Rules of engagement promote polarity in RNA trafficking

Many cell biological pathways exhibit overall polarity (net movement of molecules in one direction) even though individual molecular interactions in the pathway are freely reversible. The A2 RNA trafficking pathway exhibits polarity in moving specific RNA molecules from the nucleus to localization sites in the myelin compartment of oligodendrocytes or dendritic spines in neurons. The A2 pathway is mediated by a ubiquitously expressed trans-acting trafficking factor (hnRNP A2) that interacts with a specific 11 nucleotide cis-acting trafficking sequence termed the A2 response element (A2RE) found in several localized RNAs. Five different molecular partners for hnRNP A2 have been identified in the A2 pathway: hnRNP A2 itself, transportin, A2RE RNA, TOG (tumor overexpressed gene) and hnRNP E1, each playing a key role in one particular step of the A2 pathway. Sequential interactions of hnRNP A2 with different molecular partners at each step mediate directed movement of trafficking intermediates along the pathway. Specific "rules of engagement" (both and, either or, only if) govern sequential interactions of hnRNP A2 with each of its molecular partners. Rules of engagement are defined experimentally using three component binding assays to measure differential binding of hnRNP A2 to one partner in the presence of each of the other partners in the pathway. Here we describe rules of engagement for hnRNP A2 binding to each of its molecular partners and discuss how these rules of engagement promote polarity in the A2 RNA trafficking pathway. For molecules with multiple binding partners, specific rules of engagement govern different molecular interactions. Rules of engagement are ultimately determined by structural relationships between binding sites on individual molecules. In the A2 RNA trafficking pathway rules of engagement governing interactions of hnRNP A2 with different binding partners provide the basis for polarity of movement of intermediates along the pathway

Predictive validity of the CriSTAL tool for short-term mortality in older people presenting at Emergency Departments: a prospective study

© 2018, The Author(s). Abstract: To determine the validity of the Australian clinical prediction tool Criteria for Screening and Triaging to Appropriate aLternative care (CRISTAL) based on objective clinical criteria to accurately identify risk of death within 3 months of admission among older patients. Methods: Prospective study of ≥ 65 year-olds presenting at emergency departments in five Australian (Aus) and four Danish (DK) hospitals. Logistic regression analysis was used to model factors for death prediction; Sensitivity, specificity, area under the ROC curve and calibration with bootstrapping techniques were used to describe predictive accuracy. Results: 2493 patients, with median age 78–80 years (DK–Aus). The deceased had significantly higher mean CriSTAL with Australian mean of 8.1 (95% CI 7.7–8.6 vs. 5.8 95% CI 5.6–5.9) and Danish mean 7.1 (95% CI 6.6–7.5 vs. 5.5 95% CI 5.4–5.6). The model with Fried Frailty score was optimal for the Australian cohort but prediction with the Clinical Frailty Scale (CFS) was also good (AUROC 0.825 and 0.81, respectively). Values for the Danish cohort were AUROC 0.764 with Fried and 0.794 using CFS. The most significant independent predictors of short-term death in both cohorts were advanced malignancy, frailty, male gender and advanced age. CriSTAL’s accuracy was only modest for in-hospital death prediction in either setting. Conclusions: The modified CriSTAL tool (with CFS instead of Fried’s frailty instrument) has good discriminant power to improve prognostic certainty of short-term mortality for ED physicians in both health systems. This shows promise in enhancing clinician’s confidence in initiating earlier end-of-life discussions

Auto-titrating continuous positive airway pressure for patients with acute transient ischemic attack: a randomized feasibility trial

BACKGROUND AND PURPOSE: Transient ischemic attack (TIA) patients are at risk of recurrent vascular events. The primary objectives were to evaluate among TIA patients the prevalence of sleep apnea and among patients with sleep apnea auto-titrating continuous positive airway pressure (auto-CPAP) adherence. The secondary objective was to describe among TIA patients with sleep apnea the recurrent vascular event rate by auto-CPAP use category. METHODS: All intervention patients received auto-CPAP for 2 nights, but only intervention patients with evidence of sleep apnea received auto-CPAP for the remainder of the 90-day period. Intervention patients received polysomnography at 90 days after TIA. Control patients received polysomnography at baseline and at 90 days. Acceptable auto-CPAP adherence was defined as >or=4 hours per night for >or=75% of nights. Vascular events included recurrent TIA, stroke, hospitalization for congestive heart failure, myocardial infarction, or death. RESULTS: We enrolled 70 acute TIA patients: 45 intervention and 25 control. The majority of patients had sleep apnea: 57% at baseline and 59% at 90 days. Among the 30 intervention patients with airflow obstruction, 12 (40%) had acceptable auto-CPAP adherence, 18 (60%) had some use, and none had no use. Three intervention patients (12%) had recurrent events compared with 1 (2%;P=0.13) control patient. The vascular event rate was highest among sleep apnea patients with no CPAP use: none, 16%;some, 5%;acceptable adherence 0% (P=0.08). CONCLUSIONS: Sleep apnea is common among acute TIA patients. It appears feasible to provide auto-CPAP in the acute TIA period. Larger studies should evaluate whether a strategy of diagnosing and treating sleep apnea can reduce recurrent vascular events after TIA

Training in the practice of noninvasive brain stimulation: Recommendations from an IFCN committee

As the field of noninvasive brain stimulation (NIBS) expands, there is a growing need for comprehensive guidelines on training practitioners in the safe and effective administration of NIBS techniques in their various research and clinical applications. This article provides recommendations on the structure and content of this training. Three different types of practitioners are considered (Technicians, Clinicians, and Scientists), to attempt to cover the range of education and responsibilities of practitioners in NIBS from the laboratory to the clinic. Basic or core competencies and more advanced knowledge and skills are discussed, and recommendations offered regarding didactic and practical curricular components. We encourage individual licensing and governing bodies to implement these guidelines

Discussing prognosis with older people with musculoskeletal pain: a cross-sectional study in general practice

<p>Abstract</p> <p>Background</p> <p>Prognosis has been described as an important but neglected branch of clinical science. While patients' views have been sought in the context of life-threatening illness, similar research is lacking for patients presenting with common, non-life-threatening musculoskeletal complaints. The aim of this study was to gauge whether and why older patients with musculoskeletal pain think prognostic information is important, and how often they felt prognosis was discussed in the general practice consultation.</p> <p>Methods</p> <p>A cross-sectional survey of consecutive patients aged 50 years of over presenting with non-inflammatory musculoskeletal pain to 5 Central Cheshire general practices. The frequency of responses to the prognostic questions were described and the association with sociodemographic, presenting pain complaint, and psychosocial variables explored using logistic regression.</p> <p>Results</p> <p>502 participants (77%) responded to the postal questionnaire. 165 (33%) participants reported discussing prognosis in the consultation with their GP. Discussions about prognosis were more often reported by male patients (OR 1.72, 95% CI 1.09, 2.71) and those for whom this was their first consultation (OR 1.81, 95% CI 1.16, 2.80). 402 (82%) participants thought that prognostic information was important. This was highest among those currently in paid employment (OR 2.95, 95% CI 1.33, 6.57). The reasons patients gave for believing prognostic information was important included 'knowing for the sake of knowing' and planning future activity. Reasons for not believing prognostic information to be important included the belief that progression of pain was inevitable and that nothing could be done to help.</p> <p>Conclusion</p> <p>Prognostic information is thought to be important amongst older people with musculoskeletal pain yet discussions occur infrequently in primary care. Barriers to effective prognostic communication and the exact information needs of patients are still unknown and warrant further research.</p

Training in the practice of noninvasive brain stimulation: Recommendations from an IFCN committee

© 2020 As the field of noninvasive brain stimulation (NIBS) expands, there is a growing need for comprehensive guidelines on training practitioners in the safe and effective administration of NIBS techniques in their various research and clinical applications. This article provides recommendations on the structure and content of this training. Three different types of practitioners are considered (Technicians, Clinicians, and Scientists), to attempt to cover the range of education and responsibilities of practitioners in NIBS from the laboratory to the clinic. Basic or core competencies and more advanced knowledge and skills are discussed, and recommendations offered regarding didactic and practical curricular components. We encourage individual licensing and governing bodies to implement these guidelines

Mutation of von Hippel–Lindau Tumour Suppressor and Human Cardiopulmonary Physiology

BACKGROUND: The von Hippel–Lindau tumour suppressor protein–hypoxia-inducible factor (VHL–HIF) pathway has attracted widespread medical interest as a transcriptional system controlling cellular responses to hypoxia, yet insights into its role in systemic human physiology remain limited. Chuvash polycythaemia has recently been defined as a new form of VHL-associated disease, distinct from the classical VHL-associated inherited cancer syndrome, in which germline homozygosity for a hypomorphic VHL allele causes a generalised abnormality in VHL–HIF signalling. Affected individuals thus provide a unique opportunity to explore the integrative physiology of this signalling pathway. This study investigated patients with Chuvash polycythaemia in order to analyse the role of the VHL–HIF pathway in systemic human cardiopulmonary physiology. METHODS AND FINDINGS: Twelve participants, three with Chuvash polycythaemia and nine controls, were studied at baseline and during hypoxia. Participants breathed through a mouthpiece, and pulmonary ventilation was measured while pulmonary vascular tone was assessed echocardiographically. Individuals with Chuvash polycythaemia were found to have striking abnormalities in respiratory and pulmonary vascular regulation. Basal ventilation and pulmonary vascular tone were elevated, and ventilatory, pulmonary vasoconstrictive, and heart rate responses to acute hypoxia were greatly increased. CONCLUSIONS: The features observed in this small group of patients with Chuvash polycythaemia are highly characteristic of those associated with acclimatisation to the hypoxia of high altitude. More generally, the phenotype associated with Chuvash polycythaemia demonstrates that VHL plays a major role in the underlying calibration and homeostasis of the respiratory and cardiovascular systems, most likely through its central role in the regulation of HIF

The role of venture capitalists in the regional innovation ecosystem : a comparison of networking patterns between private and publicly backed venture capital funds

This paper empirically examines the development of social networks among venture capitalists and other professionals of the regional innovation ecosystem. Using an online survey of venture capitalists, the article considers their networking behaviour, focusing particularly on the distinction between those employed by private and those employed by publicly backed venture capital funds, and on the composition and spatial search of their networks. It investigates whether the frequency of interaction between venture capitalists and other members of the innovation ecosystem is associated with the nature of the venture capital funds. The paper provides the first detailed investigation of the relationship between different types of venture capitalists and other players of the innovation ecosystem such as universities incubators, research institutes, and business support organisations. The results show that there are distinctive differences within the two seemingly similar professional groups (private and public venture capitalists), and public dependence of the venture capital fund is strongly and significantly associated with higher volumes of interactions. The more publicly dependent a fund is, the more it interacts with other players of the innovation system. This finding has important implications for both academics and practitioners and suggests that publicly backed funds have a wider role to play in mobilising the different players of the regional innovation ecosystem

Gene duplications and evolution of vertebrate voltage-gated sodium channels

Author Posting. © The Author(s), 2006. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Journal of Molecular Evolution 63 (2006): 208-221, doi:10.1007/s00239-005-0287-9.Voltage-gated sodium channels underlie action potential generation in excitable tissue. To establish the evolutionary mechanisms that shaped the vertebrate sodium channel a-subunit (SCNA) gene family and their encoded Nav1 proteins, we identified all SCNA genes in several teleost species. Molecular cloning revealed that teleosts have eight SCNA genes, comparable to the number in another vertebrate lineage, mammals. Prior phylogenetic analyses had indicated that teleosts and tetrapods share four monophyletic groups of SCNA genes and that tandem duplications selectively expanded the number of genes in two of the four mammalian groups. However, the number of genes in each group varies between teleosts and tetrapods suggesting different evolutionary histories in the two vertebrate lineages. Our findings from phylogenetic analysis and chromosomal mapping of Danio rerio genes indicate that tandem duplications are an unlikely mechanism for generation of the extant teleost SCNA genes. Instead, analysis of other closely mapped genes in D. rerio supports the hypothesis that a whole genome duplication was involved in expansion of the SCNA gene family in teleosts. Interestingly, despite their different evolutionary histories, mRNA analyses demonstrated a conservation of expression patterns for SCNA orthologues in teleosts and tetrapods, suggesting functional conservation.The authors’ work was supported by NIH grants (NS 38937; AEN, ADT and ABR, NS 25513; HHZ and YL and NSF IBN 0236147; MCJ)