COT drives resistance to RAF inhibition through MAP kinase pathway reactivation

Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies. Here we expressed ～600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.     

AID is required for germinal center-derived lymphomagenesis

Most human B cell non-Hodgkin's lymphomas (B-NHLs) derive from germinal centers (GCs), the structure in which B cells undergo somatic hypermutation (SHM) and class switch recombination (CSR) before being selected for high-affinity antibody production. The pathogenesis of B-NHL is associated with distinct genetic lesions, including chromosomal translocations and aberrant SHM, which arise from mistakes occurring during CSR and SHM. A direct link between these DNA remodeling events and GC lymphoma development, however, has not been demonstrated. Here we have crossed three mouse models of B cell lymphoma driven by oncogenes (Myc, Bcl6 and Myc/Bcl6; refs. 5,6) with mice lacking activation-induced cytidine deaminase (AID), the enzyme required for both CSR and SHM. We show that AID deficiency prevents Bcl6-dependent, GC-derived B-NHL, but has no impact on Myc-driven, pre-GC lymphomas. Accordingly, abrogation of AID is associated with the disappearance of CSR- and SHM-mediated structural alterations. These results show that AID is required for GC-derived lymphomagenesis, supporting the notion that errors in AID-mediated antigen-receptor gene modification processes are principal contributors to the pathogenesis of human B-NHL.     

Nonnative Phragmites australis invasion into Utah wetlands

Phragmites australis (Cav.) Trin. ex Steud. (common reed), already one of the world’s most widespread plant species, has realized rapid range expansion in coastal wetlands of North America in the past century, but little is known about P. australis range expansion in inland wetland systems. We used genetic analyses, aerial photographs, field surveys, and a greenhouse experiment to study the extent and mechanism of nonnative P. australis invasion of Utah wetlands. We collected and genetically analyzed 39 herbarium samples across the state and 225 present-day samples from northern Utah’s major wetland complexes. All samples collected before 1993 and all samples collected outside the major wetlands of northern Utah, including some as recent as 2001, were identified as native (haplotypes A, B, D, and H). Only 10 (4%) of the present-day samples were native, each from small, discrete, low-density stands; the remaining samples were nonnative (haplotype M). Our earliest nonnative sample was collected near the Great Salt Lake in 1993. Around the Great Salt Lake, which contains 40% of Utah’s wetlands, P. australis cover has increased from 20% to 56% over the past 27 years—an increase that appears attributable to the nonnative strain. In a 3-month-long greenhouse experiment, the nonnative haplotype grew taller, had more aboveground biomass, and had a greater above- to belowground biomass ratio than the native haplotypes regardless of nitrogen, phosphorus, or water availability. Nonnative P. australis is rapidly invading the wetlands of northern Utah. Areas in Utah where the native P. australis remains should be identified and protected. Phragmites australis (Cav.) Trin ex Steud (carrizo), una de las especies de plantas más ampliamente distribuida en el mundo, se ha extendido rápidamente en los humedales costeros de Norteamérica en el último siglo, pero se conoce poco sobre la expansión de P. australis en sistemas de humedales del interior. Utilizamos análisis genéticos, fotografías aéreas, estudios de campo y un experimento en invernadero para examinar el alcance y el mecanismo de la invasión de la variedad no nativa de P. australis en los humedales de Utah. Recolectamos 39 muestras de herbario a lo largo del estado y 225 muestras actuales de los mayores complejos de humedales en el norte de Utah, y las sometimos a un análisis genético. Todas las muestras recolectadas antes de 1993 y las que se recolectaron fuera de los mayores humedales del norte de Utah, siendo las más recientes del 2001, fueron identificadas como nativas (haplotipos A, B, D y H). Solo 10 (4%) de las muestras actuales fueron nativas, todas de pequeños carrizales separados con baja densidad; las restantes fueron nonativas (haplotipo M). Nuestra muestra no nativa más antigua se recolectó cerca del Gran Lago Salado en 1993. Alrededor del Gran Lago Salado, el cual contiene el 40% de los humedales del estado de Utah, la cubierta de P. australis incrementó del 20% al 56% durante los últimos 27 años, un aumento que parece atribuirse a la variedad no nativa. En un experimento de invernadero de tres meses, el haplotipo no naivo creció más alto, tenía más biomasa sobre el nivel de la tierra y una mayor proporción de biomasa sobre el nivel de la tierra por biomasa subterránea que los haplotipos nativos sin importar la disponibilidad de nitrógeno, fósforo o agua. El haplotipo no nativo de P. australis está invadiendo rápidamente los humedales del norte de Utah. Las áreas en Utah en donde las variedades nativas permanecen deben ser identificadas y protegidas durante el manejo de carrizos.     

Acoustic ecology of an anuran assemblage in the arid Caatinga of northeastern Brazil

Differences in advertisement calls and calling sites are important mechanisms that regulate interactions in anuran assemblages. Individuals might have preferences for ranges of acoustic parameters and calling sites that reduce overlap and ensure coexistence. Herein, acoustic and ecological data were used to investigate the relationships among 12 anurans that co-occur in temporary ponds in the Caatinga, Cabaceiras municipality, Paraíba state, Brazil. Anurans exhibited calling activity correlated with rainfall, but were also spatially dispersed. High overlap levels in calling microhabitats and acoustic parameters were observed, especially among pairs of closely related species. Analysis of null models showed a lack of structure in the spatial and acoustic niche, indicating the lack of detected competition. Results suggest that the calling activity of the species is strongly influenced by rainfall, moreover, the temporal partition appears to ensure coexistence. Finally, strong historical effects were detected in Leiuperinae, Leptodactylidae and in the partition Hylidae–Leptodactyliformes.     

从“火”箭到卫星——意中空间科技合作回眸与展望

 意大利作为世界重要航天国家和欧洲航天局主要成员国,与中国有着久远的人文与科技交流,为人类探索太空的许多里程碑任务做出了不可忽略的贡献。追溯了意大利悠久的空间科技发展史和诸多亮点,包括中国火药对其“火”箭技术发展的促进作用;归纳了意-中在载人航天、地震空间电磁监测、空间科学卫星等领域开展的重要合作以及系列丰硕的成果;并指出意中科技文化交流源远流长,共同促进了文明的进步,如“西学东渐”等自然和社会科学知识的传播活动等。展望未来,在“一带一路”倡议的推动下,意中携手,可在探索浩瀚宇宙奥秘征程中为人类做出新的贡献。     

Regulation of DNA methylation of Rasgrf1.

In mammals, DNA is methylated at cytosines within CpG dinucleotides. Properly regulated methylation is crucial for normal development. Inappropriate methylation may contribute to tumorigenesis by silencing tumor-suppressor genes or by activating growth-stimulating genes. Although many genes have been identified that acquire methylation and whose expression is methylation-sensitive, little is known about how DNA methylation is controlled. We have identified a DNA sequence that regulates establishment of DNA methylation in the male germ line at Rasgrf1. In mice, the imprinted Rasgrf1 locus is methylated on the paternal allele within a differentially methylated domain (DMD) 30 kbp 5' of the promoter. Expression is exclusively from the paternal allele in neonatal brain. Methylation is regulated by a repeated sequence, consisting of a 41-mer repeated 40 times, found immediately 3' of the DMD. This sequence is present in organisms in which Rasgrf1 is imprinted. In addition, DMD methylation is required for imprinted Rasgrf1 expression. Together the DMD and repeat element constitute a binary switch that regulates imprinting at the locus.