Methylating mushrooms

Peptide N-methylation is an important strategy used by medicinal chemists to improve cell permeability, oral bioavailability, and target affinity of peptide-based inhibitors. Correspondingly, N-methyl amides appear extensively in bioactive natural products. In the case of the immunosuppressant cyclosporine, for example, specific N-methylation of seven out of ten backbone amide nitrogens in the cyclic decapeptide is thought to allow a conformational ‘shapeshifting’ that hides polar N–H moieties and facilitates passive diffusion across cell membranes. Until now, N-methylation has primarily been the mark of peptide natural products from complex nonribosomal peptide synthetase (NRPS) assembly lines, and has not previously been found among their cousins, the ribosomally synthesized and post-translationally modified peptide (RiPP) natural products. In this issue, van der Velden et al. uncover the biosynthetic origins of the omphalotins, peptide natural products from the bioluminescent fungus O. olearius (Fig. 1a), and bring peptide backbone N-methylation into the realm of peptide post-translational modifications

Functional Interactions between Retinoblastoma and c-MYC in a Mouse Model of Hepatocellular Carcinoma

Inactivation of the RB tumor suppressor and activation of the MYC family of oncogenes are frequent events in a large spectrum of human cancers. Loss of RB function and MYC activation are thought to control both overlapping and distinct cellular processes during cell cycle progression. However, how these two major cancer genes functionally interact during tumorigenesis is still unclear. Here, we sought to test whether loss of RB function would affect cancer development in a mouse model of c-MYC-induced hepatocellular carcinoma (HCC), a deadly cancer type in which RB is frequently inactivated and c-MYC often activated. We found that RB inactivation has minimal effects on the cell cycle, cell death, and differentiation features of liver tumors driven by increased levels of c-MYC. However, combined loss of RB and activation of c-MYC led to an increase in polyploidy in mature hepatocytes before the development of tumors. There was a trend for decreased survival in double mutant animals compared to mice developing c-MYC-induced tumors. Thus, loss of RB function does not provide a proliferative advantage to c-MYC-expressing HCC cells but the RB and c-MYC pathways may cooperate to control the polyploidy of mature hepatocytes

Testing in Mice the Hypothesis That Melanin Is Protective in Malaria Infections

Malaria has had the largest impact of any infectious disease on shaping the human genome, exerting enormous selective pressure on genes that improve survival in severe malaria infections. Modern humans originated in Africa and lost skin melanization as they migrated to temperate regions of the globe. Although it is well documented that loss of melanization improved cutaneous Vitamin D synthesis, melanin plays an evolutionary ancient role in insect immunity to malaria and in some instances melanin has been implicated to play an immunoregulatory role in vertebrates. Thus, we tested the hypothesis that melanization may be protective in malaria infections using mouse models. Congenic C57BL/6 mice that differed only in the gene encoding tyrosinase, a key enzyme in the synthesis of melanin, showed no difference in the clinical course of infection by Plasmodium yoelii 17XL, that causes severe anemia, Plasmodium berghei ANKA, that causes severe cerebral malaria or Plasmodium chabaudi AS that causes uncomplicated chronic disease. Moreover, neither genetic deficiencies in vitamin D synthesis nor vitamin D supplementation had an effect on survival in cerebral malaria. Taken together, these results indicate that neither melanin nor vitamin D production improve survival in severe malaria

Murine Models and Cell Lines for the Investigation of Pheochromocytoma: Applications for Future Therapies?

Pheochromocytomas (PCCs) are slow-growing neuroendocrine tumors arising from adrenal chromaffin cells. Tumors arising from extra-adrenal chromaffin cells are called paragangliomas. Metastases can occur up to approximately 60% or even more in specific subgroups of patients. There are still no well-established and clinically accepted “metastatic” markers available to determine whether a primary tumor is or will become malignant. Surgical resection is the most common treatment for non-metastatic PCCs, but no standard treatment/regimen is available for metastatic PCC. To investigate what kind of therapies are suitable for the treatment of metastatic PCC, animal models or cell lines are very useful. Over the last two decades, various mouse and rat models have been created presenting with PCC, which include models presenting tumors that are to a certain degree biochemically and/or molecularly similar to human PCC, and develop metastases. To be able to investigate which chemotherapeutic options could be useful for the treatment of metastatic PCC, cell lines such as mouse pheochromocytoma (MPC) and mouse tumor tissue (MTT) cells have been recently introduced and they both showed metastatic behavior. It appears these MPC and MTT cells are biochemically and molecularly similar to some human PCCs, are easily visualized by different imaging techniques, and respond to different therapies. These studies also indicate that some mouse models and both mouse PCC cell lines are suitable for testing new therapies for metastatic PCC

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Baixa percepção de risco entre adolescentes espanhóis em relação ao consumo de álcool

Según los estudios recientes, los adolescentes españoles muestran una baja percepción del riesgo asociado al consumo de alcohol. El objetivo de la presente investigación es analizar los factores que favorecen esta baja percepción a partir de la opinión de un grupo de 32 profesionales/expertos en adolescencia, familia, escuela, medios de comunicación y políticas locales. Se utilizó una metodología cualitativa, fundamentada en Grounded Theory, a partir de la información obtenida mediante 5 grupos de discusión guiados por entrevistas semiestructuradas. Se identificaron 12 factores o subcategorías agrupados en 4 categorías generales: riesgo a corto plazo, inmediatez y percepción de invulnerabilidad (categoría ¿pensamiento adolescente¿); concepción benévola del alcohol, normalización del consumo y binomio alcohol-diversión (categoría ¿normas sociales¿); consumo habitual en los padres, inconsistencia verbal-no verbal en el modelado parental, consumo sin riesgo en los medios, consumo con resultados positivos en los medios (categoría ¿modelos sociales¿); excesivo contenido sanitario, riesgo a largo plazo (categoría ¿discurso preventivo¿). Tras discutir los resultados en el contexto de la literatura científica actual, se realizan varias propuestas con el objetivo de aumentar la percepción del riesgo en los adolescentes: incidir con mayor fuerza en contenidos sobre los riesgos a corto plazo del alcohol; orientar las estrategias educativas dirigidas al adolescente, también hacia los agentes de socialización, especialmente los padres; incidir en políticas centradas en la sustancia y en reducir la oferta.According to recent studies, Spanish adolescents show low perception of risk in alcohol consumption. The current study aims to analyze the factors that favor this low perception based on the opinion of a group of 32 professional experts on adolescence, family, school, mass media, and local policies. A qualitative methodology was used, based on Grounded Theory, using information from 5 focus groups guided by semi-structured interviews. Twelve factors or subcategories were identified, grouped in 4 general categories: short-term risk, immediacy, and perception of invulnerability (¿adolescent thinking¿ category); benevolent view of alcohol, normalization of consumption, and alcohol-entertainment binomial (¿social norms¿ category); parents¿ habitual consumption, verbal/non-verbal inconsistency in parental model, risk-free consumption depicted in the mass media, consumption with positive results in the media (¿social models¿ category); and excessive health content, long-term risk (¿preventive discourse¿ category). After discussing the results in the context of the current scientific literature, the article offers various proposals for increasing risk perception in adolescents: stronger impact of contents on short-term risks of alcohol; educational strategies targeted to adolescents to include agents of socialization, especially parents; and policies centered on the substance and reduction of supply.De acordo com estudos recentes, os adolescentes espanhóis mostram baixa percepção de risco em relação ao consumo de álcool. O estudo tem como objetivo analisar os fatores associados com a baixa percepção de risco, com base nas opiniões de um grupo de 32 especialistas em adolescência, família, escola, mídia e políticas locais. Foi utilizada uma metodologia qualitativa, baseada na Teoria Fundamentada, usando informações de cinco grupos focais orientados por entrevistas semi-estruturadas. Foram identificados 12 fatores ou subcategorias, agrupados em quatro categorias gerais: risco no curto prazo, imediatismo e percepção de invulnerabilidade (categoria de ¿pensamento adolescente¿); visão benevolente em relação ao álcool, normalização do consumo e binômio álcool-entretenimento (categoria de ¿normas sociais¿); consumo habitual pelos pais, inconsistência na comunicação verbal versus não verbal no modelo representado pelos pais, consumo isento de risco retratado pela mídia, consumo com resultados positivos na mídia (categoria de ¿modelos sociais¿) e excesso de conteúdo relacionado à saúde, risco no longo prazo (categoria de ¿discurso preventivo¿). Depois de discutir os resultados no contexto da literatura científica atual, o artigo oferece várias propostas para aumentar a percepção de risco entre os adolescentes: impacto mais forte de conteúdos sobre os riscos do álcool no curto prazo; estratégias educativas orientadas aos adolescentes para incluir os agentes da socialização, especialmente os pais, além de políticas centradas na substância e na redução da oferta.Departamento de Educación y Psicología SocialVersión del edito