Wheat pathogen Zymoseptoria tritici N-myristoyltransferase inhibitors: on-target antifungal activity and an unusual metabolic defense mechanism

Zymoseptoria tritici is the causative agent of Septoria tritici blotch (STB), which costs billions of dollars annually to major wheat-producing countries in terms of both fungicide use and crop loss. Agricultural pathogenic fungi have acquired resistance to most commercially available fungicide classes, and the rate of discovery and development of new fungicides has stalled, demanding new approaches and insights. Here we investigate a potential mechanism of targeting an important wheat pathogen Z. tritici via inhibition of N-myristoyltransferase (NMT). We characterize Z. tritici NMT biochemically for the first time, profile the in vivo Z. tritici myristoylated proteome and identify and validate the first Z. tritici NMT inhibitors. Proteomic investigation of the downstream effects of NMT inhibition identified an unusual and novel mechanism of defense against chemical toxicity in Z. tritici through the application of comparative bioinformatics to deconvolute function from the previously largely unannotated Z. tritici proteome. Research into novel fungicidal modes-of-action is essential to satisfy an urgent unmet need for novel fungicide targets, and we anticipate that this study will serve as a useful proteomics and bioinformatics resource for researchers studying Z. tritici

Efecto de la suplementación con Bacillus amyloliquefaciens y heptanoato sódico sobre los parámetros de crecimiento en conejos en cebo

El objetivo de este trabajo fue evaluar el efecto de suplementar con B. amyloliquefaciens (Ecobiol; EU aditivo zootécnico para piensos número 4b1822; contenido de 1 x 109 CFU de B. amyloliquefaciens CECT 5940 / g) y heptanoato sódico (Hepton) sobre los parámetros de crecimiento del conejo. Se formuló un pienso control (17,3% PB y 36,2% FND, sobre % MS), y otros tres piensos suplementando el pienso control con 500 y 1000 g B. amyloliquefaciens/t (BA1 y BA2) y con 1000 g heptanoato sódico/t. Se utilizaron gazapos destetados a los 25 d gazapos (67/pienso). Los conejos suplementados con el pienso BA2 tendieron a comer menos que el grupo control (P = 0,073), y comieron un 6% menos que los del grupo BA1 (P = 0,036) durante el periodo de 25 a 40 d de edad, si bien no afectó a la ganancia de peso, ni en la eficacia alimenticia. Durante el periodo de 40 a 63 d de edad los gazapos alimentados con el pienso BA2 comieron un 10% menos que el pienso control (P = 0,002), sin modificar la ganancia de peso, lo que se tradujo en una tendencia a mejorar la eficacia alimenticia (P = 0,063). Los animales del pienso BA2 incrementaron la eficacia alimenticia un 8% comparado con los del grupo BA1 durante el periodo de 40 a 63 d (P = 0,031), sin mostrar diferencias en el consumo o en la ganancia de peso. Al evaluar el periodo global, incrementar la dosis de B. amyloliquefaciens (BA2 vs. BA1) tendió a disminuir el consumo medio diario (P = 0,069) y a aumentar la eficiencia alimenticia un 6% (P = 0,006). La suplementación con B. amyloliquefaciens, independientemente de la dosis utilizada (BA2 o BA1), no afectó a la mortalidad en el periodo global del cebo. Durante todo el periodo experimental de 25 a 63 d de edad, la suplementación con heptanoato sódico redujo el consumo de pienso un 5% en comparación con el grupo control (P = 0,050) y, al no modificar la velocidad de crecimiento, aumentó la eficacia alimenticia un 7% (P = 0,003). En comparación con el promedio de los gazapos suplementados con B. amyloliquefaciens los conejos que recibieron heptanoato sódico mostraron una mayor ganancia de peso (5%, P = 0,012), y eficiencia alimenticia (4%, P = 0,024), alcanzando un peso final superior (P = 0,012)

Projected t-SNE for batch correction

Motivation: Low-dimensional representations of high-dimensional data are routinely employed in biomedical research to visualize, interpret and communicate results from different pipelines. In this article, we propose a novel procedure to directly estimate t-SNE embeddings that are not driven by batch effects. Without correction, interesting structure in the data can be obscured by batch effects. The proposed algorithm can therefore significantly aid visualization of high-dimensional data. Results: The proposed methods are based on linear algebra and constrained optimization, leading to efficient algorithms and fast computation in many high-dimensional settings. Results on artificial single-cell transcription profiling data show that the proposed procedure successfully removes multiple batch effects from t-SNE embeddings, while retaining fundamental information on cell types. When applied to single-cell gene expression data to investigate mouse medulloblastoma, the proposed method successfully removes batches related with mice identifiers and the date of the experiment, while preserving clusters of oligodendrocytes, astrocytes, and endothelial cells and microglia, which are expected to lie in the stroma within or adjacent to the tumours. Contact: [email protected]

Ant colonies: building complex organizations with minuscule brains and no leaders

Thus far the articles in the series JOD calls the “Organization Zoo” have employed the notion of a “zoo” metaphorically to describe an array of human institutions. Here we take the term literally to consider the design of the most complex organizations in the living world beside those of humans, a favorite of insect zoos around the world: ant colonies. We consider individuality and group identity in the functioning of ant organizations; advantages of a flat organization without hierarchies or leaders; self-organization; direct and indirect communication; job specialization; labor coordination; and the role of errors in innovation. The likely value and limitations of comparing ant and human organizations are briefly examined

Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy

Despite progress in the treatment of acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL) has limited treatment options, particularly in the setting of relapsed/refractory disease. Using an unbiased genome-scale CRISPR-Cas9 screen we sought to identify pathway dependencies for T-ALL which could be harnessed for therapy development. Disruption of the one-carbon folate, purine and pyrimidine pathways scored as the top metabolic pathways required for T-ALL proliferation. We used a recently developed inhibitor of SHMT1 and SHMT2, RZ-2994, to characterize the effect of inhibiting these enzymes of the one-carbon folate pathway in T-ALL and found that T-ALL cell lines were differentially sensitive to RZ-2994, with the drug inducing a S/G2 cell cycle arrest. The effects of SHMT1/2 inhibition were rescued by formate supplementation. Loss of both SHMT1 and SHMT2 was necessary for impaired growth and cell cycle arrest, with suppression of both SHMT1 and SHMT2 inhibiting leukemia progression in vivo. RZ-2994 also decreased leukemia burden in vivo and remained effective in the setting of methotrexate resistance in vitro. This study highlights the significance of the one-carbon folate pathway in T-ALL and supports further development of SHMT inhibitors for treatment of T-ALL and other cancers

Combined In Silico, In Vivo, and In Vitro Studies Shed Insights into the Acute Inflammatory Response in Middle-Aged Mice

We combined in silico, in vivo, and in vitro studies to gain insights into age-dependent changes in acute inflammation in response to bacterial endotoxin (LPS). Time-course cytokine, chemokine, and NO2-/NO3- data from "middle-aged" (6-8 months old) C57BL/6 mice were used to re-parameterize a mechanistic mathematical model of acute inflammation originally calibrated for "young" (2-3 months old) mice. These studies suggested that macrophages from middle-aged mice are more susceptible to cell death, as well as producing higher levels of pro-inflammatory cytokines, vs. macrophages from young mice. In support of the in silico-derived hypotheses, resident peritoneal cells from endotoxemic middle-aged mice exhibited reduced viability and produced elevated levels of TNF-α, IL-6, IL-10, and KC/CXCL1 as compared to cells from young mice. Our studies demonstrate the utility of a combined in silico, in vivo, and in vitro approach to the study of acute inflammation in shock states, and suggest hypotheses with regard to the changes in the cytokine milieu that accompany aging. © 2013 Namas et al

Efecto de los B-glucanos de levaduras y oligoquitosanos sobre los rendimientos productivos en gazapos

El objetivo de este trabajo fue estudiar el efecto de la suplementación con B-glucanos de levaduras y quitosanos sobre los rendimientos productivos de los gazapos

Genotoxicity and epigenotoxicity of carbazole-derived molecules on mcf-7 breast cancer cells

The carbazole compounds PK9320 (1-(9-ethyl-7-(furan-2-yl)-9H-carbazol-3-yl)-N-methylmethanamine) and PK9323 (1-(9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)-N-methylmethanamine), second-generation analogues of PK083 (1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine), restore p53 signaling in Y220C p53-mutated cancer cells by binding to a mutation-induced surface crevice and acting as molecular chaperones. In the present paper, these three molecules have been tested for mutant p53-independent genotoxic and epigenomic effects on wild-type p53 MCF-7 breast adenocarcinoma cells, employing a combination of Western blot for phospho-γH2AX histone, Comet assay and methylation-sensitive arbitrarily primed PCR to analyze their intrinsic DNA damageinducing and DNA methylation-changing abilities. We demonstrate that small modifications in the substitution patterns of carbazoles can have profound effects on their intrinsic genotoxic and epigenetic properties, with PK9320 and PK9323 being eligible candidates as “anticancer compounds” and “anticancer epi-compounds” and PK083 a “damage-corrective” compound on human breast adenocarcinoma cells. Such different properties may be exploited for their use as anticancer agents and chemical probes

Anchors aweigh: the sources, variety, and challenges of mission drift

The growing number of studies which reference the concept of mission drift imply that such drift is an undesirable strategic outcome related to inconsistent organizational action, yet beyond such references little is known about how mission drift occurs, how it impacts organizations, and how organizations should respond. Existing management theory more broadly offers initial albeit equivocal insight for understanding mission drift. On the one hand, prior studies have argued that inconsistent or divergent action can lead to weakened stakeholder commitment and reputational damage. On the other hand, scholars have suggested that because environments are complex and dynamic, such action is necessary for ensuring organizational adaptation and thus survival. In this study, we offer a theory of mission drift that unpacks its origin, clarifies its variety, and specifies how organizations might respond to external perceptions of mission drift. The resulting conceptual model addresses the aforementioned theoretical tension and offers novel insight into the relationship between organizational actions and identity