Restriction of memory B cell differentiation at the germinal center B cell positive selection stage

Memory B cells (MBCs) are key for protection from reinfection. However, it is mechanistically unclear how germinal center (GC) B cells differentiate into MBCs. MYC is transiently induced in cells fated for GC expansion and plasma cell (PC) formation, so-called positively selected GC B cells. We found that these cells coexpressed MYC and MIZ1 (MYC-interacting zinc-finger protein 1 [ZBTB17]). MYC and MIZ1 are transcriptional activators; however, they form a transcriptional repressor complex that represses MIZ1 target genes. Mice lacking MYC-MIZ1 complexes displayed impaired cell cycle entry of positively selected GC B cells and reduced GC B cell expansion and PC formation. Notably, absence of MYC-MIZ1 complexes in positively selected GC B cells led to a gene expression profile alike that of MBCs and increased MBC differentiation. Thus, at the GC positive selection stage, MYC-MIZ1 complexes are required for effective GC expansion and PC formation and to restrict MBC differentiation. We propose that MYC and MIZ1 form a module that regulates GC B cell fate

Challenge 6: Ethical, legal, economic, and social implications

In six decades of history, AI has become a mature and strategic discipline, successfully embedded in mainstream ICT and powering innumerable online applications and platforms. Several official documents stating specific AI policies have been produced by international organisations ( like the OCDE ), regional bodies ( EU ), several countries ( US, China, Spain, Germany, UK, Sweden, Brazil, Mexico...) as well as major AI-powered firms ( Google, Facebook, Amazon ). These examples demonstrate public interest and awareness of the economic and societal value of AI and the urgency of discussing the ethical, legal, economic and social implications of deploying AI systems on a massive scale. There is widespread agreement about the relevancy of addressing ethical aspects of AI, an urgency to demonstrate AI is used for the common good, and the need for better training, education and regulation to foster responsible research and innovation in AI. This chapter is organised around four main areas : ethics, law, economics and society ( ELES ). These areas shape the development of AI research and innovation, which in turn, influence these four areas of human activity. This interplay opens questions and demands new methods, objectives and ways to design future technologies. This chapter identifies the main impacts and salient challenges in each of these four areas.Peer reviewe

Tecnología y sociedad: ¿Por qué no llega el hogar digital?

In this work we analyze the reasons that hinder the arrival of the digital home. To this end, we study the evolution of technology and demographic and housing changes over the last decade, contrasting the forecasts made at the time with the complex reality that finally happened. During this time, the real estate sector experienced one of its greatest growth periods, but, paradoxically, the technological innovation was barely significant in this industry. The changes in the composition of families together with a greater cultural openness towards new ways of inhabiting also brought new opportunities to the home automation market, which so far has not been capable to achieve a significant success. Finally, we provide some explanatory keys and future prospects.<br><br>Se analizan los motivos que lastran el despegue del hogar digital a través del estudio de la evolución de la tecnología y los cambios demográficos y de vivienda a lo largo de la última década, contrastando los pronósticos realizados en la época con la compleja realidad que finalmente aconteció. Durante este periodo, el sector inmobiliario experimentó uno de los mayores periodos de crecimiento de las últimas décadas y, sin embargo, la innovación en materia tecnológica apenas fue significativa en esta industria. Los cambios en la composición de las familias y su mayor apertura cultural sobre nuevas formas de habitar también abrieron posibilidades a un mercado domótico que no termina de insertarse en la vivienda española. Se plantean algunas claves explicativas y opciones de futuro

Identification of CRF66_BF, a New HIV-1 Circulating Recombinant Form of South American Origin

Circulating recombinant forms (CRFs) are important components of the HIV-1 pandemic. Among 110 reported in the literature, 17 are BF1 intersubtype recombinant, most of which are of South American origin. Among these, all 5 identified in the Southern Cone and neighboring countries, except Brazil, derive from a common recombinant ancestor related to CRF12_BF, which circulates widely in Argentina, as deduced from coincident breakpoints and clustering in phylogenetic trees. In a HIV-1 molecular epidemiological study in Spain, we identified a phylogenetic cluster of 20 samples from 3 separate regions which were of F1 subsubtype, related to the Brazilian strain, in protease-reverse transcriptase (Pr-RT) and of subtype B in integrase. Remarkably, 14 individuals from this cluster (designated BF9) were Paraguayans and only 4 were native Spaniards. HIV-1 transmission was predominantly heterosexual, except for a subcluster of 6 individuals, 5 of which were men who have sex with men. Ten additional database sequences, from Argentina (n = 4), Spain (n = 3), Paraguay (n = 1), Brazil (n = 1), and Italy (n = 1), branched within the BF9 cluster. To determine whether it represents a new CRF, near full-length genome (NFLG) sequences were obtained for 6 viruses from 3 Spanish regions. Bootscan analyses showed a coincident BF1 recombinant structure, with 5 breakpoints, located in p17 gag , integrase, gp120, gp41-rev overlap, and nef, which was identical to that of two BF1 recombinant viruses from Paraguay previously sequenced in NFLGs. Interestingly, none of the breakpoints coincided with those of CRF12_BF. In a maximum likelihood phylogenetic tree, all 8 NFLG sequences grouped in a strongly supported clade segregating from previously identified CRFs and from the CRF12_BF "family" clade. These results allow us to identify a new HIV-1 CRF, designated CRF66_BF. Through a Bayesian coalescent analysis, the most recent common ancestor of CRF66_BF was estimated around 1984 in South America, either in Paraguay or Argentina. Among Pr-RT sequences obtained by us from HIV-1-infected Paraguayans living in Spain, 14 (20.9%) of 67 were of CRF66_BF, suggesting that CRF66_BF may be one of the major HIV-1 genetic forms circulating in Paraguay. CRF66_BF is the first reported non-Brazilian South American HIV-1 CRF_BF unrelated to CRF12_BF.This work was funded through Acción Estratégica en Salud Intramural (AESI), Instituto de Salud Carlos III, projects PI16CIII/00033 and PI19CIII/00042; Red de Investigación en SIDA (RIS), Instituto de Salud Carlos III, Subdirección General de Evaluación y Fondo Europeo de Desarrollo Regional (FEDER), Plan Nacional I+D+I, project RD16ISCIII/0002/0004; and scientific agreements with Consellería de Sanidade, Government of Galicia (MVI 1004/16) and Osakidetza-Servicio Vasco de Salud, Government of Basque Country (MVI 1001/16).S

Flow cytometry for fast screening and automated risk assessment in systemic light-chain amyloidosis

Early diagnosis and risk stratification are key to improve outcomes in light-chain (AL) amyloidosis. Here we used multidimensional-flow-cytometry (MFC) to characterize bone marrow (BM) plasma cells (PCs) from a series of 166 patients including newly-diagnosed AL amyloidosis (N = 94), MGUS (N = 20) and multiple myeloma (MM, N = 52) vs. healthy adults (N = 30). MFC detected clonality in virtually all AL amyloidosis (99%) patients. Furthermore, we developed an automated risk-stratification system based on BMPCs features, with independent prognostic impact on progression-free and overall survival of AL amyloidosis patients (hazard ratio: ≥ 2.9;P ≤ .03). Simultaneous assessment of the clonal PCs immunophenotypic protein expression profile and the BM cellular composition, mapped AL amyloidosis in the crossroad between MGUS and MM; however, lack of homogenously-positive CD56 expression, reduction of B-cell precursors and a predominantly-clonal PC compartment in the absence of an MM-like tumor PC expansion, emerged as hallmarks of AL amyloidosis (ROC-AUC = 0.74;P < .001), and might potentially be used as biomarkers for the identification of MGUS and MM patients, who are candidates for monitoring pre-symptomatic organ damage related to AL amyloidosis. Altogether, this study addressed the need for consensus on how to use flow cytometry in AL amyloidosis, and proposes a standardized MFC-based automated risk classification ready for implementation in clinical practice

The language factor in the attainment of millennium development goals: the case of multilingual sub-Saharan Africa

Millennium Development Goals (MDGs) offered an opportunity to the world to address the problem of underdevelopment especially in the developing countries. In order to realize these goals, governments around the world came up with different strategies. Language however, did not appear on the development strategies of many governments especially in Africa. This gave rise to debate among scholars about the significance of language in the realization of these goals. Whereas other continents like Europe were closer to realizing the MDGs by the deadline of 2015, Sub-Saharan Africa still lagged far behind. By the time the 8 MDGs expired in December 2015 and were replaced with 17 Sustainable Development Goals (SDGs), most African countries were far from attaining the goals. This paper argues that in order to attain the MDGs in Sub-Saharan Africa, languages of the Africa masses needed to be part of the strategy. The paper further argues that in a region that has a high linguistic diversity like Sub-Saharan Africa, local languages had a significant role to play in the attainment of the MDGs. The paper calls for the empowerment of languages of the African masses so as to effectively involve the masses in development and eventual attainment of SDGs by the set deadline of the year 2030

Discursive Frameworks for the Development of Inclusive Robotics

Important ethical-political ideas are analysed in this contribution: autonomy, dependency, vulnerability, functioning, care and disability, within the relevant discursive frameworks for development of an inclusive robotics. This development will have to take into account the regulatory framework of the UN Convention on the Rights of Persons with Disabilities, and prospectively orient itself towards facilitating autonomy in the achievement of human functionings in inclusive environments, guaranteeing the conditions for good care. To this end, it will be important to also pay attention to theoretical frameworks such as the capability approach (Sen, Nussbaum) and ethical conceptions of care (Tronto, Kittay). Additionally, we feel another social group that should be considered regarding the consequences coming from the introduction of robotics is the group made up of children and adolescents. For the responsible integration of inclusive and interactive robotics, as a mediating factor in the socialisation process, it is necessary to maintain careful protections in regard to the inherent vulnerability of this group; this requires that the general regulatory obligations regarding protection, full development and wellbeing underlying the discourse in the Convention on the Rights of the Child be used as a reference in order to always safeguard the greater interests of the minor.Peer reviewe

Nutritional status and prevalence of dysphagia in cerebral palsy: usefulness of the Eating and Drinking Ability Classification System scale and correlation with the degree of motor impairment according to the Gross Motor Function Classification System

Introduction and objectives: Digestive disorders are one of the most common comorbidities among children with cerebral palsy (CP). The aim of this study is to examine the nutritional status of patients with CP, the prevalence of dysphagia by degree of motor impairment, and the impact of digestive disorders on quality of life. Material and methods: We conducted a descriptive, cross-sectional, open-label study of out-patients with CP from a tertiary hospital in the Region of Madrid using a structured interview, classifying dysphagia using the Eating and Drinking Ability Classification System (EDACS). We gathered demographical and anthropometric data, and analysed the correlation between severity of dysphagia and functional status as measured with the Gross Motor Function Classification System (GMFCS). Results: Our sample included 44 patients (65.9% boys), with a mean (standard deviation) age of 9.34 (5) years and a mean BMI of 18.5 (4.9). Forty-three percent presented safety and efficiency limitations (EDACS level > II). Safety and efficiency limitations were associated with more extensive motor involvement (60% had tetraparesis), more varied clinical manifestations (87% had mixed forms) and poorer functional capacity (100% on GMFCS V). The impact on nutritional status increased with higher EDACS and GMFCS scores. Conclusions: This is the first study into the usefulness of the EDACS scale in a representative sample of Spanish children and adolescents with CP. Our findings underscore the importance of screening for dysphagia in these patients, regardless of the level of motor impairment, and the need for early treatment to prevent the potential consequences: malnutrition (impaired growth, micronutrient deficiencies, osteopaenia, etc.), microaspiration, or recurrent infections that may worsen patients’ neurological status. Resumen: Introducción y objetivos: La enfermedad digestiva es una de las comorbilidades más frecuentes en niños con parálisis cerebral infantil (PCI). Nuestro objetivo es analizar el estado nutricional de los pacientes PCI, la prevalencia de disfagia según afectación motriz (GMFCS) y su repercusión en la calidad de vida. Material y métodos: Estudio descriptivo transversal y abierto en pacientes con PCI seguidos en un Hospital Terciario de la Comunidad de Madrid mediante entrevista estructurada y clasificación de disfagia según la escala Eating and Drinking Ability Classification System (EDACS). Recogimos datos demográficos y antropométricos y relacionamos el nivel de disfagia con el nivel funcional según el Gross Motor Function Classification System (GMFCS). Resultados: La muestra incluyó 44 pacientes (65,9% varones), con una edad media de 9,34 ± 5 años y un IMC de 18,5 ± 4,9. El 43% tenía limitaciones en seguridad y/o eficiencia (EDACS > II). El porcentaje de pacientes afectados fue mayor cuanto más extensa desde el punto de vista topográfico (tetraparesia 60%), más variada semiología clínica (87% en formas mixtas) y peor nivel funcional (100% en GMFCS V). La repercusión nutricional fue mayor cuanto mayor nivel EDACS y GMFCS. Conclusiones: Presentamos el primer estudio sobre la utilidad de la escala EDACS en una muestra representativa de niños y adolescentes españoles con PCI. Los resultados deben hacernos reflexionar sobre la importancia del screening de disfagia en estos pacientes, independientemente del grado de afectación motriz y la necesidad de una intervención precoz para evitar sus principales consecuencias: desnutrición (hipocrecimiento, déficit de micronutrientes, osteopenia, etc.), microaspiraciones o infecciones de repetición que empeoran el estado neurológico

Robotics as an Instrument for Social Mediation

The relationship of a community with a robotic device happens by means of a social discourse comprised of social values, practices and representations of this device. But the robot that connects with the user community also brings with it values, practices and representations coming from the communities responsible for its idea, design, development and manufacturing, marketing, commercialization and distribution. This artefactual discourse, brought to life in the device, is present in the environments where it is used and might come to modify the discourse in the community. As devices that mediate actions, robots not only transforms the practices carried out in an environment, but also its characteristic values.Peer reviewe