Fuzzy classification with distance-based depth prototypes: High-dimensional unsupervised and/or supervised problems

Supervised and unsupervised classification is crucial in many areas where different types of data sets are common, such as biology, medicine, or industry, among others. A key consideration is that some units are more typical of the group they belong to than others. For this reason, fuzzy classification approaches are necessary. In this paper, a fuzzy supervised classification method, which is based on the construction of prototypes, is proposed. The method obtains the prototypes from an objective function that includes label information and a distance-based depth function. It works with any distance and it can deal with data sets of a wide nature variety. It can further be applied to data sets where the use of Euclidean distance is not suitable and to high-dimensional data (data sets in which the number of features is larger than the number of observations , often written as ). In addition, the model can also cope with unsupervised classification, thus becoming an interesting alternative to other fuzzy clustering methods. With synthetic data sets along with high-dimensional real biomedical and industrial data sets, we demonstrate the good performance of the supervised and unsupervised fuzzy proposed procedures.This research was partially supported: II by the Spanish ‘Ministerio de Economia y Competitividad’ (PID2019-106942RB-C31). CA by grant 2021SGR01421 (GRBIO) from the Departament de Economia i Coneixement de la Generalitat de Catalunya, Spain. II, CA and BS by the Spanish ‘Ministerio de Economia Competitividad’ (PID2021-122402OB-C21)

Estatistika metodoak distantzietan oinarrituriko ikuspegitik

Lan honetan analisi anizkoitzaren baitan biltzen diren distantzietan oinarrituriko hainbat metodoren berrikusketa egin da. Oinarrizko kontzeptuak aurkeztu dira lehenik, ondoren metodoen funtsa laburki azaldu ahal izateko. Zehazki, erregresioa, diskriminazio-analisia, cluster-analisia, tipikotasuna eta sakonera aztertzen dituzten metodoak bildu ditugu. Metodologia honek berezitasun nabarmena du, edozein datu motaren gainean aplikagarria baita, datuek erakusten duten banaketa zein den ezagutu beharrik gabe. Azkenik, metodo hauen erabilgarritasuna erakusteko, funtzio-datu errealen gainean aplikatu eta lortutako emaitzak azaldu dira

Apoptosis-associated microRNAs are modulated in mouse, rat and human neural differentiation

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRs or miRNAs) regulate several biological processes in the cell. However, evidence for miRNAs that control the differentiation program of specific neural cell types has been elusive. Recently, we have shown that apoptosis-associated factors, such as p53 and caspases participate in the differentiation process of mouse neural stem (NS) cells. To identify apoptosis-associated miRNAs that might play a role in neuronal development, we performed global miRNA expression profiling experiments in NS cells. Next, we characterized the expression of proapoptotic miRNAs, including miR-16, let-7a and miR-34a in distinct models of neural differentiation, including mouse embryonic stem cells, PC12 and NT2N cells. In addition, the expression of antiapoptotic miR-19a and 20a was also evaluated.</p> <p>Results</p> <p>The expression of miR-16, let-7a and miR-34a was consistently upregulated in neural differentiation models. In contrast, expression of miR-19a and miR-20a was downregulated in mouse NS cell differentiation. Importantly, differential expression of specific apoptosis-related miRNAs was not associated with increased cell death. Overexpression of miR-34a increased the proportion of postmitotic neurons of mouse NS cells.</p> <p>Conclusions</p> <p>In conclusion, the identification of miR-16, let-7a and miR-34a, whose expression patterns are conserved in mouse, rat and human neural differentiation, implicates these specific miRNAs in mammalian neuronal development. The results provide new insights into the regulation of neuronal differentiation by apoptosis-associated miRNAs.</p

Risk Factors for Mortality in Nursing Home Residents: An Observational Study

Purpose: Identifying mortality risk factors in people living in nursing homes could help healthcare professionals to individualize or develop specific plans for predicting future care demands and plan end-of-life care in this population. This study aims to identify mortality risk factors in elderly nursing home (NH) residents, based on variables adapted to this environment, routinely collected and easily accessible to their healthcare professionals. Methods: A prospective, longitudinal, observational study of NH residents aged 65 years and older was carried out collecting sociodemographic, functional and cognitive status, nutritional variables, comorbidities, and other health variables. These variables were analyzed as mortality risk factors by Cox proportional hazard models. Results: A total of 531 residents (75.3% female; average age 86.7 years (SD: 6.6)) were included: 25.6% had total dependence, 53.4% had moderate to severe cognitive impairment, 84.5% were malnourished or at risk of malnutrition, and 79.9% were polymedicated. Risk of mortality (hazard ratio, HR) increased in totally dependent residents (HR = 1.52; p = 0.02) and in those with moderate or severe cognitive impairment ((HR = 1.59; p = 0.031) and (HR = 1.93; p = 0.002), respectively). Male gender (HR = 1.88; p < 0.001), age 80 years (HR = 1.73; p = 0.034), hypertension (HR = 1.53; p = 0.012), atrial fibrillation/arrhythmia (HR = 1.43; p = 0.048), and previous record of pneumonia (HR = 1.65; p = 0.029) were also found to be mortality drivers. Conclusion: Age and male gender (due to the higher prevalence of associated comorbidity in these two variables), certain comorbidities (hypertension, atrial fibrillation/arrhythmia, and pneumonia), higher functional and cognitive impairment, and frequency of medical emergency service care increased the risk of mortality in our study. Given their importance and their easy identification by healthcare professionals in nursing homes, these clinical variables should be used for planning care in institutionalized older adults.Grupo Ballesol (Valencia, Spain) provided financial support for conducting the research and publishing the article. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscriptEnfermerí

Corrigendum: A Novel Small Molecule p53 Stabilizer for Brain Cell Differentiation

Brain tumor, as any type of cancer, is assumed to be sustained by a small subpopulation of stem-like cells with distinctive properties that allow them to survive conventional therapies and drive tumor recurrence. Thus, the identification of new molecules capable of controlling stemness properties may be key in developing effective therapeutic strategies for cancer by inducing stem-like cells differentiation. Spiropyrazoline oxindoles have previously been shown to induce apoptosis and cell cycle arrest, as well as upregulate p53 steady-state levels, while decreasing its main inhibitor MDM2 in the HCT116 human colorectal carcinoma cell line. In this study, we made modifications in this scaffold by including combinations of different substituents in the pyrazoline ring in order to obtain novel small molecules that could modulate p53 activity and act as differentiation inducer agents. The antiproliferative activity of the synthesized compounds was assessed using the isogenic pair of HCT116 cell lines differing in the presence or absence of the p53 gene. Among the tested spirooxindoles, spiropyrazoline oxindole 1a was selective against the cancer cell line expressing wild-type p53 and presented low cytotoxicity. This small molecule induced neural stem cell (NSC) differentiation through reduced SOX2 (marker of multipotency) and increased βIII-tubulin (marker of neural differentiation) which suggests a great potential as a non-toxic inducer of cell differentiation. More importantly, in glioma cancer cells (GL-261), compound 1a reduced stemness, by decreasing SOX2 protein levels, while also promoting chemotherapy sensitization. These results highlight the potential of p53 modulators for brain cell differentiation, with spirooxindole 1a representing a promising lead molecule for the development of new brain antitumor drugs.</p

A Novel Small Molecule p53 Stabilizer for Brain Cell Differentiation

Brain tumor, as any type of cancer, is assumed to be sustained by a small subpopulation of stem-like cells with distinctive properties that allow them to survive conventional therapies and drive tumor recurrence. Thus, the identification of new molecules capable of controlling stemness properties may be key in developing effective therapeutic strategies for cancer by inducing stem-like cells differentiation. Spiropyrazoline oxindoles have previously been shown to induce apoptosis and cell cycle arrest, as well as upregulate p53 steady-state levels, while decreasing its main inhibitor MDM2 in the HCT116 human colorectal carcinoma cell line. In this study, we made modifications in this scaffold by including combinations of different substituents in the pyrazoline ring in order to obtain novel small molecules that could modulate p53 activity and act as differentiation inducer agents. The antiproliferative activity of the synthesized compounds was assessed using the isogenic pair of HCT116 cell lines differing in the presence or absence of the p53 gene. Among the tested spirooxindoles, spiropyrazoline oxindole 1a was selective against the cancer cell line expressing wild-type p53 and presented low cytotoxicity. This small molecule induced neural stem cell (NSC) differentiation through reduced SOX2 (marker of multipotency) and increased βIII-tubulin (marker of neural differentiation) which suggests a great potential as a non-toxic inducer of cell differentiation. More importantly, in glioma cancer cells (GL-261), compound 1a reduced stemness, by decreasing SOX2 protein levels, while also promoting chemotherapy sensitization. These results highlight the potential of p53 modulators for brain cell differentiation, with spirooxindole 1a representing a promising lead molecule for the development of new brain antitumor drugs

B-cell profile, B-cell activating factor concentration and IgG levels in human cutaneous and mucosal leishmaniasis

Aims: The aim of this study was to evaluate characteristics of B cells in human tegumentary leismaniasis (TL) analysing cutaneous leishmaniasis (CL), most prevalent form and mucosal leishmaniasis (ML), aggressive form characterized by the destruction of the oral-nasal-pharyngeal cavities. Methods and results: By flow cytometry analysis, we found decreased percentages of non–class-switched memory B cells in TL with the degree of the loss related to clinical severity. Using commercial ELISA, we reported high levels of B-cell activating factor (BAFF) and IgG preferentially in aggressive CL and markedly in ML together with decreased BAFF receptors in the latter. We also found lower levels of BAFF after clinical recovery suggesting a relation between BAFF and disease activity. Mucosal leishmaniasis history of therapeutic failure presented high levels of BAFF accompanied by detectable concentrations of IFN-γ and IL-6 (assayed by commercial ELISA and cytometric bead arrays respectively), cytokines involved in exaggerated inflammatory responses and tissue damage in TL. Conclusion: We demonstrate B-cell disturbances in TL with the degree of the alterations related to clinical severity. We suggest a relation between excess of BAFF and disease activity and point towards a possible implication of BAFF in the inflammatory phenomenon of ML.Fil: Parodi Ramoneda, Cecilia María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; ArgentinaFil: Barrio, Alejandra. Universidad Nacional de Salta. Facultad de Cs.de la Salud. Cátedra de Microbiología; ArgentinaFil: Garcia Bustos, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; ArgentinaFil: González Prieto, Ana Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Salta. Facultad de Cs.de la Salud. Cátedra de Microbiología; ArgentinaFil: Pimentel Solá, María Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; ArgentinaFil: Badano, Maria Noel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Albareda, María Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”. Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben”; ArgentinaFil: Castro Eiro, Melisa Daiana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”. Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben”; ArgentinaFil: Laucella, Susana Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”. Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben”; ArgentinaFil: Elizalde de Bracco, María Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

p53 Interaction with JMJD3 Results in Its Nuclear Distribution during Mouse Neural Stem Cell Differentiation

Conserved elements of apoptosis are also integral components of cellular differentiation. In this regard, p53 is involved in neurogenesis, being required for neurite outgrowth in primary neurons and for axonal regeneration in mice. Interestingly, demethylases regulate p53 activity and its interaction with co-activators by acting on non-histone proteins. In addition, the histone H3 lysine 27-specific demethylase JMJD3 induces ARF expression, thereby stabilizing p53 in mouse embryonic fibroblasts. We hypothesized that p53 interacts with key regulators of neurogenesis to redirect stem cells to differentiation, as an alternative to cell death. Specifically, we investigated the potential cross-talk between p53 and JMJD3 during mouse neural stem cell (NSC) differentiation. Our results demonstrated that JMJD3 mRNA and protein levels were increased early in mouse NSC differentiation, when JMJD3 activity was readily detected. Importantly, modulation of JMJD3 in NSCs resulted in changes of total p53 protein, coincident with increased ARF mRNA and protein expression. ChIP analysis revealed that JMJD3 was present at the promoter and exon 1 regions of ARF during neural differentiation, although without changes in H3K27me3. Immunoprecipitation assays demonstrated a direct interaction between p53 and JMJD3, independent of the C-terminal region of JMJD3, and modulation of p53 methylation by JMJD3-demethylase activity. Finally, transfection of mutant JMJD3 showed that the demethylase activity of JMJD3 was crucial in regulating p53 cellular distribution and function. In conclusion, JMJD3 induces p53 stabilization in mouse NSCs through ARF-dependent mechanisms, directly interacts with p53 and, importantly, causes nuclear accumulation of p53. This suggests that JMJD3 and p53 act in a common pathway during neurogenesis

Distinct Regulatory Functions of Calpain 1 and 2 during Neural Stem Cell Self-Renewal and Differentiation

Calpains are calcium regulated cysteine proteases that have been described in a wide range of cellular processes, including apoptosis, migration and cell cycle regulation. In addition, calpains have been implicated in differentiation, but their impact on neural differentiation requires further investigation. Here, we addressed the role of calpain 1 and calpain 2 in neural stem cell (NSC) self-renewal and differentiation. We found that calpain inhibition using either the chemical inhibitor calpeptin or the endogenous calpain inhibitor calpastatin favored differentiation of NSCs. This effect was associated with significant changes in cell cycle-related proteins and may be regulated by calcium. Interestingly, calpain 1 and calpain 2 were found to play distinct roles in NSC fate decision. Calpain 1 expression levels were higher in self-renewing NSC and decreased with differentiation, while calpain 2 increased throughout differentiation. In addition, calpain 1 silencing resulted in increased levels of both neuronal and glial markers, β-III Tubulin and glial fibrillary acidic protein (GFAP). Calpain 2 silencing elicited decreased levels of GFAP. These results support a role for calpain 1 in repressing differentiation, thus maintaining a proliferative NSC pool, and suggest that calpain 2 is involved in glial differentiation

Efecto del porcentaje de pildorado sobre la implantación y productividad de alfalfa (Medicago sativa L.)

El pildorado consiste en revestir a la semilla de alfalfa con una mezcla de rizobios, un fungicida o un insecticida, carbonato de calcio y un aglutinante. El objetivo fue comparar porcentajes de pildorado (10%, 20%, 30%, 50% y 75%) y semilla desnuda, con respecto a la densidad de plantas establecidas y la producción forrajera. Se implantó un ensayo con tres repeticiones en otoño de 2013 con una densidad fija (10 kg por ha), y se analizó el número de plantas por m2 a diferentes días de la siembra, y al finalizar la primera temporada y la producción forrajera. Hasta los 17 y 29 días las plantas por m2 fueron superiores en los dos tratamientos con semilla desnuda. A partir de los 46 días, los tratamientos con menor porcentaje de pildorado se ubicaron entre los mayores valores de plantas por m2. Los niveles altos de pildorado (30, 50 y 75%) presentaron la menor cantidad de plantas por m2. Las mayores producciones de forraje se obtuvieron con bajos porcentajes de pildorado y con semilla desnuda. Las semillas con 75% de pildorado tuvieron el menor rendimiento acumulado de forraje y uno de los menores valores de número de plantas por m2 al final de la temporada.Alfalfa seed coating consists of coating the seed with a mixture of rhizobia, a fungicide or an insecticide, calcium carbonate and a binding substance. The aim of the study was to compare seed coat percentages (10%, 20%, 30%, 50% and 75%) and naked seed in relation to established plants and forage yield. Following a design with 3 reps, a trial was established in 2013 at 10 kg per ha in which the number of plants per m2 was studied by counting at different days of sowing and at the end of the first season and forage yield. Up to 17 and 29 days after sowing the number of plants per m2 was higher in the two naked seed treatments. After 46 days of sowing, the treatments with the lowest seed coating percentage showed the highest numbers of plants per m2. High seed coating percentages (30%, 50% and 75%) had the lowest number of plants per m2. The highest forage yields were obtained with low seed coating percentages and naked seed treatments. By contrast, seeds with 75% coating treatment exhibited the lowest accumulated forage yield and one of the lowest values of number of plants per m2 at the end of the season.Fil: Odorizzi, Ariel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Manfredi. Mejoramiento Genético de Alfalfa; ArgentinaFil: Arolfo, Valeria. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Manfredi. Mejoramiento Genético de Alfalfa; ArgentinaFil: Basigalup, Daniel Horacio Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Manfredi. Mejoramiento Genético de Alfalfa; ArgentinaFil: Solá, Susana. Rizobacter. Investigación y Calidad de Semillas; Argentin