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

BGEM: An In Situ Hybridization Database of Gene Expression in the Embryonic and Adult Mouse Nervous System

This article describes an open-access gene expression database analyzed for more than 2,000 genes on mouse nervous system tissue in the coronal, sagittal, and transverse orientation representing multiple developmental ages

Hormonal signaling in cnidarians : do we understand the pathways well enough to know whether they are being disrupted?

Author Posting. © The Author, 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 Ecotoxicology 16 (2007): 5-13, doi:10.1007/s10646-006-0121-1.Cnidarians occupy a key evolutionary position as basal metazoans and are ecologically important as predators, prey and structure-builders. Bioregulatory molecules (e.g., amines, peptides and steroids) have been identified in cnidarians, but cnidarian signaling pathways remain poorly characterized. Cnidarians, especially hydras, are regularly used in toxicity testing, but few studies have used cnidarians in explicit testing for signal disruption. Sublethal endpoints developed in cnidarians include budding, regeneration, gametogenesis, mucus production and larval metamorphosis. Cnidarian genomic databases, microarrays and other molecular tools are increasingly facilitating mechanistic investigation of signaling pathways and signal disruption. Elucidation of cnidarian signaling processes in a comparative context can provide insight into the evolution and diversification of metazoan bioregulation. Characterizing signaling and signal disruption in cnidarians may also provide unique opportunities for evaluating risk to valuable marine resources, such as coral reefs

Myelin Proteomics: Molecular Anatomy of an Insulating Sheath

Fast-transmitting vertebrate axons are electrically insulated with multiple layers of nonconductive plasma membrane of glial cell origin, termed myelin. The myelin membrane is dominated by lipids, and its protein composition has historically been viewed to be of very low complexity. In this review, we discuss an updated reference compendium of 342 proteins associated with central nervous system myelin that represents a valuable resource for analyzing myelin biogenesis and white matter homeostasis. Cataloging the myelin proteome has been made possible by technical advances in the separation and mass spectrometric detection of proteins, also referred to as proteomics. This led to the identification of a large number of novel myelin-associated proteins, many of which represent low abundant components involved in catalytic activities, the cytoskeleton, vesicular trafficking, or cell adhesion. By mass spectrometry-based quantification, proteolipid protein and myelin basic protein constitute 17% and 8% of total myelin protein, respectively, suggesting that their abundance was previously overestimated. As the biochemical profile of myelin-associated proteins is highly reproducible, differential proteome analyses can be applied to material isolated from patients or animal models of myelin-related diseases such as multiple sclerosis and leukodystrophies

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

At the End of Palsgraf, There is Chaos: An Assessment of Proximate Cause in Light of Chaos Theory

Palsgraf articulated the doctrine of proximate cause, necessary to prove the tort of negligence. Palsgraf needs to be reexamined in light of today\u27s understanding of cause and effect. The case concerned a woman (Mrs. Palsgraf) standing on a train platform who was injured by a roof tile that fell as the result of the vibrations caused by the explosion of another passenger\u27s package. Mrs. Palsgraf sued the railway for negligence and prevailed at the trial court level. The New York Court of Appeals reversed the trial court, however, holding that the railway company\u27s actions were not the proximate cause of Mrs. Palsgraf\u27s injuries. Modern science recognizes that the railway station constituted a complex dynamic system. Palsgraf was decided in 1928 at a time when understanding of cause and effect in complex dynamics was minimal and steeped in a linear mind-set. Because the understanding of cause and effect in these systems has been significantly advanced by the field of nonlinear dynamics in recent years, the case should be reexamined in this new light. Linear systems have outputs that are proportional to their inputs and are therefore predictable. But linearity inadequately models most of the real world. Nonlinear systems, though not recognized by most as such, are more prevalent than linear systems and have outputs disproportionate to their input. A subset within the group of nonlinear systems are chaotic systems, the main focus of this essay. The title “chaotic” is misleading as these systems still follow discrete physical laws. But it is their sensitivity to initial conditions that makes them unpredictable. What appears as a random result may actually be a strong reaction to immeasurable inputs at the beginning of a sequence of events. The weather is a good example of this principle, termed deterministic chaos. There is no way to isolate and define each initial condition that goes into a weather pattern, but as will be shown, each initial condition may radically affect the resulting systems. Chaotic systems exist alongside predictable linear systems. In Palsgraf, the train station had both regular, predictable systems, such as the track being able to carry the weight of the train, and some unpredictable, chaotic systems, such as the interaction of the exploding package, the roof tiles, and Mrs. Palsgraf. If an accident happened that involved a regular system, then it is more likely that the railway should have been held liable. This is because the engineers who designed the station should have known the linear parameters within which the station could be used safely. Had they neglected to act on this knowledge, the company would have been negligent. However, because the system involved was a high dimension chaotic system-many interacting degrees of freedom-the system was subject to the principle of sensitivity to initial conditions, and Mrs. Palsgraf\u27s injuries were in no way foreseeable or direct even though chaos theory elucidates the causal link between explosion and injury. Because they were in no way foreseeable or direct, the defendant had no duty toward the plaintiff with regard to the roof tile. So, according to the doctrine of proximate cause as articulated in this case, it still holds that the company was not negligent and the court\u27s finding is supported. There is a second way to look at proximate cause and Palsgraf in light of modern scientific theories. Modern theories postulate that the apparently chaotic phenomenon which are occurring at the station are actually following rules. A deterministic pattern of behavior exists even though it is not readily discernible. All of the operative degrees of freedom define a phase space, and phase space analysis may elucidate the system\u27s deterministic behavioral patterns. Phase space analysis is a tool used to visualize the behavior of a dynamic system over time. Many dynamic systems generally behave in a stable manner, but intrusions from outside a system can alter the stability in varying degrees. Depending on the disturbance, the system may return to its original pattern, or may be permanently disrupted, adopting a completely new pattern of behavior. Phase space analysis provides a second way to look at Palsgraf . In a system made of a train station and a train, there are a number of phase space portraits which demonstrate predictable patterns, such as the location of the station\u27s platform. Other portraits, such as those that include the movement of passengers, are never stable. The railway company has a responsibility to maintain the stable system within safe parameters so that it is not permanently disturbed by outside systems. Because the roof tiles at the train station were loose, they were subject to being disturbed. The loose tiles created what scientists call a zone of danger, and the accident was therefore foreseeable. The railway station did not take the proper precautions, and liability results. Using phase space analysis, Palsgraf would have been resolved as Judge Andrews suggested in his dissent, and the train company would have been liable. These same theories and scientific principles can be applied to most proximate cause tort cases. The appendix following this essay contains examples of actual cases decided using these principles

Beam-position measurement system at the Argonne Rapid-Cycling Synchrotron

The position measurement system for the Rapid-Cycling Synchrotron (RCS) was originally designed with a four-plate, combined function, capacitive pickup pi electrode situated in each of the six short straight sections. During subsequent operation, it was discovered that these electrodes were limiting the aperture and, therefore, were being activated by the circulating proton beam. In addition, the activation made it difficult to maintain the active electronic components in the RCS tunnel. The new position measurement system has been designed to eliminate these problems. The electrode's horizontal and vertical dimensions have been increased and the plates reorientated for simpler, separate function signal processing. A passive impedance matching network has replaced the active cathode follower, eliminating maintenance requirements in the accelerator tunnel. The Radio Frequency (RF) beam signals are transmitted directly to the Main Control Room (MCR) for processing