Dkk4 and Eda Regulate Distinctive Developmental Mechanisms for Subtypes of Mouse Hair

The mouse hair coat comprises protective “primary” and thermo-regulatory “secondary” hairs. Primary hair formation is ectodysplasin (Eda) dependent, but it has been puzzling that Tabby (Eda-/y) mice still make secondary hair. We report that Dickkopf 4 (Dkk4), a Wnt antagonist, affects an auxiliary pathway for Eda-independent development of secondary hair. A Dkk4 transgene in wild-type mice had no effect on primary hair, but secondary hairs were severely malformed. Dkk4 action on secondary hair was further demonstrated when the transgene was introduced into Tabby mice: the usual secondary follicle induction was completely blocked. The Dkk4-regulated secondary hair pathway, like the Eda-dependent primary hair pathway, is further mediated by selective activation of Shh. The results thus reveal two complex molecular pathways that distinctly regulate subtype-based morphogenesis of hair follicles, and provide a resolution for the longstanding puzzle of hair formation in Tabby mice lacking Eda

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Machine learning for high energy astronomy surveys

This thesis presents new machine learning techniques for producing high energy astronomy survey catalogues. A novel source detector is developed for application to images from the INTEGRAL satellite. This source detector utilises convolutional neural networks (CNNs) to confidently identify genuine astrophysical sources whilst rejecting instrumental artefacts. This CNN-based source detector is substantially faster than previous methods, enabling the search for sources on shorter timescales than older techniques used in the production of previous INTEGRAL catalogues. The new capabilities afforded by the CNN source detector resulted in a 5% increase in sources found from the same dataset used to produce the previous INTEGRAL catalogue. A Bayesian source combination technique is also presented that rapidly and reliably combines excess detections into a list of distinct sources. This method is superior to previous approaches because it requires no human intervention, and thus is less prone to human bias. It also is insensitive to the order in which excesses are presented to the algorithm, thereby providing consistent source catalogues regardless of how new detections are included. Finally, a burst detection tool built with long short-term memory (LSTM) networks is presented. This burst detector reliably detects outbursts in simulated data sets (where the ground truth is known) with the same accuracy as previous tools but operating at substantially faster speeds. The burst detector demonstrates potential for applying reliable burst detection to massive data sets like those expected to be produced by the next generation of high energy surveys. Overall, this thesis presents a powerful set of tools that could transform the way high energy astronomy surveys operate. Whilst this thesis demonstrates the advantages of using these tools for catalogue production, they have potential applications in real-time survey operations such as follow up triggers after real-time outburst detection. Tools like those presented here will be vital for high energy astrophysics in the era of big data

Special Topics in Behavior Analysis

This open educational SPECIAL TOPICS IN BEHAVIOR resource is hosted online for download, remix, and adoption by any individual with an internet connection. The authors and contributors hope this will create a disruption in the current publication climate and also have long-lasting impact on the community of individuals who may want to learn about the science of applied behavior analysis. Chapters are written by BCBAs and graduate students with peer reviews by a team of volunteer BCBAs, BCBA-Ds, and other doctoral-level collegiate faculty in order to ensure accuracy and readability. As an OER, this resource is open to addition and editing and welcomes additional comments or reviews. The editor and authors have provided contact information in each section. The text should continue to improve and evolve as a growing support for the dissemination of behavior science.https://digitalcommons.lindenwood.edu/textbooks/1000/thumbnail.jp