Lithologic Controls on Focused Erosion and Intraplate Earthquakes in the Eastern Tennessee Seismic Zone

We present a new geomorphic model for the intraplate eastern Tennessee seismic zone (ETSZ). Previous studies document that the Upper Tennessee drainage basin is in a transient state of adjustment to ~150 m of base level fall that occurred in the Late Miocene. Using quantitative geomorphology, we demonstrate that base level fall resulted in the erosion of ~3,500 km3 of highly erodibility rock in an ~70 km wide by ~350‐km‐long corridor in the Paleozoic fold‐thrust belt above the ETSZ. Models of modern incision rates show a NE‐SW trending swath of elevated erosion ~30 km southeast of the center of the ETSZ. Stress modeling shows that lithologically focused erosion has affected fault clamping stress on preexisting, favorably oriented faults. We argue that the lithologically controlled transient erosional response to base level fall in the Upper Tennessee basin has given rise to and is sustaining earthquake activity in the ETSZ

The Δ40p53 isoform inhibits p53-dependent eRNA transcription and enables regulation by signal-specific transcription factors during p53 activation

The naturally occurring &Delta;40p53 isoform heterotetramerizes with wild-type p53 (WTp53) to regulate development, aging, and stress responses. How &Delta;40p53 alters WTp53 function remains enigmatic because their co-expression causes tetramer heterogeneity. We circumvented this issue with a well-tested strategy that expressed &Delta;40p53:WTp53 as a single transcript, ensuring a 2:2 tetramer stoichiometry. Human MCF10A cell lines expressing &Delta;40p53:WTp53, WTp53, or WTp53:WTp53 (as controls) from the native TP53 locus were examined with transcriptomics (precision nuclear run-on sequencing [PRO-seq] and RNA sequencing [RNA-seq]), metabolomics, and other methods. &Delta;40p53:WTp53 was transcriptionally active, and, although phenotypically similar to WTp53 under normal conditions, it failed to induce growth arrest upon Nutlin-induced p53 activation. This occurred via &Delta;40p53:WTp53-dependent inhibition of enhancer RNA (eRNA) transcription and subsequent failure to induce mRNA biogenesis, despite similar genomic occupancy to WTp53. A different stimulus (5-fluorouracil [5FU]) also showed &Delta;40p53:WTp53-specific changes in mRNA induction; however, other transcription factors (TFs; e.g., E2F2) could then drive the response, yielding similar outcomes vs. WTp53. Our results establish that &Delta;40p53 tempers WTp53 function to enable compensatory responses by other stimulus-specific TFs. Such modulation of WTp53 activity may be an essential physiological function for &Delta;40p53. Moreover, &Delta;40p53:WTp53 functional distinctions uncovered herein suggest an eRNA requirement for mRNA biogenesis and that human p53 evolved as a tetramer to support eRNA transcription. &nbsp;</p

Assistência pré-natal à adolescente e os atributos da Atenção Primária à Saúde

OBJECTIVE: evaluate prenatal care for adolescents in health units, in accordance with the attributes of Primary Health Care (PHC) guidelines. METHOD: quantitative study conducted with health professionals, using the Primary Care Assessment Tool-Brazil to assess the presence and extent of PHC attributes. RESULTS: for all the participating units, the attribute Access scored =6.6; the attributes Longitudinality, Coordination (integration of care), Coordination (information systems) and Integrality scored =6.6, and the Essential Score =6.6. Comparing basic units with family health units, the attribute scores were equally distributed; Accessibility scored =6.6, the others attributes scored =6.6; however, in the basic units, the Essential Score was =6.6 and, in the family health units, =6.6. CONCLUSION: expanding the coverage of family health units and the training of professionals can be considered strategies to qualify health care.OBJETIVO: evaluar la atención prenatal a las adolescentes en unidades de salud, según los atributos de la Atención Primaria a la Salud. MÉTODO: estudio de abordaje cuantitativo, realizado con profesionales de la salud, utilizando el instrumento Primary Care Assessment Tool-Brasil para analizar la presencia y extensión de los atributos vinculados a la APS en las unidades de salud. RESULTADOS: para todas las unidades participantes, el atributo Acceso obtuvo un puntaje =6,6; los atributos Longitudinalidad, Coordinación (integración de cuidados), Coordinación (sistemas de información) e Integralidad obtuvieron puntajes =6,6 y el Puntaje Esencial fue =6,6. Comparando las unidades básicas de salud y las unidades de salud de la familia, los puntajes están igualmente distribuidos: Accesibilidad =6,6 y los demás atributos con puntajes =6,6; sin embargo, el puntaje Esencial en las unidades básicas fue =6,6 y el de las unidades de salud de la familia fue =6,6. CONCLUSIÓN: la ampliación de la cobertura de las unidades de salud de la familia y la capacitación profesional pueden ser estrategias para calificar la atención a la salud.OBJETIVO: avaliar a atenção pré-natal às adolescentes em unidades de saúde, segundo os atributos da Atenção Primária à Saúde. MÉTODO: estudo de abordagem quantitativa, realizado com profissionais de saúde, utilizando-se o instrumento Primary Care Assessment Tool-Brasil, para analisar a presença e extensão dos atributos. RESULTADOS: para todas as unidades participantes, o atributo acesso obteve escore =6,6; os atributos longitudinalidade, coordenação (integração de cuidados), coordenação (sistemas de informação) e integralidade obtiveram escores =6,6 e escore essencial =6,6. Comparando-se as unidades básicas e as unidades de saúde da família, os escores estão igualmente distribuídos: acessibilidade: =6,6 e os demais atributos com escores =6,6, no entanto, o escore essencial nas unidades básicas foi =6,6 e nas unidades de saúde da família foi =6,6. CONCLUSÃO: a ampliação da cobertura das unidades de saúde da família e a capacitação profissional podem ser estratégias para qualificar a atenção à saúde

Improving influenza vaccine virus selectionReport of a WHO informal consultation held at WHO headquarters, Geneva, Switzerland, 14–16 June 2010

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90035/1/j.1750-2659.2011.00277.x.pd

Suppression of p53 response by targeting p53-Mediator binding with a stapled peptide

DNA-binding transcription factors (TFs) remain challenging to target with molecular probes. Many TFs function in part through interaction with Mediator, a 26-subunit complex that controls RNA polymerase II activity genome-wide. We sought to block p53 function by disrupting the p53-Mediator interaction. Through rational design and activity-based screening, we characterize a stapled peptide, with functional mimics of both p53 activation domains, that blocks p53-Mediator binding and selectively inhibits p53-dependent transcription in human cells; importantly, this &ldquo;bivalent&rdquo; peptide has negligible impact, genome-wide, on non-p53 target genes. Our proof-of-concept strategy circumvents the TF entirely and targets the TF-Mediator interface instead, with desired functional outcomes (i.e., selective inhibition of p53 activation). Furthermore, these results demonstrate that TF activation domains represent viable starting points for Mediator-targeting molecular probes, as an alternative to large compound libraries. Different TFs bind Mediator through different subunits, suggesting this strategy could be broadly applied to selectively alter gene expression programs. &nbsp;</p

Cross-Lineage Influenza B and Heterologous Influenza A Antibody Responses in Vaccinated Mice: Immunologic Interactions and B/Yamagata Dominance

The annually reformulated trivalent inactivated influenza vaccine (TIV) includes both influenza A/subtypes (H3N2 and H1N1) but only one of two influenza B/lineages (Yamagata or Victoria). In a recent series of clinical trials to evaluate prime-boost response across influenza B/lineages, influenza-naïve infants and toddlers originally primed with two doses of 2008–09 B/Yamagata-containing TIV were assessed after two doses of B/Victoria-containing TIV administered in the subsequent 2009–10 and 2010–11 seasons. In these children, the Victoria-containing vaccines strongly recalled antibody to the initiating B/Yamagata antigen but induced only low B/Victoria antibody responses. To further evaluate this unexpected pattern of cross-lineage vaccine responses, we conducted additional immunogenicity assessment in mice. In the current study, mice were primed with two doses of 2008–09 Yamagata-containing TIV and subsequently boosted with two doses of 2010–11 Victoria-containing TIV (Group-Yam/Vic). With the same vaccines, we also assessed the reverse order of two-dose Victoria followed by two-dose Yamagata immunization (Group-Vic/Yam). The Group-Yam/Vic mice showed strong homologous responses to Yamagata antigen. However, as previously reported in children, subsequent doses of Victoria antigen substantially boosted Yamagata but induced only low antibody response to the immunizing Victoria component. The reverse order of Group-Vic/Yam mice also showed low homologous responses to Victoria but subsequent heterologous immunization with even a single dose of Yamagata antigen induced substantial boost response to both lineages. For influenza A/H3N2, homologous responses were comparably robust for the differing TIV variants and even a single follow-up dose of the heterologous strain, regardless of vaccine sequence, substantially boosted antibody to both strains. For H1N1, two doses of 2008–09 seasonal antigen significantly blunted response to two doses of the 2010–11 pandemic H1N1 antigen. Immunologic interactions between influenza viruses considered antigenically distant and in particular the cross-lineage influenza B and dominant Yamagata boost responses we have observed in both human and animal studies warrant further evaluation