Collective ERK/Akt activity waves orchestrate epithelial homeostasis by driving apoptosis-induced survival.

Cell death events continuously challenge epithelial barrier function yet are crucial to eliminate old or critically damaged cells. How such apoptotic events are spatio-temporally organized to maintain epithelial homeostasis remains unclear. We observe waves of extracellular-signal-regulated kinase (ERK) and AKT serine/threonine kinase (Akt) activity pulses that originate from apoptotic cells and propagate radially to healthy surrounding cells. This requires epidermal growth factor receptor (EGFR) and matrix metalloproteinase (MMP) signaling. At the single-cell level, ERK/Akt waves act as spatial survival signals that locally protect cells in the vicinity of the epithelial injury from apoptosis for a period of 3-4 h. At the cell population level, ERK/Akt waves maintain epithelial homeostasis (EH) in response to mild or intense environmental insults. Disruption of this spatial signaling system results in the inability of a model epithelial tissue to ensure barrier function in response to environmental insults

Report of the Snowmass 2021 Topical Group on Lattice Gauge Theory

Lattice gauge theory continues to be a powerful theoretical and computational approach to simulating strongly interacting quantum field theories, whose applications permeate almost all disciplines of modern-day research in High-Energy Physics. Whether it is to enable precision quark- and lepton-flavor physics, to uncover signals of new physics in nucleons and nuclei, to elucidate hadron structure and spectrum, to serve as a numerical laboratory to reach beyond the Standard Model, or to invent and improve state-of-the-art computational paradigms, the lattice-gauge-theory program is in a prime position to impact the course of developments and enhance discovery potential of a vibrant experimental program in High-Energy Physics over the coming decade. This projection is based on abundant successful results that have emerged using lattice gauge theory over the years: on continued improvement in theoretical frameworks and algorithmic suits; on the forthcoming transition into the exascale era of high-performance computing; and on a skillful, dedicated, and organized community of lattice gauge theorists in the U.S. and worldwide. The prospects of this effort in pushing the frontiers of research in High-Energy Physics have recently been studied within the U.S. decadal Particle Physics Planning Exercise (Snowmass 2021), and the conclusions are summarized in this Topical Report.Comment: 57 pages, 1 figure. Submitted to the Proceedings of the US Community Study on the Future of Particle Physics (Snowmass 2021). Topical Group Report for TF05 - Lattice Gauge Theor

Lattice QCD and Particle Physics

Contribution from the USQCD Collaboration to the Proceedings of the US Community Study on the Future of Particle Physics (Snowmass 2021).Comment: 27 pp. main text, 4 pp. appendices, 30 pp. reference

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Lattice QCD and Particle Physics

Contribution from the USQCD Collaboration to the Proceedings of the US Community Study on the Future of Particle Physics (Snowmass 2021)

Cellular mechanisms during vascular development

The vascular system is an essential organ in vertebrate animals and provides the organism with enough oxygen and nutrients. It is composed of an interconnected network of blood vessels, which form using a number of different morphogenetic mechanisms. Angiogenesis describes the formation of new blood vessels from preexisting vessels. A number of molecular pathways have been shown to be essential during angiogenesis. However, cellular architecture of blood vessels as well as cellular mechanisms involved during vessel formation and anasotmosis have remained largely unknown. The intersegmental vessels (ISVs) of the developing zebrafish embryo have served as a paradigm to study angiogenesis in vivo. ISVs sprout bilaterally from the dorsal aorta (DA) in the zebrafish trunk, grow dorsally and ultimately connect with adjacent ISVs on the dorsal side of the trunk forming the dorsal longitudinal anastomotic vessel (DLAV). We used antibody labeling of endothelial cell-cell junctions, single cell labeling and live-imaging of junctions to investigate cellular architecture and mechanisms during ISV formation and anastonosis. In contrast to previous studies, we found that a large part of ISVs consist of multicellular tubes where the lumen is surrounded by several cells. Seamless tubes with an intracellular lumen are predominantly found in the DLAV. In addition, we found distinct cellular mechanisms to be involved in ISV anastomosis, forming seamless or multicellular tubes respectively. These results show that endothelial cells a rather plastic and can use different mechanisms to form functional blood vessels

Measuring ERK Activity Dynamics in Single Living Cells Using FRET Biosensors.

Fluorescence resonance energy transfer (FRET)-based biosensors are powerful tools for measuring spatio-temporal signaling dynamics in single living cells with subcellular resolution. There are quite a number of already existing sensors and this technology is increasingly used to obtain quantitative dynamic datasets. In this chapter, we describe the analysis of endogenous extracellular signal-regulated kinase (ERK) activity in living cells using the EKAR2G (ERK activity reporter second generation) probe. We focus on the generation of stable cell lines expressing the EKAR2G sensor as well as data acquisition and analysis

Effects of a short proprioceptive neuromuscular facilitation stretching bout on quadriceps neuromuscular function, flexibility and vertical jump performance

Place, N, Blum, Y, Armand, S, Maffiuletti, NA, and Behm, DG. Effects of a short proprioceptive neuromuscular facilitation stretching bout on quadriceps neuromuscular function, flexibility, and vertical jump performance. J Strength Cond Res 27(2): 463-470, 2013-The inclusion of relatively long bouts of stretching (repeated static stretches of ∼30 seconds) in the warm-up is usually associated with a drop in muscle performance. The purpose of this study was to assess the effect of a novel self-administered proprioceptive neuromuscular facilitation (PNF) paradigm with short periods of stretching and contraction on quadriceps neuromuscular function, vertical jump performance, and articular range of motion (ROM). Twelve healthy men (age: 27.7 ± 7.3 years, height: 178.4 ± 10.4 cm, weight: 73.8 ± 16.9 kg) volunteered to participate in a PNF session and a control session separated by 2-7 days. The PNF stretching lasted 2 minutes and consisted of 4 sets of 5-second isometric hamstring contraction immediately followed by 5 seconds of passive static stretch of the quadriceps immediately followed by 5 seconds isometric quadriceps contraction for each leg. For the control session, the participants were asked to walk at a comfortable speed for 2 minutes. Active ROM of knee flexion, vertical jump performance, and quadriceps neuromuscular function were tested before, immediately after, and 15 minutes after the intervention. The PNF stretching procedure did not affect ROM, squat jump, and countermovement jump performances. Accordingly, we did not observe any change in maximal voluntary contraction force, voluntary activation level, M-wave and twitch contractile properties that could be attributed to PNF stretching. The present self-administered PNF stretching of the quadriceps with short (5-second) stretches is not recommended before sports where flexibility is mandatory for performance

Microfluidic platform for single cell analysis under dynamic spatial and temporal stimulation.

Recent research on cellular responses is shifting from static observations recorded under static stimuli to real-time monitoring in a dynamic environment. Since cells sense and interact with their surrounding microenvironment, an experimental platform where dynamically changing cellular microenvironments should be recreated in vitro. There has been a lack of microfluidic devices to support spatial and temporal stimulations in a simple and robust manner. Here, we describe a microfluidic device that generates dynamic chemical gradients and pulses in both space and time using a single device. This microfluidic device provides at least 12h of continuous stimulations that can be used to observe responses from mammalian cells. Combination of the microfluidic de-vice with live-cell imaging facilitates real-time observation of dynamic cellular response at single cell level. Using stable HEK cells with biosensors, ERK (Extracellular signal-Regulated Kinase) activities were observed un-der the pulsatile and ramping stimulations of EGF (Epidermal Growth Factor). We quantified ERK activation even at extremely low EGF concentration (0.0625µg/ml), which can not be observed using conventional techniques such as western blot. Cytoskeleton re-arrangement of the 3T3 fibroblast (stable transfection with Lifeact-GFP) was compared under abrupt and gradually changing gradient of PDGF

Temporal perturbation of ERK dynamics reveals network architecture of FGF2/MAPK signaling

Abstract Stimulation of PC‐12 cells with epidermal (EGF) versus nerve (NGF) growth factors (GFs) biases the distribution between transient and sustained single‐cell ERK activity states, and between proliferation and differentiation fates within a cell population. We report that fibroblast GF (FGF2) evokes a distinct behavior that consists of a gradually changing population distribution of transient/sustained ERK signaling states in response to increasing inputs in a dose response. Temporally controlled GF perturbations of MAPK signaling dynamics applied using microfluidics reveal that this wider mix of ERK states emerges through the combination of an intracellular feedback, and competition of FGF2 binding to FGF receptors (FGFRs) and heparan sulfate proteoglycan (HSPG) co‐receptors. We show that the latter experimental modality is instructive for model selection using a Bayesian parameter inference. Our results provide novel insights into how different receptor tyrosine kinase (RTK) systems differentially wire the MAPK network to fine‐tune fate decisions at the cell population level