Cytoplasmic aggregation of TDP-43, accompanied by its nuclear clearance, is a key common pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, a limited understanding of this RNA-binding protein (RBP) impedes the clarification of pathogenic mechanisms underlying TDP-43 proteinopathy. In contrast to RBPs that regulate splicing of conserved exons, we found that TDP-43 repressed the splicing of nonconserved cryptic exons, maintaining intron integrity. When TDP-43 was depleted from mouse embryonic stem cells, these cryptic exons were spliced into messenger RNAs, often disrupting their translation and promoting nonsense-mediated decay. Moreover, enforced repression of cryptic exons prevented cell death in TDP-43–deficient cells. Furthermore, repression of cryptic exons was impaired in ALS-FTD cases, suggesting that this splicing defect could potentially underlie TDP-43 proteinopathy.
Rapid advances in DNA synthesis techniques have made it possible to engineer viruses, biochemical pathways and assemble bacterial genomes. Here, we report the synthesis of a functional 272,871 bp designer eukaryotic chromosome, synIII, which is based on the 316,617 bp native Saccharomyces cerevisiae chromosome III. Changes to synIII include TAG/TAA stop-codon replacements, deletion of subtelomeric regions, introns, tRNAs, transposons and silent mating loci as well as insertion of loxPsym sites to enable genome scrambling. SynIII is functional in S. cerevisiae. Scrambling of the chromosome in a heterozygous diploid reveals a large increase in “a mater” derivatives resulting from loss of the MATα allele on synIII. The total synthesis of synIII represents the first complete design and synthesis of a eukaryotic chromosome, establishing S. cerevisiae as the basis for designer eukaryotic genome biology.
Background: The Coronavirus disease 2019 (COVID-19) pandemic is a major threat to public health and has had a significant impact on all aspects of life. An effective vaccine is the most anticipated resolution. This study aims to evaluate Jordanian intent to be vaccinated.Methods: This is a cross-sectional web-based study. Sample characteristics were gathered, and the participants were classified according to the degree of COVID-19 risk based on the categories of the Centers for Disease Control and Prevention (CDC). Participants' KAP toward COVID-19 were assessed, and two scores were calculated: knowledge score and practice score. The association between different sample characteristics and these scores was identified using binary logistical regressions. The participants' vaccination intention was evaluated and multinomial logistic regression was applied to identify the predictors of vaccination intention. Finally, the reasons behind the participants' vaccination refusal/hesitation were determined and categorized into different groups.Results: 1,144 participants were enrolled in the study (females = 66.5%). 30.4% of the participants were at high risk of COVID-19 complications, and 27.5% were at medium risk. Overall, participants' knowledge of COVID-19 symptoms, transmission methods, protective measures, and availability of cure were high (median of knowledge score = 17 out of 21). High protective practices were followed by many participants (median of practice score = 7 out of 10). 3.7% of participants were infected, and 6.4% suspected they were infected with the COVID-19 virus. 36.8% of the participants answered “No” when asked if they would take the vaccine once it becomes available, and 26.4% answered, “Not sure.” The main reasons for the participants' vaccination refusal or hesitancy were concerns regarding the use of vaccines and a lack of trust in them.Conclusion: Participants reported high refusal/hesitancy. Several barriers were identified, and efforts should be intensified to overcome these barriers.
Recreational Ecstasy/MDMA (3,4-methylenedioxymethamphetamine) users often take a variety of psychoactive drugs, but there is little empirical data on how these drug consumption patterns change with greater experience of Ecstasy. The aim of this study was to compare the polydrug usage patterns reported by non-Ecstasy users, novice Ecstasy users, moderate Ecstasy users, and heavy Ecstasy users. In a WWW study of 763 unpaid volunteers, 481 had never taken Ecstasy, whereas 282 reported they had taken it. The Ecstasy users comprised 109 novice users (1-9 occasions), 136 moderate Ecstasy users (10 -99 occasions), and 36 heavy Ecstasy users ( + 100 occasions). Each participant also reported their experience with a range of other psychoactive drugs. The Ecstasy users reported significantly greater psychoactive drug usage than the nonEcstasy users. The novice, moderate, and heavy Ecstasy users also differed significantly from each other in the use of cocaine, amphetamine, LSD, and psilocybin mushrooms, but not of alcohol, cannabis, or cigarettes/nicotine. Experienced Ecstasy users also took significantly more MDMA tablets on each occasion, and reported a higher maximum weekly intake. The increased use of Ecstasy is associated with more intensive patterns of Ecstasy/MDMA intake, and the greater use of illicit CNS stimulants and hallucinogens, but not of alcohol, nicotine, or cannabis. These results are discussed in the context of cross-tolerance and drug predisposition/preference.
An important aspect of the empirical study of user experience is the process by which users form aesthetic and other judgements of interactive products. The current study extends previous research by presenting test users with a context (mode of use) in which to make their judgements, using sets of web pages from specific domains rather than unrelated pages, studying the congruence of perceptions of aesthetic value over time, including judgements after use of a web site, manipulating the aesthetic design of web pages and studying the relationship between usability and aesthetic value. The results from two experiments demonstrate that context increases the stability of judgements from perceptions after brief exposure to those after self-paced exposure and from perceptions after self-paced exposure to those of after site use. Experiment 1 shows that relatively attractive pages are preferred over relatively unattractive pages after brief exposure, but only if no context is provided. Experiment 2 shows that after brief exposure, classically aesthetic pages that are information-oriented are rated as more attractive than expressively aesthetic pages. Perceptions are not correlated with measures of task performance or mental effort. We conclude that context is a pivotal factor influencing the stability of users" perceptions, which must be explicitly addressed in the study of users" product experience. Furthermore, the type of aesthetics that is relevant to users" perceptions appears to depend on the application domain. The principle "what is beautiful is usable" is not confirmed.
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ABSTRACTRecent research into user experience has identified the need for a theoretical model to build cumulative knowledge in research addressing how the overall quality or "goodness" of an interactive product is formed.An experiment tested and extended Hassenzahl"s model of aesthetic experience. The study used a 2x2x (2) experimental design with three factors: principles of screen design, principles for organizing information on a web page and experience of using a web site. Dependent variables included hedonic perceptions and evaluations of a web site as well as measures of task performance, navigation behaviour and mental effort.Measures, except Beauty, were sensitive to manipulation of web design. Beauty was influenced by hedonic attributes (identification and stimulation), but Goodness by both hedonic and pragmatic (user-perceived usability) attributes as well as task performance and mental effort. Hedonic quality was more stable with experience of web-site use than pragmatic quality and Beauty was more stable than Goodness.
Alcohol-induced hangover, defined by a series of symptoms, is the most commonly reported consequence of excessive alcohol consumption. Alcohol hangovers contribute to workplace absenteeism, impaired job performance, reduced productivity, poor academic achievement, and may compromise potentially dangerous daily activities such as driving a car or operating heavy machinery. These socioeconomic consequences and health risks of alcohol hangover are much higher when compared to various common diseases and other health risk factors. Nevertheless, unlike alcohol intoxication the hangover has received very little scientific attention and studies have often yielded inconclusive results. Systematic research is important to increase our knowledge on alcohol hangover and its consequences. This consensus paper of the Alcohol Hangover Research Group discusses methodological issues that should be taken into account when performing future alcohol hangover research. Future research should aim to (1) further determine the pathology of alcohol hangover, (2) examine the role of genetics, (3) determine the economic costs of alcohol hangover, (4) examine sex and age differences, (5) develop common research tools and methodologies to study hangover effects, (6) focus on factor that aggravate hangover severity (e.g., congeners), and (7) develop effective hangover remedies.
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