is an important biological process that involves a variety of regulatory mechanisms. This study aimed to determine whether ghrelin, a multifunctional gut-brain hormone, modulates intestinal glucose transport in goldfish (Carassius auratus). Three intestinal glucose transporters, the facilitative glucose transporter 2 (GLUT2), and the sodium/glucose co-transporters 1 (SGLT1) and 2 (SGLT2), were studied. Immunostaining of intestinal sections found colocalization of ghrelin and GLUT2 and SGLT2 in mucosal cells. Some cells containing GLUT2, SGLT1 and SGLT2 coexpressed the ghrelin/growth hormone secretagogue receptor 1a (GHS-R1a). Intraperitoneal glucose administration led to a significant increase in serum ghrelin levels, as well as an upregulation of intestinal preproghrelin, ghrelin O-acyltransferase and ghs-r1 expression. In vivo and in vitro ghrelin treatment caused a concentration- and time-dependent modulation (mainly stimulatory) of GLUT2, SGLT1 and SGLT2. These effects were abolished by the GHS-R1a antagonist [D-Lys3]-GHRP-6 and the phospholipase C inhibitor U73122, suggesting that ghrelin actions on glucose transporters are mediated by GHS-R1a via the PLC/PKC signaling pathway. Finally, ghrelin stimulated the translocation of GLUT2 into the plasma membrane of goldfish primary intestinal cells. Overall, data reported here indicate an important role for ghrelin in the modulation of glucoregulatory machinery and glucose homeostasis in fish

Influenza vaccine effectiveness against influenza A subtypes in Europe: Results from the 2021-2022 I-MOVE primary care multicentre study

Background: In 2021-2022, influenza A viruses dominated in Europe. The I-MOVE primary care network conducted a multicentre test-negative study to measure influenza vaccine effectiveness (VE). Methods: Primary care practitioners collected information on patients presenting with acute respiratory infection. Cases were influenza A(H3N2) or A(H1N1)pdm09 RT-PCR positive, and controls were influenza virus negative. We calculated VE using logistic regression, adjusting for study site, age, sex, onset date, and presence of chronic conditions. Results: Between week 40 2021 and week 20 2022, we included over 11 000 patients of whom 253 and 1595 were positive for influenza A(H1N1)pdm09 and A(H3N2), respectively. Overall VE against influenza A(H1N1)pdm09 was 75% (95% CI: 43-89) and 81% (95% CI: 45-93) among those aged 15-64 years. Overall VE against influenza A(H3N2) was 29% (95% CI: 12-42) and 25% (95% CI: -41 to 61), 33% (95% CI: 14-49), and 26% (95% CI: -22 to 55) among those aged 0-14, 15-64, and over 65 years, respectively. The A(H3N2) VE among the influenza vaccination target group was 20% (95% CI: -6 to 39). All 53 sequenced A(H1N1)pdm09 viruses belonged to clade 6B.1A.5a.1. Among 410 sequenced influenza A(H3N2) viruses, all but eight belonged to clade 3C.2a1b.2a.2. Discussion: Despite antigenic mismatch between vaccine and circulating strains for influenza A(H3N2) and A(H1N1)pdm09, 2021-2022 VE estimates against circulating influenza A(H1N1)pdm09 were the highest within the I-MOVE network since the 2009 influenza pandemic. VE against A(H3N2) was lower than A(H1N1)pdm09, but at least one in five individuals vaccinated against influenza were protected against presentation to primary care with laboratory-confirmed influenza.This project has received funding from the European Centre for Disease Prevention and Control with in the framework contract ECDC/2018/029.S

Vaccine effectiveness against symptomatic SARS-CoV-2 infection in adults aged 65 years and older in primary care: I-MOVE-COVID-19 project, Europe, December 2020 to May 2021

I-MOVE-COVID-19 primary care study team (in addition to authors above): Nick Andrews, Jamie Lopez Bernal, Heather Whitaker, Caroline Guerrisi, Titouan Launay, Shirley Masse, Sylvie van der Werf, Vincent Enouf, John Cuddihy, Adele McKenna, Michael Joyce, Cillian de Gascun, Joanne Moran, Ana Miqueleiz, Ana Navascués, Camino Trobajo-Sanmartín, Carmen Ezpeleta, Paula López Moreno, Javier Gorricho, Eva Ardanaz, Fernando Baigorria, Aurelio Barricarte, Enrique de la Cruz, Nerea Egüés, Manuel García Cenoz, Marcela Guevara, Conchi Moreno-Iribas, Carmen Sayón, Verónica Gomez, Baltazar Nunes, Rita Roquete, Adriana Silva, Aryse Melo, Inês Costa, Nuno Verdasca, Patrícia Conde, Diogo FP Marques, Anna Molesworth, Leanne Quinn, Miranda Leyton, Selin Campbell, Janine Thoulass, Jim McMenamin, Ana Martínez Mateo, Luca Basile, Daniel Castrillejo, Carmen Quiñones Rubio, Concepción Delgado-Sanz, Jesús Oliva.The I-MOVE-COVID-19 network collates epidemiological and clinical information on patients with coronavirus disease (COVID-19), including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virological characterisation in 11 European countries [1]. One component of I-MOVE-COVID-19 is the multicentre vaccine effectiveness (VE) study at primary care/outpatient level in nine European study sites in eight countries. We measured overall and product-specific COVID-19 VE against symptomatic SARS-CoV-2 infection among those aged 65 years and older. We also measured VE by time since vaccination.This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101003673.info:eu-repo/semantics/publishedVersio

2015/16 seasonal vaccine effectiveness against hospitalisation with influenza a(H1N1)pdm09 and B among elderly people in Europe: Results from the I-MOVE+ project

We conducted a multicentre test-negative caseâ\u80\u93control study in 27 hospitals of 11 European countries to measure 2015/16 influenza vaccine effectiveness (IVE) against hospitalised influenza A(H1N1)pdm09 and B among people aged â\u89¥ 65 years. Patients swabbed within 7 days after onset of symptoms compatible with severe acute respiratory infection were included. Information on demographics, vaccination and underlying conditions was collected. Using logistic regression, we measured IVE adjusted for potential confounders. We included 355 influenza A(H1N1)pdm09 cases, 110 influenza B cases, and 1,274 controls. Adjusted IVE against influenza A(H1N1)pdm09 was 42% (95% confidence interval (CI): 22 to 57). It was 59% (95% CI: 23 to 78), 48% (95% CI: 5 to 71), 43% (95% CI: 8 to 65) and 39% (95% CI: 7 to 60) in patients with diabetes mellitus, cancer, lung and heart disease, respectively. Adjusted IVE against influenza B was 52% (95% CI: 24 to 70). It was 62% (95% CI: 5 to 85), 60% (95% CI: 18 to 80) and 36% (95% CI: -23 to 67) in patients with diabetes mellitus, lung and heart disease, respectively. 2015/16 IVE estimates against hospitalised influenza in elderly people was moderate against influenza A(H1N1)pdm09 and B, including among those with diabetes mellitus, cancer, lung or heart diseases

Early neural cell death: numbers and cues from the developing neuroretina

14 páginas, 8 figuras, 13 tablas -- PAGS nros. 1515-1528Programmed cell death is a well established key process required for proper development of the nervous system. The regulatory and executor mechanisms controlling survival/death of projection neurons, as well as of other types of differentiated neurons and glial cells, have been studied intensely during neural development. Much less attention has been paid to earlier cell death events affecting neuroepithelial cells and recently born neurons and glial cells. We review here the reports on cell death during vertebrate retina development, our model system for many years, which has provided clear evidence of the importance of early neural cell death. We tentatively categorize the available observations in three death phases, namely morphogenetic cell death, early neural cell death and neurotrophic cell death. The magnitude and the precise regulation of the early phases of cell death are fully comparable to the much better characterized neurotrophic cell death. Therefore, early neural cell death deserves a profound dedicated study; this will help to obtain an integrated understanding of the development of the retina and other parts of the vertebrate nervous systemResearch in our group is supported by grants from Ministerio de Educación y Ciencia (SAF2007-66175 to EJdlR and BFU2006-00508 to PB) and from Comunidad de Madrid (CCG06-CSIC/SAL-0821 to PB). PB is a Ramón y Cajal FellowPeer reviewe

Generation of retinal ganglion cells is modulated by caspase-dependent programmed cell death

Programmed cell death occurs during both early and late neural development. The mechanisms for the regulation and execution of the early cell death as well as its developmental role are still not fully understood. In this work we have studied the early programmed cell death in the retinal neuroepithelium. Apoptotic cells were selectively located around the optic nerve head in the retinal neuroepithelium of 2- to 6-day-old chick embryos. TUNEL-positive cells and cells which were immunostained for activated caspase-3 showed overlapping distributions suggesting that caspase-3 is involved in the early retinal cell death. Caspase-3 involvement in early retinal cell death was also demonstrated by in vivo treatment with caspase inhibitors z-DEVD-fmk and Boc-D-fmk. After 6 h of treatment, the number of TUNEL-positive cells was reduced by 50%. Sustained treatments (20 h) resulted in a slight widening in the central part of the neural retina but the retinal ganglion cell axons maintained their organization and navigation towards the optic fissure. The most prominent result after inhibition of cell death was an increase in the number of retinal ganglion cells which also produced an enlargement of the ganglion cell layer and an increased number of ganglion cell axons. In conclusion, our results show that caspase-dependent programmed cell death occurs in the embryonic chick retina and that it plays a role to modulate the generation of retinal ganglion cells.The work was supported by the Swedish Research Council (12187, 08904), Mattson's, Göran Gustavsson's, KMA and KA Wallenberg's (CN 2000.13) Research Foundations and the Spanish Ministry of Science and Technology (PM99-0094). A.I.V. was supported by Comunidad Autónoma de Madrid and R.M. by Junta de Extremadura (BRV0100049 and MOV02A092)Peer Reviewe

Cell death in the nervous system: Lessons from insulin and insulin-like growth factors

Programmed cell death is an essential process for proper neural development. Cell death, with its similar regulatory and executory mechanisms, also contributes to the origin or progression of many or even all neurodegenerative diseases. An understanding of the mechanisms that regulate cell death during neural development may provide new targets and tools to prevent neurodegeneration. Many studies that have focused mainly on insulin-like growth factor-I (IGF-I), have shown that insulin-related growth factors are widely expressed in the developing and adult nervous system, and positively modulate a number of processes during neural development, as well as in adult neuronal and glial physiology. These factors also show neuroprotective effects following neural damage. Although some specific actions have been demonstrated to be anti-apoptotic, we propose that a broad neuroprotective role is the foundation for many of the observed functions of the insulin-related growth factors, whose therapeutical potential for nervous system disorders may be greater than currently acceptedResearch in the authors’ lab is supported by grants from Dirección General de Investigación Científica y Tecnológica PM99-0111 to I. V.-N. and PM99-0094 to E. J. de la R.Peer Reviewe