Modeling cancer metabolism on a genome scale

Cancer cells have fundamentally altered cellular metabolism that is associated with their tumorigenicity and malignancy. In addition to the widely studied Warburg effect, several new key metabolic alterations in cancer have been established over the last decade, leading to the recognition that altered tumor metabolism is one of the hallmarks of cancer. Deciphering the full scope and functional implications of the dysregulated metabolism in cancer requires both the advancement of a variety of omics measurements and the advancement of computational approaches for the analysis and contextualization of the accumulated data. Encouragingly, while the metabolic network is highly interconnected and complex, it is at the same time probably the best characterized cellular network. Following, this review discusses the challenges that genome‐scale modeling of cancer metabolism has been facing. We survey several recent studies demonstrating the first strides that have been done, testifying to the value of this approach in portraying a network‐level view of the cancer metabolism and in identifying novel drug targets and biomarkers. Finally, we outline a few new steps that may further advance this field

Global change effects on plant communities are magnified by time and the number of global change factors imposed

Komatsu, Kimberly J. Smithsonian Environmental Research Center, Edgewater. United States.Avolio, Meghan L. Johns Hopkins University. Department of Earth and Planetary Sciences. Baltimore, United States.Lemoine, Nathan P. Marquette University. Department of Biological Sciences. Milwaukee, United States.Chaneton, Enrique José. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura (IFEVA). Buenos Aires, Argentina.Chaneton, Enrique José. CONICET – Universidad de Buenos Aires. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura (IFEVA). Buenos Aires, Argentina.Tognetti, Pedro Maximiliano. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura (IFEVA). Buenos Aires, Argentina.Tognetti, Pedro Maximiliano. CONICET – Universidad de Buenos Aires. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura (IFEVA). Buenos Aires, Argentina.Yahdjian, María Laura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura (IFEVA). Buenos Aires, Argentina.Yahdjian, María Laura. CONICET – Universidad de Buenos Aires. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura (IFEVA). Buenos Aires, Argentina.Isbell, Forest. University of Minnesota. Department of Ecology, Evolution and Behavior. Saint Paul, United States.Grman, Emily. Eastern Michigan University. Department of Biology. Ypsilanti, United States.17867–17873Global change drivers (GCDs) are expected to alter community structure and consequently, the services that ecosystems provide. Yet, few experimental investigations have examined effects of CDs on plant community structure across multiple ecosystem types, and those that do exist present conflicting patterns. In an unprecedented global synthesis of over 100 experiments that manipulated factors linked to GCDs, we show that herbaceous plant community responses depend on experimental manipulation length and number of factors manipulated. We found that plant communities are fairly resistant to experimentally manipulated GCDs in the short term ( minor to 10 y). In contrast, long-term (major or equal to 10 y) experiments show increasing community divergence of treatments from control conditions. Surprisingly, these community responses occurred with similar frequency across the GCD types manipulated in our database. However, community responses were more common when 3 or more GCDs were simultaneously manipulated, suggesting the emergence of additive or synergistic effects of multiple drivers, particularly over long time periods. In half of the cases, GCD manipulations caused a difference in community composition without a corresponding species richness difference, indicating that species reordering or replacement is an important mechanism of community responses to GCDs and should be given greater consideration when examining consequences of GCDs for the biodiversity–ecosystem function relationship. Human activities are currently driving unparalleled global changes worldwide. Our analyses provide the most comprehensive evidence to date that these human activities may have widespread impacts on plant community composition globally, which will increase in frequency over time and be greater in areas where communities face multiple GCDs simultaneously

One-carbon metabolism in cancer

Cells require one-carbon units for nucleotide synthesis, methylation and reductive metabolism, and these pathways support the high proliferative rate of cancer cells. As such, anti-folates, drugs that target one-carbon metabolism, have long been used in the treatment of cancer. Amino acids, such as serine are a major one-carbon source, and cancer cells are particularly susceptible to deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. Recent work has also begun to decipher the specific pathways and sub-cellular compartments that are important for one-carbon metabolism in cancer cells. In this review we summarise the historical understanding of one-carbon metabolism in cancer, describe the recent findings regarding the generation and usage of one-carbon units and explore possible future therapeutics that could exploit the dependency of cancer cells on one-carbon metabolism

Progress in creating a joint research agenda that allows networked long-term socio-ecological research in southern South America : addressing crucial technological and human capacity gaps limiting its application in Chile and Argentina

Since 1980, more than 40 countries have implemented long-term ecological research (LTER) programs, which have shown their power to affect advances in basic science to understand the natural world at meaningful temporal and spatial scales and also help link research with socially relevant outcomes. Recently, a disciplinary paradigmatic shift has integrated the human dimensions of ecosystems, leading to a long-term socio-ecological research (LTSER) framework to address the world's current environmental challenges. A global gap in LTER/LTSER only exists in the latitudinal range of 40–60°S, corresponding to Argentina and Chile's temperate/sub-Antarctic biome. A team of Chilean, Argentine and US researchers has participated in an ongoing dialogue to define not only conceptual, but also practical barriers limiting LTER/LTSER in southern South America. We have found a number of existing long-term research sites and platforms throughout the region, but at the same time it has been concluded an agenda is needed to create and implement further training courses for students, postdoctoral fellows and young scientists, particularly in the areas of data and information management systems. Since LTER/LTSER efforts in Chile and Argentina are incipient, instituting such courses now will enhance human and technical capacity of the natural science and resource community to improve the collection, storage, analysis and dissemination of information in emerging LTER/LTSER platforms. In turn, having this capacity, as well as the ongoing formalization of LTER/LTSER programs at national levels, will allow the enhancement of crucial collaborations and comparisons between long-term research programs within the region and between hemispheres and continents. For Spanish version of the entire article, see Online Supporting Information (Appendix S1).Desde 1980, más de cuarenta países han implementado programas de Investigación Ecológica a Largo Plazo (LTER por sus siglas en inglés), los cuales han mostrado su capacidad para influir sobre los avances en las ciencias básicas que permiten entender el mundo natural en escalas temporales y espaciales significativas, y también ayudar a enfocar la investigación hacia estudios socialmente relevantes. Recientemente, gracias a un cambio de paradigma en la disciplina, se integró también la dimensión humana de los ecosistemas, llevándola a un marco conceptual de Investigación Socio-Ecológica a Largo Plazo (LTSER por sus siglas en inglés) para enfrentar los desafíos medio-ambientales del mundo actual. Existe un vacío global en LTER/LTSER en el rango latitudinal de 40–60°S, correspondiente a los biomas templados/subantárticos de Argentina y Chile. Un equipo de investigadores chilenos, argentinos y estadounidenses ha trabajado por varios años para definir cuáles son la barreras que actualmente limitan la creación de una Red de LTER/LTSER en el sur de Sudamérica, no solamente en términos conceptuales, sino también a nivel práctico. Existe un buen número de sitios de investigación a largo plazo en la región, pero también concluimos que es necesario crear e implementar más cursos de capacitación para estudiantes, investigadores post-doctorales y jóvenes científicos, particularmente en las áreas de sistemas de manejo de datos e información. Considerando que los esfuerzos LTER/LTSER en Chile y Argentina son incipientes, este tipo de cursos podría mejorar la capacidad humana y técnica en la comunidad de las ciencias y los recursos naturales, así como mejorar los procesos de recolección, almacenamiento, análisis y difusión de la información. A su vez, la formalización de cursos de programas LTER/LTSER a nivel nacional para adquirir dicha capacidad de manejo de la información, permitirá un fortalecimiento crucial de las colaboraciones y comparaciones entre programas de investigación a largo plazo dentro de la región, y entre hemisferios y continentes. La versión en castellano del artículo se encuentra disponible en forma digital como Online Supporting Information S1.Fil: Anderson, Chistopher B. University of North Texas. Department of Biological Sciences; Estados UnidosFil: Celis-Diez, Juan Luis. Pontificia Universidad Católica de Valparaíso, Escuela de Agronomía; ChileFil: Bond, Barbara J.H.G. Oregon State University. Andrews Forest Long-Term Ecological Research Site. Department of Forest Ecosystems and Society; Estados UnidosFil: Martínez Pastur, Guillermo José. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Cientificas; ArgentinaFil: Little, Christian. Universidad Austral de Chile. Facultad de Ciencias. Instituto de Ciencias de la Tierra y Evolución; Chile. Fundación Centro de los Bosques Nativos FORECOS; ChileFil: Armesto, Juan J. Pontificia Universidad Católica de Valparaíso, Escuela de Agronomía; ChileFil: Ghersa, Claudio Marco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Austin, Amy Theresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Schlichter, Tomas Miguel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche. Grupo de Ecología Forestal; ArgentinaFil: Lara, Antonio. Fundación Centro de los Bosques Nativos FORECOS; Chile. Universidad Austral de Chile. Facultad de Ciencias Forestales y Recursos Naturales. Instituto de Silvicultura; ChileFil: Carmona, Martin. Universidad de Chile. Instituto de Ecologıa y Biodiversidad; ChileFil: Chaneton, Enrique Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; Argentina. Universidad de Buenos Aires. Facultad de Agronomia. Departamento de Recursos Naturales y Ambiente; ArgentinaFil: Gutierrez, Julio R. Universidad de La Serena. Departamento de Biología. Instituto de Ecología y Biodiversidad. Centro de Estudios Avanzados en Zonas Aridas; ChileFil: Rozzi, Ricardo. Universidad de La Serena. Departamento de Biología. Instituto de Ecología y Biodiversidad; ChileFil: Vanderbilt, Kristin University of New Mexico. Department of Biology. Sevilleta Long-Term Ecological Research Site; Estados UnidosFil: Oyarce, Guillermo University of North Texas. Library and Information Sciences; Estados UnidosFil: Fernandez, Roberto J. University of North Texas, Department of Biological Sciences; Estados Unido

M2 pyruvate kinase provides a mechanism for nutrient sensing and regulation of cell proliferation

We show that the M2 isoform of pyruvate kinase (M2PYK) exists in equilibrium between monomers and tetramers regulated by allosteric binding of naturally occurring small-molecule metabolites. Phenylalanine stabilizes an inactive T-state tetrameric conformer and inhibits M2PYK with an IC(50) value of 0.24 mM, whereas thyroid hormone (triiodo-l-thyronine, T3) stabilizes an inactive monomeric form of M2PYK with an IC(50) of 78 nM. The allosteric activator fructose-1,6-bisphosphate [F16BP, AC(50) (concentration that gives 50% activation) of 7 μM] shifts the equilibrium to the tetrameric active R-state, which has a similar activity to that of the constitutively fully active isoform M1PYK. Proliferation assays using HCT-116 cells showed that addition of inhibitors phenylalanine and T3 both increased cell proliferation, whereas addition of the activator F16BP reduced proliferation. F16BP abrogates the inhibitory effect of both phenylalanine and T3, highlighting a dominant role of M2PYK allosteric activation in the regulation of cancer proliferation. X-ray structures show constitutively fully active M1PYK and F16BP-bound M2PYK in an R-state conformation with a lysine at the dimer-interface acting as a peg in a hole, locking the active tetramer conformation. Binding of phenylalanine in an allosteric pocket induces a 13° rotation of the protomers, destroying the peg-in-hole R-state interface. This distinct T-state tetramer is stabilized by flipped out Trp/Arg side chains that stack across the dimer interface. X-ray structures and biophysical binding data of M2PYK complexes explain how, at a molecular level, fluctuations in concentrations of amino acids, thyroid hormone, and glucose metabolites switch M2PYK on and off to provide the cell with a nutrient sensing and growth signaling mechanism

Environmental heterogeneity modulates the effect of plant diversity on the spatial variability of grassland biomass

Plant productivity varies due to environmental heterogeneity, and theory suggests that plant diversity can reduce this variation. While there is strong evidence of diversity effects on temporal variability of productivity, whether this mechanism extends to variability across space remains elusive. Here we determine the relationship between plant diversity and spatial variability of productivity in 83 grasslands, and quantify the effect of experimentally increased spatial heterogeneity in environmental conditions on this relationship. We found that communities with higher plant species richness (alpha and gamma diversity) have lower spatial variability of productivity as reduced abundance of some species can be compensated for by increased abundance of other species. In contrast, high species dissimilarity among local communities (beta diversity) is positively associated with spatial variability of productivity, suggesting that changes in species composition can scale up to affect productivity. Experimentally increased spatial environmental heterogeneity weakens the effect of plant alpha and gamma diversity, and reveals that beta diversity can simultaneously decrease and increase spatial variability of productivity. Our findings unveil the generality of the diversity-stability theory across space, and suggest that reduced local diversity and biotic homogenization can affect the spatial reliability of key ecosystem functions.Fil: Daleo, Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Alberti, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Chaneton, Enrique Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Iribarne, Oscar Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Tognetti, Pedro Maximiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Bakker, Jonathan. University of Washington; Estados UnidosFil: Borer, Elizabeth. University of Minnesota; Estados UnidosFil: Bruschetti, Carlos Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: MacDougall, Andrew S.. University Of Guelph. Department Of Integrative Biology.; CanadáFil: Pascual, Jesus Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Sankaran, Mahesh. University of Leeds; Reino Unido. Tata Institute of Fundamental Research; IndiaFil: Seabloom, Eric. University of Minnesota; Estados UnidosFil: Wang, Shaopeng. Peking University; ChinaFil: Bagchi, Sumanta. Indian Institute of Science; IndiaFil: Brudvig, Lars A.. Michigan State University; Estados UnidosFil: Catford, Jane A.. University of Melbourne; Australia. Kings College London (kcl);Fil: Dickman, Chris R.. The University Of Sydney; AustraliaFil: Dickson, Tymothy L.. University of Nebraska; Estados UnidosFil: Donohue, Ian. Trinity College Dublin; Reino UnidoFil: Eisenhauer, Nico. Universitat Leipzig; Alemania. German Centre for Integrative Biodiversity Research; AlemaniaFil: Gruner, Daniel S.. University of Maryland; Estados UnidosFil: Haider, Sylvia. German Centre for Integrative Biodiversity Research; Alemania. Martin Luther University Halle-Wittenberg; Alemania. Leuphana University of Lüneburg; AlemaniaFil: Jentsch, Anke. University of Bayreuth; AlemaniaFil: Knops, Johannes M. H.. Xi’an Jiaotong-Liverpool University; ChinaFil: Lekberg, Ylva. University of Montana; Estados UnidosFil: McCulley, Rebecca L.. University of Kentucky; Estados UnidosFil: Moore, Joslin L.. University of Melbourne; Australia. Monash University; Australia. Arthur Rylah Institute for Environmental Research; AustraliaFil: Mortensen, Brent. Benedictine College; Estados UnidosFil: Peri, Pablo Luis. Instituto Nacional de Tecnología Agropecuaria; Argentina. Universidad Nacional de la Patagonia Austral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rocca, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentin

MiR-122 targets pyruvate kinase M2 and affects metabolism of hepatocellular carcinoma

10.1371/journal.pone.0086872PLoS ONE91-POLN

Local Loss and Spatial Homogenization of Plant Diversity Reduce Ecosystem Multifunctionality

Biodiversity is declining in many local communities while also becoming increasingly homogenized across space. Experiments show that local plant species loss reduces ecosystem functioning and services, but the role of spatial homogenization of community composition and the potential interaction between diversity at different scales in maintaining ecosystem functioning remains unclear, especially when many functions are considered (ecosystem multifunctionality). We present an analysis of eight ecosystem functions measured in 65 grasslands worldwide. We find that more diverse grasslands—those with both species-rich local communities (α-diversity) and large compositional differences among localities (β-diversity)—had higher levels of multifunctionality. Moreover, α- and β-diversity synergistically affected multifunctionality, with higher levels of diversity at one scale amplifying the contribution to ecological functions at the other scale. The identity of species influencing ecosystem functioning differed among functions and across local communities, explaining why more diverse grasslands maintained greater functionality when more functions and localities were considered. These results were robust to variation in environmental drivers. Our findings reveal that plant diversity, at both local and landscape scales, contributes to the maintenance of multiple ecosystem services provided by grasslands. Preserving ecosystem functioning therefore requires conservation of biodiversity both within and among ecological communities

Identification of sortase A (SrtA) substrates in Streptococcus uberis: evidence for an additional hexapeptide (LPXXXD) sorting motif

Sortase (a transamidase) has been shown to be responsible for the covalent attachment of proteins to the bacterial cell wall. Anchoring is effected on secreted proteins containing a specific cell wall motif toward their C-terminus; that for sortase A (SrtA) in Gram-positive bacteria often incorporates the sequence LPXTG. Such surface proteins are often characterized as virulence determinants and play important roles during the establishment and persistence of infection. Intramammary infection with Streptococcus uberis is a common cause of bovine mastitis, which impacts on animal health and welfare and the economics of milk production. Comparison of stringently produced cell wall fractions from S. uberis and an isogenic mutant strain lacking SrtA permitted identification of 9 proteins likely to be covalently anchored at the cell surface. Analysis of these sequences implied the presence of two anchoring motifs for S. uberis, the classical LPXTG motif and an additional LPXXXD motif