There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.

/pdf/ampk-and-mtor-regulate-autophagy-through-direct-14wqsz16ke.pdf

AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1

In 2004, the first American Heart Association scientific statement on “Air Pollution and Cardiovascular Disease” concluded that exposure to particulate matter (PM) air pollution contributes to card...

https://cdr.lib.unc.edu/downloads/p2676x621

Particulate Matter Air Pollution and Cardiovascular Disease An Update to the Scientific Statement From the American Heart Association

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.

For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.

Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

/pdf/guidelines-for-the-use-and-interpretation-of-assays-for-ijf2t30pbq.pdf

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

CA : A Cancer Journal for Clinicians

A patient safety system (PSS) (100) uses optical tracking in a linear accelerator treatment room to prevent gross setup errors. A patient (150) undergoes a computed tomography (CT) treatment-simulation scan while a CT ball bearing (BB) is on patient's surface. The CT BB is replaced with an infrared reflective marker (IRRM) (160) before radiotherapy treatment starts. Coordinates of the CT BB relative to an isocenter of the treatment room are used as reference for tracking. The coordinate system of an optical tracking system is converted to a coordinate system of the treatment room. The PSS evaluates setup accuracy for a radiotherapy session by comparing real-time position of the single IRRM determined by the optical tracking technology with a predicted reference position, and displays results on a graphical user interface. The PSS stops radiation when a deviation between real-time coordinates and predicted coordinates of the IRRM (160) exceeds a predefined threshold.

Prevention of setup errors in radiotherapy

BACKGROUND An accurate injury severity measurement is essential for the evaluation of pediatric trauma care and outcome research. The traditional Injury Severity Score (ISS) does not consider the differential risks of the Abbreviated Injury Scale (AIS) from different body regions nor is it pediatric specific. The objective of this study was to develop a weighted ISS (wISS) system for pediatric blunt trauma patients with better predictive power than ISS. METHODS Based on the association between mortality and AIS from each of the six ISS body regions, we generated different weights for the component AIS scores used in the calculation of ISS. The weights and wISS were generated using the National Trauma Data Bank. The Nationwide Emergency Department Sample (NEDS) was used to validate our main results. Pediatric blunt trauma patients younger than 16 years were included, and mortality was the outcome. Discrimination (areas under the receiver operating characteristic curve, sensitivity, specificity, positive predictive value, negative predictive value, concordance) and calibration (Hosmer-Lemeshow statistic) were compared between the wISS and ISS. RESULTS The areas under the receiver operating characteristic curves from the wISS and ISS are 0.88 versus 0.86 in ISS of 1 to 74 and 0.77 versus 0.64 in ISS of 25 to 74 (p < 0.0001). The wISS showed higher specificity, positive predictive value, negative predictive value, and concordance when they were compared at similar levels of sensitivity. The wISS had better calibration (smaller Hosmer-Lemeshow statistic) than the ISS (11.6 vs. 19.7 for ISS = 1-74 and 10.9 vs. 12.6 for ISS = 25-74). The wISS showed even better discrimination with the Nationwide Emergency Department Sample. CONCLUSION By weighting the AIS from different body regions, the wISS had significantly better predictive power for mortality than the ISS, especially in critically injured children. LEVEL OF EVIDENCE AND STUDY TYPE Prognostic/epidemiological, level IV.

A new weighted injury severity scoring system: Better predictive power for pediatric trauma mortality.

Comparing outcomes across different levels of trauma centers is vital in evaluating regionalized trauma care. With observational data, it is critical to adjust for patient characteristics to render...

Triplet Matching for Estimating Causal Effects With Three Treatment Arms: A Comparative Study of Mortality by Trauma Center Level

Objectives California and Massachusetts are the only 2 states in the United States with municipalities that have local laws prohibiting the sale of tobacco products by pharmacies. The impacts of the tobacco-free pharmacy laws remain understudied. This study aims to fill this gap by examining the association between tobacco-free pharmacy laws and smoking prevalence among adults over time in California and Massachusetts. Design This study used a series of cross-sectional surveys. The data source for this study was the Behavioral Risk Factor Surveillance Survey for each year from 2005 to 2013. Setting The longitudinal changes in smoking prevalence at the city or county level were estimated and comparisons were made between cities or counties with tobacco-free pharmacy laws and those without the laws. Participants The participants used to estimate smoking prevalence were representative of adults within California and Massachusetts. Intervention The implementation of tobacco-free pharmacy laws was considered to be the intervention in this study. Main outcome measures The outcome measures were smoking prevalence among adults. Mixed-effects negative binomial models were performed primarily to examine longitudinal changes in outcome measures. Results The prevalence of smoking decreased in both states over time. In Massachusetts, there was a statistically significant decrease in smoking prevalence among cities with tobacco-free pharmacy laws compared with those without such laws. Despite the presence of an 8.6% decrease in prevalence after the implementation of tobacco-free pharmacy laws, this reduction was not statistically significant after controlling for the negative trend in smoking rates overall and other factors. Conclusion This study evaluated tobacco-free pharmacy laws with regard to the real-world impacts. Our findings highlight the need for future research on the effects of tobacco-free pharmacy laws with a prolonged time span and a comprehensive understanding of the law's implementation and enforcement.

Bo Lu

Papers

Prevention of setup errors in radiotherapy

A new weighted injury severity scoring system: Better predictive power for pediatric trauma mortality.

Triplet Matching for Estimating Causal Effects With Three Treatment Arms: A Comparative Study of Mortality by Trauma Center Level

The impact of tobacco-free pharmacy policies on smoking prevalence.

Lithium-Mediated Neuroprotection During Cranial Irradiation: A Phase I Trial