Selective aqueous acetylation controls the photoanomerization of α-cytidine-5′-phosphate

Nucleic acids are central to information transfer and replication in living systems, providing the molecular foundations of Darwinian evolution. Here we report that prebiotic acetylation of the non-natural, but prebiotically plausible, ribonucleotide α-cytidine-5′-phosphate, selectively protects the vicinal diol moiety. Vicinal diol acetylation blocks oxazolidinone formation and prevents C2′-epimerization upon irradiation with UV-light. Consequently, acetylation enhances (4-fold) the photoanomerization of α-cytidine-5′-phosphate to produce the natural β-pyrimidine ribonucleotide-5′-phosphates required for RNA synthesis

Evidence and modeling of turbulence bifurcation in L-mode confinement transitions on Alcator C-Mod

© 2020 Author(s). Analysis and modeling of rotation reversal hysteresis experiments show that a single turbulent bifurcation is responsible for the Linear to Saturated Ohmic Confinement (LOC/SOC) transition and concomitant intrinsic rotation reversal on Alcator C-Mod. Plasmas on either side of the reversal exhibit different toroidal rotation profiles and therefore different turbulence characteristics despite the profiles of density and temperature, which are indistinguishable within measurement uncertainty. Elements of this bifurcation are also shown to persist for auxiliary heated L-modes. The deactivation of subdominant (in the linear growth rate and contribution to heat transport) ion temperature gradient and trapped electron mode instabilities is identified as the only possible change in turbulence within a reduced quasilinear transport model across the reversal, which is consistent with the measured profiles and inferred heat and particle fluxes. Experimental constraints on a possible change from strong to weak turbulence, outside the description of the quasilinear model, are also discussed. These results indicate an explanation for the LOC/SOC transition that provides a mechanism for the hysteresis through the dynamics of subdominant modes and changes in their relative populations and does not involve a change in the most linearly unstable ion-scale drift-wave instability

Thoracoscopy and talc poudrage compared with intercostal drainage and talc slurry infusion to manage malignant pleural effusion: the TAPPS RCT

Background: There are around 40,000 new cases of malignant pleural effusion in the UK each year. Insertion of talc slurry via a chest tube is the current standard treatment in the UK. However, some centres prefer local anaesthetic thoracoscopy and talc poudrage. There is no consensus as to which approach is most effective. Objective: This trial tested the hypothesis that thoracoscopy and talc poudrage increases the proportion of patients with successful pleurodesis at 3 months post procedure, compared with chest drain insertion and talc slurry. Design: This was a multicentre, open-label, randomised controlled trial with embedded economic evaluation. Follow-up took place at 1, 3 and 6 months. Setting: This trial was set in 17 NHS hospitals in the UK. Participants: A total of 330 adults with a confirmed diagnosis of malignant pleural effusion needing pleurodesis and fit to undergo thoracoscopy under local anaesthetic were included. Those adults needing a tissue diagnosis or with evidence of lung entrapment were excluded. Interventions: Allocation took place following minimisation with a random component, performed by a web-based, centralised computer system. Participants in the control arm were treated with a bedside chest drain insertion and 4 g of talc slurry. In the intervention arm, participants underwent local anaesthetic thoracoscopy with 4 g of talc poudrage. Main outcome measures: The primary outcome measure was pleurodesis failure at 90 days post randomisation. Secondary outcome measures included mortality and patient-reported symptoms. A cost–utility analysis was also performed. Results: A total of 166 and 164 patients were allocated to poudrage and slurry, respectively. Participants were well matched at baseline. For the primary outcome, no significant difference in pleurodesis failure was observed between the treatment groups at 90 days, with rates of 36 out of 161 (22%) and 38 out of 159 (24%) noted in the poudrage and slurry groups, respectively (odds ratio 0.91, 95% confidence interval 0.54 to 1.55; p = 0.74). No differences (or trends towards difference) were noted in adverse events or any of the secondary outcomes at any time point, including pleurodesis failure at 180 days [poudrage 46/161 (29%), slurry 44/159 (28%), odds ratio 1.05, 95% confidence interval 0.63 to 1.73; p = 0.86], mean number of nights in hospital over 90 days [poudrage 12 nights (standard deviation 13 nights), slurry 11 nights (standard deviation 10 nights); p = 0.35] and all-cause mortality at 180 days [poudrage 66/166 (40%), slurry 68/164 (42%); p = 0.70]. At £20,000 per quality-adjusted life-year gained, poudrage would have a 0.36 probability of being cost-effective compared with slurry. Limitations: Entry criteria specified that patients must be sufficiently fit to undergo thoracoscopy, which may make the results less applicable to those patients presenting with a greater degree of frailty. Furthermore, the trial was conducted on an open-label basis, which may have influenced the results of patient-reported measures. Conclusions: The TAPPS (evaluating the efficacy of Thoracoscopy And talc Poudrage versus Pleurodesis using talc Slurry) trial has robustly demonstrated that there is no additional clinical effectiveness or cost-effectiveness benefit in performing talc poudrage at thoracoscopy over bedside chest drain and talc slurry for the management of malignant pleural effusion. Trial registration: Current Controlled Trials ISRCTN47845793. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 26. See the NIHR Journals Library website for further project information

Calcium Homeostasis in Myogenic Differentiation Factor 1 (MyoD)-Transformed, Virally-Transduced, Skin-Derived Equine Myotubes

Dysfunctional skeletal muscle calcium homeostasis plays a central role in the pathophysiology of several human and animal skeletal muscle disorders, in particular, genetic disorders associated with ryanodine receptor 1 (RYR1) mutations, such as malignant hyperthermia, central core disease, multiminicore disease and certain centronuclear myopathies. In addition, aberrant skeletal muscle calcium handling is believed to play a pivotal role in the highly prevalent disorder of Thoroughbred racehorses, known as Recurrent Exertional Rhabdomyolysis. Traditionally, such defects were studied in human and equine subjects by examining the contractile responses of biopsied muscle strips exposed to caffeine, a potent RYR1 agonist. However, this test is not widely available and, due to its invasive nature, is potentially less suitable for valuable animals in training or in the human paediatric setting. Furthermore, increasingly, RYR1 gene polymorphisms (of unknown pathogenicity and significance) are being identified through next generation sequencing projects. Consequently, we have investigated a less invasive test that can be used to study calcium homeostasis in cultured, skin-derived fibroblasts that are converted to the muscle lineage by viral transduction with a MyoD (myogenic differentiation 1) transgene. Similar models have been utilised to examine calcium homeostasis in human patient cells, however, to date, there has been no detailed assessment of the cells’ calcium homeostasis, and in particular, the responses to agonists and antagonists of RYR1. Here we describe experiments conducted to assess calcium handling of the cells and examine responses to treatment with dantrolene, a drug commonly used for prophylaxis of recurrent exertional rhabdomyolysis in horses and malignant hyperthermia in humans

New physics searches at near detectors of neutrino oscillation experiments

We systematically investigate the prospects of testing new physics with tau sensitive near detectors at neutrino oscillation facilities. For neutrino beams from pion decay, from the decay of radiative ions, as well as from the decays of muons in a storage ring at a neutrino factory, we discuss which effective operators can lead to new physics effects. Furthermore, we discuss the present bounds on such operators set by other experimental data currently available. For operators with two leptons and two quarks we present the first complete analysis including all relevant operators simultaneously and performing a Markov Chain Monte Carlo fit to the data. We find that these effects can induce tau neutrino appearance probabilities as large as O(10^{-4}), which are within reach of forthcoming experiments. We highlight to which kind of new physics a tau sensitive near detector would be most sensitive.Comment: 20 pages, 2 figures, REVTeX

Can disordered mobile phone use be considered a behavioral addiction? An update on current evidence and a comprehensive model for future research

Despite the many positive outcomes, excessive mobile phone use is now often associated with potentially harmful and/or disturbing behaviors (e.g., symptoms of deregulated use, negative impact on various aspects of daily life such as relationship problems, and work intrusion). Problematic mobile phone use (PMPU) has generally been considered as a behavioral addiction that shares many features with more established drug addictions. In light of the most recent data, the current paper reviews the validity of the behavioral addiction model when applied to PMPU. On the whole, it is argued that the evidence supporting PMPU as an addictive behavior is scarce. In particular, it lacks studies that definitively show behavioral and neurobiological similarities between mobile phone addiction and other types of legitimate addictive behaviors. Given this context, an integrative pathway model is proposed that aims to provide a theoretical framework to guide future research in the field of PMPU. This model highlights that PMPU is a heterogeneous and multi-faceted condition

On the conservation of the slow conformational dynamics within the amino acid kinase family: NAGK the paradigm

N-Acetyl-L-Glutamate Kinase (NAGK) is the structural paradigm for examining the catalytic mechanisms and dynamics of amino acid kinase family members. Given that the slow conformational dynamics of the NAGK (at the microseconds time scale or slower) may be rate-limiting, it is of importance to assess the mechanisms of the most cooperative modes of motion intrinsically accessible to this enzyme. Here, we present the results from normal mode analysis using an elastic network model representation, which shows that the conformational mechanisms for substrate binding by NAGK strongly correlate with the intrinsic dynamics of the enzyme in the unbound form. We further analyzed the potential mechanisms of allosteric signalling within NAGK using a Markov model for network communication. Comparative analysis of the dynamics of family members strongly suggests that the low-frequency modes of motion and the associated intramolecular couplings that establish signal transduction are highly conserved among family members, in support of the paradigm sequence→structure→dynamics→function © 2010 Marcos et al

Unique case of esophageal rupture after a fall from height

<p>Abstract</p> <p>Background</p> <p>Traumatic ruptures of the esophagus are relatively rare. This condition is associated with high morbidity and mortality. Most traumatic ruptures occur after motor vehicle accidents.</p> <p>Case Presentation</p> <p>We describe a unique case of a 23 year old woman that presented at our trauma resuscitation room after a fall from 8 meters. During physical examination there were no clinical signs of life-threatening injuries. She did however have a massive amount of subcutaneous emphysema of the chest and neck and pneumomediastinum. Flexible laryngoscopy revealed a lesion in the upper esophagus just below the level of the upper esophageal sphincter. Despite preventive administration of intravenous antibiotics and nutrition via a nasogastric tube, the patient developed a cervical abscess, which drained spontaneously. Normal diet was gradually resumed after 2.5 weeks and the patient was discharged in a reasonable condition 3 weeks after the accident.</p> <p>Conclusions</p> <p>This case report presents a high cervical esophageal rupture without associated local injuries after a fall from height.</p

Perceptions of primary healthcare professionals towards their role in type 2 diabetes mellitus patient education in Brazil

<p>Abstract</p> <p>Background</p> <p>The aim of the current study was to analyze the perceptions, knowledge, and practices of primary healthcare professionals in providing patient education to people with type 2 diabetes mellitus.</p> <p>Methods</p> <p>A total of 23 health professionals working in primary healthcare units in Belo Horizonte, Minas Gerais State, Brazil, participated in a focus group in order to discuss their patient education practices and the challenges for effective patient education in diabetes self-management.</p> <p>Results</p> <p>The results were categorized as follows: 1) lack of preparation and technical knowledge among the health professionals on some aspects of diabetes mellitus and the health professionals' patient education practices; 2) work conditions and organization; 3) issues related or attributed to the clientele themselves; and 4) diabetes care model.</p> <p>Conclusions</p> <p>This study highlights the importance of reorienting the patient education practices, health professionals' skills and work goals, and evaluation of the educational interventions, in order to establish strategies for health promotion and prevention and control of the disease.</p> <p>Descriptors</p> <p>Health Education; Prevention of Diabetes Mellitus; Primary Healthcare</p