The CAFA challenge reports improved protein function prediction and new functional annotations for hundreds of genes through experimental screens

Background The Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function. Results Here, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes. Specifically, we performed experimental whole-genome mutation screening in Candida albicans and Pseudomonas aureginosa genomes, which provided us with genome-wide experimental data for genes associated with biofilm formation and motility. We further performed targeted assays on selected genes in Drosophila melanogaster, which we suspected of being involved in long-term memory. Conclusion We conclude that while predictions of the molecular function and biological process annotations have slightly improved over time, those of the cellular component have not. Term-centric prediction of experimental annotations remains equally challenging; although the performance of the top methods is significantly better than the expectations set by baseline methods in C. albicans and D. melanogaster, it leaves considerable room and need for improvement. Finally, we report that the CAFA community now involves a broad range of participants with expertise in bioinformatics, biological experimentation, biocuration, and bio-ontologies, working together to improve functional annotation, computational function prediction, and our ability to manage big data in the era of large experimental screens.Peer reviewe

The CAFA challenge reports improved protein function prediction and new functional annotations for hundreds of genes through experimental screens

BackgroundThe Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function.ResultsHere, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes. Specifically, we performed experimental whole-genome mutation screening in Candida albicans and Pseudomonas aureginosa genomes, which provided us with genome-wide experimental data for genes associated with biofilm formation and motility. We further performed targeted assays on selected genes in Drosophila melanogaster, which we suspected of being involved in long-term memory.ConclusionWe conclude that while predictions of the molecular function and biological process annotations have slightly improved over time, those of the cellular component have not. Term-centric prediction of experimental annotations remains equally challenging; although the performance of the top methods is significantly better than the expectations set by baseline methods in C. albicans and D. melanogaster, it leaves considerable room and need for improvement. Finally, we report that the CAFA community now involves a broad range of participants with expertise in bioinformatics, biological experimentation, biocuration, and bio-ontologies, working together to improve functional annotation, computational function prediction, and our ability to manage big data in the era of large experimental screens.</p

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Ecdysteroid responses to urban heat island conditions during development of the western black widow spider (Latrodectus hesperus).

The steroid hormone 20-hydroxyecdysone (20E) controls molting in arthropods. The timing of 20E production, and subsequent developmental transitions, is influenced by a variety of environmental factors including nutrition, photoperiod, and temperature, which is particularly relevant in the face of climate change. Environmental changes, combined with rapid urbanization, and the increasing prevalence of urban heat islands (UHI) have contributed to an overall decrease in biodiversity making it critical to understand how organisms respond to elevating global temperatures. Some arthropods, such as the Western black widow spider, Latrodectus hesperus, appear to thrive under UHI conditions, but the physiological mechanism underlying their success has not been explored. Here we examine the relationship between hemolymph 20E titers and spiderling development under non-urban desert (27°C), intermediate (30°C), and urban (33°C) temperatures. We found that a presumptive molt-inducing 20E peak observed in spiders at non-urban desert temperatures was reduced and delayed at higher temperatures. Intermolt 20E titers were also significantly altered in spiders reared under UHI temperatures. Despite the apparent success of black widows in urban environments, we noted that, coincident with the effects on 20E, there were numerous negative effects of elevated temperatures on spiderling development. The differential effects of temperature on pre-molt and intermolt 20E titers suggest distinct hormonal mechanisms underlying the physiological, developmental, and behavioral response to heat, allowing spiders to better cope with urban environments

Urban heat island conditions experienced by the Western black widow spider (Latrodectus hesperus): Extreme heat slows development but results in behavioral accommodations.

While shifts in organismal biology stemming from climate change are receiving increased attention, we know relatively little about how organisms respond to other forms of anthropogenic disturbance. The urban heat island (UHI) effect describes the capture of heat by built structures (e.g. asphalt), resulting in elevated urban temperatures. The UHI is a well-studied phenomenon, but only a handful of studies have investigated trait-based shifts resulting from the UHI, and even fewer have attempted to quantify the magnitude of the UHI experienced at the microclimate scale. Here, using a common urban exploiter, the Western black widow spider (Latrodectus hesperus), we show that the UHI experienced by spiders in July in their urban Phoenix, AZ refuges is 6°C hotter (33°C) than conditions in the refuges of spiders from Sonoran Desert habitat outside of Phoenix's development (27°C). We then use this field microclimate UHI estimate to compare the development speed, mass gain and mortality of replicate siblings from 36 urban lineages reared at 'urban' and 'desert' temperatures. We show that extreme heat is slowing the growth of spiderlings and increasing mortality. In contrast, we show that development of male spiders to their penultimate moult is accelerated by 2 weeks. Lastly, in terms of behavioral shifts, UHI temperatures caused late-stage juvenile male spiders to heighten their foraging voracity and late-stage juvenile female spiders to curtail their web-building behavior. Trait-based approaches like the one presented herein help us better understand the mechanisms that lead to the explosive population growth of urban (sometimes invasive) species, possibly at the expense of urban biodiversity. Studies of organismal responses to the present day UHI can be used as informative surrogates that help us grasp the impact that projected climate change will have on biodiversity

Proximal hamstring tendon avulsions: comparable clinical outcomes of operative and non-operative treatment at 1-year follow-up using a shared decision-making model

OBJECTIVE: To prospectively evaluate 1-year clinical and radiological outcomes after operative and non-operative treatment of proximal hamstring tendon avulsions. METHODS: Patients with an MRI-confirmed proximal hamstring tendon avulsion were included. Operative or non-operative treatment was selected by a shared decision-making process. The primary outcome was the Perth Hamstring Assessment Tool (PHAT) score. Secondary outcome scores were Proximal Hamstring Injury Questionnaire, EQ-5D-3L, Tegner Activity Scale, return to sports, hamstring flexibility, isometric hamstring strength and MRI findings including proximal continuity. RESULTS: Twenty-six operative and 33 non-operative patients with a median age of 51 (IQR: 37-57) and 49 (IQR: 45-56) years were included. Median time between injury and initial visit was 12 (IQR 6-19) days for operative and 21 (IQR 12-48) days for non-operative patients (p=0.004). Baseline PHAT scores were significantly lower in the operative group (32±16 vs 45±17, p=0.003). There was no difference in mean PHAT score between groups at 1 year follow-up (80±19 vs 80±17, p=0.97). Mean PHAT score improved by 47 (95% CI 39 to 55, p<0.001) after operative and 34 (95% CI 27 to 41, p<0.001) after non-operative treatment. There were no relevant differences in secondary clinical outcome measures. Proximal continuity on MRI was present in 20 (95%, 1 recurrence) operative and 14 (52%, no recurrences) non-operative patients (p=0.008). CONCLUSION: In a shared decision-making model of care, both operative and non-operative treatment of proximal hamstring tendon avulsions resulted in comparable clinical outcome at 1-year follow-up. Operative patients had lower pretreatment PHAT scores but improved substantially to reach comparable PHAT scores as non-operative patients. We recommend using this shared decision model of care until evidence-based indications in favour of either treatment option are available from high-level clinical trials

Proximal hamstring tendon avulsions: comparable clinical outcomes of operative and non-operative treatment at 1-year follow-up using a shared decision-making model

OBJECTIVE: To prospectively evaluate 1-year clinical and radiological outcomes after operative and non-operative treatment of proximal hamstring tendon avulsions. METHODS: Patients with an MRI-confirmed proximal hamstring tendon avulsion were included. Operative or non-operative treatment was selected by a shared decision-making process. The primary outcome was the Perth Hamstring Assessment Tool (PHAT) score. Secondary outcome scores were Proximal Hamstring Injury Questionnaire, EQ-5D-3L, Tegner Activity Scale, return to sports, hamstring flexibility, isometric hamstring strength and MRI findings including proximal continuity. RESULTS: Twenty-six operative and 33 non-operative patients with a median age of 51 (IQR: 37-57) and 49 (IQR: 45-56) years were included. Median time between injury and initial visit was 12 (IQR 6-19) days for operative and 21 (IQR 12-48) days for non-operative patients (p=0.004). Baseline PHAT scores were significantly lower in the operative group (32±16 vs 45±17, p=0.003). There was no difference in mean PHAT score between groups at 1 year follow-up (80±19 vs 80±17, p=0.97). Mean PHAT score improved by 47 (95% CI 39 to 55, p<0.001) after operative and 34 (95% CI 27 to 41, p<0.001) after non-operative treatment. There were no relevant differences in secondary clinical outcome measures. Proximal continuity on MRI was present in 20 (95%, 1 recurrence) operative and 14 (52%, no recurrences) non-operative patients (p=0.008). CONCLUSION: In a shared decision-making model of care, both operative and non-operative treatment of proximal hamstring tendon avulsions resulted in comparable clinical outcome at 1-year follow-up. Operative patients had lower pretreatment PHAT scores but improved substantially to reach comparable PHAT scores as non-operative patients. We recommend using this shared decision model of care until evidence-based indications in favour of either treatment option are available from high-level clinical trials