RESUMEN
Unpaid work in the sciences is advocated as an entry route into scientific careers. We compared the success of UK science graduates who took paid or unpaid work six-months after graduation in obtaining a high salary or working in a STEM (Science, Technology Engineering and Mathematics) field 3.5 years later. Initially taking unpaid work was associated with lower earnings and lower persistence in STEM compared with paid work, but those using personal connections to obtain unpaid positions were as likely to persist in STEM as paid workers. Obtaining a position in STEM six months after graduation was associated with higher rates of persistence in STEM compared with a position outside STEM for both paid and unpaid workers, but the difference is considerably smaller for unpaid workers. Socio-economic inequality in the likelihood of obtaining entry in STEM by taking an unpaid position is a well-founded concern for scientific workforce diversity.
Asunto(s)
Salarios y Beneficios/estadística & datos numéricos , Ciencia/economía , Adulto , Demografía , Femenino , Humanos , Masculino , Factores Socioeconómicos , Encuestas y CuestionariosRESUMEN
The epidermis is hypothesized to play a signalling role during plant development. One class of mutants showing defects in signal transduction and radial patterning are those in sterol biosynthesis. The expectation is that living cells require sterols, but it is not clear that all cell types express sterol biosynthesis genes. The HYDRA1 (HYD1) gene of Arabidopsis encodes sterol Δ8-Δ7 isomerase, and although hyd1 seedlings are defective in radial patterning across several tissues, we show that the HYD1 gene is expressed most strongly in the root epidermis. Transgenic activation of HYD1 transcription in the epidermis of hyd1 null mutants reveals a major role in root patterning and growth. HYD1 expression in the vascular tissues and root meristem, though not endodermis or pericycle, also leads to some phenotypic rescue. Phenotypic rescue is associated with rescued patterning of the PIN1 and PIN2 auxin efflux carriers. The importance of the epidermis in controlling root growth and development is proposed to be, in part, due to its role as a site for sterol biosynthesis, and auxin is a candidate for the non-cell-autonomous signal.
Asunto(s)
Proteínas de Arabidopsis/metabolismo , Arabidopsis/crecimiento & desarrollo , Meristema/crecimiento & desarrollo , Raíces de Plantas/crecimiento & desarrollo , Esteroide Isomerasas/metabolismo , Esteroles/metabolismo , Arabidopsis/embriología , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Regulación de la Expresión Génica de las Plantas/genética , Ácidos Indolacéticos/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Meristema/embriología , Epidermis de la Planta/citología , Epidermis de la Planta/genética , Epidermis de la Planta/metabolismo , Plantones/embriología , Plantones/genética , Transducción de Señal/genética , Esteroide Isomerasas/genética , Activación Transcripcional/genéticaRESUMEN
The pyrroloquinoline alkaloid family of natural products, which includes the immunosuppressant lymphostin, has long been postulated to arise from tryptophan. We now report the molecular basis of lymphostin biosynthesis in three marine Salinispora species that maintain conserved biosynthetic gene clusters harboring a hybrid nonribosomal peptide synthetase-polyketide synthase that is central to lymphostin assembly. Through a series of experiments involving gene mutations, stable isotope profiling, and natural product discovery, we report the assembly-line biosynthesis of lymphostin and nine new analogues that exhibit potent mTOR inhibitory activity.
Asunto(s)
Actinomycetales/metabolismo , Alcaloides/metabolismo , Alcaloides/farmacología , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Pirroles/metabolismo , Pirroles/farmacología , Quinolinas/metabolismo , Quinolinas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Actinomycetales/química , Alcaloides/química , Inhibidores Enzimáticos/química , Pirroles/química , Quinolinas/química , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Fungi are well known for their vast diversity of secondary metabolites that include many life-saving drugs and highly toxic mycotoxins. In general, fungal cultures producing such metabolites are immune to their toxic effects. However, some are known to produce self-toxic compounds that can pose production optimization challenges if the metabolites are needed in large amounts for chemical modification. One such culture, LV-2841, was identified as the lead for one of our exploratory projects. This culture was found to be a slow grower that produced trace amounts of a known metabolite, cercosporamide, under the standard flask fermentation conditions, and extensive medium optimization studies failed to yield higher titers. Poor growth of the culture in liquid media was attributed to the self-toxicity of cercosporamide to the producing organism, and the minimum inhibitory concentration (MIC) of cercosporamide was estimated to be in the range of 8-16 microg/ml. Fermentations carried out in media containing Diaion HP20 resin afforded significantly higher titers of the desired compound. While several examples of resin-based fermentations of soil streptomyces have been published, this approach has rarely been used for fungal fermentations. Over a 100-fold increase in the production titer of cercosporamide, a self-toxic secondary metabolite, was achieved by supplementing the production medium with a commercially available neutral adsorbent resin.
Asunto(s)
Antifúngicos/metabolismo , Antifúngicos/toxicidad , Benzofuranos/metabolismo , Benzofuranos/toxicidad , Hongos/efectos de los fármacos , Hongos/metabolismo , Medios de Cultivo/química , Fermentación , Resinas de Intercambio Iónico/metabolismo , Pruebas de Sensibilidad Microbiana , Poliestirenos/metabolismoRESUMEN
3-Normeridamycin (1), isolated from fermentation extracts of the soil actinomycete Streptomyces sp. LL-C31037, demonstrated potent neuroprotective activity. When challenged with the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), known to induce parkinsonism, 1 restored functional dopamine uptake in a concentration-dependent manner, with an EC50 of 110 nM in dopaminergic neurons. The structure of 1 was determined via spectroscopic methods, and the immunosuppressive and immunophilin binding properties of the compound were also measured.