The age of chocolate: A diversification history of Theobroma and Malvaceae

Dated molecular phylogenies of broadly distributed lineages can help to compare patterns of diversification in different parts of the world. An explanation for greater Neotropical diversity compared to other parts of the tropics is that it was an accident of the Andean orogeny. Using dated phylogenies, of chloroplast ndhF and nuclear DNA WRKY sequence datasets, generated using BEAST we demonstrate that the diversification of the genera Theobroma and Herrania occurred from 12.7 (11.6-14.9 [95% HPD]) million years ago (Ma) and thus coincided with Andean uplift from the mid-Miocene and that this lineage had a faster diversification rate than other major clades in Malvaceae. We also demonstrate that Theobroma cacao, the source of chocolate, diverged from its most recent common ancestor 9.9 (7.7-12.9 [95% HPD]) Ma, in the mid-to late-Miocene, suggesting that this economically important species has had ample time to generate significant within-species genetic diversity that is useful information for a developing chocolate industry. In addition, we address questions related to the latitudinal gradient in species diversity within Malvaceae. A faster diversification rate is an explanation for the greater species diversity at lower latitudes. Alternatively, tropical conditions may have existed for longer and occupied greater areas than temperate ones meaning that tropical lineages have had more time and space in which to diversify. Our dated molecular phylogeny of Malvaceae demonstrated that at least one temperate lineage within the family diverged from tropical ancestors then diversified at a rate comparable with many tropical lineages in the family. These results are consistent with the hypothesis that Malvaceae are more species rich in the tropics because tropical lineages within the family have existed for longer and occupied more space than temperate ones, and not because of differences in diversification rate. © 2015 Richardson, Whitlock, Meerow and Madriñán

Flexible use of a dynamic energy landscape buffers a marine predator against extreme climate variability

Animal migrations track predictable seasonal patterns of resource availability and suitable thermal habitat. As climate change alters this 'energy landscape', some migratory species may struggle to adapt. We examined how climate variability influences movements, thermal habitat selection and energy intake by juvenile Pacific bluefin tuna (Thunnus orientalis) during seasonal foraging migrations in the California Current. We tracked 242 tuna across 15 years (2002-2016) with high-resolution archival tags, estimating their daily energy intake via abdominal warming associated with digestion (the 'heat increment of feeding'). The poleward extent of foraging migrations was flexible in response to climate variability, allowing tuna to track poleward displacements of thermal habitat where their standard metabolic rates were minimized. During a marine heatwave that saw temperature anomalies of up to +2.5 degrees C in the California Current, spatially explicit energy intake by tuna was approximately 15% lower than average. However, by shifting their mean seasonal migration approximately 900 km poleward, tuna remained in waters within their optimal temperature range and increased their energy intake. Our findings illustrate how tradeoffs between physiology and prey availability structure migration in a highly mobile vertebrate, and suggest that flexible migration strategies can buffer animals against energetic costs associated with climate variability and change

C-Reactive Protein and the Disease Analog Model May Identify Predisposed Pre-Obese African-American Women

While the obesity rate in the Unites States has been reported to have hit a plateau, the overall percentage of obese Americans remains alarmingly high (27% self-reported, 33% population estimate). While the subgroup with the highest 2010 obesity rate is Black, non-Hispanic women (41.9%), there remains a disparity in the research with regards to this population group. The implication of an elevated obese population puts a strain on health care, overall quality of life, and is associated with a number of other co-morbidities. Given this background, pilot work to evaluate a disease analog model for obesity would be useful with the potential for identifying seemingly normal-weight individuals who are most susceptible to developing obesity

Dabrafenib, alone or in combination with trametinib, in BRAF V600–mutated pediatric Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a rare, heterogenous, neoplastic disorder primarily affecting children. BRAF mutations have been reported in >50% of patients with LCH. The selective BRAF inhibitor, dabrafenib, in combination with the MEK1/2 inhibitor, trametinib, has been approved in select BRAF V600–mutant solid tumors. Two open-label phase 1/2 studies were conducted in pediatric patients with BRAF V600–mutant, recurrent/refractory malignancies treated with dabrafenib monotherapy (CDRB436A2102; NCT01677741) or dabrafenib plus trametinib (CTMT212X2101; NCT02124772). The primary objectives of both studies were to determine safe and tolerable doses that achieve similar exposure to the approved doses for adults. Secondary objectives included safety, tolerability, and preliminary antitumor activity. Thirteen and 12 patients with BRAF V600–mutant LCH received dabrafenib monotherapy and in combination with trametinib, respectively. Investigator-assessed objective response rates per Histiocyte Society criteria were 76.9% (95% confidence interval [CI], 46.2-95.0) and 58.3% (95% CI, 27.7-84.8) in the monotherapy and combination studies, respectively. More than 90% of responses were ongoing at study completion. The most common treatment-related adverse events (AEs) were vomiting and increased blood creatinine with monotherapy and pyrexia, diarrhea, dry skin, decreased neutrophil count, and vomiting with combination therapy. Two patients each discontinued treatment with monotherapy and combination therapy because of AEs. Overall, dabrafenib monotherapy or in combination with trametinib demonstrated clinical efficacy and manageable toxicity in relapsed/refractory BRAF V600–mutant pediatric LCH, with most responses ongoing. Safety was consistent with that reported in other pediatric and adult conditions treated with dabrafenib plus trametinib

Effect of Kisspeptin on Regulation of Growth Hormone

Kisspeptin ( KP ), a neuroendocrine regulator of reproduction, is hypothesized to be an integrator of metabolism and hormones critical to the regulation of reproduction. Lactation is associated with enhanced growth hormone (GH) responsiveness and reduced fertility. Our study was designed to determine the effects of lactation on KP-stimulated GH and luteinizing hormone (LH) secretion. Five non-lactating and five lactating dairy cows were used in the study. Experiments were conducted with lactating cows at weeks 1, 5 and 11 after parturition. The experimental treatments ( saline and KP [100 and 400 pmol / kg body weight]) were given intravenously and blood was collected and plasma was stored until later assay to determine concentrations of GH, LH, progesterone and non-esterified fatty acids. We found that neither dose of KP stimulated an increase in GH secretion. The low dose of KP increased (P \u3c0. 05) LH concentrations only in lactating cows. The higher dose of KP elicited an increase in circulating LH concentrations in both lactating and non-lactating cows. The lower dose of KP increased (P \u3c 0. 05) the area under the curve for LH only in cows during week 5 of lactation, and the area under the curve of LH following the highest dose of KP was greater (P \u3c 0. 05) in cows during week 5 of lactation than that for the other groups of cows. In summary, lactation status and stage of lactation did not change the sensitivity of the GH system to KP. However, an effect of stage of lactation on KP-stimulated LH secretion was detected in the dairy cows. Study of the KP system during lactation in dairy cows may provide critical insights into the mechanisms for lactation associated changes in the reproductive axis

Protocol: Evaluating the impact of a nation-wide train-the-trainer educational initiative to enhance the quality of palliative care for children with cancer

Background: There are identified gaps in the care provided to children with cancer based on the self-identified lack of education for health care professionals in pediatric palliative care and in the perceptions of bereaved parents who describe suboptimal care. In order to address these gaps, we will implement and evaluate a national roll-out of Education in Palliative and End-of-Life Care for Pediatrics (EPEC (R)-Pediatrics), using a 'Train-the-Trainer' model.Methods/design: In this study we are using a pre-post-test design and an integrated knowledge translation approach to assess the impact of the educational roll-out in four areas: 1) self-assessed knowledge of health professionals; 2) knowledge dissemination outcomes; 3) practice change outcomes; and 4) quality of palliative care. The quality of palliative care will be assessed using data from three sources: a) parent and child surveys about symptoms, quality of life and care provided; b) health record reviews of deceased patients; and c) bereaved parent surveys about end-of-life and bereavement care. After being trained in EPEC (R)-Pediatrics, 'Master Facilitators' will train 'Regional Teams' affiliated with 16 pediatric oncology programs in Canada. Each team will consist of three to five health professionals representing oncology, palliative care, and the community. Each team member will complete online modules and attend one of two face-to-face conferences, where they will receive training and materials to teach the EPEC (R)-Pediatrics curriculum to 'End-Users' in their region. Regional Teams will also choose a Tailored Implementation of Practice Standards (TIPS) Kit to guide implementation of a quality improvement project in their region; support will be provided via quarterly meetings with Co-Leads and via a listserv and webinars with other teams.Discussion: Through this study we aim to raise the level of pediatric palliative care education amongst health care professionals in Canada. Our study will be a significant step forward in evaluation of the impact of EPEC (R)-Pediatrics both on dissemination outcomes and on care quality at a national level. Based on the anticipated success of our project we hope to expand the EPEC (R)-Pediatrics roll-out to health professionals who care for children with non-oncological life-threatening conditions

Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600–Mutant Low-Grade Glioma

PURPOSE: BRAF V600 mutations occur in many childhood cancers, including approximately 20% of low-grade gliomas (LGGs). Here, we describe a phase I/II study establishing pediatric dosing and pharmacokinetics of trametinib with or without dabrafenib, as well as efficacy and safety in a disease-specific cohort with BRAF V600–mutant LGG; other cohorts will be reported elsewhere. METHODS: This is a four-part, phase I/II study (ClinicalTrials.gov identifier: NCT02124772 ) in patients age < 18 years with relapsed/refractory malignancies: trametinib monotherapy dose finding (part A) and disease-specific expansion (part B), and dabrafenib + trametinib dose finding (part C) and disease-specific expansion (part D). The primary objective assessed in all patients in parts A and C was to determine pediatric dosing on the basis of steady-state pharmacokinetics. Disease-specific efficacy and safety (across parts A-D) were secondary objectives. RESULTS: Overall, 139 patients received trametinib (n = 91) or dabrafenib + trametinib (n = 48). Trametinib dose-limiting toxicities in > 1 patient (part A) included mucosal inflammation (n = 3) and hyponatremia (n = 2). There were no dose-limiting toxicities with combination therapy (part C). The recommended phase II dose of trametinib, with or without dabrafenib, was 0.032 mg/kg once daily for patients age < 6 years and 0.025 mg/kg once daily for patients age ≥ 6 years; dabrafenib dosing in the combination was as previously identified for monotherapy. In 49 patients with BRAF V600–mutant glioma (LGG, n = 47) across all four study parts, independently assessed objective response rates were 15% (95% CI, 1.9 to 45.4) for monotherapy (n = 13) and 25% (95% CI, 12.1 to 42.2) for combination (n = 36). Adverse event–related treatment discontinuations were more common with monotherapy (54% v 22%). CONCLUSION: The trial design provided efficient evaluation of pediatric dosing, safety, and efficacy of single-agent and combination targeted therapy. Age-based and weight-based dosing of trametinib with or without dabrafenib achieved target concentrations with manageable safety and demonstrated clinical efficacy and tolerability in BRAF V600–mutant LGG

Evolution of the Bovine TLR Gene Family and Member Associations with Mycobacterium avium Subspecies paratuberculosis Infection

Members of the Toll-like receptor (TLR) gene family occupy key roles in the mammalian innate immune system by functioning as sentries for the detection of invading pathogens, thereafter provoking host innate immune responses. We utilized a custom next-generation sequencing approach and allele-specific genotyping assays to detect and validate 280 biallelic variants across all 10 bovine TLR genes, including 71 nonsynonymous single nucleotide polymorphisms (SNPs) and one putative nonsense SNP. Bayesian haplotype reconstructions and median joining networks revealed haplotype sharing between Bos taurus taurus and Bos taurus indicus breeds at every locus, and specialized beef and dairy breeds could not be differentiated despite an average polymorphism density of 1 marker/158 bp. Collectively, 160 tagSNPs and two tag insertion-deletion mutations (indels) were sufficient to predict 100% of the variation at 280 variable sites for both Bos subspecies and their hybrids, whereas 118 tagSNPs and 1 tagIndel predictively captured 100% of the variation at 235 variable sites for B. t. taurus. Polyphen and SIFT analyses of amino acid (AA) replacements encoded by bovine TLR SNPs indicated that up to 32% of the AA substitutions were expected to impact protein function. Classical and newly developed tests of diversity provide strong support for balancing selection operating on TLR3 and TLR8, and purifying selection acting on TLR10. An investigation of the persistence and continuity of linkage disequilibrium (r2≥0.50) between adjacent variable sites also supported the presence of selection acting on TLR3 and TLR8. A case-control study employing validated variants from bovine TLR genes recognizing bacterial ligands revealed six SNPs potentially eliciting small effects on susceptibility to Mycobacterium avium spp paratuberculosis infection in dairy cattle. The results of this study will broadly impact domestic cattle research by providing the necessary foundation to explore several avenues of bovine translational genomics, and the potential for marker-assisted vaccination

Blinatumomab versus historical standard therapy in pediatric patients with relapsed/refractory Ph-negative B-cell precursor acute lymphoblastic leukemia

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Sexual selection protects against extinction

Reproduction through sex carries substantial costs, mainly because only half of sexual adults produce offspring. It has been theorised that these costs could be countered if sex allows sexual selection to clear the universal fitness constraint of mutation load. Under sexual selection, competition between (usually) males, and mate choice by (usually) females create important intraspecific filters for reproductive success, so that only a subset of males gains paternity. If reproductive success under sexual selection is dependent on individual condition, which depends on mutation load, then sexually selected filtering through ‘genic capture’ could offset the costs of sex because it provides genetic benefits to populations. Here, we test this theory experimentally by comparing whether populations with histories of strong versus weak sexual selection purge mutation load and resist extinction differently. After evolving replicate populations of the flour beetle Tribolium castaneum for ~7 years under conditions that differed solely in the strengths of sexual selection, we revealed mutation load using inbreeding. Lineages from populations that had previously experienced strong sexual selection were resilient to extinction and maintained fitness under inbreeding, with some families continuing to survive after 20 generations of sib × sib mating. By contrast, lineages derived from populations that experienced weak or non-existent sexual selection showed rapid fitness declines under inbreeding, and all were extinct after generation 10. Multiple mutations across the genome with individually small effects can be difficult to clear, yet sum to a significant fitness load; our findings reveal that sexual selection reduces this load, improving population viability in the face of genetic stress