From the digital twins in healthcare to the Virtual Human Twin: a moon-shot project for digital health research

The idea of a systematic digital representation of the entire known human pathophysiology, which we could call the Virtual Human Twin, has been around for decades. To date, most research groups focused instead on developing highly specialised, highly focused patient-specific models able to predict specific quantities of clinical relevance. While it has facilitated harvesting the low-hanging fruits, this narrow focus is, in the long run, leaving some significant challenges that slow the adoption of digital twins in healthcare. This position paper lays the conceptual foundations for developing the Virtual Human Twin (VHT). The VHT is intended as a distributed and collaborative infrastructure, a collection of technologies and resources (data, models) that enable it, and a collection of Standard Operating Procedures (SOP) that regulate its use. The VHT infrastructure aims to facilitate academic researchers, public organisations, and the biomedical industry in developing and validating new digital twins in healthcare solutions with the possibility of integrating multiple resources if required by the specific context of use. The VHT infrastructure can also be used by healthcare professionals and patients for clinical decision support or personalised health forecasting. As the European Commission launched the EDITH coordination and support action to develop a roadmap for the development of the Virtual Human Twin, this position paper is intended as a starting point for the consensus process and a call to arms for all stakeholders

Selected aspects of the human gut microbiota

The gut microbiota represents a highly complex assembly of microbes, which interact with each other and with their host. These interactions have various implications in terms of health and disease, and this multi-author review issue will address a number of selected aspects pertaining to gut microbiota research.Peer reviewe

Revealing methyl-esterification patterns of pectins by enzymatic fingerprinting:Beyond the degree of blockiness

Citrus pectins were studied by enzymatic fingerprinting using a simultaneous enzyme treatment with endo-polygalacturonase (endo-PG) from Kluyveromyces fragilis and pectin lyase (PL) from Aspergillus niger to reveal the methyl-ester distribution patterns over the pectin backbone. Using HILIC-MS combined with HPAEC enabled the separation and identification of the diagnostic oligomers released. Structural information on the pectins was provided by using novel descriptive parameters such as degree of blockiness of methyl-esterified oligomers by PG (DBPGme) and degree of blockiness of methyl-esterified oligomers by PL (DBPLme). This approach enabled us to clearly differentiate citrus pectins with various methyl-esterification patterns. The simultaneous use of PG and PL showed additional information, which is not revealed in digests using PG or PL alone. This approach can be valuable to differentiate pectins having the same DM and to get specific structural information on pectins and therefore to be able to better predict their physical and biochemical functionalities

The impact of the level and distribution of methyl-esters of pectins on TLR2-1 dependent anti-inflammatory responses

Pectins have anti-inflammatory effects via Toll-like receptor (TLR) inhibition in a degree of methyl-esterification-(DM)-dependent manner. However, pectins also vary in distribution of methyl-esters over the galactumnic-acid (GalA) backbone (Degree of Blockiness - DB) and impact of this on anti-inflammatory capacity is unknown. Pectins mainly inhibit TLR2-1 but magnitude depends on both DM and DB. Low DM pectins (DM18/19) with both low (DB86) and high DB (DB94) strongly inhibit TLR2-1. However, pectins with intermediate DM (DM43/ DM49) and high DB (DB60), but not with low DB (DB33), inhibit TLR2-1 as strongly as low DM. High DM pectins (DM84/88) with DB71 and DB91 do not inhibit TLR2-1 strongly. Pectin-binding to TLR2 was confirmed by capture-ELISA. In human macrophages, low DM and intermediate DM pectins with high DB inhibited TLR2-1 induced IL-6 secretion. Both high number and blockwise distribution of non-esterified GalA in pectins are responsible for the anti-inflammatory effects via inhibition of TLR2-1

Adapting to the sea:Human habitation in the coastal area of the northern Netherlands before medieval dike building

Before medieval dike building, the coastal area of the northern Netherlands was a wide, regularly inundated salt-marsh area. Despite the dynamic natural conditions, the area was inhabited already in the Iron Age. The inhabitants adapted to this marine environment by living on artificial dwelling mounds, so-called terps. Terp habitation was a highly successful way of life for over 1500 years, and may be re-introduced as a useful strategy for present and future communities in low-lying coastal regions that are facing accelerated sea-level rise. This already has been recommended in several reports, but detailed knowledge of the technology of terp habitation is usually lacking. The aim of this paper is to present nearly two decades of archaeological research in the coastal region of the northern Netherlands, in order to inform the current debate on the possibilities of adapting to the effects of climate change in low-lying coastal areas. It presents the multi-disciplinary methods of this research and its results, supplying details of terp construction and other strategies such as the construction of low summer dikes that are still useful today. The results and discussion of the presented research also make it possible to describe the conditions that must be met to make terp habitation possible. Terp habitation could have continued, were it not for the considerable subsidence of inland areas due to peat reclamation. That made the entire coastal area increasingly vulnerable to the sea. In response to this threat, dike building began in the 11th or 12th century, but these increasingly higher dikes decreased the water storage capacity and caused impoundment of seawater during storm surges. Moreover, accretion through sedimentation was halted from then on. Unlike terp habitation, the construction of high dikes therefore cannot be considered a sustainable solution for living in low-lying coastal areas in the long term

Identification of Lactobacillus plantarum genes modulating the cytokine response of human peripheral blood mononuclear cells

<p>Abstract</p> <p>Background</p> <p>Modulation of the immune system is one of the most plausible mechanisms underlying the beneficial effects of probiotic bacteria on human health. Presently, the specific probiotic cell products responsible for immunomodulation are largely unknown. In this study, the genetic and phenotypic diversity of strains of the <it>Lactobacillus plantarum </it>species were investigated to identify genes of <it>L. plantarum </it>with the potential to influence the amounts of cytokines interleukin 10 (IL-10) and IL-12 and the ratio of IL-10/IL-12 produced by peripheral blood mononuclear cells (PBMCs).</p> <p>Results</p> <p>A total of 42 <it>Lactobacillus plantarum </it>strains isolated from diverse environmental and human sources were evaluated for their capacity to stimulate cytokine production in PBMCs. The <it>L. plantarum </it>strains induced the secretion of the anti-inflammatory cytokine IL-10 over an average 14-fold range and secretion of the pro-inflammatory cytokine IL-12 over an average 16-fold range. Comparisons of the strain-specific cytokine responses of PBMCs to comparative genome hybridization profiles obtained with <it>L. plantarum </it>WCFS1 DNA microarrays (also termed gene-trait matching) resulted in the identification of 6 candidate genetic loci with immunomodulatory capacities. These loci included genes encoding an <it>N</it>-acetyl-glucosamine/galactosamine phosphotransferase system, the LamBDCA quorum sensing system, and components of the plantaricin (bacteriocin) biosynthesis and transport pathway. Deletion of these genes in <it>L. plantarum </it>WCFS1 resulted in growth phase-dependent changes in the PBMC IL-10 and IL-12 cytokine profiles compared with wild-type cells.</p> <p>Conclusions</p> <p>The altered PBMC cytokine profiles obtained with the <it>L. plantarum </it>WCFS1 mutants were in good agreement with the predictions made by gene-trait matching for the 42 <it>L. plantarum </it>strains. This study therefore resulted in the identification of genes present in certain strains of <it>L. plantarum </it>which might be responsible for the stimulation of anti- or pro-inflammatory immune responses in the gut.</p

TLR 2/1 interaction of pectin depends on its chemical structure and conformation

Citrus pectins have demonstrated health benefits through direct interaction with Toll-like receptor 2. Methyl-ester distribution patterns over the homogalacturonan were found to contribute to such immunomodulatory activity, therefore molecular interactions with TLR2 were studied. Molecular-docking analysis was performed using four GalA-heptamers, GalA7Me0, GalA7Me1,6, GalA7Me1,7 and GalA7Me2,5. The molecular relations were measured in various possible conformations. Furthermore, commercial citrus pectins were characterized by enzymatic fingerprinting using polygalacturonase and pectin-lyase to determine their methyl-ester distribution patterns. The response of 12 structurally different pectic polymers on TLR2 binding and the molecular docking with four pectic oligomers clearly demonstrated interactions with human-TLR2 in a structure-dependent way, where blocks of (non)methyl-esterified GalA were shown to inhibit TLR2/1 dimerization. Our results may be used to understand the immunomodulatory effects of certain pectins via TLR2. Knowledge of how pectins with certain methyl-ester distribution patterns bind to TLRs may lead to tailored pectins to prevent inflammation.</p

Attenuation of Doxorubicin-Induced Small Intestinal Mucositis by Pectins is Dependent on Pectin's Methyl-Ester Number and Distribution

Scope Intestinal mucositis is a common side effect of the chemotherapeutic agent doxorubicin, which is characterized by severe Toll-like receptor (TLR) 2-mediated inflammation. The dietary fiber pectin is shown to prevent this intestinal inflammation through direct inhibition of TLR2 in a microbiota-independent manner. Recent in vitro studies show that inhibition of TLR2 is determined by the number and distribution of methyl-esters of pectins. Therefore, it is hypothesized that the degree of methyl-esterification (DM) and the degree of blockiness (DB) of pectins determine attenuating efficacy on doxorubicin-induced intestinal mucositis. Methods and Results Four structurally different pectins that differed in DM and DB are tested on inhibitory effects on murine TLR2 in vitro, and on doxorubicin-induced intestinal mucositis in mice. These data demonstrate that low DM pectins or intermediate DM pectins with high DB have the strongest inhibitory impact on murine TLR2-1 and the strongest attenuating effect on TLR2-induced apoptosis and peritonitis. Intermediate DM pectin with a low DB is, however, also effective in preventing the induction of doxorubicin-induced intestinal damage. Conclusion These pectin structures with stronger TLR2-inhibiting properties may prevent the development of doxorubicin-induced intestinal damage in patients undergoing chemotherapeutic treatment with doxorubicin

Endo-1,3(4)-β-Glucanase-Treatment of Oat β-Glucan Enhances Fermentability by Infant Fecal Microbiota, Stimulates Dectin-1 Activation and Attenuates Inflammatory Responses in Immature Dendritic Cells

Background: Non-digestible carbohydrates are added to infant formula to mimic the effects of human milk oligosaccharide by acting as prebiotics and stimulating the immune system. Although not yet used in infant formulas, β-glucans are known to have beneficial health effects, and are therefore of potential interest for supplementation. Methods and results: We investigated the in vitro fermentation of native and endo-1,3(4)-β-glucanase-treated oat β-glucan using pooled fecal inocula of 2-and 8-week-old infants. While native oat β-glucan was not utilized, both inocula specifically utilized oat β-glucan oligomers containing β(1→4)-linkages formed upon enzyme treatment. The fermentation rate was highest in the fecal microbiota of 2-week-old infants, and correlated with a high lactate production. Fermentation of media supplemented with native and enzyme-treated oat β-glucans increased the relative abundance of Enterococcus and attenuated proinflammatory cytokine production (IL-1β, IL-6, TNFα) in immature dendritic cells. This attenuating effect was more pronounced after enzyme treatment. This attenuation might result from the enhanced ability of fermented oat β-glucan to stimulate Dectin-1 receptors. Conclusion: Our findings demonstrate that endo-1,3(4)-β-glucanase treatment enhances the fermentability of oat β-glucan and attenuates pro-inflammatory responses. Hence, this study shows that especially enzyme-treated oat β-glucans have a high potential for supplementation of infant formula.</p