Identification and characterization of novel factors that act in the nonsense-mediated mRNA decay pathway in nematodes, flies and mammals

Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that degrades mRNAs harboring premature termination codons (PTCs). We have conducted a genome-wide RNAi screen in Caenorhabditis elegans that resulted in the identification of five novel NMD genes that are conserved throughout evolution. Two of their human homologs, GNL2 (ngp-1) and SEC13 (npp-20), are also required for NMD in human cells. We also show that the C. elegans gene noah-2, which is present in Drosophila melanogaster but absent in humans, is an NMD factor in fruit flies. Altogether, these data identify novel NMD factors that are conserved throughout evolution, highlighting the complexity of the NMD pathway and suggesting that yet uncovered novel factors may act to regulate this process

Dynamics of Quasi-ordered Structure in a Regio-regulated pi-Conjugated Polymer:Poly(4-methylthiazole-2,5-diyl)

Dynamics of regio-regulated Poly(4-methylthiazole-2,5-diyl) [HH-P4MeTz] was inves tigated by solid-state 1H, 2D, 13C NMR spectroscopies, and differential scanning calorimetry(DSC) measurements. DSC, 2D quadrupolar echo NMR, 13C cross-polarization and magic-angle spinning(CPMAS) NMR, and 2D spin-echo(2DSE) CPMAS NMR spectroscopy suggest existence of a quasi-ordered phase in which backbone twists take place with weakened pi-stackings. Two-dimensional exchange 2D NMR(2DEX) detected slow dynamics with a rate of an order of 10^2Hz for the CD_3 group in d_3-HH-P4MeTz at 288K. The frequency dependence of proton longitudinal relaxation rate at 288K shows a omega^-1/2 dependence, which is due to the one-dimensional diffusion-like motion of backbone conformational modulation waves. The diffusion rate was estimated as 3+/-2 GHz, which was approximately 10^7 times larger than that estimated by 2DEX NMR measurements. These results suggest that there exists anomalous dispersion of modulation waves in HH-P4MeTz. The one-dimensional group velocity of the wave packet is responsible for the behavior of proton longitudinal relaxation time. On the other hand, the 2DEX NMR is sensitive to phase velocity of the nutation of methyl groups that is associated with backbone twists. From proton T_1 and T_2 measurements, the activation energy was estimated as 2.9 and 3.4 kcal/mol, respectively. These were in agreement with 3.0 kcal/mol determined by Moller-Plesset(MP2) molecular orbital(MO) calculation. We also performed chemical shielding calculation of the methyl-carbon in order to understand chemical shift tensor behavior, leading to the fact that a quasi-ordered phase coexist with the crystalline phase.Comment: 14 pages, 11 figures, to appear in Phys.Rev.

Double Dissociation of Auditory Attention and Visual Scanning in Long Term Survivors of Childhood Cerebellar Tumor: A Deterministic Tractography and Volumetric Study of the Cerebellar-Frontal and the Superior Longitudinal Fasciculus Pathways

Background. Right cerebellar-left frontal (RC-LF) white matter integrity (WMI) has been associated with working memory. Right Superior Longitudinal Fasciculus II (SLF II) WMI has been associated with visual attention. These relationships have held true for neurotypical controls and brain tumor survivors. The current study examined the relationships between RC-LF WMI and processing speed, attention, and working memory. SLF II WMI and visual attention were included as a control tract and task to demonstrate a correlational double dissociation. This study also examined the relationship between the volume of brain regions within the RC-LF network and RC-LF WMI. Methods. Adult survivors of childhood brain tumors (n= 29, age: M=22 years (SD= 5), 45% female) were treated with neurosurgery, and combinations of radiation therapy and chemotherapy. Age- and gender-matched controls (n=29) were also included. Tests of auditory attention span, working memory, visual attention, and processing speed served as cognitive measures. Participants completed a 3T MRI diffusion imaging scan. WMI (FA, RD) and volume served as neuroimaging measures. In the survivor group, partial correlations between WMI and cognitive scores included controlling for type of treatment. Results. A correlational double dissociation was found. RC-LF WMI was associated with auditory attention span (FA: r=.42, p=.03; RD: r=-.50, p=.01), and was not associated with visual attention (FA: r=-.11, p=.59; RD: r=-.11, p=.57). SLF II FA WMI was associated with visual attention (FA: r=.44, p=.02; RD: r=-.17, p=.40), and was not associated with auditory attention span (FA: r=.24, p=.22; RD: r=-.10, p=.62). The relationship between RC-LF WMI and auditory attention span robustly dissociated from working memory and visual attention. In the radiation group, thalamic-frontal segment of RC-LF WMI associated with the volumetric measures of each structure of the RC-LF pathway, whereas in the no radiation group cerebellar-rubral segment of RC-LF WMI associated with the volumetric measures. Conclusions. The current study advances the understanding of structural brain changes following cerebellar tumor resection and treatment because the results show that RC-LF WMI is associated with auditory attention span rather that working memory, provide evidence for a correlational double dissociation, and suggest distinct relationships between WMI and volume based on treatment

Longitudinal Analysis of Risk Factors Affecting Reading Trajectories in Children Diagnosed with Pediatric Brain Tumors

Prior research suggests aggressive cancer treatments contribute to cognitive impairments in children diagnosed with pediatric brain tumors. The literature also suggests that younger age at diagnosis (AAD) and treatment may result in disrupted cognitive trajectories due to limited brain plasticity. In line with this research, we hypothesized an interaction between radiation therapy (RT) and young AAD of brain tumors, where young AAD and RT results in lower standard scores on the WRAT-R Reading Comprehension Subtest. Analyses included archival data; the sample consists of 134 children diagnosed with pediatric brain tumors with multiple assessments resulting in 487 cases for analysis. Participants were diagnosed with mixed tumor types and locations. A two level multilevel model was used to analyze reading trajectories while taking into account AAD, time since diagnosis, socioeconomic status (SES), and RT. Results detected a positive interaction between AAD and RT (γ =2.08, p=.02). For participants with RT, younger AAD was associated with lower reading scores, whereas AAD had no effect for participants without RT. Results also detected a negative interaction between radiation and time (γ =-2.29, p=.00) indicating that children treated with RT have reading scores that decrease over time. These data suggested that children diagnosed with pediatric brain tumors treated with RT are at higher risk of reading impairment as reflected in their reading scores

Survivors of Childhood Cerebellar Tumors: Atrophy, Lack of Lesion Specificity, and the Impact on Behavioral Performance

Research suggests that the cerebellum is involved in cognition, but its exact role is unclear. The efficiency theory posits that the cerebellum supports processing speed. Other researchers argue that the cerebellum is functionally heterogeneous, and damage to lobes of the cerebellum causes selective loss of cognitive functions. This study sought to determine whether selective impairment in motor, verbal fluency, or processing speed occurred depending on the lobe of the cerebellum that was lesioned. Lesion mapping was used to measure lesion size and volumetric methods were used to measure atrophy in 25 adult survivors of cerebellar tumors. Participants had too a high degree of heterogeneous cerebellar lesions and accompanying atrophy to explore specialization. However, total cerebellar atrophy negatively impacted written and oral processing speed to a greater degree than total cerebellar lesion size. Younger ages at diagnosis and radiation therapy were associated with greater cerebellar atrophy

The Conserved VPS-50 Protein Functions in Dense-Core Vesicle Maturation and Acidification and Controls Animal Behavior

The modification of behavior in response to experience is crucial for animals to adapt to environmental changes. Although factors such as neuropeptides and hormones are known to function in the switch between alternative behavioral states, the mechanisms by which these factors transduce, store, retrieve, and integrate environmental signals to regulate behavior are poorly understood. The rate of locomotion of the nematode Caenorhabditis elegans depends on both current and past food availability. Specifically, C. elegans slows its locomotion when it encounters food, and animals in a food-deprived state slow even more than animals in a well-fed state. The slowing responses of well-fed and food-deprived animals in the presence of food represent distinct behavioral states, as they are controlled by different sets of genes, neurotransmitters, and neurons. Here we describe an evolutionarily conserved C. elegans protein, VPS-50, that is required for animals to assume the well-fed behavioral state. Both VPS-50 and its murine homolog mVPS50 are expressed in neurons, are associated with synaptic and dense-core vesicles, and control vesicle acidification and hence synaptic function, likely through regulation of the assembly of the V-ATPase complex. We propose that dense-core vesicle acidification controlled by the evolutionarily conserved protein VPS-50/mVPS50 affects behavioral state by modulating neuropeptide levels and presynaptic neuronal function in both C. elegans and mammals.National Institutes of Health (U.S.) (Grant GM024663

Commensurability and defect-induced phason gaps in incommensurate systems

Journal ArticleThe phason energy gap has been observed to increase on going from the incommensurate to higher-order commensurate phases in the "devil's staircase" compound [N(CH3)4]2ZnCl4. The gap was determined via the phason-induced 1 4N spin-lattice relaxation contribution, which was obtained from the variation of the effective spin- lattice relaxation rate over the inhomogeneous incommensurate frequency distribution. Here, as well as in Rb2ZnCl4 and Rb2ZnBr4 , the phason gap in the incommensurate phase is defect induced

31P NMR spin-lattice relaxation: structural glass dynamics in Rb1-x(ND4)xD2PO4

Journal ArticleWe performed 3 1P NMR measurements of the temperature-dependent spin-lattice relaxation time in several mixed single crystals of Rbi_x(ND4 ) xD2P04 [DRADP] having different ammonium concentration x (x =0.22, 0.44, 0.78) as well as in three pure single crystals (ND4)D2P04 [DADP], (NH4)H2P04 [ADP], and RbH2P04 [RDP]. The 3 1P NMR spin-lattice relaxation-time measurements in mixed crystals show that the phosphorus nuclei are strongly influenced by the gradual slowing down of the motions of protons in the nearby O-D • • • O acid bonds in the structural spin-glass states. In addition to a common Tl minimum observed in all ammonium-containing systems, a second Tl minimum is observed in the temperature region of the glass transition in mixed spin-glass systems but not in pure ADP, DADP, or RDP. We attribute this lower temperature Tx minimum to the extreme slowing down of the O-D • • • O intrabond motion, which is unique to the glass system. In addition, the correlation times and activation energies for the Tx minima in all samples were determined. A comparison between the pure and mixed systems reveals that the mixed system 7^ minimum must be fit to a distribution of correlation functions but that each pure system requires only a single correlation function. Furthermore, measurements on systems having x =0.78 and 0.22 show that 3 1P NMR can be used to determine the threshold concentrations that characterize the glass phase

Production of 2-butanol through meso-2,3-butanediol consumption in lactic acid bacteria

2-Butanol has been an issue of industries in many areas, for example, biofuel production (as an advanced alternate fuel), fermented beverages, and food (as taste-altering component). Thus, its source of production, the biological pathway, and the enzymes involved are of high interest. In this study, 42 different isolates of lactic acid bacteria from nine different species were screened for their capability to consume meso-2,3-butanediol and produce 2-butanol. Lactobacillus brevis was the only species that showed any production of 2-butanol. Five of ten tested isolates of L.brevis were able to convert meso-2,3-butanediol to 2-butanol in a synthetic medium (SM2). However, none of them showed the same capability in a complex medium such as MRS indicating that the ability to produce 2-butanol is subject to some kind of repression mechanism. Furthermore, by evaluating the performance of the enzymes required to convert meso-2,3-butanediol to 2-butanol, that is, the secondary alcohol dehydrogenase and the diol dehydratase, it was shown that the latter needed the presence of a substrate to be expressed