Characterization of endogenous Kv1.3 channel isoforms in T cells

Producción CientíficaVoltage-dependent potassium channel Kv1.3 plays a key role on T-cell activation; however, lack of reliable antibodies has prevented its accurate detection under endogenous circumstances. To overcome this limitation, we created a Jurkat T-cell line with endogenous Kv1.3 channel tagged, to determine the expression, location, and changes upon activation of the native Kv1.3 channels. CRISPR-Cas9 technique was used to insert a Flag-Myc peptide at the C terminus of the KCNA3 gene. Basal or activated channel expression was studied using western blot analysis and imaging techniques. We identified two isoforms of Kv1.3 other than the canonical channel (54 KDa) differing on their N terminus: a longer isoform (70 KDa) and a truncated isoform (43 KDa). All three isoforms were upregulated after T-cell activation. We focused on the functional characterization of the truncated isoform (short form, SF), because it has not been previously described and could be present in the available Kv1.3−/− mice models. Overexpression of SF in HEK cells elicited small amplitude Kv1.3-like currents, which, contrary to canonical Kv1.3, did not induce HEK proliferation. To explore the role of endogenous SF isoform in a native system, we generated both a knockout Jurkat clone and a clone expressing only the SF isoform. Although the canonical isoform (long form) localizes mainly at the plasma membrane, SF remains intracellular, accumulating perinuclearly. Accordingly, SF Jurkat cells did not show Kv1.3 currents and exhibited depolarized resting membrane potential (VM), decreased Ca2+ influx, and a reduction in the [Ca2+]i increase upon stimulation. Functional characterization of these Kv1.3 channel isoforms showed their differential contribution to signaling pathways involved in formation of the immunological synapse. We conclude that alternative translation initiation generates at least three endogenous Kv1.3 channel isoforms in T cells that exhibit different functional roles. For some of these functions, Kv1.3 proteins do not need to form functional plasma membrane channels.Ministerio de Economía y Competitividad (grant PID 2020‐118517RB‐I00)Junta de Castilla y León (grants VA172P20) and (CLU-2019-02)Funds from Institut Curie, INSERM,Agence Nationale de la Recherche RetroTact (ANR‐20CE15‐0009‐01,ANR‐10‐IDEX‐0001‐02 PSL*, and ANR‐11‐LABX‐0043)Fondation pour la Recherche Médicale FRM (EQU202003010280

Comparison between Holocene recent pollen sequences of Calvero de la Higuera archaeopalaeontological site (Pinilla del Valle, Madrid) and Rascafria peat-bog (Madrid)

El análisis polínico de una turbera (Rascafría) y dos sitios arqueopaleontológicos (Cueva de la Buena Pinta y el Abrigo de Navalmaíllo pertenecientes al yacimiento Calvero de la Higuera, Pinilla del Valle, Madrid) han permitido reconstruir la dinámica de las comunidades vegetales de los últimos 5000 años, así como las características de la antropización desde la Prehistoria hasta la actualidad. Los registros polínicos holocenos de esta región permiten interpretar el tránsito desde unas condiciones más o menos forestales, caracterizadas por la profusión de pinares y melojares, así como de otros elementos mesófilos como el abedul, a la instalación progresiva de un medio forestal abierto y la proliferación de unidades de paisaje relacionadas con la antropización del medio. Un paleopaisaje de pastizales vivaces dedicados a actividades ganaderas trashumantes y transterminantes define diferentes niveles de presión antrópica. En particular, se ha podido determinar que los primeros eventos claros de antropización y deforestación de los bosques del Valle del Lozoya ocurrieron durante el III milenio cal. BC y que la fisionomía actual del paisaje en el área es la misma desde la Edad Media.The pollen analysis of a peat bogs (Rascafría), two archaeopalaeontological sites (Buena Pinta Cave and Navalmaíllo Rockshelter, located in the Calvero de la Higuera Place, Pinilla del Valle, Madrid)) allowed to reconstruct the dynamic of the vegetation comunities of the last 5000 years, as well as the anthropic signals from the Prehistoric to the present time. The Holocene pollen records of this region allow to interpret a more or less forest conditions in its beginnings, characterized by the profusion of pine-groves and oak forests as well as of other mesophyle elements like the birch, followed by a progressive opening of the forest and the proliferation of landscape units related to anthropic effects. A paleo-landscape of pasture dedicated to transhumant and transterminant cattle activities define different levels of anthropic pressure. Particularly, it has been possible to determine that the first clear events of anthropization and deforestation of the Lozoya Valley forests occurred during the 3rd millennium BC, and the landscape physiognomy has not changed since the Middle Age.Depto. de Geodinámica, Estratigrafía y PaleontologíaFac. de Ciencias GeológicasTRUEpu

Enhancing the effects of neurofeedback training: the motivational value of the reinforcers

The brain activity that is measured by electroencephalography (EEG) can be modified through operant conditioning, specifically using neurofeedback (NF). NF has been applied to several disorders claiming that a change in the erratic brain activity would be accompanied by a reduction of the symptoms. However, the expected results are not always achieved. Some authors have suggested that the lack of an adequate response may be due to an incorrect application of the operant conditioning principles. A key factor in operant conditioning is the use of reinforcers and their value in modifying behavior, something that is not always sufficiently taken into account. This work aims to clarify the relevance of the motivational value versus the purely informational value of the reinforcer. In this study, 113 subjects were randomly assigned two different reinforcer conditions: a selected reinforcer—the subjects subjectively selected the reinforcers—or an imposed reinforcer— the reinforcers were assigned by the experimenter—and both groups undertook NF sessions to enhance the sensorimotor rhythm (SMR). In addition, the selected reinforcer group was divided into two subgroups: one receiving real NF and the other one sham NF. There were no significant differences between the groups at baseline in terms of SMR amplitude. After the intervention, only those subjects belonging to the selected reinforcer group and receiving real NF increased their SMR. Our results provide evidence for the importance of the motivational value of the reinforcer in Neurofeedback succes

Benefits of Living Over Deceased Donor Kidney Transplantation in Elderly Recipients. A Propensity Score Matched Analysis of a Large European Registry Cohort

Although kidney transplantation from living donors (LD) offers better long-term results than from deceased donors (DD), elderly recipients are less likely to receive LD transplants than younger ones. We analyzed renal transplant outcomes from LD versus DD in elderly recipients with a propensity-matched score. This retrospective, observational study included the first single kidney transplants in recipients aged >= 65 years from two European registry cohorts (2013-2020, n = 4,257). Recipients of LD (n = 408), brain death donors (BDD, n = 3,072), and controlled cardiocirculatory death donors (cDCD, n = 777) were matched for donor and recipient age, sex, dialysis time and recipient diabetes. Major graft and patient outcomes were investigated. Unmatched analyses showed that LD recipients were more likely to be transplanted preemptively and had shorter dialysis times than any DD type. The propensity score matched Cox's regression analysis between LD and BDD (387-pairs) and LD and cDCD (259-pairs) revealing a higher hazard ratio for graft failure with BDD (2.19 [95% CI: 1.16-4.15], p = 0.016) and cDCD (3.38 [95% CI: 1.79-6.39], p < 0.001). One-year eGFR was higher in LD transplants than in BDD and cDCD recipients. In elderly recipients, LD transplantation offers superior graft survival and renal function compared to BDD or cDCD. This strategy should be further promoted to improve transplant outcomes. [Graphical Abstract

Machine learning and natural language processing (NLP) approach to predict early progression to first-line treatment in real-world hormone receptor-positive (HRþ)/HER2-negative advanced breast cancer patients.

Este artículo ha sido publicado en la revista European Journal of Cancer. Esta versión tiene Licencia Creative Commons CC-BY-NC-NDBackground: CDK4/6 inhibitors plus endocrine therapies are the current standard of care in the first-line treatment of HRþ/HER2-negative metastatic breast cancer, but there are no well-established clinical or molecular predictive factors for patient response. In the era of personalised oncology, new approaches for developing predictive models of response are needed. Materials and methods: Data derived from the electronic health records (EHRs) of real-world patients with HRþ/HER2-negative advanced breast cancer were used to develop predictive models for early and late progression to first-line treatment. Two machine learning approaches were used: a classic approach using a data set of manually extracted features from reviewed (EHR) patients, and a second approach using natural language processing (NLP) of freetext clinical notes recorded during medical visits. Results: Of the 610 patients included, there were 473 (77.5%) progressions to first-line treatment, of which 126 (20.6%) occurred within the first 6 months. There were 152 patients (24.9%) who showed no disease progression before 28 months from the onset of first-line treatment. The best predictive model for early progression using the manually extracted dataset achieved an area under the curve (AUC) of 0.734 (95% CI 0.687e0.782). Using the NLP free-text processing approach, the best model obtained an AUC of 0.758 (95% CI 0.714 e0.800). The best model to predict long responders using manually extracted data obtained an AUC of 0.669 (95% CI 0.608e0.730). With NLP free-text processing, the best model attained an AUC of 0.752 (95% CI 0.705e0.799). Conclusions: Using machine learning methods, we developed predictive models for early and late progression to first-line treatment of HRþ/HER2-negative metastatic breast cancer, also finding that NLP-based machine learning models are slightly better than predictive models based on manually obtained data

NUP98 is fused to HOXA9 in a variant complex t(7;11;13;17) in a patient with AML-M2

The t(7;11)(p15;p15.4) has been reported to fuse the NUP98 gene (11p15), a component of the nuclear pore complex, with the class-1 homeobox gene HOXA9 at 7p15. This translocation has been associated with myeloid leukemias, predominantly acute myeloid leukemia (AML) M2 subtype with trilineage myelodysplastic features, and with a poor prognosis. The derived fusion protein retains the FG repeat motif of NUP98 N-terminus and the homeodomain shared by the HOX genes, acting as an oncogenic transcription factor critical for leukemogenesis. We report here a new complex t(7;11)-variant, i.e., t(7;11;13;17)(p15;p15;p?;p1?2) in a patient with AML-M2 and poor prognosis. The NUP98-HOXA9 fusion transcript was detected by RT-PCR, suggesting its role in the malignant transformation as it has been postulated for other t(7;11)-associated leukemias. No other fusion transcripts involving the NUP98 or HOXA9 genes were present, although other mechanisms involving several genes on chromosomes 13 and 17 may also be involved. To our knowledge, this is the first t(7;11) variant involving NUP98 described in hematological malignancies

A combined analysis of the short-term effects of photochemical air pollutants on mortality within the EMECAM project.

In recent years, some epidemiologic studies have attributed adverse effects of air pollutants on health not only to particles and sulfur dioxide but also to photochemical air pollutants (nitrogen dioxide and ozone). The effects are usually small, leading to some inconsistencies in the results of the studies. Furthermore, the different methodologic approaches of the studies used has made it difficult to derive generic conclusions. We provide here a quantitative summary of the short-term effects of photochemical air pollutants on mortality in seven Spanish cities involved in the EMECAM project, using generalized additive models from analyses of single and multiple pollutants. Nitrogen dioxide and ozone data were provided by seven EMECAM cities (Barcelona, Gijón, Huelva, Madrid, Oviedo, Seville, and Valencia). Mortality indicators included daily total mortality from all causes excluding external causes, daily cardiovascular mortality, and daily respiratory mortality. Individual estimates, obtained from city-specific generalized additive Poisson autoregressive models, were combined by means of fixed effects models and, if significant heterogeneity among local estimates was found, also by random effects models. Significant positive associations were found between daily mortality (all causes and cardiovascular) and NO(2), once the rest of air pollutants were taken into account. A 10 microg/m(3) increase in the 24-hr average 1-day NO(2)level was associated with an increase in the daily number of deaths of 0.43% [95% confidence interval (CI), -0.003-0.86%] for all causes excluding external. In the case of significant relationships, relative risks for cause-specific mortality were nearly twice as much as that for total mortality for all the photochemical pollutants. Ozone was independently related only to cardiovascular daily mortality. No independent statistically significant relationship between photochemical air pollutants and respiratory mortality was found. The results in this study suggest that, given the present levels of photochemical pollutants, people living in Spanish cities are exposed to health risks derived from air pollution

Big Data en Educación III: recomendaciones personalizadas de actuación ante estudiantes en riesgo de abandono

En este proyecto se elaboran un conjunto de recomendaciones personalizadas para guiar la actuación del profesor con estudiantes que hayan sido detectados en riesgo de abandono de una asignatura o de la titulación en general. Con carácter previo, se desarrollan métodos estadísticos que permitan la detección del riesgo de abandono de un estudiante

Autoimmune Diseases and COVID-19 as Risk Factors for Poor Outcomes: Data on 13,940 Hospitalized Patients from the Spanish Nationwide SEMI-COVID-19 Registry

(1) Objectives: To describe the clinical characteristics and clinical course of hospitalized patients with COVID-19 and autoimmune diseases (ADs) compared to the general population. (2) Methods: We used information available in the nationwide Spanish SEMI-COVID-19 Registry, which retrospectively compiles data from the first admission of adult patients with COVID-19. We selected all patients with ADs included in the registry and compared them to the remaining patients. The primary outcome was all-cause mortality during admission, readmission, and subsequent admissions, and secondary outcomes were a composite outcome including the need for intensive care unit (ICU) admission, invasive and non-invasive mechanical ventilation (MV), or death, as well as in-hospital complications. (3) Results: A total of 13,940 patients diagnosed with COVID-19 were included, of which 362 (2.6%) had an AD. Patients with ADs were older, more likely to be female, and had greater comorbidity. On the multivariate logistic regression analysis, which involved the inverse propensity score weighting method, AD as a whole was not associated with an increased risk of any of the outcome variables. Habitual treatment with corticosteroids (CSs), age, Barthel Index score, and comorbidity were associated with poor outcomes. Biological disease-modifying anti-rheumatic drugs (bDMARDs) were associated with a decrease in mortality in patients with AD. (4) Conclusions: The analysis of the SEMI-COVID-19 Registry shows that ADs do not lead to a different prognosis, measured by mortality, complications, or the composite outcome. Considered individually, it seems that some diseases entail a different prognosis than that of the general population. Immunosuppressive/immunoregulatory treatments (IST) prior to admission had variable effects