ATM germline variants in a young adult with chronic lymphocytic leukemia: 8 years of genomic evolution

The authors thank the Hematopathology Collection registered at the Biobank of Hospital Clínic—Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) as well as Sílvia Martín for the technical support. This study was supported by the “la Caixa” Foundation (CLLEvolution-LCF/PR/HR17/52150017, Health Research 2017 Program HR17-00221, to EC), the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (810287, BCLLatlas, to EC, and HH), CERCA Program/Generalitat de Catalunya, Generalitat de Catalunya Suport Grups de Recerca AGAUR 2017-SGR-1142 (to EC), CIBERONC (CB16/12/00225 to EC), Ministerio de Ciencia e Innovación PID2020-117185RB-I00 (to XSP), FEDER: European Regional Development Fund “Una manera de hacer Europa”, and Fundación Asociación Española Contra el Cáncer FUNCAR-PRYGN211258SUÁR (to XSP). The authors thankfully acknowledge the computer resources at MareNostrum4 and the technical support provided by Barcelona Supercomputing Center (RES activity BCV-2018-3-0001). FN acknowledge research support from the American Association for Cancer Research (2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research, Grant Number 21-40-11-NADE), the European Hematology Association (EHA Junior Research Grant 2021, Grant Number RG-202012-00245), and the Lady Tata Memorial Trust (International Award for Research in Leukemia 2021–2022, Grant Number LADY_TATA_21_3223). EC is an Academia Researcher of the “Institució Catalana de Recerca i Estudis Avançats” (ICREA) of the Generalitat de Catalunya. This work was partially developed at the Centre Esther Koplowitz (CEK, Barcelona, Spain).Peer Reviewed"Article signat per 11 autors/es: Romina Royo, Laura Magnano, Julio Delgado, Sara Ruiz-Gil, Josep Ll. Gelpí, Holger Heyn, Malcom A. Taylor, Tatjana Stankovic, Xose S. Puente, Ferran Nadeu & Elías Campo"Postprint (published version

El laboratorio de matemáticas como estrategia docente

En esta experiencia docente se pone en práctica una forma diferente de llevar a cabo las clases prácticas de algunas asignaturas de matemáticas de primer curso de la Facultad de Ciencias de la Universidad de Alicante. El objetivo es sustituir las habituales clases prácticas, donde el profesor realiza los ejercicios en la pizarra, por la resolución de problemas por parte de los alumnos incorporando además otras estrategias docentes; es decir, además de las hojas de ejercicios que el profesor prepara para los alumnos, los docentes preparan unas actividades prácticas para que sean realizadas en clase por los estudiantes, en grupos reducidos y guiados por el profesor. Estas actividades son puntuadas por el tutor y, tras ser devueltas a los alumnos, éstos deberán observar y analizar sus errores con la ayuda extra de las tutorías presenciales y virtuales. Con este método se consigue una mayor interacción entre alumno y profesor, un estudio continuo de la asignatura y una constante evaluación del profesor al alumno y del alumno a la asignatura

Plasmodium species differentiation by non-expert on-line volunteers for remote malaria field diagnosis

BACKGROUND: Routine field diagnosis of malaria is a considerable challenge in rural and low resources endemic areas mainly due to lack of personnel, training and sample processing capacity. In addition, differential diagnosis of Plasmodium species has a high level of misdiagnosis. Real time remote microscopical diagnosis through on-line crowdsourcing platforms could be converted into an agile network to support diagnosis-based treatment and malaria control in low resources areas. This study explores whether accurate Plasmodium species identification-a critical step during the diagnosis protocol in order to choose the appropriate medication-is possible through the information provided by non-trained on-line volunteers. METHODS: 88 volunteers have performed a series of questionnaires over 110 images to differentiate species (Plasmodium falciparum, Plasmodium ovale, Plasmodium vivax, Plasmodium malariae, Plasmodium knowlesi) and parasite staging from thin blood smear images digitalized with a smartphone camera adapted to the ocular of a conventional light microscope. Visual cues evaluated in the surveys include texture and colour, parasite shape and red blood size. RESULTS: On-line volunteers are able to discriminate Plasmodium species (P. falciparum, P. malariae, P. vivax, P. ovale, P. knowlesi) and stages in thin-blood smears according to visual cues observed on digitalized images of parasitized red blood cells. Friendly textual descriptions of the visual cues and specialized malaria terminology is key for volunteers learning and efficiency. CONCLUSIONS: On-line volunteers with short-training are able to differentiate malaria parasite species and parasite stages from digitalized thin smears based on simple visual cues (shape, size, texture and colour). While the accuracy of a single on-line expert is far from perfect, a single parasite classification obtained by combining the opinions of multiple on-line volunteers over the same smear, could improve accuracy and reliability of Plasmodium species identification in remote malaria diagnosis.M.L. holds a postdoctoral Fellowship of the Spanish Ministry of Economy and Competitiveness (FPDI-2013-16409). JMB thanks the support by MINECO through research Grants BIO2013-44565R and BIO2016-77430R. MP, SGC, DC and MLO work was supported by the Universidad Politécnica de Madrid (COOP-XVII-02), Madrid Regional Government (TOPUS S2013/MIT-3024), the European Regional Development Funds, Amazon Web Services and Fundación Renta CorporaciónS

Laboratorio de Matemáticas

En este trabajo mostramos la forma planteada por los miembros de la red para llevar a cabo la evaluación continua de una asignatura de matemáticas impartida en los grados de Química y Geología de la Facultad de Ciencias de la Universidad de Alicante. La idea principal es cambiar las tradicionales clases prácticas de pizarra por parte del profesor por otras estrategias más participativas por parte del alumno. Así además de las clásicas hojas de problemas que el profesor prepara para la resolución por parte del alumno, éstas se combinan con unas prácticas se preparan por parte de los componentes de la red y que son realizadas en clase por parte de los alumnos trabajando en grupos reducidos. Tras su elaboración los profesores puntúan y devuelven dichas prácticas a los alumnos para que puedan notar y examinar sus errores. La idea es acercar e interactuar de manera constante entre el alumno y el profesor así como realizar una evaluación continua basada en una gran cantidad de información

In vitro evaluation of the efficacy of gold metallophosphazenes as antitumor compounds

Motivation: The presence of side effects due to therapeutic cancer strategies is a constant driver in the development of new alternatives [1]. One of them is the use of metallic compounds like gold metallophosphazenes. The purpose of this study was the evaluation in vitro of the cytotoxic capacity of two metallophosphazenes (1 and 2), with different gold content, in two tumor cell lines: MCF-7 and HepG2. Methods: The cytotoxicity of both metallophosphazenes was evaluated by in vitro toxicity assays. On the one hand, the Neutral Red Uptake assay (NRU), based on the inhibition of lysosomal uptake of the NR dye. Only living cells, take it and show absorbance variations measured in the spectrophotometer [2]. On the other hand, the Alamar Blue assay (AB). It allows to determine the proliferation of a cell culture, based on the properties of resazurin, a redox indicator with color changes by chemical reduction and production of fluorescence [3]. Cells were exposed during 48h from 0 µM to 8 µM. Median efective concentration (EC50) was calculated and statistical distribution of the data was evaluated with the GraphPad program using Dunnet's test, considering significant values those with p<0.05. Results: Both metallophosphazenes had EC50 values lower than 2,5 μM. In relation to compound 1, the MCF-7 cell line showed statistical significant differences with respect to the negative control from concentrations 1 μM and 2 μM, with EC50 values of 1.572 μM for the biomarker NR and 2.340 µM for AB, respectively. In the HepG2 cell line, results showed significant differences from concentrations 2 µM and 0.5 µM, with EC50 values of 2.471 µM for NR and 2.378 µM for AB, respectively. With respect to compound 2, both cell lines were more sensitive. In the MCF-7 cell line, results showed significant differences with respect to negative control from concentration 0.5 μM, with EC50 values of 1.262 μM for NR and 1.378 μM for AB. In the HepG2 cell line, results showed significant differences from concentrations 0.5 µM and 0.125 µM, with EC50 values of 1.557 µM for NR and 1.693 µM for AB, respectively. Conclusions: Compound 2 was more potent to both cells lines. The reason could be the extra gold atom of compound 2. The greater the number of gold atoms, the greater the antitumor activity. The uptake of NR was more sensitive than AB and MCF-7 was more sensitive than HepG2 cell line. In order to confirm the findings, other studies are necessary to determine mechanisms of action

In vitro evaluation of the production of reactive oxygen species in silver metallophosphazenes

Motivation: Phosphazenes (FZ) are polymers that have been shown to have a high therapeutic potential in recent years (Andrianov and Allcock, 2018). Among its derivatives, metalphosphazenes should be highlighted due to the interest in the biological activity of metal complexes (Gascón et al., 2020). Likewise, the estimation of the toxic risk of a substance is a complex process in which the risks and benefits for organisms or populations are related (Reppeto y Repetto 2009). In vitro models of the cell culture type allow studying the toxicity of xenobiotics at the systemic, cellular and molecular level (Meseguer, 2016). Methods: In the present work, the oxidative stress induction of two silver-FZ complexes was evaluated by studying the generation of reactive oxygen species (ROS) (Meseguer, 2016) in the MCF-7 cell line. The intracellular formation of ROS was determined fluorimetrically with the reagent 2´, 7´-dichlorodifluorescein 3´, 6´-diacetate (Hempel et al., 1999); using tert-butyl hydroperoxide and hydrogen peroxide as positive controls. The concentrations used were the EC50 and its sub-concentrations, being for compound 1: 2.34 µM, 1.17 µM and 0.585 µM; and for compound 2, 1.60 µM, 0.80 µM and 0.40 µM. These concentrations were determined using the alamar blue and neutral red cytotoxicity tests. ROS production was measured every 30 min, from time 0 to 120 min. Statitical significance between concentrations and the control was determined by Dunnett´s Multiple Comparison Test, using GraphPad Software. Results: Compound 1 showed the disappearance of ROS observed (t = 0 min p <0.01) throughout the test time, observing non-significant differences with respect to the control at the end of the same (t = 120 min). However, compound 2 maintained a statistically significant difference throughout the experiment for all concentrations, except for the maximum concentration tested (1.60 µM), which shows a decrease at the end time (t = 120 min). Conclusions: In view of the results obtained, it is observed that the cells exposed to compound 1 seem to recover over time from the initial induction of ROS. Compound 2 induces ROS in MCF-7 cells. This difference in behavior could be related to the different proportion of silver present in both compounds, of one and two molecules, respectively. It is necessary to carry out a more exhaustive evaluation of the oxidative profile of these compounds, in order to determine if antioxidant defense mechanisms could be active

Early dysfunction of functional connectivity in healthy elderly with subjective memory complaints

It is still an open question whether subjective memory complaints (SMC) can actually be considered to be clinically relevant predictors for the development of an objective memory impairment and even dementia. There is growing evidence that suggests that SMC are associated with an increased risk of dementia and with the presence of biological correlates of early Alzheimer's disease. In this paper, in order to shed some light on this issue, we try to discern whether subjects with SMC showed a different profile of functional connectivity compared with subjects with mild cognitive impairment (MCI) and healthy elderly subjects. In the present study, we compare the degree of synchronization of brain signals recorded with magnetoencephalography between three groups of subjects (56 in total): 19 with MCI, 12 with SMC and 25 healthy controls during a memory task. Synchronization likelihood, an index based on the theory of nonlinear dynamical systems, was used to measure functional connectivity. Briefly, results show that subjects with SMC have a very similar pattern of connectivity to control group, but on average, they present a lower synchronization value. These results could indicate that SMC are representing an initial stage with a hypo-synchronization (in comparison with the control group) where the brain system is still not compensating for the failing memory networks, but behaving as controls when compared with the MCI subjects

MAU2 and NIPBL variants impair the heterodimerization of the cohesin loader subunits and cause Cornelia de Lange syndrome

The NIPBL/MAU2 heterodimer loads cohesin onto chromatin. Mutations inNIPBLaccount for most cases ofthe rare developmental disorder Cornelia de Lange syndrome (CdLS). Here we report aMAU2 variant causing CdLS, a deletion of seven amino acids that impairs the interaction between MAU2 and the NIPBL N terminus.Investigating this interaction, we discovered that MAU2 and the NIPBL N terminus are largely dispensable fornormal cohesin and NIPBL function in cells with a NIPBL early truncating mutation. Despite a predicted fataloutcome of an out-of-frame single nucleotide duplication inNIPBL, engineered in two different cell lines,alternative translation initiation yields a form of NIPBL missing N-terminal residues. This form cannot interactwith MAU2, but binds DNA and mediates cohesin loading. Altogether, our work reveals that cohesin loading can occur independently of functional NIPBL/MAU2 complexes and highlights a novel mechanism protectiveagainst out-of-frame mutations that is potentially relevant for other genetic conditions