The role of neural crest cells in the development, organisation and migration of the thymus

Neural Crest (NC) derived mesenchyme has previously been shown to play an important role in the early development of the foetal thymus. Using Wnt1-Cre and Sox10-Cre mice crossed to Rosa26eYfp reporter mice, NC derived mesenchymal cells were revealed in the adult murine thymus. It is reported here that NC derived cells infiltrate the thymus before E13.5, and differentiate into cells with characteristics of smooth muscle cells associated with large vessels, and pericytes associated with capillaries. In the adult organ at three months of age, NC derived perivascular cells continue to be associated with the vasculature providing structural support to the blood vessels and possibly regulating endothelial cell function. Thymus organogenesis requires co-ordinated interactions of multiple cell types including NC cells that orchestrate the formation, separation and subsequent migration of the developing thymus from the third pharyngeal pouch to the thoracic cavity. The molecular mechanisms driving these processes are unclear, however NC derived mesenchyme has been shown to be important. Here, it is shown that the separation process of the thymus from the pouch is independent of ephrin-B2 expression on thymic NC derived mesenchyme, however in its absence the thymus remains in the cervical area instead of migrating into the thoracic cavity. Analyses of individual NC derived thymic mesenchymal cells shows that the absence of ephrin-B2 impairs their polarisation, and thus motility, as a result of defective EphB receptor signalling. This implies a NC derived cell specific role of EphB-ephrin-B2 interactions in the collective migration of the thymic rudiment during organogenesis

Preparations for Recoil Detection System at the Cooler T-Site

This research was sponsored by the National Science Foundation Grant NSF PHY-931478

Report on Experiment CE06: Measurements of Nuclear Reactions using Recoil Detection

This research was sponsored by the National Science Foundation Grant NSF PHY-931478

Side-by-side comparison of published small molecule inhibitors against thapsigargin-induced store-operated Ca2+ entry in HEK293 cells

Calcium (Ca2+) is a key second messenger in eukaryotes, with store-operated Ca2+ entry (SOCE) being the main source of Ca2+ influx into non-excitable cells. ORAI1 is a highly Ca2+-selective plasma membrane channel that encodes SOCE. It is ubiquitously expressed in mammals and has been implicated in numerous diseases, including cardiovascular disease and cancer. A number of small molecules have been identified as inhibitors of SOCE with a variety of potential therapeutic uses proposed and validated in vitro and in vivo. These encompass both nonselective Ca2+ channel inhibitors and targeted selective inhibitors of SOCE. Inhibition of SOCE can be quantified both directly and indirectly with a variety of assay setups, making an accurate comparison of the activity of different SOCE inhibitors challenging. We have used a fluorescence based Ca2+ addback assay in native HEK293 cells to generate dose-response data for many published SOCE inhibitors. We were able to directly compare potency. Most compounds were validated with only minor and expected variations in potency, but some were not. This could be due to differences in assay setup relating to the mechanism of action of the inhibitors and highlights the value of a singular approach to compare these compounds, as well as the general need for biorthogonal validation of novel bioactive compounds. The compounds observed to be the most potent against SOCE in our study were: 7-azaindole 14d (12), JPIII (17), Synta-66 (6), Pyr 3 (5), GSK5503A (8), CM4620 (14) and RO2959 (7). These represent the most promising candidates for future development of SOCE inhibitors for therapeutic use

Efficacy of a Commercial Weight Management Program Compared with a Do-It-Yourself Approach: A Randomized Clinical Trial

Importance: Given the prevalence of obesity, accessible and effective treatment options are needed to manage obesity and its comorbid conditions. Commercial weight management programs are a potential solution to the lack of available treatment, providing greater access at lower cost than clinic-based approaches, but few commercial programs have been rigorously evaluated. Objective: To compare the differences in weight change between individuals randomly assigned to a commercial weight management program and those randomly assigned to a do-it-yourself (DIY) approach. Design, Setting, and Participants: This 1-year, randomized clinical trial conducted in the United States, Canada, and United Kingdom between June 19, 2018, and November 30, 2019, enrolled 373 adults aged 18 to 75 years with a body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 25 to 45. Assessors were blinded to treatment conditions. Interventions: A widely available commercial weight management program that included reduced requirements for dietary self-monitoring and recommendations for a variety of DIY approaches to weight loss. Main Outcomes and Measures: The primary outcomes were the difference in weight change between the 2 groups at 3 and 12 months. The a priori hypothesis was that the commercial program would result in greater weight loss than the DIY approach at 3 and 12 months. Analyses were performed on an intention-To-Treat basis. Results: The study include 373 participants (272 women [72.9%]; mean [SD] BMI, 33.8 [5.2]; 77 [20.6%] aged 18-34 years, 74 [19.8%] aged 35-43 years, 82 [22.0%] aged 44-52 years, and 140 [37.5%] aged 53-75 years). At 12 months, retention rates were 88.8% (166 of 187) for the commercial weight management program group and 95.7% (178 of 186) for the DIY group. At 3 months, participants in the commercial program had a mean (SD) weight loss of-3.8 (4.1) kg vs-1.8 (3.7) kg among those in the DIY group. At 12 months, participants in the commercial program had a mean (SD) weight loss of-4.4 (7.3) kg vs-1.7 (7.3) kg among those in the DIY group. The mean difference between groups was-2.0 kg (97.5% CI,-2.9 to-1.1 kg) at 3 months (P <.001) and-2.6 kg (97.5% CI,-4.3 to-0.8 kg) at 12 months (P <.001). A greater percentage of participants in the commercial program group than participants in the DIY group achieved loss of 5% of body weight at both 3 months (40.7% [72 of 177] vs 18.6% [34 of 183]) and 12 months (42.8% [71 of 166] vs 24.7% [44 of 178]). Conclusions and Relevance: Adults randomly assigned to a commercial weight management program with reduced requirements for dietary self-monitoring lost more weight and were more likely to achieve weight loss of 5% at 3 and 12 months than adults following a DIY approach. This study contributes data on the efficacy of commercial weight management programs and DIY weight management approaches. Trial Registration: ClinicalTrials.gov Identifier: NCT03571893

Twenty five years after KLS: A celebration of non-equilibrium statistical mechanics

When Lenz proposed a simple model for phase transitions in magnetism, he couldn't have imagined that the "Ising model" was to become a jewel in field of equilibrium statistical mechanics. Its role spans the spectrum, from a good pedagogical example to a universality class in critical phenomena. A quarter century ago, Katz, Lebowitz and Spohn found a similar treasure. By introducing a seemingly trivial modification to the Ising lattice gas, they took it into the vast realms of non-equilibrium statistical mechanics. An abundant variety of unexpected behavior emerged and caught many of us by surprise. We present a brief review of some of the new insights garnered and some of the outstanding puzzles, as well as speculate on the model's role in the future of non-equilibrium statistical physics.Comment: 3 figures. Proceedings of 100th Statistical Mechanics Meeting, Rutgers, NJ (December, 2008

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Observation of a new chi_b state in radiative transitions to Upsilon(1S) and Upsilon(2S) at ATLAS

The chi_b(nP) quarkonium states are produced in proton-proton collisions at the Large Hadron Collider (LHC) at sqrt(s) = 7 TeV and recorded by the ATLAS detector. Using a data sample corresponding to an integrated luminosity of 4.4 fb^-1, these states are reconstructed through their radiative decays to Upsilon(1S,2S) with Upsilon->mu+mu-. In addition to the mass peaks corresponding to the decay modes chi_b(1P,2P)->Upsilon(1S)gamma, a new structure centered at a mass of 10.530+/-0.005 (stat.)+/-0.009 (syst.) GeV is also observed, in both the Upsilon(1S)gamma and Upsilon(2S)gamma decay modes. This is interpreted as the chi_b(3P) system.Comment: 5 pages plus author list (18 pages total), 2 figures, 1 table, corrected author list, matches final version in Physical Review Letter