The scalable precision medicine open knowledge engine (SPOKE): a massive knowledge graph of biomedical information.

MOTIVATION: Knowledge graphs (KGs) are being adopted in industry, commerce and academia. Biomedical KG presents a challenge due to the complexity, size and heterogeneity of the underlying information. RESULTS: In this work, we present the Scalable Precision Medicine Open Knowledge Engine (SPOKE), a biomedical KG connecting millions of concepts via semantically meaningful relationships. SPOKE contains 27 million nodes of 21 different types and 53 million edges of 55 types downloaded from 41 databases. The graph is built on the framework of 11 ontologies that maintain its structure, enable mappings and facilitate navigation. SPOKE is built weekly by python scripts which download each resource, check for integrity and completeness, and then create a 'parent table' of nodes and edges. Graph queries are translated by a REST API and users can submit searches directly via an API or a graphical user interface. Conclusions/Significance: SPOKE enables the integration of seemingly disparate information to support precision medicine efforts. AVAILABILITY AND IMPLEMENTATION: The SPOKE neighborhood explorer is available at https://spoke.rbvi.ucsf.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Mutations in domain IV of elongation factor EF-G confer -1 frameshifting.

A recent crystal structure of a ribosome complex undergoing partial translocation in the absence of elongation factor EF-G showed disruption of codon-anticodon pairing and slippage of the reading frame by -1, directly implicating EF-G in preservation of the translational reading frame. Among mutations identified in a random screen for dominant-lethal mutations of EF-G were a cluster of six that map to the tip of domain IV, which has been shown to contact the codon-anticodon duplex in trapped translocation intermediates. In vitro synthesis of a full-length protein using these mutant EF-Gs revealed dramatically increased -1 frameshifting, providing new evidence for a role for domain IV of EF-G in maintaining the reading frame. These mutations also caused decreased rates of mRNA translocation and rotational movement of the head and body domains of the 30S ribosomal subunit during translocation. Our results are in general agreement with recent findings from Rodnina and coworkers based on in vitro translation of an oligopeptide using EF-Gs containing mutations at two positions in domain IV, who found an inverse correlation between the degree of frameshifting and rates of translocation. Four of our six mutations are substitutions at positions that interact with the translocating tRNA, in each case contacting the RNA backbone of the anticodon loop. We suggest that EF-G helps to preserve the translational reading frame by preventing uncoupled movement of the tRNA through these contacts; a further possibility is that these interactions may stabilize a conformation of the anticodon that favors base-pairing with its codon.

Engaging the agricultural community in the development of mental health interventions: a qualitative research study.

BACKGROUND: Farmers and those involved in the wider agricultural industry have a high suicide rate. They are also a 'hard to reach' group who make less than average use of mental health services. There is therefore a need to understand how best to develop interventions that meet their needs. The aims of this study were to develop a deeper understanding of the farming context and target population and to engage farmers in the shaping of two potential mental health interventions that could be incorporated in a pilot RCT. METHODS: The study was informed throughout by a reference group, who assisted in co-production of the research materials. A snowball approach was used to recruit interested individuals who had an association with farming. Twenty one telephone interviews were undertaken and analysed using the six phases of thematic analysis proposed by Braun and Clarke. RESULTS: Key themes (and sub-themes shown in brackets) related to the study aims were: everyday life (work-life balance; isolation and loneliness); farm management (technology and social media; production, people management, learning and teaching; external pressures; livestock and farm production; financial aspects); demographics (effects of aging); engagement (appropriate wording when talking about mental health; recognising need for help; religion; normalising mental health issues; approaching the conversation); training (mental health training for supporters of the farming community; health & safety and the inclusion of mental health training); and personal stories and experiences, which was an emerging theme. CONCLUSIONS: Recruiting farmers into research studies is best done by meeting farmers where they are found, for example, farmers marts. Accessibility of content, tailoring to the farming community, and guided support are key to effective recruitment and retention.

A biomedical open knowledge network harnesses the power of AI to understand deep human biology.

Knowledge representation and reasoning (KR&R) has been successfully implemented in many fields to enable computers to solve complex problems with AI methods. However, its application to biomedicine has been lagging in part due to the daunting complexity of molecular and cellular pathways that govern human physiology and pathology. In this article we describe concrete uses of SPOKE, an open knowledge network that connects curated information from 37 specialized and human-curated databases into a single property graph, with 3 million nodes and 15 million edges to date. Applications discussed in this article include drug discovery, COVID-19 research and chronic disease diagnosis and management.

Sun protection education for adolescents: a feasibility study of a wait-list controlled trial of an intervention involving a presentation, action planning, and SMS messages and using objective measurement of sun exposure.

BACKGROUND: People increase their risk of melanoma unless they are protected from the harmful effects of sun exposure during childhood and adolescence. We aimed to assess the feasibility of a three-component sun protection intervention- presentation, action planning, and SMS messages - and trial parameters. METHODS: This feasibility wait-list trial was conducted in the United Kingdom in 2018. Students aged 13-15 years were eligible. Feasibility outcomes were collected for recruitment rates; data availability rates for objective measurements of melanin and erythema using a Mexameter and self-reported sunburn occurrences, severity and body location, tanning, sun protection behaviours and Skin Self-Examination (SSE) collected before (baseline) and after the school summer holidays (follow-up); intervention reach, adherence, perceived impact and acceptability. Quantitative data were analysed using descriptive statistics; qualitative data were analysed thematically. RESULTS: Five out of eight schools expressing an interest in participating with four allocated to act as intervention and one control. Four parents/carers opted their child out of the study. Four hundred and eighty-seven out of 724 students on the school register consented to the study at baseline (67%). Three hundred and eighty-five were in intervention group schools. Objective skin measurements were available for 255 (66%) of the intervention group at baseline and 237 (61%) of the group at follow up. Melanin increased; erythema decreased. Complete self-report data were available for 247 (64%) students in the intervention group. The number of students on the school register who attended the presentation and given the booklet was 379 (98%) and gave their mobile phone number was 155 (40%). No intervention component was perceived as more impactful on sun protection behaviours. Adolescents did not see the relevance of sun protection in the UK or for their age group. CONCLUSIONS: This is the first study to use a Mexameter to measure skin colour in adolescents. Erythema (visible redness) lasts no more than three days and its measurement before and after a six week summer holiday may not yield relevant or meaningful data. A major challenge is that adolescents do not see the relevance of sun protection and SSE. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN11141528. Date registered 0/2/03/2018; last edited 31/05/2018. Retrospectively registered.

Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models.

The gut microbiota regulates T cell functions throughout the body. We hypothesized that intestinal bacteria impact the pathogenesis of multiple sclerosis (MS), an autoimmune disorder of the CNS and thus analyzed the microbiomes of 71 MS patients not undergoing treatment and 71 healthy controls. Although no major shifts in microbial community structure were found, we identified specific bacterial taxa that were significantly associated with MS. Akkermansia muciniphila and Acinetobacter calcoaceticus, both increased in MS patients, induced proinflammatory responses in human peripheral blood mononuclear cells and in monocolonized mice. In contrast, Parabacteroides distasonis, which was reduced in MS patients, stimulated antiinflammatory IL-10-expressing human CD4+CD25+ T cells and IL-10+FoxP3+ Tregs in mice. Finally, microbiota transplants from MS patients into germ-free mice resulted in more severe symptoms of experimental autoimmune encephalomyelitis and reduced proportions of IL-10+ Tregs compared with mice "humanized" with microbiota from healthy controls. This study identifies specific human gut bacteria that regulate adaptive autoimmune responses, suggesting therapeutic targeting of the microbiota as a treatment for MS.

ATP-induced reversed thermal sensitivity of O2 binding in both major haemoglobin polymorphs of the non-endothermic Atlantic cod, Gadus morhua.

Atlantic cod is a species that is affected by climate change, with some populations being exposed to higher temperatures than others. The two polymorphs of its major haemoglobin type (HbI) show an inverse change in frequency along a latitudinal temperature cline in the North East Atlantic, which has been associated with differences in population performance and behavioural traits. An earlier study at the northern distribution limit of the species reported differential temperature sensitivities of red blood cell oxygen (O2) affinity between the northern cold-water HbI-2 polymorph and its southern, warm-water HbI-1 counter-part, which has since widely been held as adaptive for the species across its distributional range. The present study critically re-examined this hypothesis by comparing the thermal sensitivity of O2 binding in both purified HbI polymorphs from the southern, high-temperature distribution limit of the species under controlled conditions of allosteric modifiers of Hb function. Contrary to the prevailing view, the O2 affinity of the major HbI polymorphs did not differ from each other under any of the tested conditions. Depending on pH and ATP concentration, the temperature-sensitive and temperature-insensitive Hb-O2 affinity phenotypes - previously exclusively ascribed to HbI-1 and HbI-2, respectively - could be induced in both HbI polymorphs. These results are the first to establish a molecular mechanism behind a reversed temperature dependence of red blood cell O2 affinity in a non-endotherm fish and lay the basis for future studies on alternative mechanisms behind the differences in distribution, performance and behavioural traits associated with the different HbI polymorphs of Atlantic cod.

A randomised control crossover trial of a theory based intervention to improve sun-safe and healthy behaviours in construction workers: study protocol.

BACKGROUND: Exposure to sunlight can have both positive and negative health impacts. Excessive exposure to ultra-violet (UV) radiation from the sun can cause skin cancer, however insufficient exposure to sunlight has a detrimental effect on production of Vitamin D. In the construction industry there are onsite proactive behaviours for safety, but sun-safety remains a low priority. There is limited research on understanding the barriers to adopting sun-safe behaviours and the association this may have with Vitamin D production. This paper reports a protocol for an intervention study, using text messaging in combination with a supportive smartphone App. The intervention aims to both reduce UV exposure during months with higher UV levels and promote appropriate dietary changes to boost Vitamin D levels during months with low UV levels. METHOD/DESIGN: Approximately 60 construction workers will be recruited across the United Kingdom. A randomised control crossover trial (RCCT) will be used to test the intervention, with randomisation at site level - i.e. participants will receive both the control (no text messages or supportive App support) and intervention (daily text messages and supportive App). Using the Theory of Planned Behaviour (TPB) the intervention focuses on supporting sun-safety and healthy dietary decisions in relation to Vitamin D intake. The intervention emphasises cultivating the perception of normative support in the workplace, increasing awareness of control and self-efficacy in taking sun-protective behaviours, making healthier eating choices to boost Vitamin D, and tackling stigmas attached to image and group norms. Each study epoch will last 21 days with intervention text messages delivered on workdays only. The supportive App will provide supplementary information about sun protective behaviours and healthy dietary choices. The primary outcome measure is 25-hydroxy-Vitamin D [25(OH)D] level (obtained using blood spot sampling), which will be taken pre and post control and intervention periods. Secondary outcome measures are two-fold, (1) using the TPB to detect changes in behaviour, and (2) quantifying UV exposure during the UK peak radiation season (April-September) using body-mounted UV sensors. DISCUSSION: This study will provide important information about the effectiveness of a technology-based intervention to promote sun-safety and healthy behaviours in outdoor construction workers. TRIAL REGISTRATION: ISRCTN15888934 retrospectively registered 15.01.2018.

Transcriptomic and metabolic responses of Calotropis procera to salt and drought stress.

BACKGROUND: Calotropis procera is a wild plant species in the family Apocynaceae that is able to grow in harsh, arid and heat stressed conditions. Understanding how this highly adapted plant persists in harsh environments should inform future efforts to improve the hardiness of crop and forage plant species. To study the plant response to droµght and osmotic stress, we treated plants with polyethylene glycol and NaCl and carried out transcriptomic and metabolomics measurements across a time-course of five days. RESULTS: We identified a highly dynamic transcriptional response across the time-course including dramatic changes in inositol signaling, stress response genes and cytokinins. The resulting metabolome changes also involved sharp increases of myo-inositol, a key signaling molecule and elevated amino acid metabolites at later times. CONCLUSIONS: The data generated here provide a first glimpse at the expressed genome of C. procera, a plant that is exceptionally well adapted to arid environments. We demonstrate, through transcriptome and metabolome analysis that myo-inositol signaling is strongly induced in response to drought and salt stress and that there is elevation of amino acid concentrations after prolonged osmotic stress. This work should lay the foundations of future studies in adaptation to arid environments.

Polymorphisms in HLA Class II Genes Are Associated With Susceptibility to Staphylococcus aureus Infection in a White Population.

BACKGROUND: Staphylococcus aureus can cause life-threatening infections. Human susceptibility to S. aureus infection may be influenced by host genetic variation. METHODS: A genome-wide association study (GWAS) in a large health plan-based cohort included biologic specimens from 4701 culture-confirmed S. aureus cases and 45 344 matched controls; 584 535 single-nucleotide polymorphisms (SNPs) were genotyped on an array specific to individuals of European ancestry. Coverage was increased by imputation of >25 million common SNPs, using the 1000 Genomes Reference panel. In addition, human leukocyte antigen (HLA) serotypes were also imputed. RESULTS: Logistic regression analysis, performed under the assumption of an additive genetic model, revealed several imputed SNPs (eg, rs115231074: odds ratio [OR], 1.22 [P = 1.3 × 10(-10)]; rs35079132: OR, 1.24 [P = 3.8 × 10(-8)]) achieving genome-wide significance on chromosome 6 in the HLA class II region. One adjacent genotyped SNP was nearly genome-wide significant (rs4321864: OR, 1.13; P = 8.8 × 10(-8)). These polymorphisms are located near the genes encoding HLA-DRA and HLA-DRB1. Results of further logistic regression analysis, in which the most significant GWAS SNPs were conditioned on HLA-DRB1*04 serotype, showed additional support for the strength of association between HLA class II genetic variants and S. aureus infection. CONCLUSIONS: Our study results are the first reported evidence of human genetic susceptibility to S. aureus infection.

A genome-wide association study of variants associated with acquisition of Staphylococcus aureus bacteremia in a healthcare setting.

BACKGROUND: Humans vary in their susceptibility to acquiring Staphylococcus aureus infection, and research suggests that there is a genetic basis for this variability. Several recent genome-wide association studies (GWAS) have identified variants that may affect susceptibility to infectious diseases, demonstrating the potential value of GWAS in this arena. METHODS: We conducted a GWAS to identify common variants associated with acquisition of S. aureus bacteremia (SAB) resulting from healthcare contact. We performed a logistic regression analysis to compare patients with healthcare contact who developed SAB (361 cases) to patients with healthcare contact in the same hospital who did not develop SAB (699 controls), testing 542,410 SNPs and adjusting for age (by decade), sex, and 6 significant principal components from our EIGENSTRAT analysis. Additionally, we evaluated the joint effect of the host and pathogen genomes in association with severity of SAB infection via logistic regression, including an interaction of host SNP with bacterial genotype, and adjusting for age (by decade), sex, the 6 significant principal components, and dialysis status. Bonferroni corrections were applied in both analyses to control for multiple comparisons. RESULTS: Ours is the first study that has attempted to evaluate the entire human genome for variants potentially involved in the acquisition or severity of SAB. Although this study identified no common variant of large effect size to have genome-wide significance for association with either the risk of acquiring SAB or severity of SAB, the variant (rs2043436) most significantly associated with severity of infection is located in a biologically plausible candidate gene (CDON, a member of the immunoglobulin family) and may warrant further study. CONCLUSIONS: The genetic architecture underlying SAB is likely to be complex. Future investigations using larger samples, narrowed phenotypes, and advances in both genotyping and analytical methodologies will be important tools for identifying causative variants for this common and serious cause of healthcare-associated infection.

Developing rainbow trout (Oncorhynchus mykiss) lose branchial plasma accessible carbonic anhydrase expression with hatch and the transition to pH-sensitive, adult hemoglobin polymorphs.

Salmonids possess a unique respiratory system comprised of three major components: highly pH-sensitive hemoglobins, red blood cell (RBC) intracellular pH (pHi) protection, and a heterogeneous distribution of plasma accessible carbonic anhydrase (paCA), specifically with absence of paCA at the gills. These characteristics are thought to have evolved to enhance oxygen unloading to the tissues while protecting uptake at the gills. Our knowledge of this system is detailed in adults, but little is known about it through development. Developing rainbow trout (Oncorhynchus mykiss) express embryonic RBCs containing hemoglobins that are relatively insensitive to pH; however, availability of gill paCA and RBC pHi protection is unknown. We show that pre-hatch rainbow trout express gill paCA, which is lost in correlation with the emergence of highly pH-sensitive adult hemoglobins and RBC pHi protection. Rainbow trout therefore exhibit a switch in respiratory strategy with hatch. We conclude that gill paCA likely represents an embryonic trait in rainbow trout and is constrained in adults due to their highly pH-sensitive hemoglobins.

An investigation of gill and blood carbonic anhydrase characteristics in three basal actinopterygian species: alligator gar (Atractosteus spatula), white sturgeon (Acipenser transmontanus) and Senegal bichir (Polypterus senegalus).

Many teleosts possess a unique set of respiratory characteristics allowing enhanced oxygen unloading to the tissues during stress. This system comprises three major components: highly pH sensitive haemoglobins (large Bohr and Root effects), rapid red blood cell (RBC) intracellular pH (pHi) protection, and a heterogeneous distribution of membrane-bound plasma-accessible carbonic anhydrase (paCA; absence in the gills). The first two components have received considerable research effort; however, the evolutionary loss of branchial paCA has received little attention. In the current study, we investigated the availability of branchial membrane-bound CA, along with several other CA-related characteristics in species belonging to three basal actinopterygian groups: the Lepisosteiformes, Acipenseriformes and Polypteriformes to assess the earlier hypothesis that Root effect haemoglobins constrain branchial paCA availability. We present the first evidence suggesting branchial membrane-bound CA presence in a basal actinopterygian species: the Senegal bichir (Polypterus senegalus) and show that like the teleosts, white sturgeon (Acipenser transmontanus) and alligator gar (Atractosteus spatula) do not possess branchial membrane-bound CA. We discuss the varying respiratory strategies for these species and propose that branchial paCA may have been lost much earlier than previously thought, likely in relation to the changes in haemoglobin buffer capacity associated with the increasing magnitude of the Bohr effect. The findings described here represent an important advancement in our understanding of the evolution of the unique system of enhanced oxygen unloading thought to be present in most teleosts, a group that encompasses half of all vertebrates.

Improving the mental health of farmers: what types of remote support are acceptable, feasible, and improve outcomes? A feasibility RCT.

BACKGROUND: The farming community have high rates of poor mental health, and are relatively 'hard to reach' with mental health services. The aim of this study was therefore to undertake a feasibility RCT, based on two mental health interventions. These were (1) CBT based 'Living Life to the Full for Farming Communities' (LLTTF-F; www.llttf.com ), and (2) a holistic social and emotional support service delivered by the Royal Scottish Agricultural Benevolent Institution (RSABI). The feasibility was supplemented by process evaluation. METHODS: This feasibility study aimed to recruit 40 individuals from the farming community who were experiencing a common health problem defined as a score of > = 8 on PHQ-9. A snowball approach was used to recruit interested individuals who had an association with farming. An initial telephone call screened for eligibility and obtained consent to randomisation to the two specified interventions, or to a thirdly group receiving a combination of both LLTTF-F and 'Social and emotional support'. Participants were permitted to override the randomised option if they expressed a strong preference before the interventions began. RESULTS: Thirty-two participants provided baseline and three-month data. All three interventions showed positive improvements on PHQ-9 scores as follows: the 'combined intervention' mean baseline score was 18.1 compared to 12.0 at 3-month follow-up (mean change 6.1). 'Social and emotional support' mean baseline score was 11.3 compared to 6.7 at 3-month follow-up (mean change 4.6). 'LLTTF-F CBT-based intervention only' mean baseline score was 11.8 compared to 4.5 at 3-month follow-up (mean change 7.3). The retention rate was 81% at three months. In a sub-group of the LLTTF-F CBT-based intervention online materials were supplemented by telephone guided support. This approach received very positive feedback. CONCLUSIONS: Recruitment from the farming community required intense effort, and good engagement can then be retained for at least three months. There is evidence that the interventions used were feasible, and tentative evidence that they had a demonstrable effect on mental wellbeing, with the LLTTFF providing the largest effect on PHQ-9 scores. Trial Registration Number ISRCTN27173711, submitted 25/08/2023, confirmed 22/092023.

Leveraging electronic health records and knowledge networks for Alzheimer's disease prediction and sex-specific biological insights.

Identification of Alzheimer's disease (AD) onset risk can facilitate interventions before irreversible disease progression. We demonstrate that electronic health records from the University of California, San Francisco, followed by knowledge networks (for example, SPOKE) allow for (1) prediction of AD onset and (2) prioritization of biological hypotheses, and (3) contextualization of sex dimorphism. We trained random forest models and predicted AD onset on a cohort of 749 individuals with AD and 250,545 controls with a mean area under the receiver operating characteristic of 0.72 (7 years prior) to 0.81 (1 day prior). We further harnessed matched cohort models to identify conditions with predictive power before AD onset. Knowledge networks highlight shared genes between multiple top predictors and AD (for example, APOE, ACTB, IL6 and INS). Genetic colocalization analysis supports AD association with hyperlipidemia at the APOE locus, as well as a stronger female AD association with osteoporosis at a locus near MS4A6A. We therefore show how clinical data can be utilized for early AD prediction and identification of personalized biological hypotheses.

Cosmic kidney disease: an integrated pan-omic, physiological and morphological study into spaceflight-induced renal dysfunction.

Missions into Deep Space are planned this decade. Yet the health consequences of exposure to microgravity and galactic cosmic radiation (GCR) over years-long missions on indispensable visceral organs such as the kidney are largely unexplored. We performed biomolecular (epigenomic, transcriptomic, proteomic, epiproteomic, metabolomic, metagenomic), clinical chemistry (electrolytes, endocrinology, biochemistry) and morphometry (histology, 3D imaging, miRNA-ISH, tissue weights) analyses using samples and datasets available from 11 spaceflight-exposed mouse and 5 human, 1 simulated microgravity rat and 4 simulated GCR-exposed mouse missions. We found that spaceflight induces: 1) renal transporter dephosphorylation which may indicate astronauts' increased risk of nephrolithiasis is in part a primary renal phenomenon rather than solely a secondary consequence of bone loss; 2) remodelling of the nephron that results in expansion of distal convoluted tubule size but loss of overall tubule density; 3) renal damage and dysfunction when exposed to a Mars roundtrip dose-equivalent of simulated GCR.

Nature-based social prescribing programmes: opportunities, challenges, and facilitators for implementation.

BACKGROUND: Evidence on the health benefits of spending time in nature has highlighted the importance of provision of blue and green spaces where people live. The potential for health benefits offered by nature exposure, however, extends beyond health promotion to health treatment. Social prescribing links people with health or social care needs to community-based, non-clinical health and social care interventions to improve health and wellbeing. Nature-based social prescribing (NBSP) is a variant that uses the health-promoting benefits of activities carried out in natural environments, such as gardening and walking. Much current NBSP practice has been developed in the UK, and there is increasing global interest in its implementation. This requires interventions to be adapted for different contexts, considering the needs of populations and the structure of healthcare systems. METHODS: This paper presents results from an expert group participatory workshop involving 29 practitioners, researchers, and policymakers from the UK and Germany's health and environmental sectors. Using the UK and Germany, two countries with different healthcare systems and in different developmental stages of NBSP practice, as case studies, we analysed opportunities, challenges, and facilitators for the development and implementation of NBSP. RESULTS: We identified five overarching themes for developing, implementing, and evaluating NBSP: Capacity Building; Accessibility and Acceptability; Networks and Collaborations; Standardised Implementation and Evaluation; and Sustainability. We also discuss key strengths, weaknesses, opportunities, and threats for each overarching theme to understand how they could be developed to support NBSP implementation. CONCLUSIONS: NBSP could offer significant public health benefits using available blue and green spaces. We offer guidance on how NBSP implementation, from wider policy support to the design and evaluation of individual programmes, could be adapted to different contexts. This research could help inform the development and evaluation of NBSP programmes to support planetary health from local and global scales.

Time-aware Embeddings of Clinical Data using a Knowledge Graph.

Meaningful representations of clinical data using embedding vectors is a pivotal step to invoke any machine learning (ML) algorithm for data inference. In this article, we propose a time-aware embedding approach of electronic health records onto a biomedical knowledge graph for creating machine readable patient representations. This approach not only captures the temporal dynamics of patient clinical trajectories, but also enriches it with additional biological information from the knowledge graph. To gauge the predictivity of this approach, we propose an ML pipeline called TANDEM (Temporal and Non-temporal Dynamics Embedded Model) and apply it on the early detection of Parkinson's disease. TANDEM results in a classification AUC score of 0.85 on unseen test dataset. These predictions are further explained by providing a biological insight using the knowledge graph. Taken together, we show that temporal embeddings of clinical data could be a meaningful predictive representation for downstream ML pipelines in clinical decision-making.

An atlas of plasma-accessible carbonic anhydrase availability in the model teleost, the rainbow trout.

The unique teleost oxygenation system that permits enhanced oxygen unloading during stress comprises three main characteristics: pH-sensitive haemoglobin, red blood cell (RBC) intracellular pH (pHi) protection, and a heterogeneous distribution of plasma-accessible carbonic anhydrase (paCA). A heterogeneous distribution of paCA is essential; its presence permits enhanced oxygen unloading during stress, while its absence at the gills maintains conditions for oxygen uptake by pH-sensitive haemoglobins. We hypothesised that paCA would be absent in all four gill arches, as has been previously indicated for arch two, and that paCA would be present in all other tissues. Through a suite of biochemical and molecular methods, we confirmed the absence of paCA from all four arches. We also found evidence for paCA in nine other tissues and a lack of paCA availability in the stomach. Expression was highly variable between tissues and suggests these differences may be associated with their respective metabolic activities. Additionally, we analysed the specific CA-IV isoform expressed within each tissue and showed almost complete separation of expression between tissues; CA-IVa was detected in the heart, brain, anterior intestine, and liver, whereas CA-IVb was detected in all intestine sections, pyloric caeca, kidney, and white muscle. This adds to a growing collection of work suggesting CA-IVa and b play divergent roles in gas exchange and ion/acid-base balance, respectively. The current study represents the first comprehensive atlas of paCA availability within the circulatory system of the model teleost, rainbow trout, and fills important gaps in our knowledge of this unique oxygenation system.

Ammonia transport is independent of PNH3 gradients across the gastrointestinal epithelia of the rainbow trout: A role for the stomach.

Although the gastrointestinal tract (GIT) is an important site for nitrogen metabolism in teleosts, the mechanisms of ammonia absorption and transport remain to be elucidated. Both protein catabolism in the lumen and the metabolism of the GIT tissues produce ammonia which, in part, enters the portal blood through the anterior region of the GIT. The present study examined the possible roles of different GIT sections of rainbow trout (Oncorhynchus mykiss) in transporting ammonia in its unionized gas form-NH3 -by changing the PNH3 gradient across GIT epithelia using in vitro gut sac preparations. We also surveyed messenger RNA expression patterns of three of the identified Rh proteins (Rhbg, Rhcg1, and  Rhcg2) as potential NH3 transporters and NKCC as a potential ammonium ion (NH4 + ) transporter along the GIT of rainbow trout. We found that ammonia absorption is not dependent on the PNH3 gradient despite expression of Rhbg and Rhcg2 in the intestinal tissues, and Rhcg2 in the stomach. We detected no expression of Rhbg in the stomach and no expression of Rhcg1 in any GIT tissues. There was also a lack of correlation between ammonia transport and [NH4 + ] gradient despite NKCC expression in all GIT tissues. Regardless of PNH3 gradients, the stomach showed the greatest absorption and net tissue consumption of ammonia. Overall, our findings suggest nitrogen metabolism zonation of GIT, with stomach serving as an important site for the absorption, handling and transport of ammonia that is independent of the PNH3 gradient.