AP-1 transcription factor network explains diverse patterns of cellular plasticity in melanoma

SummaryCellular plasticity associated with fluctuations in transcriptional programs allows individual cells in a tumor to adopt heterogeneous differentiation states and switch phenotype during their adaptive responses to therapies. Despite increasing knowledge of such transcriptional programs, the molecular basis of cellular plasticity remains poorly understood. Here, we combine multiplexed transcriptional and protein measurements at population and single-cell levels with multivariate statistical modeling to show that the state of AP-1 transcription factor network plays a unifying role in explaining cellular plasticity in melanoma. We find that a tightly regulated balance between AP-1 factors cJUN, FRA2, FRA1 and cFOS determines the intrinsic diversity of differentiation states and adaptive responses to MAPK inhibitors in individual melanoma cells. Perturbing this balance through genetic depletion of specific AP-1 proteins, or by MAPK inhibitors, shifts cellular heterogeneity in a predictable fashion. Thus, AP-1 may serve as a critical node for manipulating cellular plasticity with potential therapeutic implications.

Physical Drivers of Emission-line Diversity of SDSS Seyfert 2s and LINERs after Removal of Contributions from Star Formation

Ionization sources other than H ii regions give rise to the right-hand branch in the standard ([N ii]) BPT diagram, populated by Seyfert 2s and LINERs. However, because the majority of Seyfert/LINER hosts are star-forming (SF), H ii regions contaminate the observed lines to some extent, making it unclear if the position along the branch is merely due to various degrees of mixing between pure Seyferts/LINERs and SF, or whether it reflects the intrinsic diversity of Seyfert/LINER ionizing sources. In this study, we empirically remove SF contributions in ∼100,000 Seyferts/LINERs from SDSS using the doppelganger method. We find that mixing is not the principal cause of the extended morphology of the observed branch. Rather, Seyferts/LINERs intrinsically have a wide range of line ratios. Variations in ionization parameter and metallicity can account for much of the diversity of Seyfert/LINER line ratios, but the hardness of the ionization field also varies significantly. Furthermore, our k-means classification on seven decontaminated emission lines reveals that LINERs are made up of two populations, which we call soft and hard LINERs. The Seyfert 2s differ from both types of LINERs primarily by higher ionization parameter, whereas the two LINER types mainly differ from each other (and from star-forming regions) in the hardness of the radiation field. We confirm that the [N ii] BPT diagram more efficiently identifies LINERs than [S ii] and [O i] diagnostics, because in the latter many LINERs, especially soft ones, occupy the same location as pure starformers, even after the SF has been removed from LINER emission.

Will Next-Generation Immunotherapy Overcome the Intrinsic Diversity and Low Immunogenicity of Sarcomas to Improve Clinical Benefit?

Sarcomas are a rare type of a heterogeneous group of tumours arising from mesenchymal cells that form connective tissues. Surgery is the most common treatment for these tumours, but additional neoadjuvant or adjuvant chemotherapy or radiation therapies may be necessary. Unfortunately, a significant proportion of patients treated with conventional therapies will develop metastatic disease that is resistant to therapies. Currently, there is an urgent need to develop more effective and durable therapies for the treatment of sarcomas. In recent years immunotherapies have revolutionised the treatment of a variety of cancers by restoring patient anti-tumour immune responses or through the adoptive infusion of immune effectors able to kill and eliminate malignant cells. The clinicopathologic and genetic heterogeneity of sarcomas, together with the generally low burden of somatic mutations potentially generating neoantigens, are currently limited to broad application of immunotherapy for patients with sarcomas. Nevertheless, a better understanding of the microenvironmental factors hampering the efficacy of immunotherapy and the identification of new and suitable therapeutic targets may help to overcome current limitations. Moreover, the recent advances in the development of immunotherapies based on the direct exploitation or targeting of T cells and/or NK cells may offer new opportunities to improve the treatment of sarcomas, particularly those showing recurrence or resistance to standard of care treatments.

Chamada para a inclusão da educação para a diversidade por meio das culturas-línguas no Ensino Fundamental I da escola pública

Este artigo apresenta os conceitos básicos que sustentam uma educação para a diversidade no ensino Fundamental I no Brasil por meio da descoberta da diversidade das culturas-línguas como campo de saber transdisciplinar. As descobertas sonoras e visuais de várias culturas-línguas nacionais e não nacionais introduzem naturalmente a diversidade pela escuta de um outro ser diferente. A variedade das culturas-línguas se torna então um catalisador didático da diversidade global do mundo, compondo assim o eixo didático transdisciplinar que visa, coletivamente, à alteridade como supra objetivo educativo. Desta maneira, cada campo de saber escolar pode expressar a diversidade intrínseca da origem dos saberes humanos que o constituem. Nesta abordagem educativa, a alteridade, necessária para a paz social, ultrapassa as fronteiras nacionais para alcançar os outros locutores diferentes no mundo destacando, de forma precoce e simultânea, a identidade humana comum e a riqueza das diferenças. De forma concreta, o artigo sugere alguns conteúdos didáticos de uma abordagem da diversidade do 1º ao 5º ano do Ensino Fundamental elaborados de maneira a incluir gradativamente a complexidade do mundo (do próximo para o distante) e as interligações constantes com os outros saberes escolares (matemática, história, biologia, geografia, etc.). A mutação societal para um convívio mais harmonioso e equitativo passa por uma metamorfose da escola que vem a considerar a alteridade como aprendizagem humanista primordial, presidindo as abordagens dos outros componentes escolares. Esta mutação depende também de uma parceria estreita entre escola e família na qual se valorizaria a troca frequente de competências e experiências de cada sujeito.Palavras-chave: Diversidade. Culturas. Línguas.Call for inclusion of education for diversity through cultures language in elementary education of public schoolABSTRACTThis article presents the basic concepts that support an education for diversity in Elementary Education in Brazil through the discovery of cultures-languages diversity as a transdisciplinary field of knowledge. The sound and visual discoveries of various national and non-national cultures languages naturally introduce diversity through another different human being. The variety of cultures-languages then becomes a didactic catalyst of the world diversity, thus composing the transdisciplinary didactic axis that collectively aims at alterity as a supra educational goal. Therefore, each field of knowledge at school can express the intrinsic diversity of the origin of the human knowledge that constitutes it. In this educational approach, alterity, which is necessary for social peace, goes beyond national boundaries to reach the other different speakers in the world, highlighting, at an early stage, the common human identity and the richness of differences. Specifically, the article suggests didactic contents of an approach of diversity from 1st to 5th year of Elementary School, elaborated in a way that gradually includes the complexity of the world (from a near to distant perspective) and the constant interconnections with the other school knowledge (Mathematics, History, Biology, Geography, etc.). The societal transformation to a more harmonious and equitable conviviality depends on a metamorphosis of the school that begins to consider alterity as primordial humanistic learning, presiding over the approaches of other school subjects. This mutation also depends on a close partnership between school and family in which the frequent exchange of skills and experiences of each subject is valued.Keywords: Diversity. Cultures. Languages.Llamada para la inclusión de la educación a la diversidad a través de las culturas-lenguas en la Escuela PrimariaRESUMENEse artículo presenta a los conceptos básicos que apoyan une educación para la diversidad en la Escuela Primaria en Brasil através del descubrimiento de la diversidad de las culturas-lenguas como área de conocimiento transdisciplinaria. Las descubiertas sonoras y visuales de varias culturas-lenguas nacionales y no nacionales introducen naturalmente a la diversidad a través de otro ser diferente. La variedad de las culturas-lenguas se vuelve por lo tanto en catalizador didáctico de la diversidad global del mondo así componiendo el eje didáctico transdisciplanario que suele lograr colectivamente a la alteridad como supra meta educativa. De este modo, cada área de conocimiento académico puede expresar la diversidad intrínseca del origen des les conocimientos humanos que la constituyen. Con ese enfoque académico, la alteridad, necesaria para la paz social, excede las fronteras nacionales para alcanzar a otros interlocutores diferentes del mondo subrayando, de modo precoz y simultaneo, la identidad humana común y la riqueza de las diferencias. De forma concreta, el articulo sugiere algunos contenidos didácticos de un planteamiento de la diversidad del 1º hasta el 5º año de la Escuela Primaria elaborado de modo a incluir gradualmente la complejidad del mondo (de su alrededor hasta más lejos) y las interconexiones constantes con los otros conocimientos académicos (matemáticas, historia, biología, geografía, etc.). La conversión societal hacia una convivencia más harmoniosa y ecuánime sucede a una metamorfosis de la escuela que empieza a considerar a la alteridad como enseñanza humanista primordial presidiendo los enfoques de los otros componentes académicos. Esa mutación depende también de una asociación estrecha entre escuela y familia en la cual se valora el intercambio frecuente de competencias y experiencias de cada sujeto.Palabras clave: Diversidad. Culturas. Lenguas.

The aspherical explosion of the Type IIP SN 2017gmr†

ABSTRACT Type IIP supernovae (SNe IIP), which represent the most common class of core-collapse (CC) SNe, show a rapid increase in continuum polarization just after entering the tail phase. This feature can be explained by a highly asymmetric helium core, which is exposed when the hydrogen envelope becomes transparent. Here we report the case of an SN IIP (SN 2017gmr) that shows an unusually early rise of the polarization, ≳30 d before the start of the tail phase. This implies that SN 2017gmr is an SN IIP that has very extended asphericity. The asymmetries are not confined to the helium core, but reach out to a significant part of the outer hydrogen envelope, hence clearly indicating a marked intrinsic diversity in the aspherical structure of CC explosions. These observations provide new constraints on the explosion mechanism, where viable models must be able to produce such extended deviations from spherical symmetry, and account for the observed geometrical diversity.

Transcriptional profiling reveals extraordinary diversity among skeletal muscle tissues

Skeletal muscle comprises a family of diverse tissues with highly specialized functions. Many acquired diseases, including HIV and COPD, affect specific muscles while sparing others. Even monogenic muscular dystrophies selectively affect certain muscle groups. These observations suggest that factors intrinsic to muscle tissues influence their resistance to disease. Nevertheless, most studies have not addressed transcriptional diversity among skeletal muscles. Here we use RNAseq to profile mRNA expression in skeletal, smooth, and cardiac muscle tissues from mice and rats. Our data set, MuscleDB, reveals extensive transcriptional diversity, with greater than 50% of transcripts differentially expressed among skeletal muscle tissues. We detect mRNA expression of hundreds of putative myokines that may underlie the endocrine functions of skeletal muscle. We identify candidate genes that may drive tissue specialization, including Smarca4, Vegfa, and Myostatin. By demonstrating the intrinsic diversity of skeletal muscles, these data provide a resource for studying the mechanisms of tissue specialization.

Expert Listening beyond the Limits of Hearing: Music and Deafness

Attitudes to the relationship between music and deafness suffer from two related misconceptions: the enduring assumption that hearing is central to musical experience in conjunction with an extreme impression of deafness as total aural loss; and, more recently, the tendency to reduce deaf listening to tactility, as narratives about inborn sensory acuities among the deaf proliferate in the popular imaginary. Increasingly, deafness symbolizes a set of sensory polarities that obscure an intrinsic diversity of musical experiences from which musicology stands to gain, a diversity that encompasses members of Deaf culture and non-culturally deaf people alike, and that is signaled through the person-centered compound “d/Deaf.” My article builds on recent music scholarship on disability to offer a pluralistic understanding of music and deafness. Beginning with Scottish deaf percussionist Evelyn Glennie, I investigate a range of d/Deaf accounts of music, including those of Deaf sign language users, hearing aid wearers, and cochlear implant recipients, and of people with music-induced hearing loss. Deafness resists automatic entry points into music, unsettling any straightforward hierarchy of the senses. Deaf people reflect on the musical status of aurality in markedly different ways, just as they offer a complex understanding of vision and touch. For instance, vision is a highly versatile listening strategy and is often more reliable than vibration; touch is feasible because of its contextual dependence on visual cues, and is further tied to a set of material and environmental variables. Ultimately, I argue that d/Deaf listeners enrich customary notions of musical expertise: deafness belongs in musicology as a diverse set of experiences within the full spectrum of listening.