Discovery Of Pathways Research Articles

Insect Gut Isolate Pseudomonas sp. Strain Nvir Degrades the Toxic Plant Metabolite Nitropropionic Acid.

ABSTRACTNitropropionic acid (NPA) is a widely distributed naturally occurring nitroaliphatic toxin produced by leguminous plants and fungi. The Southern green shield bug feeds on leguminous plants and shows no symptoms of intoxication. Likewise, its gut-associated microorganisms are subjected to high levels of this toxic compound. In this study, we isolated a bacterium from this insect's gut system, classified as Pseudomonas sp. strain Nvir, that was highly resistant to NPA and was fully degrading it to inorganic nitrogen compounds and carbon dioxide. In order to understand the metabolic fate of NPA, we traced the fate of all atoms of the NPA molecule using isotope tracing experiments with [15N]NPA and [1-13C]NPA, in addition to experiments with uniformly 13C-labeled biomass that was used to follow the incorporation of 12C atoms from [U-12C]NPA into tricarboxylic acid cycle intermediates. With the help of genomics and transcriptomics, we uncovered the isolate’s NPA degradation pathway, which involves a putative propionate-3-nitronate monooxygenase responsible for the first step of NPA degradation. The discovered protein shares only 32% sequence identity with previously described propionate-3-nitronate monooxygenases. Finally, we advocate that NPA-degrading bacteria might find application in biotechnology, and their unique enzymes might be used in biosynthesis, bioremediation, and in dealing with postharvest NPA contamination in economically important products.IMPORTANCE Plants have evolved sophisticated chemical defense mechanisms, such as the production of plant toxins in order to deter herbivores. One example of such a plant toxin is nitropropionic acid (NPA), which is produced by leguminous plants and also by certain fungi. In this project, we have isolated a bacterium from the intestinal tract of a pest insect, the Southern green shield bug, that is able to degrade NPA. Through a multiomics approach, we identified the respective metabolic pathway and determined the metabolic fate of all atoms of the NPA molecule. In addition, we provide a new genetic marker that can be used for genome mining toward NPA degradation. The discovery of degradation pathways of plant toxins by environmental bacteria opens new possibilities for pretreatment of contaminated food and feed sources and characterization of understudied enzymes allows their broad application in biotechnology.

The Potential Connection between Molecular Changes and Biomarkers Related to ALS and the Development and Regeneration of CNS.

Neurodegenerative diseases are one of the greatest medical burdens of the modern age, being mostly incurable and with limited prognostic and diagnostic tools. Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by the loss of motoneurons, with a complex etiology, combining genetic, epigenetic, and environmental causes. The neuroprotective therapeutic approaches are very limited, while the diagnostics rely on clinical examination and the exclusion of other diseases. The recent advancement in the discovery of molecular pathways and gene mutations involved in ALS has deepened the understanding of the disease pathology and opened the possibility for new treatments and diagnostic procedures. Recently, 15 risk loci with distinct genetic architectures and neuron-specific biology were identified as linked to ALS through common and rare variant association analyses. Interestingly, the quantity of related proteins to these genes has been found to change during early postnatal development in mammalian spinal cord tissue (opossum Monodelphis domestica) at the particular time when neuroregeneration stops being possible. Here, we discuss the possibility that the ALS-related genes/proteins could be connected to neuroregeneration and development. Moreover, since the regulation of gene expression in developmental checkpoints is frequently regulated by non-coding RNAs, we propose that studying the changes in the composition and quantity of non-coding RNA molecules, both in ALS patients and in the developing central nervous (CNS) system of the opossum at the time when neuroregeneration ceases, could reveal potential biomarkers useful in ALS prognosis and diagnosis.

Molecular Pathways in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension is a multifactorial, chronic disease process that leads to pulmonary arterial endothelial dysfunction and smooth muscular hypertrophy, resulting in impaired pliability and hemodynamics of the pulmonary vascular system, and consequent right ventricular dysfunction. Existing treatments target limited pathways with only modest improvement in disease morbidity, and little or no improvement in mortality. Ongoing research has focused on the molecular basis of pulmonary arterial hypertension and is going to be important in the discovery of new treatments and genetic pathways involved. This review focuses on the molecular pathogenesis of pulmonary arterial hypertension.

Robustness under parameter and problem domain alterations of Bayesian optimization methods for chemical reactions

The related problems of chemical reaction optimization and reaction scope search concern the discovery of reaction pathways and conditions that provide the best percentage yield of a target product. The space of possible reaction pathways or conditions is too large to search in full, so identifying a globally optimal set of conditions must instead draw on mathematical methods to identify areas of the space that should be investigated. An intriguing contribution to this area of research is the recent development of the Experimental Design for Bayesian optimization (EDBO) optimizer [1]. Bayesian optimization works by building an approximation to the true function to be optimized based on a small set of simulations, and selecting the next point (or points) to be tested based on an acquisition function reflecting the value of different points within the input space. In this work, we evaluated the robustness of the EDBO optimizer under several changes to its specification. We investigated the effect on the performance of the optimizer of altering the acquisition function and batch size, applied the method to other existing reaction yield data sets, and considered its performance in the new problem domain of molecular power conversion efficiency in photovoltaic cells. Our results indicated that the EDBO optimizer broadly performs well under these changes; of particular note is the competitive performance of the computationally cheaper acquisition function Thompson Sampling when compared to the original Expected Improvement function, and some concerns around the method’s performance for “incomplete” input domains.

Hairy roots: An untapped potential for production of plant products.

While plants are an abundant source of valuable natural products, it is often challenging to produce those products for commercial application. Often organic synthesis is too expensive for a viable commercial product and the biosynthetic pathways are often so complex that transferring them to a microorganism is not trivial or feasible. For plants not suited to agricultural production of natural products, hairy root cultures offer an attractive option for a production platform which offers genetic and biochemical stability, fast growth, and a hormone free culture media. Advances in metabolic engineering and synthetic biology tools to engineer hairy roots along with bioreactor technology is to a point where commercial application of the technology will soon be realized. We discuss different applications of hairy roots. We also use a case study of the advancements in understanding of the terpenoid indole alkaloid pathway in Catharanthus roseus hairy roots to illustrate the advancements and challenges in pathway discovery and in pathway engineering.

Revealing the role of liquid preordering in crystallisation of supercooled liquids

The recent discovery of non-classical crystal nucleation pathways has revealed the role of fluctuations in the liquid structural order, not considered in classical nucleation theory. On the other hand, classical crystal growth theory states that crystal growth is independent of interfacial energy, but this is questionable. Here we elucidate the role of liquid structural ordering in crystal nucleation and growth using computer simulations of supercooled liquids. We find that suppressing the crystal-like structural order in the supercooled liquid through a new order-killing strategy can reduce the crystallisation rate by several orders of magnitude. This indicates that crystal-like liquid preordering and the associated interfacial energy reduction play an essential role in nucleation and growth processes, forcing critical modifications of the classical crystal growth theory. Furthermore, we evaluate the importance of this additional factor for different types of liquids. These findings shed new light on the fundamental understanding of crystal growth kinetics.

The emerging era of personalized medicine in advanced colorectal cancer.

Colorectal cancer (CRC) is a genetically heterogeneous disease with its pathogenesis often driven by varying genetic or epigenetic alterations. This has led to a substantial number of patients developing chemoresistance and treatment failure, resulting in a high mortality rate for advanced disease. Deep molecular analysis has allowed for the discovery of key intestinal signaling pathways which impacts colonic epithelial cell fate, and the integral role of the tumor microenvironment on cancer growth and dissemination. Through transitioning pre-clinical knowledge in research into clinical practice, many potential druggable targets within these pathways have been discovered in the hopes of overcoming the roadblocks encountered by conventional therapies. A personalized approach tailoring treatment according to the histopathological and molecular features of individual tumors can hopefully translate to better patient outcomes, and reduce the rate of recurrence in patients with advanced CRC. Herein, the latest understanding on the molecular science behind CRC tumorigenesis, and the potential treatment targets currently at the forefront of research are summarized.

Discovery of Druggable Cancer-Specific Pathways with Application in Acute Myeloid Leukemia

Discovery of Druggable Cancer-Specific Pathways with Application in Acute Myeloid Leukemia

Discovery of Druggable Cancer-Specific Pathways with Application in Acute Myeloid Leukemia

Discovery of Druggable Cancer-Specific Pathways with Application in Acute Myeloid Leukemia

Metabolomic and transcriptomic study to understand changes in metabolic and immune responses in steers under heat stress.

Heat stress (HS) damages livestock by adversely affecting physiological and immunological functions. However, fundamental understanding of the metabolic and immunological mechanisms in animals under HS remains elusive, particularly in steers. To understand the changes on metabolic and immune responses in steers under HS condition, we performed RNA-sequencing and proton nuclear magnetic resonance spectroscopy-based metabolomics on HS-free (THI value: 64.92 ± 0.56) and HS-exposed (THI value: 79.13 ± 0.56) Jersey steer (n = 8, body weight: 559.67 ± 32.72 kg). This study clarifies the metabolic changes in 3 biofluids (rumen fluid, serum, and urine) and the immune responses observed in the peripheral blood mononuclear cells of HS-exposed steers. This integrated approach allowed the discovery of HS-sensitive metabolic and immunological pathways. The metabolomic analysis indicated that HS-exposed steers showed potential HS biomarkers such as isocitrate, formate, creatine, and riboflavin (P < 0.05). Among them, there were several integrative metabolic pathways between rumen fluid and serum. Furthermore, HS altered mRNA expression and immune-related signaling pathways. A meta-analysis revealed that HS decreased riboflavin metabolism and the expression of glyoxylate and dicarboxylate metabolism-related genes. Moreover, metabolic pathways, such as the hypoxia-inducible factor-1 signaling pathway, were downregulated in immune cells by HS (P < 0.05). These findings, along with the datasets of pathways and phenotypic differences as potential biomarkers in steers, can support more in-depth research to elucidate the inter-related metabolic and immunological pathways. This would help suggest new strategies to ameliorate the effects of HS, including disease susceptibility and metabolic disorders, in Jersey steers.

The apparent paradox of phenotypic diversity and shared mechanisms across dystonia syndromes.

We describe here how such mechanisms shared by different genetic forms can give rise to motor performance dysfunctions with a clinical aspect of dystonia. The continuing discoveries of genetic causes for dystonia syndromes are transforming our view of these disorders. They share unexpectedly common underlying mechanisms, including dysregulation in neurotransmitter signaling, gene transcription, and quality control machinery. The field has further expanded to include forms recently associated with endolysosomal dysfunction. The discovery of biological pathways shared between different monogenic dystonias is an important conceptual advance in the understanding of the underlying mechanisms, with a significant impact on the pathophysiological understanding of clinical phenomenology. The functional relationship between dystonia genes could revolutionize current dystonia classification systems, classifying patients with different monogenic forms based on common pathways. The most promising effect of these advances is on future mechanism-based therapeutic approaches.

The Role of Ferritin in Health and Disease: Recent Advances and Understandings.

Systemic iron homeostasis needs to be tightly controlled, as both deficiency and excess iron cause major global health concerns, such as iron deficiency anemia, hemochromatosis, etc. In mammals, sufficient dietary acquisition is critical for fulfilling the systemic iron requirement. New questions are emerging about whether and how cellular iron transport pathways integrate with the iron storage mechanism. Ferritin is the intracellular iron storage protein that stores surplus iron after all the cellular needs are fulfilled and releases it in the face of an acute demand. Currently, there is a surge in interest in ferritin research after the discovery of novel pathways like ferritinophagy and ferroptosis. This review emphasizes the most recent ferritin-related discoveries and their impact on systemic iron regulation.

Resolution of Inflammation after Skeletal Muscle Ischemia-Reperfusion Injury: A Focus on the Lipid Mediators Lipoxins, Resolvins, Protectins and Maresins.

Skeletal muscle ischemia reperfusion is very frequent in humans and results not only in muscle destruction but also in multi-organ failure and death via systemic effects related to inflammation and oxidative stress. In addition to overabundance of pro-inflammatory stimuli, excessive and uncontrolled inflammation can also result from defects in resolution signaling. Importantly, the resolution of inflammation is an active process also based on specific lipid mediators including lipoxins, resolvins and maresins that orchestrate the potential return to tissue homeostasis. Thus, lipid mediators have received growing attention since they dampen deleterious effects related to ischemia–reperfusion. For instance, the treatment of skeletal muscles with resolvins prior to ischemia decreases polymorphonuclear leukocyte (PMN) infiltration. Additionally, remote alterations in lungs or kidneys are reduced when enhancing lipid mediators’ functions. Accordingly, lipoxins prevented oxidative-stress-mediated tissue injuries, macrophage polarization was modified and in mice lacking DRV2 receptors, ischemia/reperfusion resulted in excessive leukocyte accumulation. In this review, we first aimed to describe the inflammatory response during ischemia and reperfusion in skeletal muscle and then discuss recent discoveries in resolution pathways. We focused on the role of specialized pro-resolving mediators (SPMs) derived from polyunsaturated fatty acids (PUFAs) and their potential therapeutic applications.

Abstract 610: The expression of the PVRIG/TIGIT pathway is dominant in the bone marrow of patients with multiple myeloma

Abstract Blocking inhibitory immune receptors has shown limited clinical benefit in patients with multiple myeloma (MM), warranting the discovery of alternative immune inhibitory pathways. Blockade of the immune checkpoint TIGIT was shown to enhance anti-tumor immunity in MM pre-clinical models. In addition to TIGIT, the DNAM1 axis includes the novel inhibitory receptor PVRIG. Both TIGIT and PVRIG deliver inhibitory signals to T and NK cells and compete with the co-activating receptor DNAM1 for binding to PVR and PVRL2, respectively. Accordingly, TIGIT and PVRIG co-blockade was shown to synergize in enhancing anti-tumor immunity in preclinical models. PVRL2 and PVR were shown to be expressed on MM plasma cells in the bone marrow (BM). In this study, we evaluated DNAM1 axis receptor expression in the BM of patients with MM. BM mononuclear cells derived from 21 patients with MM were analyzed for the expression of PD1 and DNAM1 axis molecules by flow cytometry. Patients classified with progressed disease (PD), or complete response (CR) were treated with multiple lines of therapies including targeted therapies, chemotherapies, proteasome inhibitors. PVRIG demonstrated the highest expression among all evaluated receptors on NK (88%), NKT (81%) and CD8+ T cells (79%), significantly higher than PD1 (p&amp;lt;0.0001) and TIGIT (P&amp;lt;0.001). TIGIT showed substantially increased expression on NK (64%, P&amp;lt;0.0001) and CD8+ T cells (58%, p&amp;lt;0.05) compared to PD1 (expressed on 12% of NK cells and 42% of CD8+ T cells). Importantly, 50% and 60% of CD8+ and NK cells, respectively, co-expressed TIGIT and PVRIG, and all examined cell populations showed increased levels of DNAM1 (&amp;gt;50%). Additionally, the expression of PVRIG ligand, PVRL2, on BM plasma cells from 6 patients with MM was demonstrated by immuno-histochemistry and flow cytometry. A fraction of CD8+ T cells were DNAM1- and positive for PVRIG/TIGIT/PD1 (22%), suggesting the accumulation of an exhausted CD8+ T cell population in the MM tumor microenvironment. PVRIG showed significantly higher (p&amp;lt;0.0001) expression on DNAM+ CD8+ T cells (81%), compared to TIGIT (43%) and PD1 (34%), supporting the potential of PVRIG blockade to enhance DNAM1 signaling and subsequent CD8+ T cell activation. Finally, patients with CR had a trend towards higher DNAM1 expression on CD8+ T cells (75%) compared to PD patients (54%, p=0.057). To conclude, DNAM1 axis receptors are dominantly expressed on MM BM lymphocytes, with PVRIG exhibiting the most prominent expression. The reduced expression of DNAM1 in patients with PD suggests a link between DNAM1 axis and clinical outcome. Our findings highlight for the first time the dominant expression of PVRIG, as well as TIGIT and suggest that combined blockade of these checkpoints may potentially benefit patients with MM, placing the DNAM1 axis as a promising therapeutic pathway in MM therapy. Citation Format: Masha Frenkel, Zoya Alteber, Ning Xu, Mingjie Li, Haiming Chen, Gady Cojocaru, James Berenson, Eran Ophir. The expression of the PVRIG/TIGIT pathway is dominant in the bone marrow of patients with multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 610.

Abstract LB501: Making discoveries with Kids First Variant DataBase and WorkBench

Abstract The Gabriella Miller Kids First Pediatric Research Program (Kids First) aims at facilitating researchers to uncover new insights into the biology of childhood cancer (CC) and structural birth defects (SBD), including the discovery of shared genetic pathways between these disorders. Kids First has two initiatives, which are whole genome sequencing (WGS) of biospecimens from families with CC/SBD, and establishing Kids First Data Resource. Kids First Data Resource Center (KFDRC) developed Kids First Data Resource Portal (KFDRP; https://portal.kidsfirstdrc.org/), which is a centralized platform to search, view, analyze, and identify currently accessible data from both Kids First and collaborative cohorts, incorporating omics and phenotypic information of 30 studies and 26,300 participants. Recently KFDRC released two new KFDRP components named Variant DataBase (VDB) and Variant WorkBench (VWB), enabling users to query, mangle, analyze and visualize germline genomic variants. The current release includes ~309 million unique variants in a matrix of more than 61.3 billion individual-chromosomal position occurrences from over 11,500 participants in 17 studies. While VDB provides a quick variant summary, VWB supports scripting languages such as Python, Spark, SQL, R, and MarkDown as in-depth analysis tools enabled by Apache Zeppelin notebooks. In addition to variant calls and phenotypic information such as Human Phenotype Ontology (HPO) terms and Mondo IDs, VWB hosts rich external variant annotations in the public domain, such as Cancer Hotspots, ClinVar, COSMIC, dbNSFP, gnomAD, TOPMed, as well as gene-phenotype links provided by OMIM, HPO, Orphanet, and the Deciphering Developmental Disorders Project. Users can also load additional databases within a notebook (such as the subscription-based Human Gene Mutation Database [HGMD]), import custom datasets as temporary query tables, export analysis outputs to local drives, visualize analysis results in multiple chart styles, display local figures, and save notebooks for sharing, further use and Cavatica projects. In an effort to screen tier 1 genes (n=578) from the most recent Cancer Gene Census provided by COSMIC for rare deleterious variants in all six currently available CC cohorts in KFDRP, we identified over 1.2 million germline variants that are with minor allele frequency no more than 0.00001 among gnomAD/TOPMed datasets and with ratio of number of “damaging” predictions over number of all predictions in dbNSFP between 0.5 and 1, or that are already cataloged in the most recent version of ClinVar/HGMD. The whole process took less than two hours which is much faster than conventional methods. These variant tools in KFDRP enable efficient genomic variant analysis in cancer research with advanced big data technology. Citation Format: Yiran Guo, Jeremy Costanza, Christophe Botek, Miguel Brown, David Higgins, Yuankun Zhu, Bailey Farrow, Allison Heath, Adam Resnick, Vincent Ferretti, Kids First Data Resource Center. Making discoveries with Kids First Variant DataBase and WorkBench [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB501.

Transcriptional Perturbations of 2,6-Diaminopurine and 2-Aminopurine.

2,6-Diaminopurine (Z) is a naturally occurring adenine (A) analog that bacteriophages employ in place of A in their genetic alphabet. Recent discoveries of biogenesis pathways of Z in bacteriophages have stimulated substantial research interest in this DNA modification. Here, we systematically examined the effects of Z on the efficiency and fidelity of DNA transcription. Our results showed that Z exhibited no mutagenic yet substantial inhibitory effects on transcription mediated by purified T7 RNA polymerase and by human RNA polymerase II in HeLa nuclear extracts and in human cells. A structurally related adenine analog, 2-aminopurine (2AP), strongly blocked T7 RNA polymerase but did not impede human RNA polymerase II in vitro or in human cells, where no mutant transcript could be detected. The lack of mutagenic consequence and the presence of a strong blockage effect of Z on transcription suggest a role of Z in transcriptional regulation. Z is also subjected to removal by transcription-coupled nucleotide-excision repair (TC-NER), but not global-genome NER in human cells. Our findings provide new insight into the effects of Z on transcription and its potential biological functions.

Similarity of competing risks models with constant intensities in an application to clinical healthcare pathways involving prostate cancer surgery

The recent availability of routine medical data, especially in a university-clinical context, may enable the discovery of typical healthcare pathways, that is, typical temporal sequences of clinical interventions or hospital readmissions. However, such pathways are heterogeneous in a large provider such as a university hospital, and it is important to identify similar care pathways that can still be considered typical pathways. We understand the pathway as a temporal process with possible transitions from a single initial treatment state to hospital readmission of different types, which constitutes a competing risks setting. In this article, we propose a multi-state model-based approach to uncover pathway similarity between two groups of individuals. We describe a new bootstrap procedure for testing the similarity of constant transition intensities from two competing risk models. In a large simulation study, we investigate the performance of our similarity approach with respect to different sample sizes and different similarity thresholds. The studies are motivated by an application from urological clinical routine and we show how the results can be transferred to the application example.

Animal Models of Exercise From Rodents to Pythons.

Acute and chronic animal models of exercise are commonly used in research. Acute exercise testing is used, often in combination with genetic, pharmacological, or other manipulations, to study the impact of these manipulations on the cardiovascular response to exercise and to detect impairments or improvements in cardiovascular function that may not be evident at rest. Chronic exercise conditioning models are used to study the cardiac phenotypic response to regular exercise training and as a platform for discovery of novel pathways mediating cardiovascular benefits conferred by exercise conditioning that could be exploited therapeutically. The cardiovascular benefits of exercise are well established, and, frequently, molecular manipulations that mimic the pathway changes induced by exercise recapitulate at least some of its benefits. This review discusses approaches for assessing cardiovascular function during an acute exercise challenge in rodents, as well as practical and conceptual considerations in the use of common rodent exercise conditioning models. The case for studying feeding in the Burmese python as a model for exercise-like physiological adaptation is also explored.

Cluster Head Selection and Energy Efficient Multicast Routing Protocol-Based Optimal Route Selection for Mobile Ad Hoc Networks

Wireless networks with a large number of peer nodes are known as mobile ad hoc networks (MANETs). In MANETs, the mobility of nodes causes a number of challenges, including path preservation, battery life, safety, dependability, and unexpected connection characteristics. As a result, the network’s quality of service (QoS) would be compromised (QoS). For the discovery and maintenance of pathways in MANETs, the routing protocol is critical. By implementing the multicast routing protocol, the MANET network’s reliability may be improved significantly. Evaluation of multicast routing for quality of service (QoS) is the primary goal of this study. In multicasting, data packets from one node are transmitted to a set of receiver nodes at a time, simultaneously. Multicasting reduces transmission costs. Cluster head selection is one of the challenges in MANET. This proposed research paper optimal route selection (ORS) provides the cluster head selection and alternate cluster head selection for avoiding the failure of the cluster head, generation of the optimal path between the cluster head and member node based on reliability pair factor and node’s energy, and establishment of the path based on maximum energy and number of hops between the nodes (minimum number of hops). In comparison to existing methods, ORS is more effective in the energy-efficient path between base station and cluster head, and member node is provided by an ORS route. Results show that the proposed ORSMAN has higher throughput, minimum latency, minimum jitter, and maximum packet delivery ratio, when compared to the existing methodologies.

Implications of considering peri-implant bone loss a disease, a narrative review.

BackgroundPeri‐implantitis has been suggested to cause significant increasing proportions of implant failure with increasing time.PurposeTo assess whether implant failure rates in long term studies are matching the supposed high prevalence of peri‐implantitis.Material and MethodsThis paper is written as a narrative review of the long‐term clinical investigations available in the literature.ResultsSome implant systems have seen unacceptable marginal bone loss figures with time coupled to increased implant failure rates, resulting in the withdrawal of these systems. The reasons for such mishap are generally unknown, with the exception of one system failure that was found to be due to improper clinical handling. Modern, moderately rough implant systems have functioned excellently over 10–15 years of follow up with minor problems with marginal bone loss and implant failure rates within a few per cent. Machined implants have functioned adequately over 20–30 years of follow up. Implant failures occur predominantly during the first few years after implant placement. No significant increase of implant failures has been observed thereafter over 20–30 years of follow up.Over the years of our new millennium, scientific and technical advances have allowed the discovery of numerous molecular pathways and cellular interactions between the skeletal and immune system promoting the development of the interdisciplinary field called osteoimmunology. Nowadays, this knowledge has not only allowed the emergence of new etiologic paradigms for bone disease but also a new dynamic approach on the concept of osseointegration and MBL around oral implants, re‐evaluating our older disease oriented outlook. This facilitates at the same time the emergence of translational applications with immunological perspectives, scientific approaches based on omics sciences, and the beginning of an era of personalized dental implant therapy to improve the prognosis of oral implant treatment.ConclusionsOral implant systems have been found to function with very good clinical outcome over follow‐up times of 20–30 years. Registered implant failures have occurred predominantly during the first few years after implantation, and there has been no significant increase in late failures due to peri‐implantitis.