Uncertainty in phylogenetic tree estimates

Estimating phylogenetic trees is an important problem in evolutionary biology, environmental policy and medicine. Although trees are estimated, their uncertainties are discarded by mathematicians working in tree space. Here we explicitly model the multivariate uncertainty of tree estimates. We consider both the cases where uncertainty information arises extrinsically (through covariate information) and intrinsically (through the tree estimates themselves). The importance of accounting for tree uncertainty in tree space is demonstrated in two case studies. In the first instance, differences between gene trees are small relative to their uncertainties, while in the second, the differences are relatively large. Our main goal is visualization of tree uncertainty, and we demonstrate advantages of our method with respect to reproducibility, speed and preservation of topological differences compared to visualization based on multidimensional scaling. The proposal highlights that phylogenetic trees are estimated in an extremely high-dimensional space, resulting in uncertainty information that cannot be discarded. Most importantly, it is a method that allows biologists to diagnose whether differences between gene trees are biologically meaningful, or due to uncertainty in estimation.Comment: Final version accepted to Journal of Computational and Graphical Statistic

GTRACK: A PC program for computing Goldstein's growth constancy index and an alternative measure of tracking

This paper reviews Goldstein's `growth constancy index,' [xi], a measure of tracking which can be used to determine whether or not individuals maintain their relative positions in the distribution of a given measurement as that distribution changes over time. We suggest that [xi] is an appropriate measure of tracking when the (standardized) measurements arise in the context of a Model I ANOVA, but that the intraclass correlation coefficient, rl, may be preferred when a Model II ANOVA is applicable. We also describe -- and make available -- a PC program which allows the user to choose between Model I and Model II, and computes the appropriate tracking index and confidence intervals for the corresponding parameter.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31409/1/0000326.pd

Structural Requirements for Dihydrobenzoxazepinone Anthelmintics:Actions against Medically Important and Model Parasites: Trichuris muris, Brugia malayi, Heligmosomoides polygyrus, and Schistosoma mansoni

Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of ex vivo Trichuris muris. Here, we report a systematic investigation of the structure–activity relationship of the anthelmintic activity of DHB compounds. We synthesized 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQs) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against Brugia malayi and Heligmosomoides polygyrus. We also demonstrated activity of DHB compounds against the trematode Schistosoma mansoni, a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics

Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit

Notum is a carboxylesterase that suppresses Wnt signaling through deacylation of an essential palmitoleate group on Wnt proteins. There is a growing understanding of the role Notum plays in human diseases such as colorectal cancer and Alzheimer's disease, supporting the need to discover improved inhibitors, especially for use in models of neurodegeneration. Here, we have described the discovery and profile of 8l (ARUK3001185) as a potent, selective, and brain-penetrant inhibitor of Notum activity suitable for oral dosing in rodent models of disease. Crystallographic fragment screening of the Diamond-SGC Poised Library for binding to Notum, supported by a biochemical enzyme assay to rank inhibition activity, identified 6a and 6b as a pair of outstanding hits. Fragment development of 6 delivered 8l that restored Wnt signaling in the presence of Notum in a cell-based reporter assay. Assessment in pharmacology screens showed 8l to be selective against serine hydrolases, kinases, and drug targets

PC program extending the two-stage polynomial growth curve model to allow missing data

A stand-alone, menu-driven PC program, written in GAUSS386i, extending the analysis of one-sample longitudinal data sets satisfying the two-stage polynomial growth curve model (Ten Have et al., Am J Hum Biol, 3 (1991) 269-279) to allow missing data is described, illustrated and made available to interested readers. The method and the program are illustrated using data previously analyzed by the authors (Schneiderman and Kowalski, Am J Phys Anthropol, 67 (1985) 323-333) but with several randomly chosen data points discarded and treated as missing.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30475/1/0000103.pd

Virtual teaching kitchen classes and cardiovascular disease prevention counselling among medical trainees

Background: Hands-on culinary medicine education for medical trainees has emerged as a promising tool for cardiovascular health promotion. Purpose: To determine whether virtual culinary medicine programming associates with Mediterranean diet (MedDiet) adherence and lifestyle medicine competencies among medical trainees across the USA. Method: A total of 1433 medical trainees across 19 sites over a 12-month period were included. The Cooking for Health Optimisation with Patients-Medical Trainees survey composed of 61 questions regarding demographics, nutritional attitudes, dietary habits including MedDiet score and lifestyle medicine counselling competencies. Multivariable logistic regression assessed the association of virtual culinary medicine education with MedDiet intake and nutritional attitudes. Results: There were 519 medical trainees who participated in virtual culinary medicine education and 914 medical trainees who participated in their standard nutrition curricula. More than one-half of participants were women (n=759) and the mean age was 27 years old. Compared with students enrolled in traditional nutrition curricula, participants in virtual culinary medicine education were 37% more likely to adhere to MedDiet guidelines for fruit intake (OR 1.37, 95% CI 1.03 to 1.83, p=0.03). Virtual culinary medicine education was associated with higher proficiency in lifestyle medicine counselling categories, notably recommendations involving fibre (OR 4.03; 95% CI 3.05 to 5.34), type 2 diabetes prevention (OR 4.69; 95% CI 3.51 to 6.27) and omega fatty acids (OR 5.21; 95% CI 3.87 to 7.02). Virtual culinary medicine education had a similar, although higher magnitude association with MedDiet counselling competency (OR 5.73, 95% CI 4.26 to 7.70) when compared with historical data previously reported using hands-on, in-person culinary medicine courseware (OR 4.97, 95% CI 3.89 to 6.36). Conclusions: Compared with traditional nutritional educational curricula, virtual culinary medicine education is associated with higher MedDiet adherence and lifestyle medicine counselling competencies among medical trainees. Both virtual and hands-on culinary medicine education may be useful for cardiovascular health promotion

Community-led, integrated, reproducible multi-omics with anvi'o

Big data abound in microbiology, but the workflows designed to enable researchers to interpret data can constrain the biological questions that can be asked. Five years after anvi'o was first published, this community-led multi-omics platform is maturing into an open software ecosystem that reduces constraints in 'omics data analyses.Non peer reviewe

Peptide Ligands for Pro-survival Protein Bfl-1 from Computationally Guided Library Screening

Pro-survival members of the Bcl-2 protein family inhibit cell death by binding short helical BH3 motifs in pro-apoptotic proteins. Mammalian pro-survival proteins Bcl-x[subscript L], Bcl-2, Bcl-w, Mcl-1, and Bfl-1 bind with varying affinities and specificities to native BH3 motifs, engineered peptides, and small molecules. Biophysical studies have determined interaction patterns for these proteins, particularly for the most-studied family members Bcl-x[subscript L] and Mcl-1. Bfl-1 is a pro-survival protein implicated in preventing apoptosis in leukemia, lymphoma, and melanoma. Although Bfl-1 is a promising therapeutic target, relatively little is known about its binding preferences. We explored the binding of Bfl-1 to BH3-like peptides by screening a peptide library that was designed to sample a high degree of relevant sequence diversity. Screening using yeast-surface display led to several novel high-affinity Bfl-1 binders and to thousands of putative binders identified through deep sequencing. Further screening for specificity led to identification of a peptide that bound to Bfl-1 with K[subscript d] < 1 nM and very slow dissociation from Bfl-1 compared to other pro-survival Bcl-2 family members. A point mutation in this sequence gave a peptide with ~50 nM affinity for Bfl-1 that was selective for Bfl-1 in equilibrium binding assays. Analysis of engineered Bfl-1 binders deepens our understanding of how the binding profiles of pro-survival proteins differ and may guide the development of targeted Bfl-1 inhibitors.National Institute of General Medical Sciences (U.S.) (Award GM084181)National Institute of General Medical Sciences (U.S.) (Award P50-GM68762

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation