Stacked or folded? impact of chelate cooperativity on the self-assembly pathway to helical nanotubes from dinucleobase monomers

Self-assembled nanotubes exhibit impressive biological functions that have always inspired supramolecular scientists in their efforts to develop strategies to build such structures from small molecules through a bottom-up approach. One of these strategies employs molecules endowed with self-recognizing motifs at the edges, which can undergo either cyclization-stacking or folding-polymerization processes that lead to tubular architectures. Which of these self-assembly pathways is ultimately selected by these molecules is, however, often difficult to predict and even to evaluate experimentally. We show here a unique example of two structurally related molecules substituted with complementary nucleobases at the edges (i.e., G:C and A:U) for which the supramolecular pathway taken is determined by chelate cooperativity, that is, by their propensity to assemble in specific cyclic structures through Watson-Crick pairing. Because of chelate cooperativities that differ in several orders of magnitude, these molecules exhibit distinct supramolecular scenarios prior to their polymerization that generate self-assembled nanotubes with different internal monomer arrangements, either stacked or coiled, which lead at the same time to opposite helicities and chiroptical propertiesFunding from the European Research Council (ERC-Starting Grant 279548 PROGRAM-NANO) MCIN (RED2018- 102331-T, PID2020-116921GB-I00, and TED2021-132602BI00), the Italian Ministry of Education, University and Research (PRIN project prot. 2017A4XRCA_003), the Ministry of Education, Youth, and Sports of the Czech Republic (CZ.02.1.01/0.0/0.0/16_019/0000754, e-INFRA CZ (ID:90254)), the Swedish Research Council (2018- 4343), and the Swedish e-Science Research Centre (SeRC) is gratefully acknowledged. The authors also acknowledge the provision of supercomputer resources from the Swedish National Infrastructure for Computing (SNIC). F.A. is grateful to MCIN and Next Generation EU funding for a “Ramon-yCajal” fellowship (RyC-2021-031538-I). A.dJ. is grateful to EU funding from a MSCA-IEF action (897507-SuprAlloCat

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data.

Funder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health); doi: https://doi.org/10.13039/100011272; Grant(s): 305444, 305444Funder: Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness); doi: https://doi.org/10.13039/501100003329Funder: Generalitat de Catalunya (Government of Catalonia); doi: https://doi.org/10.13039/501100002809Funder: EC | European Regional Development Fund (Europski Fond za Regionalni Razvoj); doi: https://doi.org/10.13039/501100008530Funder: Instituto Nacional de Bioinformática ELIXIR Implementation Studies Centro de Excelencia Severo OchoaFunder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics

Potential Antioxidant and Antiviral Activities of Hydroethanolic Extracts of Selected Lamiaceae Species

Medicinal and aromatic plants (MAPs) are potential sources of natural bioactive phytochemical compounds of an incredible worth for the food industry, such as polyphenols. Lamiaceae medicinal and aromatic plants from Granada's high plateau, concretely Origanum bastetanum, Thymus zygis gracilis, Thymus longiflorus, Thymus membranaceus and Ziziphora hispanica, were evaluated under different conventional solid-liquid extraction conditions to obtain extracts enriched in bioactive compounds. Phenolic profile was detected by HPLC-QTOF-MS, identifying a high abundance of bioactive constituents. Furthermore, antioxidant and antiviral activities of the mentioned plants were studied as biological properties of interest for the improvement of food shelf-life. Thus, Origanum bastetanum showed the highest antioxidant potential for all assays. Antiviral activity was also tested against some important foodborne viruses, feline calicivirus (FCV), murine norovirus (MNV) and hepatitis A virus (HAV), with the highest activity obtained for Ziziphora hispanica, Thymus longiflorus and Origanum bastetanum. This research proposes the studied plants as rich sources of bioactive compounds with potential use as preservatives in the food industry.This research was funded by Diputación de Granada and Research Group AGR279 Ciencias de la Alimentación y Nutrición (University of Granada, Spain). CDS is grateful for the grant JA PREDOC_00110.Peer reviewe

Relaciones entre formación integral y educación para la paz: perspectivas de 20 educadores participantes en la estrategia distrital niños, niñas y jóvenes constructores de paz

El presente trabajo es fruto de un proceso investigativo dado entre los años 2013 y 2015 en la Maestría en Docencia de la Universidad de la Salle, llevada a cabo en la línea de investigación Cultura, Fe y Formación en Valores a la luz del Macroproyecto “Formación Integral” y dirigida por la maestra Rosa Ludy Arias Campos, el cual estuvo orientado a interpretar las relaciones entre la Formación Integral y la Educación para la Paz, a partir de las ideas, conceptos y prácticas de 20 educadores (docentes, directivos docentes y docentes orientadores) que participaron en la estrategia distrital “Niños, Niñas y jóvenes Constructores de Paz”. Para tal fin, se realiza la investigación desde un enfoque cualitativo asumiendo como método un estudio de caso y como ruta para el análisis de la información la propuesta de Torres (2007), con la secuencia lógica que implicó en un primer momento la categorización y codificación de datos, siguiendo con la ordenación y clasificación de la información, en un tercer momento el establecimiento de relaciones y en cuarto lugar el establecimiento de redes causales, con lo cual se dio paso a la formulación de los hallazgos y resultados finales que respondieron a los objetivos de la investigación y a las relaciones dadas entre los temas que han sido el centro de la presente tesis: formación integral y educación para la paz. Finalmente se establecen algunas conclusiones y recomendaciones

High-Throughput CRISPR Screening in Hematological Neoplasms

CRISPR is becoming an indispensable tool in biological research, revolutionizing diverse fields of medical research and biotechnology. In the last few years, several CRISPR-based genome-targeting tools have been translated for the study of hematological neoplasms. However, there is a lack of reviews focused on the wide uses of this technology in hematology. Therefore, in this review, we summarize the main CRISPR-based approaches of high throughput screenings applied to this field. Here we explain several libraries and algorithms for analysis of CRISPR screens used in hematology, accompanied by the most relevant databases. Moreover, we focus on (1) the identification of novel modulator genes of drug resistance and efficacy, which could anticipate relapses in patients and (2) new therapeutic targets and synthetic lethal interactions. We also discuss the approaches to uncover novel biomarkers of malignant transformations and immune evasion mechanisms. We explain the current literature in the most common lymphoid and myeloid neoplasms using this tool. Then, we conclude with future directions, highlighting the importance of further gene candidate validation and the integration and harmonization of the data from CRISPR screening approaches

Impacto municipal e inframunicipal das ondas de calor e frio na saúde de homens e mulheres: A feminização da pobreza em Madrid

The purpose of this work is to analyse how the health risks linked to extreme heat events are modified by gender and socioeconomical or demographic factors. The risks of Heat Waves (HW) and Cold Spells (CS) were calculated using the Poisson regression at city and district level. The dependant variables were the data for mortality and urgent hospital admissions due to natural (CIE X: A00-R99), circulatory (CIE X: I00-I99), and respiratory causes (CIE X: J00-J99) from INE and Madrid Salud. AEMET provided daily minimum (Tmin) and maximum (Tmax) temperature data as well as relative humidity data. HWs and CSs - the independent variables - were calculated as the temperature threshold above which mortality rates increases dramatically. The models were controlled by period, trend, and daily mean levels of PM2.5, PM10, NO2 and ozone. With these models, the Relative Risk (RR) and Attributable Risk (AR) associated with the statistically significant variables (p-value < 0.05) were calculated. The results at the district level were compared with the percentage of vulnerable people – aged 65 and older –, average household income, access to HVAC systems and the green areas in the district. Results: the CS-related AR [13.5 % (7.8 - 19.0)] was higher than the HW-related AR [3.1 (0.1- 5.9)]. The admissions pattern shows than women are more vulnerable than men during the winter and the summer. The analysis at the district level reveals that household income level and owning HVAC systems could be more relevant than the number of people at risk.El objetivo del presente trabajo es analizar cómo los riesgos en la salud asociados a los eventos térmicos extremos se ven modificados por sexo y factores socioeconómicos y demográficos. Empleando la regresión de Poisson se calcularon los riesgos de morbimortalidad asociados a las olas de calor y frío. Se utilizó como variable dependiente la mortalidad diaria e ingresos hospitalarios urgentes, por causas naturales (CIE-X: A00-R99), circulatorias (CIE-X: I00-I99) y respiratorias (CIE-X: J00-J99) procedentes del INE y Madrid Salud. AEMET suministró datos de temperatura mínima (Tmin) y máxima diaria (Tmax) y humedad relativa media diaria del observatorio de Madrid Retiro. Como variable independiente se determinó el número de días con olas de calor y frío, definidas por el umbral de temperatura a partir del cual se dispara la mortalidad. Se controló por periodo, tendencia y contaminación. Con estos modelos, se calcularon los Riesgos Relativos (RR) y Atribuibles (RA) asociados a las variables estadísticamente significativas (p<0,05). Los resultados a nivel inframunicipal fueron cruzados con el porcentaje de población en riesgo –mayores de 65 años–, renta familiar media, acceso a aire acondicionado y calefacción y zonas verdes en el distrito. Como resultados, el RA de la ola de frío (13,5 % (IC 95 %: 7,8 - 19,0) es superior al de la ola de calor (3,1 % (IC 95 %: 0,1 - 5,9)). El patrón de ingresos apunta a que las mujeres son más vulnerables que los hombres en invierno y verano. El análisis a nivel de distrito revela que los factores más determinantes son el nivel de renta del hogar y los sistemas de climatización más que la población en riesgo.O objetivo deste trabalho é analisar, de que modo, os riscos para a saúde associados a eventos térmicos extremos são modificados por fatores de género, socioeconómicos e demográficos. Utilizando a regressão de Poisson, foram calculados os riscos de morbimortalidade associados às ondas de calor e frio. Foram utilizadas como variáveis dependentes, a mortalidade diária e as admissões hospitalares urgentes, por causas naturais (CIE-X: A00-R99), circulatórias (CIE-X: I00-I99) e respiratórias (CIE-X: J00-J99) provenientes do INE e Madrid Salud. A AEMET forneceu dados sobre a temperatura mínima (Tmin) e máxima diária (Tmax) e a humidade relativa média diária do observatório Madrid Retiro. Como variável independente, foi determinado o número de dias com ondas de calor e frio, definido pelo limiar de temperatura, a partir do qual há um aumento da mortalidade. Por período, foi controlada a tendência e a contaminação. Com estes modelos foram calculados o Risco Relativo (RR) e o Risco Atribuível (RA) associados às variáveis estatisticamente significativas (p < 0,05). Os resultados a nível inframunicipal foram cruzados com a percentagem da população de risco - mais de 65 anos, com o rendimento médio das famílias, com o acesso a ar condicionado e aquecimento e com as zonas verdes do distrito. Como resultados, verifica-se que o RA à vaga de frio (13,5 % (IC 95 %: 7,8 - 19,0) é superior ao da vaga de calor (3,1 % (IC 95 %: 0,1 - 5,9)). O padrão de admissões sugere que as mulheres são mais vulneráveis do que os homens no Inverno e no Verão. A análise a nível distrital revela que os fatores mais determinantes são o nível de rendimento dos agregados familiares e os sistemas de climatização, mais do que a população de risco

Robust transcriptional indicators of immune cell death revealed by spatiotemporal transcriptome analyses

Altres ajuts: CERCA Programme/Generalitat de CatalunyaRecognition of a pathogen by the plant immune system often triggers a form of regulated cell death traditionally known as the hypersensitive response (HR). This type of cell death occurs precisely at the site of pathogen recognition, and it is restricted to a few cells. Extensive research has shed light on how plant immune receptors are mechanistically activated. However, two central key questions remain largely unresolved: how does cell death zonation take place, and what are the mechanisms that underpin this phenomenon? Consequently, bona fide transcriptional indicators of HR are lacking, which prevents deeper insight into its mechanisms before cell death becomes macroscopic and precludes early or live observation. In this study, to identify the transcriptional indicators of HR we used the paradigmatic Arabidopsis thaliana-Pseudomonas syringae pathosystem and performed a spatiotemporally resolved gene expression analysis that compared infected cells that will undergo HR upon pathogen recognition with bystander cells that will stay alive and activate immunity. Our data revealed unique and time-dependent differences in the repertoire of differentially expressed genes, expression profiles, and biological processes derived from tissue undergoing HR and that of its surroundings. Furthermore, we generated a pipeline based on concatenated pairwise comparisons between time, zone, and treatment that enabled us to define 13 robust transcriptional HR markers. Among these genes, the promoter of an uncharacterized AAA-ATPase was used to obtain a fluorescent reporter transgenic line that displays a strong spatiotemporally resolved signal specifically in cells that will later undergo pathogen-triggered cell death. This valuable set of genes can be used to define cells that are destined to die upon infection with HR-triggering bacteria, opening new avenues for specific and/or high-throughput techniques to study HR processes at a single-cell level

Protein Carbonylation in Patients with Myelodysplastic Syndrome: An Opportunity for Deferasirox Therapy

Control of oxidative stress in the bone marrow (BM) is key for maintaining the interplay between self-renewal, proliferation, and differentiation of hematopoietic cells. Breakdown of this regulation can lead to diseases characterized by BM failure such as the myelodysplastic syndromes (MDS). To better understand the role of oxidative stress in MDS development, we compared protein carbonylation as an indicator of oxidative stress in the BM of patients with MDS and control subjects, and also patients with MDS under treatment with the iron chelator deferasirox (DFX). As expected, differences in the pattern of protein carbonylation were observed in BM samples between MDS patients and controls, with an increase in protein carbonylation in the former. Strikingly, patients under DFX treatment had lower levels of protein carbonylation in BM with respect to untreated patients. Proteomic analysis identified four proteins with high carbonylation levels in MDS BM cells. Finally, as oxidative stress-related signaling pathways can modulate the cell cycle through p53, we analyzed the expression of the p53 target gene p21 in BM cells, finding that it was significantly upregulated in patients with MDS and was significantly downregulated after DFX treatment. Overall, our results suggest that the fine-tuning of oxidative stress levels in the BM of patients with MDS might control malignant progression

SARS-CoV-2 vaccine response and rate of breakthrough infection in patients with hematological disorders

Background The clinical efficacy of SARS-CoV-2 vaccines according to antibody response in immunosuppressed patients such as hematological patients has not yet been established. Patients and methods A prospective multicenter registry-based cohort study conducted from December 2020 to December 2021 by the Spanish transplant and cell therapy group was used to analyze the relationship of antibody response at 3-6 weeks after full vaccination (2 doses) with breakthrough SARS-CoV-2 infection in 1394 patients with hematological disorders. Results At a median follow-up of 165 days after complete immunization, 37 out of 1394 (2.6%) developed breakthrough SARS-CoV-2 infection at median of 77 days (range 7-195) after full vaccination. The incidence rate was 6.39 per 100 persons-year. Most patients were asymptomatic (19/37, 51.4%), whereas only 19% developed pneumonia. The mortality rate was 8%. Lack of detectable antibodies at 3-6 weeks after full vaccination was the only variable associated with breakthrough infection in multivariate logistic regression analysis (Odds Ratio 2.35, 95% confidence interval 1.2-4.6, p = 0.012). Median antibody titers were lower in cases than in non-cases [1.83 binding antibody units (BAU)/mL (range 0-4854.93) vs 730.81 BAU/mL (range 0-56,800), respectively (p = 0.007)]. We identified 250 BAU/mL as a cutoff above which incidence and severity of the infection were significantly lower. Conclusions Our study highlights the benefit of developing an antibody response in these highly immunosuppressed patients. Level of antibody titers at 3 to 6 weeks after 2-dose vaccination links with protection against both breakthrough infection and severe disease for non-Omicron SARS-CoV-2 variants