CRAF R391W is a melanoma driver oncogene.

Approximately 75% of melanomas have known driver oncogenic mutations in BRAF, NRAS, GNA11 or GNAQ, while the mutations providing constitutive oncogenic signaling in the remaining melanomas are not known. We established a melanoma cell line from a tumor with none of the common driver mutations. This cell line demonstrated a signaling profile similar to BRAF-mutants, but lacked sensitivity to the BRAF inhibitor vemurafenib. RNA-seq mutation data implicated CRAF R391W as the alternative driver mutation of this melanoma. CRAF R391W was homozygous and over expressed. These melanoma cells were highly sensitive to CRAF, but not BRAF knockdown. In reconstitution experiments, CRAF R391W, but not CRAF WT, transformed NIH3T3 cells in soft-agar colony formation assays, increased kinase activity in vitro, induced MAP kinase signaling and conferred vemurafenib resistance. MAP kinase inducing activity was dependent on CRAF dimerization. Thus, CRAF is a bona fide alternative oncogene for BRAF/NRAS/GNAQ/GNA11 wild type melanomas

Solar Decathlon Africa: Artisanal Design Features for Team OCULUS Net-Zero Solar House

WPI will participate in the 2019 Solar Decathlon Africa with three partner universities to create an efficient, innovative, net-zero energy house. Our goal was to provide recommendations for the floor, insulation, and exterior envelope systems that are functional and aesthetic features of the Solar Decathlon entry. We interviewed, observed, and shadowed artisans to learn about technical details of three Moroccan crafts that will be incorporated into house features: zellige, leather, and wicker. After creating specification sheets and performing ranked analyses on the various options for each craft, we recommended using square zellige tiles, sheepskin leather poufs, and split laurel tree wicker for the flooring, insulation, and envelope systems

Functional plasticity of antibacterial EndoU toxins.

Bacteria use several different secretion systems to deliver toxic EndoU ribonucleases into neighboring cells. Here, we present the first structure of a prokaryotic EndoU toxin in complex with its cognate immunity protein. The contact-dependent growth inhibition toxin CdiA-CTSTECO31 from Escherichia coli STEC_O31 adopts the eukaryotic EndoU fold and shares greatest structural homology with the nuclease domain of coronavirus Nsp15. The toxin contains a canonical His-His-Lys catalytic triad in the same arrangement as eukaryotic EndoU domains, but lacks the uridylate-specific ribonuclease activity that characterizes the superfamily. Comparative sequence analysis indicates that bacterial EndoU domains segregate into at least three major clades based on structural variations in the N-terminal subdomain. Representative EndoU nucleases from clades I and II degrade tRNA molecules with little specificity. In contrast, CdiA-CTSTECO31 and other clade III toxins are specific anticodon nucleases that cleave tRNAGlu between nucleotides C37 and m2 A38. These findings suggest that the EndoU fold is a versatile scaffold for the evolution of novel substrate specificities. Such functional plasticity may account for the widespread use of EndoU effectors by diverse inter-bacterial toxin delivery systems

JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma.

A prominent mechanism of acquired resistance to BRAF inhibitors in BRAF (V600) -mutant melanoma is associated with the upregulation of receptor tyrosine kinases. Evidences suggested that this resistance mechanism is part of a more complex cellular adaptation process. Using an integrative strategy, we found this mechanism to invoke extensive transcriptomic, (phospho-) proteomic and phenotypic alterations that accompany a cellular transition to a de-differentiated, mesenchymal and invasive state. Even short-term BRAF-inhibitor exposure leads to an early adaptive, differentiation state change-characterized by a slow-cycling, persistent state. The early persistent state is distinct from the late proliferative, resistant state. However, both differentiation states share common signaling alterations including JUN upregulation. Motivated by the similarities, we found that co-targeting of BRAF and JUN is synergistic in killing fully resistant cells; and when used up-front, co-targeting substantially impairs the formation of the persistent subpopulation. We confirmed that JUN upregulation is a common response to BRAF inhibitor treatment in clinically treated patient tumors. Our findings demonstrate that events shared between early- and late-adaptation states provide candidate up-front co-treatment targets

Repeated Maximal Exercise Measures are Very Reliable Among Healthy College-aged Individuals

The most common way to assess cardiovascular fitness is with a maximal graded exercise test (GXT) to determine the maximal rate of oxygen consumption (VO2 max). Maximal exercise efforts during GXT testing have been shown to be quite repeatable among active and sedentary adults, as well as cardiac patients and the elderly. With young, healthy participants, familiarization and motivation could result in improved performance measures with repeated testing. The reliability of maximal exercise measures among healthy college-aged individuals during repeated Bruce Protocol GXT assessments are yet unclear. PURPOSE: To determine how repeatable the VO2max and other maximal exercise indices were with repeated GXT measures among healthy, college-aged adults. METHODS: Thirty-six apparently healthy participants (20 men, 16 women) aged 21.47 ± 0.5 years completed three GXT testing sessions following the Bruce Protocol. The maximal values for VO2, blood lactate, VE, HR and Borg Rating of Perceived Exertion (RPE) as well as time to exhaustion were recorded at the end of each session. RESULTS: Statistical analysis of the data was conducted using a one-way ANOVA by order of visit and a Tukey post-hoc analysis. With all participants combined, there were no differences in measured variables with one exception. Maximal RPE was higher in Visit 3 compared to Baseline (p=0.02). When men and the women were analyzed separately, there were no differences in RPE values among the men. Women reported a higher Max RPE in both Visit 2 and Visit 3 compared to Baseline. Despite the higher RPE values no other maximal measures were significantly different across testing sessions. CONCLUSION: This research confirms that repeated maximal GXT measures are very reliable among healthy college-aged individuals. The exception being a small but significant difference in self-reported maximal RPE values among women compared to baseline measures. Future studies could address potential reasons for the significant difference in women’s self-reported RPE values

Understanding the response to endurance exercise using a systems biology approach: combining blood metabolomics, transcriptomics and miRNomics in horses

BACKGROUND: Endurance exercise in horses requires adaptive processes involving physiological, biochemical, and cognitive-behavioral responses in an attempt to regain homeostasis. We hypothesized that the identification of the relationships between blood metabolome, transcriptome, and miRNome during endurance exercise in horses could provide significant insights into the molecular response to endurance exercise. For this reason, the serum metabolome and whole-blood transcriptome and miRNome data were obtained from ten horses before and after a 160 km endurance competition.[br/] RESULTS: We obtained a global regulatory network based on 11 unique metabolites, 263 metabolic genes and 5 miRNAs whose expression was significantly altered at T1 (post- endurance competition) relative to T0 (baseline, pre-endurance competition). This network provided new insights into the cross talk between the distinct molecular pathways (e.g. energy and oxygen sensing, oxidative stress, and inflammation) that were not detectable when analyzing single metabolites or transcripts alone. Single metabolites and transcripts were carrying out multiple roles and thus sharing several biochemical pathways. Using a regulatory impact factor metric analysis, this regulatory network was further confirmed at the transcription factor and miRNA levels. In an extended cohort of 31 independent animals, multiple factor analysis confirmed the strong associations between lactate, methylene derivatives, miR-21-5p, miR-16-5p, let-7 family and genes that coded proteins involved in metabolic reactions primarily related to energy, ubiquitin proteasome and lipopolysaccharide immune responses after the endurance competition. Multiple factor analysis also identified potential biomarkers at T0 for an increased likelihood for failure to finish an endurance competition.[br/] CONCLUSIONS: To the best of our knowledge, the present study is the first to provide a comprehensive and integrated overview of the metabolome, transcriptome, and miRNome co-regulatory networks that may have a key role in regulating the metabolic and immune response to endurance exercise in horses

Testing Lorentz Invariance with Neutrinos from Ultrahigh Energy Cosmic Ray Interactions

We have previously shown that a very small amount of Lorentz invariance violation (LIV), which suppresses photomeson interactions of ultrahigh energy cosmic rays (UHECRs) with cosmic background radiation (CBR) photons, can produce a spectrum of cosmic rays that is consistent with that currently observed by the Pierre Auger Observatory (PAO) and HiRes experiments. Here, we calculate the corresponding flux of high energy neutrinos generated by the propagation of UHECR protons through the CBR in the presence of LIV. We find that LIV produces a reduction in the flux of the highest energy neutrinos and a reduction in the energy of the peak of the neutrino energy flux spectrum, both depending on the strength of the LIV. Thus, observations of the UHE neutrino spectrum provide a clear test for the existence and amount of LIV at the highest energies. We further discuss the ability of current and future proposed detectors make such observations.Comment: final version to appear in Astroparticle Physic

Examining Youth Camping Outcomes Across Multiple States: the National 4-H Camping Research Consortium (NCRC)

The impact of residential camp participation is needed for camps focused on a variety of outcomes including education, summer fun, prevention, and youth development. One system, the Cooperative Extension Service, conducts 4-H residential camps in most states nationwide every year. These camps, though offering educational enhancement and fun activities, are focused on youth development, incorporating a framework called the essential elements of positive youth development. The National 4-H Camping Research Consortium (NCRC), a group of Extension specialists and county-level educators, designed and piloted assessment tools for 4-H camps that can be used at any camp that focuses on youth development. The camp context questionnaire measures three essential elements of youth development: relationship with a caring adult, self-determination and mastery, and safe and inclusive environments. The life skill questionnaire measures three life skills: accepting self and others, accomplishing goals, and taking responsibility. Logic models and evaluation guidelines help camp directors plan camps that work for youth

Multi-Loop Results, Charm- and Bottom-Quark Masses and the Strong Coupling Constant

The impact of recent multi-loop calculations on precise determinations of charm- and bottom-quark masses and the strong coupling constant is discussed.Comment: ICHEP08 proceedin