Stabilization and ribosome association of unspliced pre-mRNAs in a yeast upf1- mutant

Nonsense-mediated mRNA decay, the accelerated turnover of mRNAs transcribed from genes containing early nonsense mutations, is dependent on the product of the UPF1 gene in yeast. Mutations that inactivate UPF1 lead to the selective stabilization of mRNAs containing early nonsense mutations but have no effect on the half-lives of almost all other mRNAs. Since the transcripts of nonsense alleles are not typical cellular constituents, we sought to identify those RNAs that comprise normal substrates of the nonsense-mediated mRNA decay pathway. Many yeast pre-mRNAs contain early in-frame nonsense codons and we consider it possible that a role of this pathway is to accelerate the degradation of pre-mRNAs present in the cytoplasm. Consistent with this hypothesis, we find that, in a strain lacking UPF1 function, the CYH2, RP51B, and MER2 pre-mRNAs are stabilized 2- to 5-fold and are associated with ribosomes. We conclude that a major source of early nonsense codon-containing cytoplasmic transcripts in yeast is pre-mRNAs and that the UPF1 protein may be part of a cellular system that ensures that potentially deleterious nonsense fragments of polypeptides do not accumulate

The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines

The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-COV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally bioavailable compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS-COV-2 replication (EC50 range, 2.0-31.6 nM) with a selectivity index \u3e 3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17 F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19

Undergraduate Research: A Bridge to Graduate Education in Agricultural Biotechnology for Hispanics

Hispanics lag behind all other U.S. ethnic groups in education, and are especially poorly represented in science careers. Undergraduate research is an efficient method to attract undergraduate students to science, and many universities are taking advantage of this; however, much still needs to be done to fully explore its potential. In 2000, Texas A&M University-Kingsville, in collaboration with the University of Texas at Brownsville and the University of Texas Pan-American, initiated a undergraduate research internship program in citrus biotechnology to channel Hispanic undergraduate students into graduate education. To date, 51 internships have been provided, and 20 students have been channeled into graduate school, including four at the doctoral level. Most were first-generation college students

The Kolmogorov-Smirnov test and its use for the identification of fireball fragmentation

We propose an application of the Kolmogorov-Smirnov test for rapidity distributions of individual events in ultrarelativistic heavy ion collisions. The test is particularly suitable to recognise non-statistical differences between the events. Thus when applied to a narrow centrality class it could indicate differences between events which would not be expected if all events evolve according to the same scenario. In particular, as an example we assume here a possible fragmentation of the fireball into smaller pieces at the quark/hadron phase transition. Quantitative studies are performed with a Monte Carlo model capable of simulating such a distribution of hadrons. We conclude that the Kolmogorov-Smirnov test is a very powerful tool for the identification of the fragmentation process.Comment: 9 pages, 10 figure

Meta-analyses of deflazacort versus prednisone/prednisolone in patients with nonsense mutation Duchenne muscular dystrophy

Aim: Compare efficacies of deflazacort and prednisone/prednisolone in providing clinically meaningful delays in loss of physical milestones in patients with nonsense mutation Duchenne muscular dystrophy. Materials & methods: Placebo data from Phase IIb (ClinicalTrials.gov Identifier: NCT00592553) and ACT DMD (ClinicalTrials.gov Identifier: NCT01826487) ataluren nonsense mutation Duchenne muscular dystrophy clinical trials were retrospectively combined in meta-analyses (intent-to-treat population; for change from baseline to week 48 in 6-min walk distance [6MWD] and timed function tests). Results: Significant improvements in change in 6-min walk distance with deflazacort versus prednisone/prednisolone (least-squares mean difference 39.54 m [95% CI: 13.799, 65.286; p = 0.0026]). Significant and clinically meaningful improvements in 4-stair climb and 4-stair descend for deflazacort versus prednisone/prednisolone. Conclusion: Deflazacort provides clinically meaningful delays in loss of physical milestones over 48 weeks compared with prednisone/prednisolone for patients with nonsense mutation Duchenne muscular dystrophy

Evolution of dopant-induced helium nanoplasmas

Two-component nanoplasmas generated by strong-field ionization of doped helium nanodroplets are studied in a pump-probe experiment using few-cycle laser pulses in combination with molecular dynamics simulations. High yields of helium ions and a pronounced, droplet size-dependent resonance structure in the pump-probe transients reveal the evolution of the dopant-induced helium nanoplasma. The pump-probe dynamics is interpreted in terms of strong inner ionization by the pump pulse and resonant heating by the probe pulse which controls the final charge states detected via the frustration of electron-ion recombination

Robotic arm rehabilitation in chronic stroke patients with aphasia may promote speech and language recovery (but effect is not enhanced by supplementary tDCS)

Objective: This study aimed to determine the extent to which robotic arm rehabilitation for chronic stroke may promote recovery of speech and language function in individuals with aphasia. Methods: We prospectively enrolled 17 individuals from a hemiparesis rehabilitation study pairing intensive robot assisted therapy with sham or active tDCS and evaluated their speech (N = 17) and language (N = 9) performance before and after a 12-week (36 session) treatment regimen. Performance changes were evaluated with paired t-tests comparing pre- and post-test measures. There was no speech therapy included in the treatment protocol. Results: Overall, the individuals significantly improved on measures of motor speech production from pre-test to post-test. Of the subset who performed language testing (N = 9), overall aphasia severity on a standardized aphasia battery improved from pre-test baseline to post-test. Active tDCS was not associated with greater gains than sham tDCS. Conclusions: This work indicates the importance of considering approaches to stroke rehabilitation across different domains of impairment, and warrants additional exploration of the possibility that robotic arm motor treatment may enhance rehabilitation for speech and language outcomes. Further investigation into the role of tDCS in the relationship of limb and speech/language rehabilitation is required, as active tDCS did not increase improvements over sham tDCS

An all-solid-state laser source at 671 nm for cold atom experiments with lithium

We present an all solid-state narrow line-width laser source emitting $670\,\mathrm{mW}$ output power at $671\,\mathrm{nm}$ delivered in a diffraction-limited beam. The \linebreak source is based on a fre-quency-doubled diode-end-linebreak pumped ring laser operating on the ${^4F}_{3/2} \rightarrow {^4I}_{13/2}$ transition in Nd:YVO$_4$. By using periodically-poled po-tassium titanyl phosphate (ppKTP) in an external build-up cavity, doubling efficiencies of up to 86% are obtained. Tunability of the source over $100\,\rm GHz$ is accomplished. We demonstrate the suitability of this robust frequency-stabilized light source for laser cooling of lithium atoms. Finally a simplified design based on intra-cavity doubling is described and first results are presented