Pathway Mapping Research Articles

BRENDA, the ELIXIR core data resource in 2021: new developments and updates.

The BRENDA enzyme database (https://www.brenda-enzymes.org), established in 1987, has evolved into the main collection of functional enzyme and metabolism data. In 2018, BRENDA was selected as an ELIXIR Core Data Resource. BRENDA provides reliable data, continuous curation and updates of classified enzymes, and the integration of newly discovered enzymes. The main part contains >5 million data for ∼90 000 enzymes from ∼13 000 organisms, manually extracted from ∼157 000 primary literature references, combined with information of text and data mining, data integration, and prediction algorithms. Supplements comprise disease-related data, protein sequences, 3D structures, genome annotations, ligand information, taxonomic, bibliographic, and kinetic data. BRENDA offers an easy access to enzyme information from quick to advanced searches, text- and structured-based queries for enzyme-ligand interactions, word maps, and visualization of enzyme data. The BRENDA Pathway Maps are completely revised and updated for an enhanced interactive and intuitive usability. The new design of the Enzyme Summary Page provides an improved access to each individual enzyme. A new protein structure 3D viewer was integrated. The prediction of the intracellular localization of eukaryotic enzymes has been implemented. The new EnzymeDetector combines BRENDA enzyme annotations with protein and genome databases for the detection of eukaryotic and prokaryotic enzymes.

An assembly of galanin-galanin receptor signaling network.

The galanin receptor family of proteins is present throughout the central nervous system and endocrine system. It comprises of three subtypes-GalR1, GalR2, and GalR3; all of which are G-protein-coupled receptors. Galanin predominantly acts as an inhibitory, hyper-polarizing neuromodulator, which has several physiological as well as pathological functions. Galanin has a role in mediating food intake, memory, sexual behavior, nociception and is also associated with diseases such as Alzheimer's disease, epilepsy, diabetes mellitus, and chronic pain. However, the understanding of signaling mechanisms of the galanin family of neuropeptides is limited and an organized pathway map is not yet available. Therefore, a detailed literature mining of the publicly available articles pertaining to the galanin receptor was followed by manual curation of the reactions and their integration into a map. This resulted in the cataloging of molecular reactions involving 64 molecules into five categories such as molecular association, activation/inhibition, catalysis, transport, and gene regulation. For enabling easy access of biomedical researchers, the galanin-galanin receptor signaling pathway data was uploaded to WikiPathways ( https://www.wikipathways.org/index.php/Pathway:WP4970 ), a freely available database of biological pathways.

A complete map of the Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) signaling pathway.

Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) is a serine/threonine-protein kinase belonging to the Ca2+/calmodulin-dependent protein kinase subfamily. CAMKK2 has an autocatalytic site, which gets exposed when Ca2+/calmodulin (CAM) binds to it. This results in autophosphorylation and complete activation of CAMKK2. The three major known downstream targets of CAMKK2 are 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPKα), calcium/calmodulin-dependent protein kinase 1 (CAMK1) and calcium/calmodulin-dependent protein kinase 4 (CAMK4). Activation of these targets by CAMKK2 is important for the maintenance of different cellular and physiological processes within the cell. CAMKK2 is found to be important in neuronal development, bone remodeling, adipogenesis, and systemic glucose homeostasis, osteoclastgensis and postnatal myogensis. CAMKK2 is reported to be involved in pathologies like Duchenne muscular dystrophy, inflammation, osteoporosis and bone remodeling and is also reported to be overexpressed in prostate cancer, hepatic cancer, ovarian and gastric cancer. CAMKK2 is involved in increased cell proliferation and migration through CAMKK2/AMPK pathway in prostate cancer and activation of AKT in ovarian cancer. Although CAMKK2 is a molecule of great importance, a public resource of the CAMKK2 signaling pathway is currently lacking. Therefore, we carried out detailed data mining and documentation of the signaling events associated with CAMKK2 from published literature and developed an integrated reaction map of CAMKK2 signaling. This resulted in the cataloging of 285 reactions belonging to the CAMKK2 signaling pathway, which includes 33 protein-protein interactions, 74 post-translational modifications, 7 protein translocation events, and 22 activation/inhibition events. Besides, 124 gene regulation events and 25 activator/inhibitors involved in CAMKK2 activation were also cataloged. The CAMKK2 signaling pathway map data is made freely accessible through WikiPathway database ( https://www.wikipathways.org/index.php/Pathway:WP4874 ). We expect that data on a signaling map of CAMKK2 will provide the scientific community with an improved platform to facilitate further molecular as well as biomedical investigations on CAMKK2 and its utility in the development of biomarkers and therapeutic targets.

Allosteric Response of DNA Recognition Helices of Catabolite Activator Protein to cAMP and DNA Binding.

The homodimeric catabolite activator protein (CAP) regulates the transcription of several bacterial genes based on the cellular concentration of cyclic adenosine monophosphate (cAMP). The binding of cAMP to CAP triggers allosteric communication between the cAMP binding domains (CBD) and DNA binding domains (DBD) of CAP, which entails repositioning of DNA recognition helices (F-helices) in the DBD to dock favorably to the target DNA. Despite considerable progress, much remains to be understood about the mechanistic details of DNA recognition by CAP and about the map of allosteric pathways involved in CAP-mediated gene transcription. The present study uses molecular dynamics and umbrella sampling simulations to investigate the mechanism of cAMP- and DNA-induced changes in the conformation and energetics of F-helices observed during the allosteric regulation of CAP by cAMP and the subsequent binding to the DNA promoter region. Using novel collective variables, the free energy profiles associated with the orientation and dynamics of F-helices in the unliganded, cAMP-bound, and cAMP-DNA-bound states of CAP are calculated and compared. The binding-induced alterations in the resultant free energy profiles reveal important flexibility constraints imposed on DBD upon cAMP and DNA binding. A comprehensive analysis of residue-wise interaction maps reveals potential allosteric pathways between CBD and DBD that facilitate the allosteric transduction of regulatory signals in CAP. The revelation that the predicted allosteric pathways crisscross the intersubunit interface offers important clues on the microscopic origin of the intersubunit cooperativity and dimer stability of CAP.

Synthesis of a sustainable integrated biorefinery to produce value-added chemicals from palm-based biomass via mathematical optimisation

The past decade has witnessed an increase in biomass usage for combined heat and power generation. Recent advances have been focused on utilising biomass as a raw material to produce value-added bulk chemicals in integrated biorefineries. There is also a lot of opportunities for producing fine chemicals and pharmaceuticals from intermediates derived from palm-based biomass. This work focus on the incorporation of the three pillars of sustainability while converting biomass into all promising products. A mathematical optimisation model has been developed in this work to identify the optimal products that can be produced from palm-based empty fruit bunches (EFB). These products have been evaluated in terms of economic, environmental and social aspects. A comprehensive superstructure that maps all possible products that can be produced from biomass has been developed in the first stage of synthesis. Chemical reaction pathway map (CRPM) was used to illustrate the potential pathways from raw materials to intermediates and then to the final products. An economic and sustainability model was constructed to determine the most profitable configuration and the trade-offs for implementing other sustainability elements into the integrated biorefinery. Multi-objective fuzzy optimisation approach was used to identify the optimal trade-off between gross profit and sustainability index (SI). It has been observed that the sustainability elements can be maintained with minimal compromise on economic performance while synthesising several value-added products. The robustness of the optimal solution was tested by performing sensitivity analysis on production cost, capital cost, and conversion data on processes involving less mature technologies.

Tractography-Based Analysis of Morphological and Anatomical Characteristics of the Uncinate Fasciculus in Human Brains.

(1) Background: The uncinate fasciculus (UF) is a white matter bundle connecting the prefrontal cortex and temporal lobe. The functional role of the uncinate fasciculus is still uncertain. The role of the UF is attributed to the emotional empathy network. The present study aimed to more accurately the describe anatomical variability of the UF by focusing on the volume of fibers and testing for correlations with sex and age. (2) Material and Methods: Magnetic resonance imaging of adult patients with diffusion tensor imaging (DTI) was performed on 34 patients. The total number of fibers, volume of UF, and number of tracts were processed using DSI studio software. The DSI studio allows for mapping of different nerve pathways and visualizing of the obtained results using spatial graphics. (3) Results: The total number of UF tracts was significantly higher in the right hemisphere compared to the left hemisphere (right M ± SD = 52 ± 24; left: 39 ± 25, p < 0.05). A hook-shaped UF was the most common variant (91.7%). The UF volumes were larger in men (1410 ± 150.7 mm3) as compared to women (1325 ± 133.2 mm3) (p < 0.05). The mean fractional anisotropy (FA) values of the UF were significantly larger on the left side 0.597, while the right UF had an average of 0.346 (p < 0.05). Patients older than 50 years old had a significantly higher value of mean diffusivity (MD) (p = 0.034). In 73.5% of patients, a greater number of fibers terminated in the inferior part of the inferior frontal gyrus. (4) Conclusions: The morphological characteristics of the UF, unlike the shape, are associated with sex and are characterized by hemispheric dominance. These findings confirm the results of the previous studies. Future research should examine the potential correlation among the UF volume, number of fibers, and total brain volume in both sexes and patient psychological state.

CO2 Utilization Technologies in Europe: A Short Review

Carbon dioxide utilization is increasingly attracting interest. CO2 utilization involves a multitude of processes and chemical reactions. In this context, the goal of this review is to analyze the techno‐economic feasibility, sustainability, and social opportunities of CO2 utilization, as a possible contribution to CO2 mitigation in Europe. Industries and the most recent European projects related to carbon capture and utilization are also discussed, illustrating Europe's performance dynamics in science, research, and innovation in this field. The latest developments in CO2 utilization are thus reviewed, including chemicals, mineral carbonation, and biological uses. This study examines a few CO2‐based pathways at high level of maturity covering a wide range of applications, and discusses their current technical feasibility, economic viability, sustainability, and social aspects. They are then evaluated using several indicators to provide a figure of merit, where qualitative results are intended. The mapping and ranking of CO2 utilization pathways may provide a valuable means in prioritizing support and funding to facilitate the development of large‐scale CO2 utilization projects in Europe. Finally, key challenges and opportunities are discussed. The review shows that CO2 utilization may not be a complete solution for Europe, but will support climate change objectives, circular economy, and resource and energy security.

Genetic Manipulation of Vibrio fischeri.

Vibrio fischeri is a nonpathogenic organism related to pathogenic Vibrio species. The bacterium has been used as a model organism to study symbiosis in the context of its association with its host, the Hawaiian bobtail squid Euprymna scolopes. The genetic tractability of this bacterium has facilitated the mapping of pathways that mediate interactions between these organisms. The protocols included here describe methods for genetic manipulation of V. fischeri. Following these protocols, the researcher will be able to introduce linear DNA via transformation to make chromosomal mutations, to introduce plasmid DNA via conjugation and subsequently eliminate unstable plasmids, to eliminate antibiotic resistance cassettes from the chromosome, and to randomly or specifically mutagenize V. fischeri with transposons. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Transformation of V. fischeri with linear DNA Basic Protocol 2: Plasmid transfer into V. fischeri via conjugation Support Protocol 1: Removing FRT-flanked antibiotic resistance cassettes from the V. fischeri genome Support Protocol 2: Eliminating unstable plasmids from V. fischeri Alternate Protocol 1: Introduction of exogenous DNA using a suicide plasmid Alternate Protocol 2: Site-specific transposon insertion using a suicide plasmid Alternate Protocol 3: Random transposon mutagenesis using a suicide plasmid.

Anti-Respiratory Syncytial Virus Mechanism of Houttuynia cordata Thunb Exploration based on Network Pharmacology.

Respiratory Syncytial Virus (RSV) is the leading cause of infant lower respiratory tract infections with no mature vaccines and medicines available. Pneumonia caused by RSV kills many infants every year. There are unique advantages of Traditional Chinese Medicine (TCM) to fight against the virus. Houttuynia cordata Thunb is a commonly used antivirus medicine in TCM, but its mechanism has not been investigated. The current study explores the anti-RSV mechanism of H. cordata Thunb by means of network pharmacology and bioinformatics. The candidate compounds of H. cordata Thunb and the potential targets were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), PubMed, CNKI, PubChem Database, and Swiss Target Prediction database. Then the potential targets and pathways of H. cordata Thunb against RSV were screened by GeneCards, GenCLiP 3, and NCBI Database. We developed a Protein-Protein Interactions (PPI) Network and Compound-Target-Pathway Network through the Cytoscape software. Furthermore, core targets were preliminary verified by Gene Expression Omnibus (GEO) database by bioinformatics methods. At last, the first six pathways were screened out to draw a map of the main target signal pathways. A total of 12 potentially active compounds and 47 potential interaction targets were screened. PPI Network and data from GEO showed that IL-6, STAT3, TNF, AKT1, PTGS2, SRC, and MAPK3 may play a core role in the antivirus process. KEGG enrichment pathway analysis predicted that H. cordata Thunb exerted its anti-RSV effect by regulating TNF, Rap1, HIF-1, PI3KAkt, MAPK, and VEGF signaling pathways. This study preliminarily predicted the main active compounds, targets and related pathways of H. cordata Thunb in the treatment of RSV-induced diseases, which laid a good foundation for further revealing its mechanism.

Functional Mapping before and after Low-Grade Glioma Surgery: A New Way to Decipher Various Spatiotemporal Patterns of Individual Neuroplastic Potential in Brain Tumor Patients.

Simple SummaryBeyond intraoperative electrostimulation mapping in awake patients (the gold-standard for brain tumor surgery), non-invasive FNI/TMS can be repeated before and after resection(s). These techniques enable longitudinal investigation of neural reorganization, especially in low-grade gliomas, which can generate neuroplasticity in patients with usually no or slight neurological deficits, despite neoplasm within “eloquent” structures. Here, data gained from perioperative FNI/TMS mapping methods are reviewed, in order to decipher mechanisms underpinning functional cerebral reshaping induced by the tumor and its possible relapse, (re)operation(s), and postoperative rehabilitation. Heterogeneous spatiotemporal patterns of rearrangement across patients and in a single patient over time were evidenced, with structural changes as well as modifications of intra-hemispheric and inter-hemispheric functional connectivity. Such various fingerprints of neural reconfiguration were correlated to different levels of cognitive compensation. Serial multimodal studies exploring neuroplasticity might lead to new management strategies based upon multistage therapeutic approaches adapted to the individual profile of functional reallocation.Intraoperative direct electrostimulation mapping (DEM) is currently the gold-standard for glioma surgery, since functional-based resection allows an optimization of the onco-functional balance (increased resection with preserved quality of life). Besides intrasurgical awake mapping of conation, cognition, and behavior, preoperative mapping by means of functional neuroimaging (FNI) and transcranial magnetic stimulation (TMS) has increasingly been utilized for surgical selection and planning. However, because these techniques suffer from several limitations, particularly for direct functional mapping of subcortical white matter pathways, DEM remains crucial to map neural connectivity. On the other hand, non-invasive FNI and TMS can be repeated before and after surgical resection(s), enabling longitudinal investigation of brain reorganization, especially in slow-growing tumors like low-grade gliomas. Indeed, these neoplasms generate neuroplastic phenomena in patients with usually no or only slight neurological deficits at diagnosis, despite gliomas involving the so-called “eloquent” structures. Here, data gained from perioperative FNI/TMS mapping methods are reviewed, in order to decipher mechanisms underpinning functional cerebral reshaping induced by the tumor and its possible relapse, (re)operation(s), and postoperative rehabilitation. Heterogeneous spatiotemporal patterns of rearrangement across patients and in a single patient over time have been evidenced, with structural changes as well as modifications of intra-hemispheric (in the ipsi-lesional and/or contra-lesional hemisphere) and inter-hemispheric functional connectivity. Such various fingerprints of neural reconfiguration were correlated to different levels of cognitive compensation. Serial multimodal studies exploring neuroplasticity might lead to new management strategies based upon multistage therapeutic approaches adapted to the individual profile of functional reallocation.

Evaluating process-mining interoperability: stroke case analysis on Italian health real-world data

Abstract Background The Institute for Health Sciences in Aragon developed a process-mining based algorithm deployed using a container solution to describe the Stroke Care Pathway reproducible in different Health Systems. Our aim is to apply the proposed solution to administrative data of an Italian region to explore interoperability in the case of the stroke care; the study is developed in the context of the Joint Action on Health Information 'InfAct' funded by the European Commission. Methods The target population included 1538055 residents in Marche Region who received National Health System (NHS) assistance in 2017. The collected information was sex, date of birth and death, residence from NHS Beneficiaries database; admission and discharge date/time, hospital code, admission type, discharge status, up to 6 diagnoses from Hospital Discharge database; admission date/time, urgent care facility code, discharge status, diagnosis from Emergency Care database. Patients without hospital/urgent care events were excluded from NHS Beneficiaries database. Care pathway traces and map with frequency information, timing across the pathway and timeline plots with time information were the outputs obtained. Results Data included 17752 patients, 10390 hospital, and 18329 urgent care events. Results were represented graphically, easy to read and spread: 500 episodes of stroke were detected, 66% of patients was hospitalised after emergency room (ER) admissions, 19% directly hospitalised and 10% discharged after ER admission. The most frequent access and exit points of the pathway were ER admission and hospital discharge. Conclusions The application of the stroke case to Italian data demonstrates feasibility and usefulness of interoperability in analysing health care administrative data for public health purposes. A European health information system is crucial to build capacity between researchers across Europe and improve health data on Health Monitoring and Health System Performance Assessment. Key messages Sharing a process-mining methodology deployed using a container solution is a useful strategy to describe care pathways and ensures results’ reliability across European Health Systems. Developing and testing tools to encourage interoperability between researchers across Europe is essential for public health policymaker in Europe.

Defining the ATPome reveals cross-optimization of metabolic pathways

Disrupted energy metabolism drives cell dysfunction and disease, but approaches to increase or preserve ATP are lacking. To generate a comprehensive metabolic map of genes and pathways that regulate cellular ATP—the ATPome—we conducted a genome-wide CRISPR interference/activation screen integrated with an ATP biosensor. We show that ATP level is modulated by distinct mechanisms that promote energy production or inhibit consumption. In our system HK2 is the greatest ATP consumer, indicating energy failure may not be a general deficiency in producing ATP, but rather failure to recoup the ATP cost of glycolysis and diversion of glucose metabolites to the pentose phosphate pathway. We identify systems-level reciprocal inhibition between the HIF1 pathway and mitochondria; glycolysis-promoting enzymes inhibit respiration even when there is no glycolytic ATP production, and vice versa. Consequently, suppressing alternative metabolism modes paradoxically increases energy levels under substrate restriction. This work reveals mechanisms of metabolic control, and identifies therapeutic targets to correct energy failure.

Planning the scale up of brief psychological interventions using theory of change

BackgroundA large mental health treatment gap exists among conflict-affected populations, and Syrian refugees specifically. Promising brief psychological interventions for conflict-affected populations exist such as the World Health Organization’s Problem Management Plus (PM+) and the Early Adolescent Skills for Emotions (EASE) intervention, however, there is limited practical guidance for countries of how these interventions can be taken to scale. The aim of this study was to unpack pathways for scaling up PM+ and EASE for Syrian refugees.MethodsWe conducted three separate Theory of Change (ToC) workshops in Turkey, the Netherlands, and Lebanon in which PM+ and EASE are implemented for Syrian refugees. ToC is a participatory planning process involving key stakeholders, and aims to understand a process of change by mapping out intermediate and long-term outcomes on a causal pathway. 15–24 stakeholders were invited per country, and they participated in a one-day interactive ToC workshop on scaling up.ResultsA cross-country ToC map for scale up brief psychological interventions was developed which was based on three country-specific ToC maps. Two distinct causal pathways for scale up were identified (a policy and financing pathway, and a health services pathway) which are interdependent on each other. A list of key assumptions and interventions which may hamper or facilitate the scaling up process were established.ConclusionToC is a useful tool to help unpack the complexity of scaling up. Our approach highlights that scaling up brief psychological interventions for refugees builds on structural changes and reforms in policy and in health systems. Both horizontal and vertical scale up approaches are required to achieve sustainability. This paper provides the first theory-driven map of causal pathways to help support the scaling-up of evidence-based brief psychological interventions for refugees and populations in global mental health more broadly.

A pathway map of AXL receptor-mediated signaling network.

A pathway map of AXL receptor-mediated signaling network.

Open-window mapping of accessory pathways utilizing high-density mapping.

Accessory pathway (AP) mapping is currently based on point-by-point mapping and identifying if a local electrogram's origin is atrial, pathway, or ventricular, which is time-consuming and prone to insufficient mapping. We sought to determine the feasibility of automated and high-density mapping to define AP location using open-window mapping (OWM), which does not rely on defining the electrogram's origin but simply detects the sharpest local signal at each point. We enrolled 23 consecutive patients undergoing catheter ablation for atrioventricular reentrant tachycardia. High-density mapping was performed using OWM and ablation was performed. The successful site of ablation was determined by the loss of pathway function. OWM was 100% effective at identifying the successful site of ablation (average mapping time 7.3 ± 4.3min.) Permanent AP elimination was achieved using a mean radiofrequency energy time of 18.5 ± 24.5s/patient. Transiently successful ablations were 4.0 ± 1.8mm from permanently successful sites and had lower contact force (5.1 ± 2.5g vs. 11.7 ± 9.0g; P = 0.041). Unsuccessful sites had similar contact force to permanently successful sites (12.2 ± 9.2g vs. 11.7 ± 9.0g; P = 0.856) but were 6.4 ± 2.0mm away from successful sites. A novel technique of high-density, automated, and open-window mapping (OWM) effectively localizes APs without the need to differentiate the signal's site of origin. These findings suggest that OWM can be used to rapidly and successfully map and ablate APs. Both distances from the pathway and contact force were shown to be important for pathway ablation.

An Integrated Metabolomics Study of Glucosinolate Metabolism in Different Brassicaceae Genera.

Glucosinolates are a group of plant secondary metabolites that can be hydrolyzed into a variety of breakdown products such as isothiocyanates, thiocyanates, and nitriles. These breakdown products can facilitate plant defense and function as attractants to natural enemies of insect pests. As part of the diet, some of these compounds have shown cancer-preventing activities, and the levels of these metabolites in the edible parts of the plants are of interest. In this study, we systematically examined variations in glucosinolates, their precursors, and their breakdown products in 12 commonly consumed vegetables of the Brassicaceae family with gas chromatography—quadrupole time-of-flight mass spectrometer (GC-Q-TOF/MS), liquid chromatography–quadrupole time-of-flight mass spectrometer (LC-Q-TOF/MS), and liquid chromatography—triple quadrupole mass spectrometer (LC-QQQ/MS), using both untargeted and targeted approaches. The findings were integrated with data from literature to provide a comprehensive map of pathways for biosynthesis of glucosinolates and isothiocyanates. The levels of precursor glucosinolates are found to correlate well with their downstream breakdown products. Further, the types and abundances of glucosinolates among different genera are significantly different, and these data allow the classification of plants based on morphological taxonomy. Further validation on three genera, which are grown underground, in damp soil, and above ground, suggests that each genus has its specific biosynthetic pathways and that there are variations in some common glucosinolate biosynthesis pathways. Our methods and results provide a good starting point for further investigations into specific aspects of glucosinolate metabolism in the Brassica vegetables.

Complete Electroanatomic Imaging of the Diastolic Pathway Is Associated With Improved Freedom From Ventricular Tachycardia Recurrence

The development of multielectrode mapping catheters has expanded the spectrum of mappable ventricular tachycardias (VTs). Full diastolic pathway recording has been associated with a high rate of VT termination during radiofrequency ablation as well as noninducibility at study end. However, the role of diastolic pathway mapping on VT recurrence has yet to be clearly elucidated. We aimed to explore the role of complete diastolic pathway activation mapping on VT recurrence. Eighty-five consecutive patients who underwent VT ablation guided by high-density mapping were enrolled. During activation mapping, the presence of electrical activity in all segments of diastole defined the evidence of having had recorded the whole diastolic interval. Patients were categorized as having recorded the full diastolic pathway, partial diastolic pathway, or no diastolic pathway map performed. Recurrences of VT were defined as appropriate implantable cardioverter defibrillator therapies or on the basis of ECG-documented arrhythmia. Eighty-five patients were included. Complete recording of the diastolic pathway was achieved in 36/85 (42.4%) patients. Partial recording of the diastolic pathway of the clinical VT was achieved in 24/85 (28.2%) patients. No recording of the diastolic pathway of the clinical VT was feasible in 25/85 patients (29.4%). At a mean of 12.8 months, freedom from VT recurrence was 67% in the overall cohort. At a mean of 12.8 months, freedom from VT recurrence was 88%, 50%, and 55% in patients who had full diastolic activity recorded, partial diastolic activity recorded, or underwent substrate modification, respectively; the observed differences were statistically significant (P=0.02). Mapping of the entire diastolic pathway was associated with a higher freedom from VT recurrence as compared with partial diastolic pathway recording and substrate modification. The use of multielectrode mapping catheters in recording diastolic activity may help predict those VTs employing intramural circuits and further optimize ablation strategies.

MetaboMAPS: Pathway sharing and multi-omics data visualization in metabolic context.

Metabolic pathways are an important part of systems biology research since they illustrate complex interactions between metabolites, enzymes, and regulators. Pathway maps are drawn to elucidate metabolism or to set data in a metabolic context. We present MetaboMAPS, a web-based platform to visualize numerical data on individual metabolic pathway maps. Metabolic maps can be stored, distributed and downloaded in SVG-format. MetaboMAPS was designed for users without computational background and supports pathway sharing without strict conventions. In addition to existing applications that established standards for well-studied pathways, MetaboMAPS offers a niche for individual, customized pathways beyond common knowledge, supporting ongoing research by creating publication-ready visualizations of experimental data.

Integrated metabolomic and transcriptomic profiling reveals the tissue-specific flavonoid compositions and their biosynthesis pathways in Ziziphora bungeana

BackgroundZiziphora bungeana Juz. is a folk medicine from the Xinjiang Uygur Autonomous Region. The herb or the aerial parts of it have been used to medicinally treat cardiovascular diseases. Flavonoids are the main pharmacologically active ingredients in Z. bungeana. Identification of the tissue-specific distribution of flavonoids in Z. bungeana is crucial for effective and sustainable medicinal use of the plant. Furthermore, understanding of the biosynthesis pathways of these flavonoids in Z. bungeana is of great biological significance.MethodsThe flavonoids from different tissues of Z. bungeana were identified using liquid chromatography-tandem mass spectrometry (LC–MS/MS). The full-length transcriptome of Z. bungeana was determined using a strategy based on a combination of Illumina and PacBio sequencing techniques. The functions of differentially expressed unigenes were predicted using bioinformatics methods and further investigated by real-time quantitative PCR and phylogenetic relationship analysis.ResultsAmong the 12 major flavonoid components identified from Z. bungeana extracts, linarin was the most abundant component. Nine flavonoids were identified as characteristic components of specific tissues. Transcriptome profiling and bioinformatic analysis revealed that 18 genes were putatively involved in flavonoid biosynthesis. The gene expression and phylogenetic analysis results indicated that ZbPALs, Zb4CL3, ZbCHS1, and ZbCHI1 may be involved in the biosynthesis of the main flavonoid intermediate. ZbFNSII, ZbANS, and ZbFLS may be involved in the biosynthesis of flavones, anthocyanins, and flavonols, respectively. A map of the biosynthesis pathways of the 12 major flavonoids in Z. bungeana is proposed.ConclusionsThe chemical constituent analysis revealed the compositions of 9 characteristic flavonoids in different tissues of Z. bungeana. Linarin can be hydrolysed into acacetin to exert a pharmaceutical role. Apigenin-7-O-rutinoside is hypothesised to be the precursor of linarin in Z. bungeana. There was greater content of linarin in the aerial parts of the plant than in the whole herb, which provides a theoretical basis for using the aerial parts of Z. bungeana for medicine. These results provide a valuable reference for further research on the flavonoid biosynthesis pathways of Z. bungeana and will be significant for the effective utilisation and ecological protection of Z. bungeana.

Healthspan pathway maps in C. elegans and humans highlight transcription, proliferation/biosynthesis and lipids.

The molecular basis of aging and of aging-associated diseases is being unraveled at an increasing pace. An extended healthspan, and not merely an extension of lifespan, has become the aim of medical practice. Here, we define health based on the absence of diseases and dysfunctions. Based on an extensive review of the literature, in particular for humans and C. elegans, we compile a list of features of health and of the genes associated with them. These genes may or may not be associated with survival/lifespan. In turn, survival/lifespan genes that are not known to be directly associated with health are not considered. Clusters of these genes based on molecular interaction data give rise to maps of healthspan pathways for humans and for C. elegans. Overlaying healthspan-related gene expression data onto the healthspan pathway maps, we observe the downregulation of (pro-inflammatory) Notch signaling in humans and of proliferation in C. elegans. We identify transcription, proliferation/biosynthesis and lipids as a common theme on the annotation level, and proliferation-related kinases on the gene/protein level. Our literature-based data corpus, including visualization, should be seen as a pilot investigation of the molecular underpinnings of health in two different species. Web address: http://pathways.h2020awe.eu.