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The Mayo brothers, Drs. William James Mayo and Charles Horace Mayo, are celebrated for their groundbreaking contributions to modern medicine. This review examines their journey from humble beginnings to establishing the Mayo Clinic, a world-renowned medical institution. They pioneered a collaborative, team-based approach to medicine, which was revolutionary then. They emphasized the importance of specialization and interdisciplinary cooperation, laying the foundation for modern healthcare practices like integrated care and the rise of group medical practices. Their impact continues through the Mayo Clinic's patient-centered approach, which has influenced countless healthcare institutions worldwide., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Gnanapandithan et al.)

Background: Aberrant protein kinase regulation leading to abnormal substrate phosphorylation is associated with several human diseases. Despite the promise of therapies targeting kinases, many human kinases remain understudied. Most existing computational tools predicting phosphorylation cover less than 50% of known human kinases. They utilize local feature selection based on protein sequences, motifs, domains, structures, and/or functions, and do not consider the heterogeneous relationships of the proteins. In this work, we present KSFinder, a tool that predicts kinase-substrate links by capturing the inherent association of proteins in a network comprising 85% of the known human kinases. We also postulate the potential role of two understudied kinases based on their substrate predictions from KSFinder., Methods: KSFinder learns the semantic relationships in a phosphoproteome knowledge graph using a knowledge graph embedding algorithm and represents the nodes in low-dimensional vectors. A multilayer perceptron (MLP) classifier is trained to discern kinase-substrate links using the embedded vectors. KSFinder uses a strategic negative generation approach that eliminates biases in entity representation and combines data from experimentally validated non-interacting protein pairs, proteins from different subcellular locations, and random sampling. We assess KSFinder's generalization capability on four different datasets and compare its performance with other state-of-the-art prediction models. We employ KSFinder to predict substrates of 68 "dark" kinases considered understudied by the Illuminating the Druggable Genome program and use our text-mining tool, RLIMS-P along with manual curation, to search for literature evidence for the predictions. In a case study, we performed functional enrichment analysis for two dark kinases - HIPK3 and CAMKK1 using their predicted substrates., Results: KSFinder shows improved performance over other kinase-substrate prediction models and generalized prediction ability on different datasets. We identified literature evidence for 17 novel predictions involving an understudied kinase. All of these 17 predictions had a probability score ≥0.7 (nine at >0.9, six at 0.8-0.9, and two at 0.7-0.8). The evaluation of 93,593 negative predictions (probability ≤0.3) identified four false negatives. The top enriched biological processes of HIPK3 substrates relate to the regulation of extracellular matrix and epigenetic gene expression, while CAMKK1 substrates include lipid storage regulation and glucose homeostasis., Conclusions: KSFinder outperforms the current kinase-substrate prediction tools with higher kinase coverage. The strategically developed negatives provide a superior generalization ability for KSFinder. We predicted substrates of 432 kinases, 68 of which are understudied, and hypothesized the potential functions of two dark kinases using their predicted substrates., Competing Interests: The authors declare there are no competing interests., (©2023 Anandakrishnan et al.)

In this work, the density, viscosity, speed of sound, flash point, and surface tension of mixtures of military jet fuel JP-5 and biodiesels were measured at various temperatures. The biodiesels were synthesized from various oils (avocado, canola, castor, coconut, corn grapeseed, linseed, neem, oil, palm, peanut, soybean, and walnuts), bacon grease, and duck fat. The isentropic bulk modulus was calculated from the speed of sound and density. These physical properties are important for modeling the spray of fuel into a diesel engine cylinder., Competing Interests: The authors declare that they have no know competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier Inc.)

Lung cancer is the leading cause of cancer mortality worldwide. The treatment of patients with lung cancer harboring mutant EGFR with orally administered EGFR tyrosine kinase inhibitors (TKI) has been a paradigm shift. Osimertinib and rociletinib are third-generation irreversible EGFR TKIs targeting the EGFR T790M mutation. Osimertinib is the current standard of care for patients with EGFR mutations due to increased efficacy, lower side effects, and enhanced brain penetrance. Unfortunately, all patients develop resistance. Genomic approaches have primarily been used to interrogate resistance mechanisms. Here we characterized the proteome and phosphoproteome of a series of isogenic EGFR-mutant lung adenocarcinoma cell lines that are either sensitive or resistant to these drugs, comprising the most comprehensive proteomic dataset resource to date to investigate third generation EGFR TKI resistance in lung adenocarcinoma. Unbiased global quantitative mass spectrometry uncovered alterations in signaling pathways, revealed a proteomic signature of epithelial-mesenchymal transition, and identified kinases and phosphatases with altered expression and phosphorylation in TKI-resistant cells. Decreased tyrosine phosphorylation of key sites in the phosphatase SHP2 suggests its inhibition, resulting in subsequent inhibition of RAS/MAPK and activation of PI3K/AKT pathways. Anticorrelation analyses of this phosphoproteomic dataset with published drug-induced P100 phosphoproteomic datasets from the Library of Integrated Network-Based Cellular Signatures program predicted drugs with the potential to overcome EGFR TKI resistance. The PI3K/MTOR inhibitor dactolisib in combination with osimertinib overcame resistance both in vitro and in vivo . Taken together, this study reveals global proteomic alterations upon third generation EGFR TKI resistance and highlights potential novel approaches to overcome resistance. SIGNIFICANCE: Global quantitative proteomics reveals changes in the proteome and phosphoproteome in lung cancer cells resistant to third generation EGFR TKIs, identifying the PI3K/mTOR inhibitor dactolisib as a potential approach to overcome resistance., (©2021 American Association for Cancer Research.)

iPTMnet is a bioinformatics resource that integrates protein post-translational modification (PTM) data from text mining and curated databases and ontologies to aid in knowledge discovery and scientific study. The current iPTMnet website can be used for querying and browsing rich PTM information but does not support automated iPTMnet data integration with other tools. Hence, we have developed a RESTful API utilizing the latest developments in cloud technologies to facilitate the integration of iPTMnet into existing tools and pipelines. We have packaged iPTMnet API software in Docker containers and published it on DockerHub for easy redistribution. We have also developed Python and R packages that allow users to integrate iPTMnet for scientific discovery, as demonstrated in a use case that connects PTM sites to kinase signaling pathways., (© The Author(s) 2020. Published by Oxford University Press.)

Oviductosomes (OVS) are nano-sized extracellular vesicles secreted in the oviductal luminal fluid by oviductal epithelial cells and known to be involved in sperm capacitation and fertility. Although they have been shown to transfer encapsulated proteins to sperm, cargo constituents other than proteins have not been identified. Using next-generation sequencing, we demonstrate that OVS are carriers of microRNAs (miRNAs), with 272 detected throughout the estrous cycle. Of the 50 most abundant, 6 (12%) and 2 (4%) were expressed at significantly higher levels (P < 0.05) at metestrus/diestrus and proestrus/estrus. RT-qPCR showed that selected miRNAs are present in oviductal epithelial cells in significantly (P < 0.05) lower abundance than in OVS, indicating selective miRNA packaging. The majority (64%) of the top 25 OVS miRNAs are present in sperm. These miRNAs' potential target list is enriched with transcription factors, transcription regulators, and protein kinases and there are several embryonic developmentally-related genes. Importantly, OVS can deliver to sperm miRNAs, including miR-34c-5p which is essential for the first cleavage and is solely sperm-derived in the zygote. Z-stack of confocal images of sperm co-incubated with OVS loaded with labeled miRNAs showed the intracellular location of the delivered miRNAs. Interestingly, individual miRNAs were predominantly localized in specific head compartments, with miR-34c-5p being highly concentrated at the centrosome where it is known to function. These results, for the first time, demonstrate OVS' ability to contribute to the sperm's miRNA repertoire (an important role for solely sperm-derived zygotic miRNAs) and the physiological relevance of an OVS-borne miRNA that is delivered to sperm.

Protein post-translational modifications (PTMs) play a pivotal role in numerous biological processes by modulating regulation of protein function. We have developed iPTMnet (http://proteininformationresource.org/iPTMnet) for PTM knowledge discovery, employing an integrative bioinformatics approach-combining text mining, data mining, and ontological representation to capture rich PTM information, including PTM enzyme-substrate-site relationships, PTM-specific protein-protein interactions (PPIs) and PTM conservation across species. iPTMnet encompasses data from (i) our PTM-focused text mining tools, RLIMS-P and eFIP, which extract phosphorylation information from full-scale mining of PubMed abstracts and full-length articles; (ii) a set of curated databases with experimentally observed PTMs; and iii) Protein Ontology that organizes proteins and PTM proteoforms, enabling their representation, annotation and comparison within and across species. Presently covering eight major PTM types (phosphorylation, ubiquitination, acetylation, methylation, glycosylation, S-nitrosylation, sumoylation and myristoylation), iPTMnet knowledgebase contains more than 654 500 unique PTM sites in over 62 100 proteins, along with more than 1200 PTM enzymes and over 24 300 PTM enzyme-substrate-site relations. The website supports online search, browsing, retrieval and visual analysis for scientific queries. Several examples, including functional interpretation of phosphoproteomic data, demonstrate iPTMnet as a gateway for visual exploration and systematic analysis of PTM networks and conservation, thereby enabling PTM discovery and hypothesis generation., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Numerous efforts have been made for developing text-mining tools to extract information from biomedical text automatically. They have assisted in many biological tasks, such as database curation and hypothesis generation. Text-mining tools are usually different from each other in terms of programming language, system dependency and input/output format. There are few previous works that concern the integration of different text-mining tools and their results from large-scale text processing. In this paper, we describe the iTextMine system with an automated workflow to run multiple text-mining tools on large-scale text for knowledge extraction. We employ parallel processing with dockerized text-mining tools with a standardized JSON output format and implement a text alignment algorithm to solve the text discrepancy for result integration. iTextMine presently integrates four relation extraction tools, which have been used to process all the Medline abstracts and PMC open access full-length articles. The website allows users to browse the text evidence and view integrated results for knowledge discovery through a network view. We demonstrate the utilities of iTextMine with two use cases involving the gene PTEN and breast cancer and the gene SATB1.

The Protein Ontology (PRO; http://purl.obolibrary.org/obo/pr) formally defines and describes taxon-specific and taxon-neutral protein-related entities in three major areas: proteins related by evolution; proteins produced from a given gene; and protein-containing complexes. PRO thus serves as a tool for referencing protein entities at any level of specificity. To enhance this ability, and to facilitate the comparison of such entities described in different resources, we developed a standardized representation of proteoforms using UniProtKB as a sequence reference and PSI-MOD as a post-translational modification reference. We illustrate its use in facilitating an alignment between PRO and Reactome protein entities. We also address issues of scalability, describing our first steps into the use of text mining to identify protein-related entities, the large-scale import of proteoform information from expert curated resources, and our ability to dynamically generate PRO terms. Web views for individual terms are now more informative about closely-related terms, including for example an interactive multiple sequence alignment. Finally, we describe recent improvement in semantic utility, with PRO now represented in OWL and as a SPARQL endpoint. These developments will further support the anticipated growth of PRO and facilitate discoverability of and allow aggregation of data relating to protein entities., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The Protein Ontology (PRO; http://proconsortium.org) formally defines protein entities and explicitly represents their major forms and interrelations. Protein entities represented in PRO corresponding to single amino acid chains are categorized by level of specificity into family, gene, sequence and modification metaclasses, and there is a separate metaclass for protein complexes. All metaclasses also have organism-specific derivatives. PRO complements established sequence databases such as UniProtKB, and interoperates with other biomedical and biological ontologies such as the Gene Ontology (GO). PRO relates to UniProtKB in that PRO's organism-specific classes of proteins encoded by a specific gene correspond to entities documented in UniProtKB entries. PRO relates to the GO in that PRO's representations of organism-specific protein complexes are subclasses of the organism-agnostic protein complex terms in the GO Cellular Component Ontology. The past few years have seen growth and changes to the PRO, as well as new points of access to the data and new applications of PRO in immunology and proteomics. Here we describe some of these developments.

Background: In order to advance beyond basic statistical limb salvage to improved functional or quality limb salvage, a better understanding of the ischemic threshold of the limb is required. To date, models of extremity ischemia and reperfusion involve small animals and few include survival with physiologic measures of nerve and muscle recovery. In addition, the effect of hemorrhagic shock on the ischemic threshold of the extremity is unknown. This study characterized the effect of class III hemorrhagic shock on the ischemic threshold of the extremity in a large-animal model of neuromuscular recovery., Methods: Yorkshire/Landrace-cross swine (weight, 70-90 kg) were randomized to iliac artery repair either immediately or at 1, 3, or 6 hours after vessel loop occlusion and arteriotomy. A fifth group underwent excision of the arterial segment without repair to represent ligation. Class III shock was created by removing 35% of total blood volume using a variable rate model. Animals were monitored for 14 days to serially collect markers of functional recovery., Results: Animals with ≤1 hour ischemia (control) had clinically normal limb function by the end of the 2-week observation period, with minimal muscle and nerve changes on histology. Separate analysis of contralateral, nonexperimental limbs revealed normal histology and function. After 3 hours of ischemia, functional recovery was impaired, with moderate-to-severe degeneration of nerve and muscle noted on histology. Animals undergoing 6 hours of ischemia or ligation had minimal electromyelography response and severe systemic inflammation, which correlated with severe muscle and nerve degeneration. Concurrent class III hemorrhagic shock was associated with a decrement in neuromuscular recovery across all groups but was greatest in groups undergoing ≥3 hours of extremity ischemia (P < .01)., Conclusions: This study demonstrates the feasibility of combined hemorrhagic shock and extremity ischemia-reperfusion in a large-animal survival model. The presence of hemorrhagic shock compounds the effect of extremity ischemia, reducing the ischemic threshold of the limb to <3 hours. Strategies to improve functional salvage after extremity vascular injury in the setting of shock should include attempts at restoration of flow ≤60 minutes., (Published by Mosby, Inc.)

Background: Despite advances in revascularization following extremity vascular injury, the relationship between time to restoration of flow and functional limb salvage is unknown. The objectives of this study are to describe a large animal survival model of hind limb ischemia/reperfusion and define neuromuscular recovery following increasing ischemic periods., Methods: Sus scrofa swine (N = 38; weight, 87 ± 6.2 kg) were randomized to iliac artery occlusion for 0 (Control), 1 (1HR), 3 (3HR), or 6 (6HR) hours, followed by vessel repair and 14 days of recovery. Additionally, one group underwent iliac artery division with no restoration of flow (Ligation), and one group underwent iliac artery exposure only without intervention (Sham). A composite physiologic measure of recovery (PMR) was generated to assess group differences over 14 days of survival. PMR included limb function (Tarlov score) and electrophysiologic measures (compound muscle action potential amplitude, sensory nerve action potential amplitude, and nerve conduction velocity). Using the PMR and extrapolating the point at which recovery following ligation crosses the slope connecting recovery after 3 and 6 hours of ischemia, an estimate of the ischemic threshold for the hind limb is made. These results were correlated with peroneus muscle and peroneal nerve histology., Results: Baseline physiologic characteristics were similar between groups. Neuromuscular recovery in groups with early restoration of flow (Control, 1HR, 3HR) was similar and nearly complete (92%, 98%, and 88%, respectively; P > .45). While recovery was diminished in both 6HR and Ligation, Ligation, rather than repair, exhibited greater recovery (68% vs 53%; P < .05). These relationships correlated with the pathologic grade of degeneration, necrosis, and fibrosis (P < .05). The PMR model predicts minimal and similar persistent loss of function in groups undergoing early surgical restoration of flow (Control 8%, 1HR 1%, 3HR 12%; P > .45). In contrast, the Ligation group exhibited the greatest degree of injury early in the reperfusion period, followed by more complete recovery and at a faster rate than 6HR. Extrapolating from the PMR the point at which Ligation (68% recovery) crosses the slope connecting 3 hours (84% recovery) and 6 hours (53% recovery) of ischemia estimates the ischemic threshold to be 4.7 hours. Restoration of flow at ischemic intervals exceeding this are associated with less physiologic recovery than ligation., Conclusion: In this model, surgical and therapeutic adjuncts to restore extremity perfusion early (1-3 hours) after extremity vascular injury are most likely to provide outcomes benefit compared with delayed restoration of flow or ligation. Furthermore, the ischemic threshold of the extremity after which neuromuscular recovery is significantly diminished is less than 5 hours. Additional studies are necessary to determine the effect of other factors such as shock or therapeutic measures on this ischemic threshold., (Published by Mosby, Inc.)

A method for immunizing foxes against rabies was evaluated. Fifteen of 36 red foxes (Vulpes fulva) fed baits impregnated with modified live virus rabies vaccine developed serum rabies neutralizing antibody. The vaccine-bait proved unstable when held at 4 C or 25 C for 96 hours prior to feeding. For safety testing the vaccine virus was administered to opossums (Didelphis virginiana), cotton rats (Sigmodon hispidus), hamsters (Mesocricetus auratus), and chickens (Gallus domesticus) in either liquid or bait form. One of ten cotton rats fed liquid vaccine died of vaccine induced rabies. No animals which ate the vaccine-baits died of vaccine induced rabies.