#5 - Identifying cellular mechano-biological responses to PEG-based hydrogels

Cells sense and respond to mechanical stimuli from their external environment through a process called mechanotransduction. Focal adhesions are integrin-containing, multiprotein structures through which mechanical force is transmitted between the extracellular matrix and the interacting cell. Cells convert the transmitted force into biological responses including migration, proliferation and differentiation. The Garcia lab has previously engineered an integrin-specific hydrogel system resulting in changes in mesenchymal stem cell (MSC) gene expression, secretome, and ultimately regenerative capacity in a murine bone repair model. However, the mechano-biological mechanism driving this cell response to varying hydrogel biophysical and biochemical properties has yet to be studied. Here we have developed relationships between various hydrogel properties and cellular responses (cell adhesion, YAP localization, cell area, and cell shape). We engineered PEG-based hydrogel systems with two different polymerization chemistries, malemide and norbornene, to explore the effect of hydrogel chemistry on MSC cell adhesion and spreading. Using rheology, we demonstrated that hydrogel mechanical properties can be tuned by altering the weight percent of PEG macromer, while adhesion ligand type and density had no effect on hydrogel mechanical properties. PEG-4MAL gels were used for the remaining studies because that chemistry resulted in improved spreading and cell adhesion over norbornene hydrogels. By varying the density of RGD, the adhesive ligand for αvβ3 integrin, on the hydrogels, we showed that higher RGD densities resulted in greater YAP nuclear localization. We sought to understand the mechano-biological signaling pathway involved in YAP nuclear localization by inhibiting ROCK and FAK, proteins critical in mechanosensing via focal adhesion complexes. The inhibition of ROCK, and FAK decreased cell spread area, increased cell circularity and decreased YAP nuclear localization. Taken together this data demonstrates that external signals from PEG-based hydrogels as well as the intracellular signaling cascades involving ROCK and FAK can modulate YAP mechanosensing in MSCs

Distributed and parallel Ada and the Ada 9X recommendations

Recently, the DoD has sponsored work towards a new version of Ada, intended to support the construction of distributed systems. The revised version, often called Ada 9X, will become the new standard sometimes in the 1990s. It is intended that Ada 9X should provide language features giving limited support for distributed system construction. The requirements for such features are given. Many of the most advanced computer applications involve embedded systems that are comprised of parallel processors or networks of distributed computers. If Ada is to become the widely adopted language envisioned by many, it is essential that suitable compilers and tools be available to facilitate the creation of distributed and parallel Ada programs for these applications. The major languages issues impacting distributed and parallel programming are reviewed, and some principles upon which distributed/parallel language systems should be built are suggested. Based upon these, alternative language concepts for distributed/parallel programming are analyzed

Extracellular heat shock proteins in cell signaling

AbstractExtracellular stress proteins including heat shock proteins (Hsp) and glucose regulated proteins (Grp) are emerging as important mediators of intercellular signaling and transport. Release of such proteins from cells is triggered by physical trauma and behavioral stress as well as exposure to immunological “danger signals”. Stress protein release occurs both through physiological secretion mechanisms and during cell death by necrosis. After release into the extracellular fluid, Hsp or Grp may then bind to the surfaces of adjacent cells and initiate signal transduction cascades as well as the transport of cargo molecules such as antigenic peptides. In addition Hsp60 and hsp70 are able to enter the bloodstream and may possess the ability to act at distant sites in the body. Many of the effects of extracellular stress proteins are mediated through cell surface receptors. Such receptors include Toll Like Receptors 2 and 4, CD40, CD91, CCR5 and members of the scavenger receptor family such as LOX-1 and SREC-1. The possession of a wide range of receptors for the Hsp and Grp family permits binding to a diverse range of cells and the performance of complex multicellular functions particularly in immune cells and neurones

Association between Activity Space Exposure to Food Establishments and Individual Risk of Overweight

Objective: Environmental exposure to food sources may underpin area level differences in individual risk for overweight. Place of residence is generally used to assess neighbourhood exposure. Yet, because people are mobile, multiple exposures should be accounted for to assess the relation between food environments and overweight. Unfortunately, mobility data is often missing from health surveys. We hereby test the feasibility of linking travel survey data with food listings to derive food store exposure predictors of overweight among health survey participants. Methods: Food environment exposure measures accounting for non-residential activity places (activity spaces) were computed and modelled in Montreal and Quebec City, Canada, using travel surveys and food store listings. Models were then used to predict activity space food exposures for 5,578 participants of the Canadian Community Health Survey. These food exposure estimates, accounting for daily mobility, were used to model self-reported overweight in a multilevel framework. Median Odd Ratios were used to assess the proportion of between-neighborhood variance explained by such food exposure predictors. Results: Estimates of food environment exposure accounting for both residential and non-residential destinations were significantly and more strongly associated with overweight than residential-only measures of exposure for men. For women, residential exposures were more strongly associated with overweight than non-residential exposures. In Montreal, adjusted models showed men in the highest quartile of exposure to food stores were at lesser risk of being overweight considering exposure to restaurants (OR = 0.36 [0.21–0.62]), fast food outlets (0.48 [0.30–0.79]), or corner stores (0.52 [0.35–0.78]). Conversely, men experiencing the highest proportion of restaurants being fast-food outlets were at higher risk of being overweight (2.07 [1.25–3.42]). Women experiencing higher residential exposures were at lower risk of overweight. Conclusion: Using residential neighbourhood food exposure measures may underestimate true exposure and observed associations. Using mobility data offers potential for deriving activity space exposure estimates in epidemiological models

Fighting Fake News in Encrypted Messaging with the Fuzzy Anonymous Complaint Tally System (FACTS)

Recent years have seen a strong uptick in both the prevalence and real-world consequences of false information spread through online platforms. At the same time, encrypted messaging systems such as WhatsApp, Signal, and Telegram, are rapidly gaining popularity as users seek increased privacy in their digital lives. The challenge we address is how to combat the viral spread of misinformation without compromising privacy. Our FACTS system tracks user complaints on messages obliviously, only revealing the message\u27s contents and originator once sufficiently many complaints have been lodged. Our system is private, meaning it does not reveal anything about the senders or contents of messages which have received few or no complaints; secure, meaning there is no way for a malicious user to evade the system or gain an outsized impact over the complaint system; and scalable, as we demonstrate excellent practical efficiency for up to millions of complaints per day. Our main technical contribution is a new collaborative counting Bloom filter, a simple construction with difficult probabilistic analysis, which may have independent interest as a privacy-preserving randomized count sketch data structure. Compared to prior work on message flagging and tracing in end-to-end encrypted messaging, our novel contribution is the addition of a high threshold of multiple complaints that are needed before a message is audited or flagged. We present and carefully analyze the probabilistic performance of our data structure, provide a precise security definition and proof, and then measure the accuracy and scalability of our scheme via experimentation

High-g accelerometer based on an in-fiber bragg grating sensor

An accelerometer based on an in-fiber Bragg grating sensor has been fabricated and demonstrated. The grating sensor operates linearly up to accelerations of 170,000gn. The design, testing and performance of the accelerometer are discussed

The establishment and utility of Sweha-Reg: a Swedish population-based registry to understand hereditary angioedema

<p>Abstract</p> <p>Background</p> <p>The importance of acquiring comprehensive epidemiological and clinical data on hereditary angioedema has increasingly caught the attention of physicians and scientists around the world. The development of networks and creation of comprehensive policies to improve care of people suffering from rare diseases, such as hereditary angioedema, is a stated top priority of the European Union.</p> <p>Hereditary angioedema is a rare disease, that it may be life-threatening. Although the exact prevalence is unknown, current estimates suggest that it is 1/10,000–1/150,000 individuals. The low prevalence requires combined efforts to gain accurate epidemiological data on the disease and so give us tools to reduce morbidity and mortality, and improve quality of life of sufferers.</p> <p>Methods</p> <p>Sweha-Reg is a population-based registry of hereditary angioedema in Sweden with the objectives of providing epidemiological data, and so creates a framework for the study of this disease. The registry contains individual-based data on diagnoses, treatments and outcomes.</p> <p>Conclusion</p> <p>The present manuscript seeks to raise awareness of the existence of Sweha-Reg to stimulate the international collaboration of registries. A synthesis of data from similar registries across several countries is required to approach an inclusive course understanding of HAE.</p

Pain outcomes in patients with bone metastases from advanced cancer: assessment and management with bone-targeting agents

Bone metastases in advanced cancer frequently cause painful complications that impair patient physical activity and negatively affect quality of life. Pain is often underreported and poorly managed in these patients. The most commonly used pain assessment instruments are visual analogue scales, a single-item measure, and the Brief Pain Inventory Questionnaire-Short Form. The World Health Organization analgesic ladder and the Analgesic Quantification Algorithm are used to evaluate analgesic use. Bone-targeting agents, such as denosumab or bisphosphonates, prevent skeletal complications (i.e., radiation to bone, pathologic fractures, surgery to bone, and spinal cord compression) and can also improve pain outcomes in patients with metastatic bone disease. We have reviewed pain outcomes and analgesic use and reported pain data from an integrated analysis of randomized controlled studies of denosumab versus the bisphosphonate zoledronic acid (ZA) in patients with bone metastases from advanced solid tumors. Intravenous bisphosphonates improved pain outcomes in patients with bone metastases from solid tumors. Compared with ZA, denosumab further prevented pain worsening and delayed the need for treatment with strong opioids. In patients with no or mild pain at baseline, denosumab reduced the risk of increasing pain severity and delayed pain worsening along with the time to increased pain interference compared with ZA, suggesting that use of denosumab (with appropriate calcium and vitamin D supplementation) before patients develop bone pain may improve outcomes. These data also support the use of validated pain assessments to optimize treatment and reduce the burden of pain associated with metastatic bone disease