Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma

Follicular lymphoma is an incurable B cell malignancy characterized by the t(14;18) translocation and mutations affecting the epigenome. Although frequent gene mutations in key signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined, the spectrum of these mutations typically overlaps with that in the closely related diffuse large B cell lymphoma (DLBCL). Using a combination of discovery exome and extended targeted sequencing, we identified recurrent somatic mutations in RRAGC uniquely enriched in patients with follicular lymphoma (17%). More than half of the mutations preferentially co-occurred with mutations in ATP6V1B2 and ATP6AP1, which encode components of the vacuolar H+-ATP ATPase (V-ATPase) known to be necessary for amino acid−induced activation of mTORC1. The RagC variants increased raptor binding while rendering mTORC1 signaling resistant to amino acid deprivation. The activating nature of the RRAGC mutations, their existence in the dominant clone and their stability during disease progression support their potential as an excellent candidate for therapeutic targeting.Experimental Cancer Medicine Centre

A case of infant botulism in a 4-month-old baby

This case-report highlights: i) the difficulty of IB diagnosis as it is a rare syndrome with subclinical onset, ii) the need for an accurate training for physicians involved in IB management, iii) the efficacy and safety of TEqA in IB treatment, iv) homemade honey is not the only cause of IB

Sustainable use and implementation of bone char as a technology for arsenic and fluoride removal

Arsenic and fluoride are key issues in the global water challenge as they exist above the World Health Organization (WHO) recommended limits of 0.010 mg/L and 1.5 mg/L, respectively, in the natural drinking water sources of many regions of the world. The suitability of using several types of bone char as a sustainable removal technology for arsenic and fluoride in remote areas of developing countries is evaluated. The results suggest that 500˚C is the ideal charring temperature for fish bone char based on removal capacity and aesthetic concerns, such as water discoloration and smell, and that there is no significant competition found when removing fluoride and arsenic simultaneously. Current water projects often fail after one to three years for a variety of reasons. Therefore, implementation strategies will also be discussed

Differential spatial distribution of miR165/6 determines variability in plant root anatomy

A clear example of interspecific variation is the number of root cortical layers in plants. The genetic mechanisms underlying this variability are poorly understood, partly due to the lack of a convenient model. Here, we demonstrate that Cardamine hirsuta, unlike Arabidopsis thaliana, has two cortical layers that are patterned during late embryogenesis. We show that a miR165/6-dependent distribution of the HOMEODOMAIN LEUCINE ZIPPER III (HD-ZIPIII) transcription factor PHABULOSA (PHB) controls this pattern. Our findings reveal that interspecies variation in miRNA distribution can determine differences in anatomy in plants

borrelia burgdorferi infection and lyme disease in children

Summary Lyme disease is a multisystem disease that frequently affects children. It is caused by a group of related spirochetes, Borrelia burgdorferi sensu lato, that are transmitted by ticks belonging to species of the genus Ixodes . The clinical characteristics of Lyme disease in pediatrics resemble those observed in adults, although the symptoms may last for a shorter time and the outcome may be better. However, identifying Lyme disease in children can be significantly more difficult because some of its signs and symptoms can be similar to those of other common pediatric clinical manifestations. Finally, the diagnostic and therapeutic approach to childhood Lyme disease is frequently not codified, and guidelines specifically prepared for adults are used for children without having been validated. This review of the currently available data will evaluate what may be the best approach to the diagnosis and treatment of B. burgdorferi infection and disease in the pediatric population

Influence of the brood rearing temperature on honey bee development and susceptibility to intoxication by pesticides

contribution to session IV Test methodolog

Sestrin2 is a leucine sensor for the mTORC1 pathway

Leucine is a proteogenic amino acid that also regulates many aspects of mammalian physiology, in large part by activating the mTOR complex 1 (mTORC1) protein kinase, a master growth controller. Amino acids signal to mTORC1 through the Rag guanosine triphosphatases (GTPases). Several factors regulate the Rags, including GATOR1, aGTPase-activating protein; GATOR2, a positive regulator of unknown function; and Sestrin2, a GATOR2-interacting protein that inhibits mTORC1 signaling. We find that leucine, but not arginine, disrupts the Sestrin2-GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20 micromolar, which is the leucine concentration that half-maximally activates mTORC1. The leucine-binding capacity of Sestrin2 is required for leucine to activate mTORC1 in cells. These results indicate that Sestrin2 is a leucine sensor for the mTORC1 pathway.United States. National Institutes of Health (R01CA103866)United States. National Institutes of Health (AI47389)United States. Department of Defense (W81XWH-07-0448)United States. National Institutes of Health (T32 GM007753)United States. National Institutes of Health (F30 CA189333)United States. National Institutes of Health (F31 CA180271

Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway

Eukaryotic cells coordinate growth with the availability of nutrients through the mechanistic target of rapamycin complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag guanosine triphosphatases and their regulators GATOR1 and GATOR2. Sestrin2 interacts with GATOR2 and is a leucine sensor. Here we present the 2.7 angstrom crystal structure of Sestrin2 in complex with leucine. Leucine binds through a single pocket that coordinates its charged functional groups and confers specificity for the hydrophobic side chain. A loop encloses leucine and forms a lid-latch mechanism required for binding. A structure-guided mutation in Sestrin2 that decreases its affinity for leucine leads to a concomitant increase in the leucine concentration required for mTORC1 activation in cells. These results provide a structural mechanism of amino acid sensing by the mTORC1 pathway.United States. Department of Defense (W81XWH-07- 0448)Damon Runyon Cancer Research Foundation (DRG-112-12)National Institutes of Health (U.S.) (Predoctoral Training Grant T32GM007287)National Institutes of Health (U.S.) (Grants R01CA103866, AI47389, T32 GM007753, F30 CA189333, F31 CA180271, and F31 CA189437)United States. Dept. of Defense. Breast Cancer Research Program (Postdoctoral Fellowship BC120208)Massachusetts Institute of Technology. Office of the Dean for Graduate Education (Whitaker Health Sciences Fund Fellowship)Damon Runyon Cancer Research Foundation (Sally Gordon Fellowship DRG-112-12