LYL1 Degradation by the Proteasome Is Directed by a N-Terminal PEST Rich Site in a Phosphorylation-Independent Manner

Background: The Lymphoblastic leukemia 1 (LYL1) gene is a proto-oncogenic transcription factor found upregulated in patients with T-cell acute lymphoblastic leukemia (T-cell ALL). Initially, the upregulation was described to be as a result of a translocation. However, further studies revealed that transcriptional upregulation of LYL1could also occur without translocations. In addition, post-translational mechanisms, such as protein degradation could influence LYL1 expression as well. Methodology/Principal Findings: In this study, we considered possible post-translational regulation of Lyl1, and investigated fundamental mechanisms governing LYL1 degradation in cell-based culture assays. We identify a PEST sequence motif located in the N-terminus of LYL1, which determines the efficiency of LYL1 degradation by the proteasome. The absence of the PEST degradation site leads to accumulation or upregulation of LYL1. We also show that LYL1 is phosphorylated by MAPK at S36, and determined that proteasomal degradation of LYL1 occurs in a phosphorylationindependent manner. Conclusions/Significance: Understanding LYL1 degradation is a step forward not only towards deciphering the normal function and regulation of LYL1, but could suggest post-translational mechanisms for upregulation of LYL1 that ma

Drosophila Nociceptors Mediate Larval Aversion to Dry Surface Environments Utilizing Both the Painless TRP Channel and the DEG/ENaC Subunit, PPK1

A subset of sensory neurons embedded within the Drosophila larval body wall have been characterized as high-threshold polymodal nociceptors capable of responding to noxious heat and noxious mechanical stimulation. They are also sensitized by UV-induced tissue damage leading to both thermal hyperalgesia and allodynia very similar to that observed in vertebrate nociceptors. We show that the class IV multiple-dendritic(mdIV) nociceptors are also required for a normal larval aversion to locomotion on to a dry surface environment. Drosophila melanogaster larvae are acutely susceptible to desiccation displaying a strong aversion to locomotion on dry surfaces severely limiting the distance of movement away from a moist food source. Transgenic inactivation of mdIV nociceptor neurons resulted in larvae moving inappropriately into regions of low humidity at the top of the vial reflected as an increased overall pupation height and larval desiccation. This larval lethal desiccation phenotype was not observed in wild-type controls and was completely suppressed by growth in conditions of high humidity. Transgenic hyperactivation of mdIV nociceptors caused a reciprocal hypersensitivity to dry surfaces resulting in drastically decreased pupation height but did not induce the writhing nocifensive response previously associated with mdIV nociceptor activation by noxious heat or harsh mechanical stimuli. Larvae carrying mutations in either the Drosophila TRP channel, Painless, or the degenerin/epithelial sodium channel subunit Pickpocket1(PPK1), both expressed in mdIV nociceptors, showed the same inappropriate increased pupation height and lethal desiccation observed with mdIV nociceptor inactivation. Larval aversion to dry surfaces appears to utilize the same or overlapping sensory transduction pathways activated by noxious heat and harsh mechanical stimulation but with strikingly different sensitivities and disparate physiological responses

At the Biological Modeling and Simulation Frontier

We provide a rationale for and describe examples of synthetic modeling and simulation (M&S) of biological systems. We explain how synthetic methods are distinct from familiar inductive methods. Synthetic M&S is a means to better understand the mechanisms that generate normal and disease-related phenomena observed in research, and how compounds of interest interact with them to alter phenomena. An objective is to build better, working hypotheses of plausible mechanisms. A synthetic model is an extant hypothesis: execution produces an observable mechanism and phenomena. Mobile objects representing compounds carry information enabling components to distinguish between them and react accordingly when different compounds are studied simultaneously. We argue that the familiar inductive approaches contribute to the general inefficiencies being experienced by pharmaceutical R&D, and that use of synthetic approaches accelerates and improves R&D decision-making and thus the drug development process. A reason is that synthetic models encourage and facilitate abductive scientific reasoning, a primary means of knowledge creation and creative cognition. When synthetic models are executed, we observe different aspects of knowledge in action from different perspectives. These models can be tuned to reflect differences in experimental conditions and individuals, making translational research more concrete while moving us closer to personalized medicine

The Human Phenotype Ontology in 2024: phenotypes around the world

\ua9 The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs

Agent‐based modelling for SARS‐CoV

Our purpose is to assess epidemiological agent-based models– or ABMs - of the SARS-CoV-2 pandemic methodologically. The rapid spread of the outbreak requires fast-paced decision-making regarding mitigation measures. However, the evidence for the efficacy of non-pharmaceutical interventions such as imposed social distancing and school or workplace closures is scarce: few observational studies use quasi-experimental research designs, and conducting randomized controlled trials seems infeasible. Additionally, evidence from the previous coronavirus outbreaks of SARS and MERS lacks external validity, given the significant differences in contagiousness of those pathogens relative to SARS-CoV-2. To address the pressing policy questions that have emerged as a result of COVID-19, epidemiologists have produced numerous models that range from simple compartmental models to highly advanced agent-based models. These models have been criticized for involving simplifications and lacking empirical support for their assumptions. In order to address these voices and methodologically appraise epidemiological ABMs, we consider AceMod (the model of the COVID-19 epidemic in Australia) as an example of the modeling practice. Our case study shows that, although epidemiological ABMs involve simplifications of various sorts, the key characteristics of social interactions and the spread of SARS-CoV-2 are represented sufficiently accurately. This is the case because these modelers treat empirical results as inputs for constructing modeling assumptions and rules that the agents follow; and they use calibration to assert the adequacy to benchmark variables. Given this, we claim that the best epidemiological ABMs are models of actual mechanisms and deliver both mechanistic and difference-making evidence. Consequently, they may also adequately describe the effects of possible interventions. Finally, we discuss the limitations of ABMs and put forward policy recommendations

Nutritional content of savanna plant foods: implications for browser/grazer models of ungulate diversification

Models of herbivore diversification rely heavily on adaptations that reflect the nutritional quality of foods consumed. In particular, browsers and grazers are expected to show dichotomous adaptations to deal with high quality (concentrate) browse-based and poor quality grass-based diets, respectively. In this study, we test the widespread assumption that browse represents a higher quality food source than grass. We analyzed plants from a South African savanna, collected over one dry and one wet season across several habitat types, for percent nitrogen (%N), neutral detergent fiber (NDF), acid detergent fiber (ADF), and acid detergent lignin (ADL) to compare variations in nutritional value of different food types. Results show consistently higher %N and lower NDF and ADF of tree foliage and forbs compared to monocots, but the former have consistently higher ADL, implying a higher fiber digestibility in grass compared with browse. Some fruit species have a high NDF and ADL content, implying poorer nutritional value than is commonly assumed. Our findings are in agreement with several other studies depicting relatively poor digestibility of browse (tree foliage and fruit) compared to grass. Reference to browse as high quality foods is therefore misleading, and models of herbivory that rest on this assumption require revision. The more efficient fiber digestibility recorded in grazers compared to browsers cannot be treated as an adaptation to poor quality diets, but rather to maximize benefits of higher fiber digestibility of grass. Spatio-seasonal variations in plant nutritional seem to reflect seasonal and spatial diet changes expected for grazers and intermediate (mixed) feeders. We propose that future studies require further detail on variations in diet, diet quality, and digestive efficiency to properly understand mechanisms of adaptation