C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons.

Intronic hexanucleotide expansions in C9ORF72 are common in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, but it is unknown whether loss of function, toxicity by the expanded RNA or dipeptides from non-ATG-initiated translation are responsible for the pathophysiology. We determined the interactome of C9ORF72 in motor neurons and found that C9ORF72 was present in a complex with cofilin and other actin binding proteins. Phosphorylation of cofilin was enhanced in C9ORF72-depleted motor neurons, in patient-derived lymphoblastoid cells, induced pluripotent stem cell-derived motor neurons and post-mortem brain samples from ALS patients. C9ORF72 modulates the activity of the small GTPases Arf6 and Rac1, resulting in enhanced activity of LIM-kinases 1 and 2 (LIMK1/2). This results in reduced axonal actin dynamics in C9ORF72-depleted motor neurons. Dominant negative Arf6 rescues this defect, suggesting that C9ORF72 acts as a modulator of small GTPases in a pathway that regulates axonal actin dynamics

An optimization model for regional integrated solid waste management: II. Model application and sensitivity analysis

Increased environmental concerns and the emphasis on material and energy recovery are gradually changing the orientation of MSW management and planning. In this context, the application of optimisation techniques have been introduced to design the least cost solid waste management systems, considering the variety of management processes (recycling, composting, anaerobic digestion, incineration, and landfilling), and the existence of uncertainties associated with the number of system components and their interrelations. This study presents a model that was developed and applied to serve as a solid waste decision support system for MSW management taking into account both socio-economic and environmental considerations. The model accounts for solid waste generation rates, composition, collection, treatment, disposal as well as potential environmental impacts of various MSW management techniques. The model follows a linear programming formulation with the framework of dynamic optimisation. The model can serve as a tool to evaluate various MSW management alternatives and obtain the optimal combination of technologies for the handling, treatment and disposal of MSW in an economic and environmentally sustainable way. The sensitivity of various waste management policies is also addressed. The work is presented in a series of two papers: (I) model formulation, and (II) model application and sensitivity analysis. <br/

First report of fusarium oxysporum f. sp. cubense tropical race 4 causing panama disease in cavendish bananas in Pakistan and Lebanon

Panama disease of banana, caused byFusarium oxysporumf. sp.cubense(Foc), poses a great risk to global banana production. Tropical race 4 (TR4) of Foc, which affects Cavendish bananas as well as many other banana cultivars (Ploetz 2006), was confirmed for the first time outside Southeast Asia in Jordan in 2013 (García-Bastidas et al. 2014). In Pakistan, bananas are produced in the Sindh and Balochistan provinces (91% [31,000 ha] and 9% of the country’s production, respectively). Symptoms ofFusariumwilt, including wilting of leaves and vascular discoloration in rhizomes and pseudostems, were first observed in 2012 in a 2-ha Cavendish plantation in Baoo Pooran (ca. 24°N, 68°E), Sindh Province. By January 2014, approximately 121 ha were affected. In Lebanon, bananas are produced for local consumption and regional export, especially to Syria. Yellowing of leaves and internal vascular discoloration in the pseudostems was first observed in Cavendish plants in October 2013 in the Mansouri and Berghliyeh regions. Thus far, 1 ha has been affected. Infected pseudostem tissue samples from Pakistan and Lebanon were processed for Foc isolation and characterization as described byGarcía-Bastidas et al. (2014). White colonies developed from the surface sterilized (70% ethanol) tissue on Komada’s medium (Leslie and Summerell 2006) and nine single microconidia isolates were generated, four from the Pakistan sample and five from the Lebanon samples and transferred to quarter-strength PDA. All isolates phenotypically resembledF. oxysporum(Leslie and Summerell 2006) and were diagnosed as vegetative compatibility group (VCG) 01213, which was confirmed by PCR, thereby corroborating that VCG01213 only represents TR4 strains (Ploetz 2006). Subsequently, one of the isolates from Pakistan (Pak1.1A) and one isolate each from Mansouri (Leb1.1A) and Berghliyeh (Leb1.2C) in Lebanon were analyzed for pathogenicity. Inoculum production and inoculation were according toDita et al. (2010)by dipping (30 min, 106spores/ml) root-wounded 10-week-old Cavendish cv. Grand Naine plants, which were then placed in sand in 3-liter pots under 28°C, 70% relative humidity, and a 16-h diurnal light periods for 6 weeks. Sets of three plants were each treated with either Pak1.1A, Leb1.1A, Leb1.2C, or TR4 (reference isolate II-5, which was diagnosed as TR4 by PCR and pathogenicity analyses, seeDita et al. 2010). Control sets were each treated with either Foc Race1 (Cruz das Almas, Brazil, seeDita et al. 2010) or water. After 4 weeks, all plants inoculated with the isolates from Pakistan, Lebanon, and TR4 (II-5) produced typical symptoms of Fusarium wilt. After 6 weeks, internal symptoms were recorded and tissue was collected from all plants and plated on Komada’s medium. TR4 was confirmed by PCR from isolates that were recovered from all symptomatic plants. No isolates were recovered from plants infected with Race 1 or the water controls, all of which remained asymptomatic. Thus, we confirm the presence of TR4 in Pakistan and Lebanon and its continued expansion and distribution in Western Asia. Although comparatively limited production areas have been affected to date, increasing damage will undoubtedly occur in these countries in the near future

Bromo-deaza-SAH: A potent and selective DOT1L inhibitor

Chemical inhibition of proteins involved in chromatin-mediated signaling is an emerging strategy to control chromatin compaction with the aim to reprogram expression networks to alter disease states. Protein methyltransferases constitute one of the protein families that participate in epigenetic control of gene expression, and represent a novel therapeutic target class. Recruitment of the protein lysine methyltransferase DOT1L at aberrant loci is a frequent mechanism driving acute lymphoid and myeloid leukemias, particularly in infants, and pharmacological inhibition of DOT1L extends survival in a mouse model of mixed lineage leukemia. A better understanding of the structural chemistry of DOT1L inhibition would accelerate the development of improved compounds. Here, we report that the addition of a single halogen atom at a critical position in the cofactor product S-adenosylhomocysteine (SAH, an inhibitor of SAM-dependent methyltransferases) results in an 8-fold increase in potency against DOT1L, and reduced activities against other protein and non-protein methyltransferases. We solved the crystal structure of DOT1L in complex with Bromo-deaza-SAH and rationalized the observed effects. This discovery reveals a simple strategy to engineer selectivity and potency towards DOT1L into the adenosine scaffold of the cofactor shared by all methyltransferases, and can be exploited towards the development of clinical candidates against mixed lineage leukemia. © 2013 Elsevier Ltd. All rights reserved

Bromo-deaza-SAH: a potent and selective DOT1L inhibitor.

Chemical inhibition of proteins involved in chromatin-mediated signaling is an emerging strategy to control chromatin compaction with the aim to reprogram expression networks to alter disease states. Protein methyltransferases constitute one of the protein families that participate in epigenetic control of gene expression, and represent a novel therapeutic target class. Recruitment of the protein lysine methyltransferase DOT1L at aberrant loci is a frequent mechanism driving acute lymphoid and myeloid leukemias, particularly in infants, and pharmacological inhibition of DOT1L extends survival in a mouse model of mixed lineage leukemia. A better understanding of the structural chemistry of DOT1L inhibition would accelerate the development of improved compounds. Here, we report that the addition of a single halogen atom at a critical position in the cofactor product S-adenosylhomocysteine (SAH, an inhibitor of SAM-dependent methyltransferases) results in an 8-fold increase in potency against DOT1L, and reduced activities against other protein and non-protein methyltransferases. We solved the crystal structure of DOT1L in complex with Bromo-deaza-SAH and rationalized the observed effects. This discovery reveals a simple strategy to engineer selectivity and potency towards DOT1L into the adenosine scaffold of the cofactor shared by all methyltransferases, and can be exploited towards the development of clinical candidates against mixed lineage leukemia

An optimisation model for regional integrated solid waste management I. Model formulation

Increased environmental concerns and the emphasis on material and energy recovery are gradually changing the orientation of MSW management and planning. In this context, the application of optimisation techniques have been introduced to design the least cost solid waste management systems, considering the variety of management processes. This study presents a model that was developed and applied to serve as a solid waste decision support system for MSW management taking into account both socio-economic and environmental considerations. The model accounts for solid waste generation rates, composition, collection, treatment, disposal as well as potential environmental impacts of various MSW management techniques. The model follows a linear programming formulation with the framework of dynamic optimisation. The model can serve as a tool to evaluate various MSW management alternatives and obtain the optimal combination of technologies for the handling, treatment and disposal of MSW in an economic and environmentally sustainable way. The sensitivity of various waste management policies will be also addressed. The work is presented in a series of two papers: (I) model formulation, and (II) model application and sensitivity analysi