400 research outputs found
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A Principal Component Analysis of Vertical Temperature Profiles for Tracking Movements of Large Pelagic Fishes
Pop-up satellite archival tag (PSAT) technology that records depth, temperature, and light-level data has expanded the understanding of free-swimming behavior for numerous pelagic animals. Astronomical algorithms using these light-level data have allowed geolocation estimates of daily longitude and latitude. However, many pelagic animals have a crepuscular behavior pattern in which individuals are at depths below the photic layer during the day, thus precluding the use of traditional light-based movement algorithms for geolocation in such species as swordfish. A principal component analysis (PCA) of temperature profiles is described herein that utilizes depth and temperature data rather than light to estimate the horizontal movement between the initial location of tag release and transmission. PSAT data from swordfish (n=4), blue marlin (n=14), white marlin (n=2), and black marlin (n=1) were used to generate daily coordinate estimates. The marlin data provided sufficient light information to derive geolocation estimates using two light-based state space models, while the hydrographic PCA model was used to derive comparison estimates. Comparisons of the two model types show an average root mean square difference of 175.4 km demonstrating that the PCA model can be used to extract the movement of tagged swordfish and other pelagic species demonstrating crepuscular behavior. Integration of this PCA-based geolocation methods with both the best available estimates of the ocean temperature at the time of tag deployment and the existing light-based geolocation models would provide additional information on fine-scale movement of tagged fish
The Medical Action Ontology: A tool for annotating and analyzing treatments and clinical management of human disease
Clinical management; Medical action ontology; OntologyGestión clínica; Ontología de la acción médica; OntologíaGestió clínica; Ontologia de l'acció mèdica; OntologiaBackground
Navigating the clinical literature to determine the optimal clinical management for rare diseases presents significant challenges. We introduce the Medical Action Ontology (MAxO), an ontology specifically designed to organize medical procedures, therapies, and interventions.
Methods
MAxO incorporates logical structures that link MAxO terms to numerous other ontologies within the OBO Foundry. Term development involves a blend of manual and semi-automated processes. Additionally, we have generated annotations detailing diagnostic modalities for specific phenotypic abnormalities defined by the Human Phenotype Ontology (HPO). We introduce a web application, POET, that facilitates MAxO annotations for specific medical actions for diseases using the Mondo Disease Ontology.
Findings
MAxO encompasses 1,757 terms spanning a wide range of biomedical domains, from human anatomy and investigations to the chemical and protein entities involved in biological processes. These terms annotate phenotypic features associated with specific disease (using HPO and Mondo). Presently, there are over 16,000 MAxO diagnostic annotations that target HPO terms. Through POET, we have created 413 MAxO annotations specifying treatments for 189 rare diseases.
Conclusions
MAxO offers a computational representation of treatments and other actions taken for the clinical management of patients. Its development is closely coupled to Mondo and HPO, broadening the scope of our computational modeling of diseases and phenotypic features. We invite the community to contribute disease annotations using POET (https://poet.jax.org/). MAxO is available under the open-source CC-BY 4.0 license (https://github.com/monarch-initiative/MAxO).This study was supported by the National Institutes of Health (NIH): NHGRI 1U24HG011449-01A1 and NHGRI 5RM1HG010860-04. R.H. is a Wellcome Trust Investigator (109915/Z/15/Z), who receives support from the Medical Research Council (UK) (MR/V009346/1), the Addenbrookes Charitable Trust (G100142), the Evelyn Trust, the Stoneygate Trust, the Lily Foundation, Action for AT and an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care
The IκB-protein BCL-3 controls toll-like receptor-induced MAPK activity by promoting TPL-2 degradation in the nucleus
Proinflammatory responses induced by Toll-like receptors (TLRs) are dependent on the activation of the NF-ĸB and mitogen-activated protein kinase (MAPK) pathways, which coordinate the transcription and synthesis of proinflammatory cytokines. We demonstrate that BCL-3, a nuclear IĸB protein that regulates NF-ĸB, also controls TLR-induced MAPK activity by regulating the stability of the TPL-2 kinase. TPL-2 is essential for MAPK activation by TLR ligands, and the rapid proteasomal degradation of active TPL-2 is a critical mechanism limiting TLR-induced MAPK activity. We reveal that TPL-2 is a nucleocytoplasmic shuttling protein and identify the nucleus as the primary site for TPL-2 degradation. BCL-3 interacts with TPL-2 and promotes its degradation by promoting its nuclear localization. As a consequence, Bcl3−/− macrophages have increased TPL-2 stability following TLR stimulation, leading to increased MAPK activity and MAPK-dependent responses. Moreover, BCL-3–mediated regulation of TPL-2 stability sets the MAPK activation threshold and determines the amount of TLR ligand required to initiate the production of inflammatory cytokines. Thus, the nucleus is a key site in the regulation of TLR-induced MAPK activity. BCL-3 links control of the MAPK and NF-ĸB pathways in the nucleus, and BCL-3–mediated TPL-2 regulation impacts on the cellular decision to initiate proinflammatory cytokine production in response to TLR activation
Robotic-assisted laparoscopic donor nephrectomy: Decreasing length of stay
Background: The number of robotic operations performed with the da Vinci Surgical System has increased during the past decade. This system allows for greater maneuverability and control than hand-assisted laparoscopic procedures, resulting in less tissue manipulation and irritation
Role of special coagulation studies for preoperative screening of thrombotic complications in simultaneous pancreas-kidney transplantation
Background: Vascular thrombosis is a well-known complication after simultaneous pancreas-kidney (SPK) transplantation procedures. The role of preoperative special coagulation studies to screen patients at high risk for vascular thrombosis is unclear and not well studied
'Debating 'The Rediscovery of Liberalism' in Zambia: Responses to Harri Englund
In Africa 83(4) (November 2013), Harri Englund discussed several recent books on Zambia published preceding the country’s fiftieth independence anniversary. His article explored the ways in which recent publications by Zambian and Zambianist authors have launched a fresh research agenda, and he focused in particular on the scholarly engagement with liberalism. Below, we publish responses from David M.Gordon, Bizeck Jube Phiri and Giacomo Macola, whose work was discussed in this article, and a comment by James Ferguson on more scholarly directions
Defining the role of nuclear factor NF-κB p105 subunit in human macrophage by transcriptomic analysis of NFKB1 knockout THP-1 cells
Since its discovery over 30 years ago the NF-ĸB family of transcription factors has gained the status of master regulator of the immune response. Much of what we understand of the role of NF-ĸB in immune development, homeostasis and inflammation comes from studies of mice null for specific NF-ĸB subunit encoding genes. The role of inflammation in diseases that affect a majority of individuals with health problems globally further establishes NF-ĸB as an important pathogenic factor. More recently, genomic sequencing has revealed loss of function mutations in the NFKB1 gene as the most common monogenic cause of common variable immunodeficiencies in Europeans. NFKB1 encodes the p105 subunit of NF-ĸB which is processed to generate the NF-ĸB p50 subunit. NFKB1 is the most highly expressed transcription factor in macrophages, key cellular drivers of inflammation and immunity. Although a key role for NFKB1 in the control of the immune system is apparent from Nfkb1-/- mouse studies, we know relatively little of the role of NFKB1 in regulating human macrophage responses. In this study we use the THP1 monocyte cell line and CRISPR/Cas9 gene editing to generate a model of NFKB1-/- human macrophages. Transcriptomic analysis reveals that activated NFKB1-/- macrophages are more pro-inflammatory than wild type controls and express elevated levels of TNF, IL6, and IL1B, but also have reduced expression of co-stimulatory factors important for the activation of T cells and adaptive immune responses such as CD70, CD83 and CD209. NFKB1-/- THP1 macrophages recapitulate key observations in individuals with NFKB1 haploinsufficiency including decreased IL10 expression. These data supporting their utility as an in vitro model for understanding the role of NFKB1 in human monocytes and macrophages and indicate that of loss of function NFKB1 mutations in these cells is an important component in the associated pathology
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Reprogramming human T cell function and specificity with non-viral genome targeting.
Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells
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