The Green Revolution during the 50s and 60s was a milestone in the history of mankind. Based on the principles “higher yields, more food, less poverty and hunger,” it radically transformed agriculture and dramatically increased global food production Khush, . DespitePlants are massively colonized by communities of microbes that are referred to as the plant microbiota. Plant-associated beneficial microbes have long been known to provide important ecosystem services and promote plant health by enhancing growth, suppressing pathogens and training plant immunity  against important diseases in agricultural and forest ecosystems, but also metagenomic studies that provide a more holistic view on the way microbiota interact with plant immunity. In addition, one method paper presents a pipeline to dissect selected plant responses to bacteria with different lifestyles and 5 review articles summarize our current knowledge on the mechanisms by which beneficial bacteria and fungi promote host defenses and plant health in below- and aboveground plant tissues. New experimental platforms and integrated approaches that combine (meta)-omics with functional analyses are needed in future research in order to obtain a comprehensive understanding of the mechanisms by which beneficial microbes interact with phytopathogens and plant immunity.Park et al. identified Bacillus thuringiensis strain JCK-1233 and a specific diketopiperazine produced by JCK-1233 to induce resistance in pine trees thereby suppressing the wilt disease caused by the nematode Bursaphelenchus xylophilus, one of the most important pests affecting pine forests worldwide. Thus, also in forest ecosystems where the application of synthetic pesticides against devastating pests is costly and often complicated by diverse ecological risks, BCAs could be implemented as eco-friendly and cost-effective alternatives.By testing more than 500 bacterial isolates, Chen et al. studied the mechanisms by which another Bacillus strain, Bacillus velezensis CLA178, suppresses the tumors caused by Agrobacterium infection in the ornamental plant Rosa multiflora. Combined with work in Arabidopsis, the authors found that, when applied to the roots, CLA178 promoted plant growth and further primed the expression of defense genes regulated by the salicylic acid and ethylene signaling pathways. The sequenced genome of CLA178 included in the study pave the way for genome-centered future analyses in order to reveal the bacterial genetics involved in both phenomena.Wu et al. utilized pot experiments to demonstrate that the antagonism between the biocontrol strain Bacillus velezensis HN03 and the wilt pathogen of banana Fusarium oxysporum f. sp. cubense, depends on the nutritional content of the soil. In particular, the authors found that synchronous application of HN03 and compost potentiated the biocontrol outcome of individual treatments through reciprocal interactions, which the authors summarize in a conceptual model. Considering that the application of BCAs in the field often fails to deliver the anticipated outcomes, this study provides means to enhance the biocontrol activity of selected BCAs under agricultural settings.Samaras et al. provide insights into the mechanism underpinning the protective functions of Bacillus subtilis MBI 600, one of the many commercialized Bacillus strains. The authors sequenced the MBI 600 genome and through comparative genomics identified common genes to other Bacilli, but also unique genomic features related to root colonization, plant growth promotion and biocontrol activity. Interestingly, by generating an yfp-tagged strain, the authors were able to study the colonization potential of MBI 600 in the roots of cucumber in different growth substrates. Overall, this interesting study demonstrates the power of microbial genetics in dissecting the mechanisms by which beneficial microbes train immunity and improve host health.In their genomics study, Sacristán-Pérez-Minayo et al. characterized the effects of two Pseudomonas strains on sugar beet productivity. When used as soil inoculants in the field, both beneficials improved the yield and the quality of the tubers, however, they failed to provide protection against two important sugar beet pathogens. The study clearly suggests that delivering multiple traits in the field could be a difficult task; rather than the application of single microbes, the application of microbials at the community level may be a more reasonable approach.Chen et al. demonstrated that prolonged monoculture with the medicinal herb Radix pseudostellariae reduced the diversity of antagonistic Trichoderma communities in the rhizosphere, consequently increasing the abundance of pathogenic Fusarium oxysporum. Interestingly, the authors found that the application of the Trichoderma strain T. harzianum ZC51 could improve plant resistance and reduce the growth inhibitory effect stemming from the consecutive monoculture. This study clearly shows the impact of monoculture on the rhizosphere microbiome and further provides means to improve soil health through the application of soil beneficials.In their study, Anguita-Maeso et al. reveals that a wild olive variety that is otherwise resistant to the wilt fungus Verticillium dahliae becomes susceptible to the pathogen when propagated in vitro. The authors provide evidence that in vitro micropropagation of this particular olive accession alters community structure resulting in the breakdown of resistance to Verticillium. Thus, the xylem microbiomes could be exploited as a reliable resistance source to devastating root-infecting pathogens.The interesting work of Wang et al. utilized an axenic growth system and carried out metagenomic analyses to demonstrate that during seed germination, the pool of microbes that colonize the seeds are separated to distinct assemblages in the different plant tissues. Interestingly, the authors found that functions related to plant growth and pathogen suppression are enriched in the core microbiomes transferred from the seed to the newly established plants.The seedling stage is the most vulnerable time in the life cycle of a plant, and the role of seed-derived microbiota in promoting seedling health is well-established. Focusing on rice, Mikania micrantha, a fast-growing vine, is ranked amongst the top 100 worst IAPS in the world. Having the authors previously published the M. micrantha genome, the exciting metagenomics study of Yin et al. in this collection indicates that the roots of M. micrantha host more phosphate-solubilizing and pathogen-suppressive rhizobacteria than the roots of two coexisting native plant species. Thus, rhizosphere microbes seem to play important roles in the establishment of invasive plants and may even act as drivers of plant invasion.Invasive alien plant species (IAPS) may cause severe damage to natural ecosystems by reducing the richness and abundance of native plant species. Tricyrtis macropoda have an unusual phenotype with spots covering the leaf surface. Wang et al. found that the composition of the fungal microbiome in the spots differs from the fungal communities in the green parts. By analyzing the metabolome of spotted and non-spotted leaf parts, a significant correlation between the endophytic fungal communities and the production of metabolites has been established. Overall, this study provides new insights into the relationship between microbes and plant phenotypes and further demonstrates the value of -omics toward understanding the molecular cues driving microbiome assembly in the host.The leaves of the perennial herb 2O2) functions as an important signaling molecule in plants during biotic interactions. Carril et al. developed a protocol to visualize and quantify H2O2 production in wheat leaves after infection with a pathogenic bacterium or after co-inoculation of the pathogen with a beneficial bacterium. DAB staining combined with an imaging analysis pipeline revealed that co-inoculation yielded less H2O2 accumulation and less visible disease symptoms compared to the pathogen infection alone. Therefore, this protocol can successfully determine the H2O2 levels accumulating in response to bacteria with different lifestyles.Hydrogen peroxide  are soil-borne microbes that form mutualistic associations with forest trees. The review of Pršić and Ongena. The authors provide an updated overview of ISR elicitors originating from diverse rhizosphere bacterial species, such as acyl-homoserine lactones, cyclic lipopeptides, rhamnolipids, N-alkylated benzylamine derivatives, siderophores, antibiotics, and volatile organic compounds. They further emphasize on the necessity to reveal in future studies how these molecules are sensed by the host and what type of defense responses are manifested upon elicitor perception.The ability of beneficial microbes to modulate plant immunity largely relies on the secretion of a diverse array of low-molecular weight metabolites. The molecular determinants specifically involved in the phenomenon of rhizobacteria-mediated induced systemic resistance is reviewed in this article collection by The authors jointly defined the content of this Research Topic and participated in the editing process. All authors made substantial, direct and intellectual contribution to the composing of this editorial, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Not long ago, self-reactive immune activity was considered as pathological trait. A paradigm shift has now led to the recognition of autoimmune processes as part of natural maintenance of molecular homeostasis. The immune system is assigned further roles beneath the defense against pathogenic organisms. Regarding the humoral immune system, the investigation of natural autoantibodies that are frequently found in healthy individuals has led to further hypotheses involving natural autoimmunity in other processes as the clearing of cellular debris or decrease in inflammatory processes. However, their role and origin have not been entirely clarified, but accumulating evidence links their formation to immune reactions against the gut microbiome. Antibodies targeting highly conserved proteins of the commensal microflora are suggested to show self-reactive properties, following the paradigm of the molecular mimicry. Here, we discuss recent findings, which demonstrate potential links of the commensal microflora to the immunological homeostasis and highlight the possible implications for various diseases. Furthermore, specific components of the immune system, especially antibodies, have become a focus of attention for the medical management of various diseases and provide attractive treatment options in the future. Nevertheless, the development and optimization of such macromolecules still represents a very time-consuming task, shifting the need to more medical agents with simple structural properties and low manufacturing costs. Synthesizing only the biologically active sites of antibodies has become of great interest for the pharmaceutical industry and offers a wide range of therapeutic application areas as it will be discussed in the present review article. The human gut microbiome (GM) consists of a plethora of different taxa . The intFor the study of GM composition, microbial species are commonly identified by analysis of fecal samples, mainly using 16s rRNA sequencing. However, distinct strains can only be identified with high-throughput, full-length 16s sequence data that can be obtained only recently with required accuracy . AlthougColonization with microbiota occurs after birth and mainly depends on mode of delivery and breastfeeding, but also other environmental traits are able to modify the composition of the microbiome . In the The human GM plays a key role in the education and maintenance of the immune system, especially early in life ,21. The Natural antibodies are defined as circulating immunoglobulins that are components of the physiological state of the organism and are present without prior immunization. IgM antibodies are most widely studied , but alsBesides the importance to unravel the complex and versatile interplay between the GM and the host immune defense system, the implementation of immune-modulating therapeutic strategies has become of great interest for clinical applications. Particularly, commercial monoclonal antibodies are extremely valuable for the treatment of various disease pattern ranging from neurodegenerative and autoinflammatory disorders to highly aggressive and metastatic cancer types. In consideration of the tremendous progress in the development of medical treatment strategies, the trend is, nowadays, towards the manufacturing of small drug compounds with enhanced bioactivity instead of large biomolecules such as antibodies ,35. FocuIn the first part of the present review article, we want to highlight the connections between the GM and the natural antibody repertoire with special focus on systemic IgG, as well as their implications in various diseases. In the second part, we provide a comprehensive overview about current immunomodulatory treatment strategies by the exogenous supplementation of engineered therapeutic antibodies or their synthetic CDR peptides and discuss their highly specific and versatile modes of action.Escherichia coli infections [Immediately after birth, the neonate is exposed to a vast composition of microbes derived from the mother and the environment . Howeverfections . These pfections ,38.The first 2–3 years of life are crucial for the development of a healthy immune system. Variation in colonization of different microbiota early in life can alter the host immunity and even increase susceptibility for autoimmune diseases and allergic reactions . The GM A major task for the young host organism is the establishment of a tolerance to commensal, beneficial microbiota, while simultaneously educating the adaptive immune response against pathogens. Naïve T cells differentiate into effector T cells or regulatory T cells (Treg) upon contact to the gut bacteria. This depends on the type of bacteria and leads either to initiation of defense mechanisms or tolerance of the organism. Thus, the GM plays a pivotal role in the regulation of regulatory and proinflammatory T cell formation . Treg ceImmune tolerance in the gut, however, is not only established against microbiota, but also to food antigens. This priming of the immune system is referred to as oral tolerance. It mediates an active suppression of inflammatory processes against any antigens in the gastrointestinal tract, thereby preventing food allergies. There are two major ways in which oral tolerance can be promoted. On one hand, the induction of Tregs and on the other the clonal anergy of antigen-specific T cells. Both ways are not mutually exclusive and can both affect immune tolerance in a synergetic manner. Which of both mechanisms predominates is highly dependent on the amount of antigen that is administered orally. The mechanisms of oral tolerance were investigated as possible immunomodulatory treatment for various inflammatory and autoimmune diseases. Oral administration of antigens to induce tolerance and prevent an immune response is termed oral immune therapy (OIT). The efficacy of OIT has been investigated in the context of food allergies such as peanut allergy , but alsThe role of antibodies in the imparting of immune tolerance is not adequately investigated. It is currently known that humans show antigen-specific IgG, IgA and IgM to food antigens that show no apparent disease value . Recent The antibody-producing B cell repertoire as such is massively influenced by the GM and exhibits a circle of mutual control . One parNatural antibodies are antibodies that are present at a physiological state of the organism without prior immunization to the antigen. They are hypothesized to be either spontaneously secreted by B cells or to be stimulated by intrinsic factors. Their existence and function are not undisputed among the immunology community. However, evidence supporting a key role for natural autoantibodies in the homeostasis of a healthy organism is accumulating. Here, we discuss possible connections between the origin of autoantibodies and the GM with special focus on the systemic IgG repertoire .In humans, only IgG isotype antibodies can pass the placenta and can be transferred from the mother to the fetus via the neonatal Fc receptor (FcRn). Nevertheless, immunoglobulins of other classes, especially IgM, can be found in neonates . NaturalThe natural antibody repertoire was found to be composed of immunoglobulins of the classes IgM, IgG and IgA. Natural antibodies are poly-reactive and bind their antigens with low affinity. They can bind to external antigens, as well as self-antigens. The main sources for these antibodies are B1 cells. B1 cells are a subset of B cells considered to be part of the innate immune response. Their main feature is their ability to spontaneously secret low-affinity antibodies, without prior antigen exposure . This B The homeostasis of microbial and immune system interaction in the gut mainly depends on mucosal IgA secretion. However, the GM and its metabolites have not only local interactions with the host immunity at the epithelial gut barrier in the lamina propria, but they also have a major influence on systemic immunity. Several studies give evidence for the emergence of systemic IgG against intestinal microbial antigens. Their occurrence was first linked to impaired epithelial gut barrier function as observed in inflammatory bowel disease that lead to dislocation of gut bacteria ; but alsE. coli strain was capable to elicit a weak serum IgG response. They also found that these serological antibodies bind to antigens expressed on the E. coli membrane, as well as cytosolic antigens. Among these cytosolic proteins, the serum IgG antibodies predominantly bind to ribosomal proteins. Systemic IgG was also found to mainly bind to bacteria of the phylum proteobacteria [Many central studies on the effects of the GM on the systemic natural antibody repertoire were using GF mice as model systems. GF mice show an overall impaired B cell development and are at a deficit of natural autoantibodies, while showing increased susceptibility for bacterial infections . In an ebacteria .In the entirety of natural antibodies, also self-reactivity is a common characteristic. It is not unlikely to consider a cross-reactivity of anti-microbial antibodies and self-antigens, as many proteins are highly conserved and have homologues in higher vertebrates. For example, autoantibodies to heat shock proteins are frequently found in sera of diseased and healthy individuals ,70. ThisThe known immunoglobulin repertoire to commensal microbiota and the repertoire of natural antibodies exhibit some similarities. As shown for GM induced immunoglobulins , naturalThe human GM is priming the host immune system for the production of polyreactive, low-affinity antibodies as integral component of the natural antibody repertoire that serves as first broad defense line against potential pathogens. It forms a part of the innate immune system before a highly specific adaptive immune response is established. Constant stimulus of the commensal microflora helps to maintain this steady-state antibody repertoire and therefore plays a key role in immune homeostasis. In fact, natural antibodies were shown to bind several microbial and viral antigens without prior immunization, supporting the hypothesis of a function as innate defense mechanism ,76. HoweChanges in the GM have been linked to a manifold of diverse conditions, not only concerning gut health. These range from autoimmune diseases to neurodegenerative disorders and even show associations with different malignancies. A common cause for systemic diseases in association to the commensal microflora is the occurrence of dysbiosis or translocation of bacteria. Dysbiosis can be caused by changes in diet or usage of antibiotics, but also by pathogenic microorganisms, causing inflammation and alterations of the gut barrier . This caThe quality of the gut colonization can be a surrogate for general health and disease state, which is also discussed for the natural antibody repertoire. Whether there is a general causality of intestine dysbiosis and alterations in the natural (auto)antibody repertoire needs to be addressed in future studies. Currently, it cannot be clearly determined, whether gut dysbiosis and inflammation with subsequent alterations in immune homeostasis have a direct influence in autoimmune disease development. The causes for the onset of autoimmune disorders remains unknown and the mechanisms leading to pathology are not finally clarified. The loss of immunological self-tolerance is suggested to be a result of a genetic predisposition in combination with various environmental traits. Among these environmental factors, the influence of infectious processes is the most widely studied. However, the influence of microbiota, especially in the gastrointestinal tract, has also gained much interest, as changes in the GM are correlated with disease onset and progression ,82. AsidRoseburia intestinalis, a common gut colonist, and the autoepitope β2-glycoprotein I in antiphospholipid syndrome. This concept is known as molecular mimicry and is suggested to be one of the main reasons for the occurrence of autoimmune diseases. Molecular mimicry is based on similarity between microbial proteins and autoantigens. Here, sequence homologies in highly conserved proteins, e.g., the family of heat shock proteins, are especially prone to be affected by antibody cross-reactivity. However, mere systemic exposure to bacterial structures does not necessarily induce autoimmune processes, as host HLA-DR genotypes are crucial for autoimmunogenic potential of the microbial antigens [A weakened or impaired mucosal gut barrier can lead to the emergence of autoimmune diseases caused by translocation of gut microbiota. This causes a systemic immune response to the translocated microbes by secretion of IgG antibodies. In some cases, autoimmune disorders can arise in this context, when a cross-reactivity of antibodies to microbial antigens and self-antigens with high target specificity occurs. This was recently supported by Ruff and colleagues , who repantigens .Recent studies found that not only the translocation of gut microbiota is able to cause the onset of autoimmune disorders, but also the composition of the microbiome plays an essential role. A correlation between the quality of gut colonization and autoimmunity has been reported in various diseases including systemic lupus erythematosus (SLE) ,86,87, rHeliobacter pylori were found to be elevated in the serum or cerebrospinal fluid of AD patients [H. pylori infection and PD, also via related autoantibody secretion detected in sera of PD patients [Neurodegenerative diseases are also impacted by an imbalance of gut microbiota and associated immune dysregulation. The central nervous system and the enteric nervous system are linked through communication via the gut-brain-axis ,91. Beyopatients ,97,98. Tpatients ,100. Levpatients .Megamonas and Bacteroides plebeius was decreased, while Escherichia coli, Prevotellaceae and Enterobacteriaceae were found to be increased [Studies in ophthalmology provide more evidence for the interplay of GM and immune system that drives pathology. Current investigations on this topic include studies of primary open-angle glaucoma (POAG), age-related macular degeneration and diabetic retinopathy . Studiesncreased . Anotherncreased  showed tThe three disorders PD, AD and POAG share not only the commonality of altered GMs, patients also show alterations in their natural serological (auto)antibody repertoire, which have further been suggested as disease biomarkers ,105,106.The development and engineering of synthetic immune-related pharmaceuticals, particularly therapeutic antibodies, is a rapidly growing market and offers great perspectives for the medical management of various diseases. Nevertheless, high manufacturing costs and large time investments are still the limiting factors for the large-scale production of such macromolecules and illustrate the urgent need of alternative strategies in pharmaceutical development. Humanization of antibodies by CDR grafting and phase-display technologies represent the gold standard for designing antibodies with high affinities for specific target molecules , but alsSLE is as a chronic autoimmune disease mainly characterized by a systemic dysfunction of B and T cells, increased production of autoantibodies (AAB) and the enhanced formation of immune complexes . PatientBased on the previous preclinical data, the drug compound Edratide (an optimized pCDR1) developed by the company Teva Pharmaceutical Industries was tested in a human clinical trial phase II . EdratidAbnormal protein deposits are one of the common hallmarks in neurodegenerative disorders such as AD and PD and several new approaches have been developed to prevent the enhanced accumulation of these toxic protein aggregates in neuronal tissues such as the brain ,129. OneThe major advantage of gammabodies is that they are already biologically active at sub stoichiometric concentrations  and can inhibit fibril formation and their cytotoxic effects even at the nanomolar scale ,131. In However, so far the clinical application of gammabodies as therapeutic agent resulted in the amelioration of Aβ-induced cognitive defects in a high-fat-diet-induced obese rodent model for AD . In concGlaucoma is a slowly progressive neurodegenerative disease characterized by the loss of retinal ganglion cells (RGCs) and their axons resulting in irreversible blindness of the patients. In a recent publication of our group it was proven that the synthetic CDR1 peptide (CDR1 motif: ASGYTFTNYGLSWVR) triggers neuroprotective effects on RGCs during glaucomatous-like conditions ex vivo and is caused by direct interaction with the target molecule High temperature requirement protein A2 (HTRA2) . InteresThe newest findings of our group verified the inhibitory effect of synthetic CDR1 on the protease function of HTRA2 and is most likely caused by physical interaction with the PDZ domain . FurtherIn addition, the neuroprotective CDR1 sequence motif was revealed by quantitative mass spectrometry profiling of the highly diverse antibody repertoire in glaucoma patients  and is mMalignant and metastatic melanoma is one of the most aggressive forms of skin cancer and is responsible for 60–80% of lethal cases worldwide . The malThe synthetic peptide C36L1, which encodes the CDR1 from the variable light chain of an anti CD33 antibody, was identified first as bioactive molecule in a drug discovery screening for cancer therapy and showed cytotoxic effects against murine melanoma cells and a panel of human tumor cell lines in vitro . AnotherAnother antitumor effector mechanism was elicited by synthetic cyclic peptide Rb9, which represents the VHCDR3 of the monoclonal antibody RebMab200 and original targets the NaPi2B phosphate-transport protein. Synthetic Rb9 induced hyper-adherent effects, suppression of cell migration and decreased matrix invasion in murine melanoma cells and in other human cancer cell lines in vitro . Using mBesides that, the research group of Polonelli and Travassos also screened other synthetic CDR derived peptides such as AC-101 H3  and Rb44The studies presented in this review emphasize the importance of the gut microbiome on the host’s immune system. Based on the gathered evidence, the commensal microflora is hypothesized as continuous trigger for the formation and maintenance of the natural antibody repertoire. Disturbances in the complex homeostasis between GM and the natural humoral immunity is associated with various diseases. The explicit connection of commensal microbiota and natural antibodies remains underexplored and this assumption, however, is for the most part based rather on correlation then causality. Therefore, there is an urgent need to address this important topic in future studies. Nonetheless, immunomodulatory features can be exploited for specific therapeutic purposes. The present review further summarizes the great advantages of synthetic CDR peptides and specifically engineered gammabodies for the medical treatment of various diseases ranging from neurodegeneration and autoinflammation to highly aggressive and metastatic cancer types. All listed publications illustrate the versatile medical application areas of these small and highly bioactive drug compounds and will certainly make a huge contribution towards the field of personalized translational medicine in the future.


The growing number of pooled studies could improve the prediction ability of dose-effect relationships for space exposure and reduce their uncertainty level. Novel research in the field is of paramount importance to reduce damages to astronauts from cosmic radiation before Beyond Low Earth Orbit exploration in the next future. The study aims at providing an overview of the published dose-effect relationships and illustrates novel perspectives to inspire future research.Space radiobiology is an interdisciplinary science that examines the biological effects of ionizing radiation on humans involved in aerospace missions. The dose-effect models are one of the relevant topics of space radiobiology. Their knowledge is crucial for optimizing radioprotection strategies , the risk assessment of the health hazard related to human space exploration, and reducing damages induced to astronauts from galactic cosmic radiation. Dose-effect relationships describe the observed damages to normal tissues or cancer induction during and after space flights. They are developed for the various dose ranges and radiation qualities characterizing the actual and the forecast space missions [International Space Station (ISS) and solar system exploration]. Based on a Pubmed search including 53 papers reporting the collected dose-effect relationships after space missions or in ground simulations, 7 significant dose-effect relationships  have been identified. For each considered effect, the absorbed dose thresholds and the uncertainties/limitations of the developed relationships are summarized and discussed. The current knowledge on this topic can benefit from further  Space radiobiology (SPRB) is a fascinating field that has fostered a growing interest in the recent years, thanks to the increased technological capability to travel and operate in space and the consequent renewed interest from the national space agencies to plan exploratory and colonization space missions.The space radiation environment is a complex mixture of radiation species dominated by highly penetrating charged particles from different sources . In thisPlanetary magnetic fields and short-term and long-term solar activities modulate the energy spectrum and abundances of radiation species . In addiSuch particles can penetrate several hundreds of centimeters of materials, such as aluminum or tissue/water and fragment before stopping, producing lower Z secondary particles through nuclear interactions. A lower linear energy transfer (LET) characterizes the secondary particles. Such characteristics confer a higher penetration range than the primary particles .ad hoc shielding  is caused by intense and short exposure to SPEs in case of crews unable to reach areas with adequate shielding. Late radiation morbidity  is associated with continuous exposure to GCR, which is substantially different both qualitatively and quantitatively from the natural background of the radiation of Earth, depending on various above-described factors .in vitro cell or in vivo small animal studies. Such models explain and predict the clinical and subclinical effects recorded during space missions. In addition, it is possible to use clinical diagnostic or radiotherapeutic devices for performing a ground simulation of GCR scenarios and improving the space exposure radiobiological model understanding, due to the similarity of dosage and type of available particles. Moreover, the complete understanding of non-targeted effects induced by charged particles becomes mandatory  AND (radiotherapy[title/abstract] OR space[title/abstract]) AND (radiobiol* [title/abstract] OR dose [title/abstract]).The performed PubMed search uses the query string reported below to identify the proposed models for acute and late effects related to space mission/exposure and compare these effects with the threshold reported in the diagnostic or therapeutic applications using ionizing radiation. Query search included the following keywords/string: space[title/abstract] model[title/abstract] radiobiolThe research had been restricted to the last 10 years to include only the most recently published studies. The last search was done on August 30, 2021. The authors independently reviewed titles and abstracts to decide study inclusion. Full articles were retrieved when the abstract was considered relevant, and only papers published in English were considered. The bibliographies of retrieved and reviewed papers were also examined to identify other relevant articles to be included and published before 2011. Papers were considered eligible when reporting models and dose-effect correlations.*) to very high (*****) values. The reliability of models has been reported considering the number of revealed effects, statistical approaches, and information on dose and GCR spectrum and its modification through shielding materials. We also include an attempt to score the priority for future research considering the possible impact on a long-term mission in deep space, the availability of advanced facilities, and the possible synergies with related medical fields using ionizing radiation.Analyzed effects included, among others, eye flashes, cataracts, CNS effects, cardiovascular disease (CVD), biomarkers including chromosomal aberrations, cancer induction , and other possible risks never evidenced in astronauts but investigated as possible long-term irradiation for future missions to Mars and Moon . In the Based on Pubmed/Medline search, 61 papers have been found. Among this, 54 were original papers reporting/proposing radiobiology or dose-effects models, while 8 were reviews or relevant reports . About 24 papers mainly focused on data obtained from astronauts or spaceflight crews, while 37 were generated using ground experiments and/or simulations. Other reports or commentary papers were included in the discussion.The identified models based on available data from spaceflight missions or ground/simulation data have been described in The effects of radiation exposure in space can manifest themselves at different times; short-term  are observed immediately and are transient, medium-term  after several weeks/months depending on the absorbed dose, and long-term  can also occur many years (10 to 30) after exposure. The performance, characteristics, limitations, and uncertainties of these dose-effect models are discussed in the following paragraphs.−2 eye flashes per minute (20 in about 420 min of observation).More in detail, the first description of the biological consequences of the space radiation exposure on human cells was the subjective sensations of lights on eyes, commonly called eye flashes, first observed by Apollo crews . The oriCataract risk from space radiation seems linear without a threshold caused by genetic damage leading to aberrant cellular differentiation of lens epithelial cells , 12. HowThe systematic investigation of lens opacification among US astronauts studied by Cucinotta et al.  comparesP = 0.015). Cross-sectional data analysis revealed a small deleterious effect of space radiation for cortical and possibly posterior subcapsular cataract lens opacities. These results suggest increased cataract risks at smaller radiation doses than have been reported previously.The NASA Study of Cataract in Astronauts (NASCA) , 15 is aP = 0.062).Preliminary analyses of 5 years of data with an average of 3.8 exams per subject found no relationship between radiation exposure and progression rates for posterior subcapsular cataracts and nuclear cataracts, e.g., the estimated median progression rate from space radiation being 0.25 ± 0.13% lens area/Sv/year , while late CNS risks comprise neurological disorders, such as premature aging and Alzheimer's disease or other dementia.The risks of CNS are of concern for long-term exploration missions to Mars or other destinations, while the possible observation of CNS effects in astronauts participating in the past NASA missions is highly unlikely because in low earth orbit (LEO), the astronauts are partially protected by the magnetic field of the Earth, the lengths of past missions which are relatively short, and the small population size of astronauts .56Fe particles) can significantly impair learning and memory in a rodent model, while Hienz et al. . Several studies have been conducted to simulate the GCR radiation using heavy-ion or proton beams to provide evidence for the CNS health risk for missions outside of LEO. Britten et al.  have shoz et al.  demonstrRadiosensitive animals exhibited significant changes in proteins associated with dopamine receptors and transporters in the brain at mission-relevant doses and dose rates. These results indicate that susceptibility should be considered in dose-effect models predicting the radiation-induced CNS changes . FurtherSpace travel may cause cognitive detriments associated with changes in neuron morphology and plasticity. Observations in mice revealed a dependence on radiation quality and absorbed dose, suggesting that microscopic energy deposition plays an important role. Simplified 3D neuron models with properties equivalent to realistic neuron morphology have been developed using GEANT4 to describe the effect observed in rats after a dose from 0.1 to 2 Gy delivered to the hippocampus . Of noteRadiation-induced impairment of neurogenesis is a concern due to its reported association with cognitive detriments after exposure to low doses of high charge and energy particles. The possible risks to astronauts chronically exposed to space radiation could prevent astronauts from performing complex executive functions , 24, 25 Cacao E and Cucinotta FA in 2016  reportedMore recently, the first quantitative meta-analysis of the dose-response for proton and heavy-ion rodent studies has been published based on the widely used novel object recognition test, which estimates detriments in recognition or object memory . The logBased on a group of 84 flight astronauts, Delp et al.  found noCVD from low-dose radiation exposure represents an important issue for space missions  and radiRadiotherapy and recent epidemiological studies have suggested that an increased risk of CVD may also arise from low-level exposure . The stuAdditional information relied on groups of workers exposed to ionizing radiation. The latest study by Azizova et al.  examinedThe International Nuclear Workers Study (INWORKS) has recently investigated CVD mortality among over 300,000 workers from the United States, United Kingdom, and France, reporting a statistically significant increase of ERR per sievert being 0.22 , based on the cumulative recorded occupational dose received from external photons .However, the authors highlighted that the significant heterogeneities of workers preclude a reliable interpretation of the CVD ERR results. A 2008 study done by McGeoghegan et al.  on a subA study of CVD incidence from 1986 to 2012 using the data derived from the medical examinations of 53,772 Russian liquidators working in the Chernobyl zone during the first year after the accident found highly significant ERR per sievert estimates for the incidence of CVDs , 38.At present, there is an indicative evidence for a link. However, overall, the findings at low-dose exposure are not yet persuasive due to the possible influence of major nonradiation risk factors (concomitant exposure to organic solvents and acids) on the reported associations and possible misclassification of cause of death and various potential selection effects , 39.About 3% risk of exposure-induced death is generally used as a basis for setting age- and gender-specific dose limits for astronauts based on the National Council on Radiation Protection and Measurements (NCRP) report no.132 . After aCancer is a stochastic risk, and for this reason may occur even at shallow doses (defined as doses <100 mGy) which is currently estimated using the Linear-No Threshold model (LNT) according to the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) , the IntOf note, the uncertainties of cancer risk predictions to exposure to GCRs have been described within the linear-additivity model using the approach of Monte Carlo sampling from subjective error distributions. One of the sources of uncertainties is related to the behavior of quality factors (QFs) of the particles constituting the GCR at low doses. This issue represents the central gap of knowledge to quantify the overall uncertainty in risk projections. The function of particle type or charge number and energy of QFs have been intensely investigated using track structure models , 49. MorHigh-LET radiation is more efficient in producing complex-type chromosome exchanges than sparsely ionizing radiation, and this can potentially be used as a biomarker of radiation quality. Chromosomal aberrations in blood samples of astronauts increase with absorbed doses .The blood lymphocytes of the astronauts were analyzed before and after 3–4 months long duration missions to investigate the complex chromosome exchanges . The pooSimilarly, Yang et al.  showed tFurther, they estimated a relative biological effectiveness (RBE) of 2.8 for the Mir-18 mission space radiation environment. To perform the RBE, they calculated the ratio between the estimated equivalent dose from chromosomal aberrations (14.75 cSv) and the measured physical absorbed dose (5.2 cGy). The dose equivalent was derived from a dose-response relationship based on the blood samples of preflight astronauts irradiated at various doses using gamma rays.Similarly, Cucinotta et al.  showed tTwo biological response models were compared to the Mir biodosimetry for chromosome aberration in lymphocyte cells; a track-structure model and the linear-quadratic model with LET-dependent weighting coefficients. Both models are in reasonable agreement with data for aberrations in the lymphocytes of Mir crew members. Of note, the difference in the models is the increased effectiveness predicted by the track model for low charge and energy ions with LET near 10 keV/micrometres, indicating that aluminum shielding, although providing necessary mitigation of the effects of trapped radiation, provides no protective effect from the GCR in LEO . No signGao et al.  reportedSome of the proposed biomarkers to predict the risk of carcinogenesis include complex clustered DNA damage, persistent DNA repair foci, reactive oxygen species, chromosome aberrations, and inflammation. Other biomarkers discussed, often assayed for a longer period of postexposure, include mutations and telomere length changes .Experiments performed at the NASA Space Radiation Laboratory revealed that heavy ions induce expression of the TGF-β1 isoform, which can modulate late post-radiation changes and increase the risk of tumor development and metastasis even when cells were irradiated with doses as low as 0.1 Gy . FurtherProteins, microRNAs (miRNAs), and transfer ribonucleic acid (tRNA)-derived fragments in serum showed great potential as early biomarkers of exposure to energetic heavy ions and might be helpful in dose reconstruction and risk assessment of heavy-ion exposure in deep space exploration . These b56Fe-particle, radiation impacts on hippocampal glutamatergic neurotransmissions at 3 and 6 months after exposure, which might play a critical role in learning and memory, likely causing neurocognitive impairment  during extended space flights has been described as related effects . The effin vitro 3D human organotypic skin tissue model to low doses of high LET oxygen (O), silicon (Si), and iron (Fe) ions to investigate the integrity of the barrier function of the skin, which was maintained at various particles and doses  that contribute to the radiation dose within the spacecraft. The average radiation dose for the seven deceased Apollo crew was 0.59 ± 0.15 cGy (range 0.18–1.14 cGy). Using similar assumptions, astronauts in LEO would receive 50–100 mSv over a 6–12 month stay, of which the GCR would account for approximately two-thirds of this total dose. Thus, given their mean mission duration of 15.6 days, the deceased LEO astronauts would receive ~0.29 cGy, a GCR dose similar to the Apollo lunar astronauts. The estimated dose for the shortest round-trip to Mars would be in the order of >0.6 Sv .In addition, radiation risk assessment during long-term space flights has an extremely high level of uncertainties due to the space-radiation environment, the solar magnetic field activity, and the presence of shielding with different capabilities of reducing the incident radiation, thus producing heterogeneous secondary radiation particles. Early estimates of the uncertainty on cancer mortality risk due to space radiation ranged from 400 to 1,500%, with more precise estimates showing uncertainties at the 95% confidence level of 4-fold times of the point projection .Evidence shows that, at least in part, the eye flashes seen by astronauts are correlated with charged particles traversing the retina, but further studies of the role of the flux of all the GCR particles need to be investigated. Eye flashes have been the first phenomenon suggesting the possible damage to the central nervous system of the astronauts.Cataract risks for astronauts have been reported at doses (8 mSv) lower than ones proposed in the European Directive 53/2013 15–20 mSv) for workers –72. A de–20 mSv fHowever, longer follow-up may be needed to understand better regarding the impact of space radiation on cataract progression rates and characterize visual acuity changes.Space radiobiology studies of CNS effects using particle accelerators simulating space radiation and experimental models attempt to assess the CNS risk relevance relative to doses, dose-rates, and radiation quality expected on a Mars mission . HoweverOne of the most promising ways to prevent and mitigate the acute effects of CNS and the neurocognitive impairment during long-term spaceflight is based on the use of substances  . These aCardiovascular disease due to the ionizing radiation is of paramount interest for radiotherapy treatment being still one of nowadays the most critical side effects of the treatment, nevertheless the high target conformal capability of modern accelerators. CVD depends on the heart and the lung doses  and pretIn spaceflight studies, the correlation between CVD risk and absorbed doses is negative, while in ground-based studies, a relationship between CVD risk and low-level exposure to ionizing radiation is reported . One of In conclusion, a comprehensive CVD risk prediction model has not yet been achieved. Further investigation is strongly recommended before long-term exploration of space missions.Galactic cosmic ray spectrum can induce cancer, cognitive deficits, changes associated with premature ageing, and degenerative effects in many organs. Most epidemiologic data results from the astronaut cohort are from exposures incurred on missions during the Space Shuttle era, where <100 mSv was accumulated by an astronaut. Nevertheless, the nominal mission length for astronauts has increased to at least 6 months in duration with exposures of 1 mSv to 1.5 mSv per day, depending on the phase of the solar cycle, the number of spacewalks performed, and the level of solar activity .Even with increasing mission length and radiation exposures, it is noteworthy that no astronaut has been diagnosed with cancer attributable to space radiation to date. Although the sample size is small, follow-up times for significant exposures are limited, and cancer latency periods are from years to decades. Epidemiology studies from human exposures to gamma radiation may help predict the cancer risks attributed to GCR, but further work is needed to validate these findings. Age- and gender-specific dose limits based on incidence-based risk transfer for NS are used for a more accurate estimation of cancer risk. Gaining knowledge to improve transfer models, which entails knowledge of cancer initiation and promotion effects, could significantly reduce uncertainties in risk projections .In addition, the uncertainties in estimating the risks for late effects (including cancer) from space radiation exposures arise from the variability and complexity of the radiation fields due to multiple interactions with the vehicular spacecraft or human tissues. Moreover, the limited radiobiology data using high energy and high LET particles increase the uncertainty of the radiation quality and the expected dose-rate effects , 83. In Ad hoc Monte Carlo calculation tools  and radiotherapy studies. Ionizing radiation produces a significant effect in increasing chromosomal aberrations and chromosome break, and production of dicentric and ring. For this reason, chromosome gaps are very sensitive and act as helpful biomarkers to predict radiation-induced acute and late effects –96.Robust predictive models are essential to managing the risk of radiation-induced carcinogenesis. It is critical to identify early sensitive and late biomarkers that can unravel how radiation-induced cellular stress alters the risk of carcinogenesis and improves the modeling of individual risk of cancer or other long-term health consequences of exposure .Study on the biological effects after exposure to high LET particles used for radionuclide therapy might further contribute to ground simulation studies and to fully understand the biological effects on radiation-induced chromosome damage in peripheral blood lymphocytes .Auspicious preliminary results have shown that blood cytokine levels, and in general, the alteration of immune system parameters can be considered biomarkers of low doses of radiation exposure.The identification of predictive biomarkers to determine both the received radiation dose (biodosimetry), as well as the radiosensitivity of individuals, may be an essential aspect for future crew selection .At the state of the art, few models have a reliable and accurate estimation of the dose-effects correlations due to the complexities of the flux of GCR particles and their interactions with the human tissues. Data from radiotherapy might help to improve the risk models for space radiation  as for rSpace radiation and microgravity are recognized as primary and inevitable risk factors for humans traveling in space, but the reports regarding their synergistic effects remain inconclusive, and various studies highlight differences in the environmental conditions and intrinsic biological sensitivity –61.The remarkable progress made in cancer research during the last decade indicated that low=dose radiation could lead to various alterations in immune system parameters, including natural killer cell activation modulation of blood cytokine levels, which plays a crucial role in cancer development –104 as wThe expected absorbed dose range to oral cavity (2–10 Gy) for astronauts is broadly lower than the threshold for the induction of oral mucositis reported for Grade 2 or more toxicity using carbon ion therapy  or cumuFurther studies are mandatory to guide the development toward novel medical applications and to protect the astronauts during space exploration.For this reason, the improvements for health hazards related to space exploration are a unique opportunity for the safe conduction of space missions. The first ground-based GCR simulator of NASA  enables Several limitations have been pointed out regarding the capability of the existing accelerator-based test facility to emulate the particle fluxes of spacecraft or planetary atmosphere shielding. The introduced uncertainties are relatively small for the solid cancer risk while they are challenging to estimate for CNS or other hazards .Due to the new interest in human space exploration, the European Space Agency (ESA) is currently expanding its effort in identifying all the necessary research activities to create a European Space Radiation Risk Model (ESRRM)  and to oin vitro or in vivo ad hoc experiments or analyze the available information from the cohort of cancer patients, thus reinforcing our knowledge on cancer and non-cancer space-radiation induced effects. Unfortunately, the number of events helpful in modeling the radiobiological effects is still limited. Consequently, functional dose-effect models/relationships and their uncertainties need further improvement, and we suggest implementing future research to increase the understanding of biological mechanisms.Cancer and toxicity risks remain not accurately quantified despite the technological developments and conceptual advances of space radiobiology and considerable efforts. In the latest years, significant improvements have been made in the absorbed dose-effect estimation and the construction and development of novel ground-based galactic cosmic ray simulator facilities. Technological advancements might realize the dream of human space exploration, and crewed spaceflights to explore and colonize the Moon and Mars are on the agenda of space agencies. Radiological devices or linear accelerators might help conduct AB and LS conceived the manuscript and produced the first draft. AB, SS, and LS contributed to the Pubmed search. All the authors contributed to the critical discussion on the dose-effect models for space and improved the manuscript. All the authors approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Surgical resection is currently the mainstay of treatment for tracheobronchial mucoepidermoid carcinoma (TMEC). The parenchymal sparing secondary carinal resection and reconstruction for TMEC under the uniportal thoracoscopic approach has seldomly been reported in the literature. Here, we report a case of a 42-year-old male patient complaining of the incidental finding of a 1.5 × 1.2 cm neoplasm at the opening of the right bronchus intermedius and a 5.1 × 3.1 cm patchy lesion located at the left upper lobe by chest CT scans in February 2021. This patient successively underwent fiberoptic bronchoscopic biopsy of the bronchial neoplasm and CT-guided biopsy of the left upper lobe lesion. Pathological examination confirmed the diagnosis of the endobronchial mass in the right bronchus intermedius as low-grade mucoepidermoid carcinoma and left upper lobe lesion as tuberculosis. This patient successfully underwent uniportal thoracoscopic parenchymal sparing tumor resection, reconstruction of the secondary carina and lymphadenectomy at our center. Intraoperative frozen section showed no residual cancer at any bronchial stumps. Postoperative pathology indicated that no metastases were seen in any of the resected lymph nodes. The patient recovered well after surgery. He received a 9-month course of anti-tuberculosis treatment postoperatively. He did not complain of any special discomfort and there was no local recurrence at the 9-month postoperative follow-up. Although technical demanding, this case highlights that uniportal video-assisted thoracoscopic parenchymal sparing secondary carinal resection and reconstruction for TMEC is safe and feasible with the preservation of lung function and excellent outcomes. Tracheobronchial mucoepidermoid carcinoma (TMEC) is a rare malignant tumor of the lung originating from the seromucous submucosal glands of the lower respiratory tract, accounting for ~0.1–0.2% of all lung malignancies  and the fact that lung parenchymal resection might lead to decreased quality of life, the patient underwent a single-port thoracoscopic tumor resection, reconstruction of the secondary carina and systemic lymph node dissection  in March 2021 . The patTMEC was first reported by Smetana et al. and originates from the seromucous submucosal glands in the lower respiratory tract and has the gross appearance of an exophytic endobronchial circumscribed mass . The symThe aim of surgical resection is to completely remove the tumor with lymph node dissection while preserving as much of the lung parenchyma as possible . DependiUniportal thoracoscopic surgery is nowadays a well-established and popular thoracic surgery. However, single-port VATS bronchoplasty, which requires experience in microscopic sewing, tying and suturing, is still a major technical challenge for the thoracic surgeon . In addiInterventional bronchoscopic therapy, as a simple and reproducible minimally invasive treatment modality, can control and relieve the symptoms of airway obstruction due to bronchial tumor . It has In this paper, we report the first case of single-port thoracoscopic parenchymal sparing right secondary carinal resection and reconstruction and systemic lymph node dissection for the treatment of TMEC. Obviously, a right upper lung sleeve resection is simpler and more likely to ensure negative margins. However, given the patient's 30+ year history of bronchial asthma, resection of a lung lobe would have meant a reduced quality of life. Tension-free suturing of the airway is important for bronchial reconstruction. Some authors recommend interrupted sutures to facilitate better size matching, less anastomotic ischaemia and to avoid suture loosening and winding. Considering the technical difficulty of using interrupted sutures under a single hole, a continuous suture minimizes the difficulty of suturing and also avoids the interference of visualization and suture manipulation caused by having multiple sutures in the incision at the same time. Therefore, we have adopted continuous sutures for bronchial anastomoses. In addition, the anterior bronchial wall is reinforced with interrupted sutures and the anterior mediastinal fatty tissue is freed to cover the anastomosis, further reducing the risk of postoperative bronchopleural fistula or anastomotic dehiscence .In conclusion, this case highlights that uniportal video-assisted thoracoscopic parenchymal sparing secondary carinal resection and reconstruction for TMEC is safe and feasible under the hands of surgeon with extensive VATS experience. It can preserve lung function and result in excellent short-term outcomes. Moreover, further follow-up is required to assess the long-term outcomes of this patient.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Clinical Research Ethics Committee of the Second Xiangya Hospital. The patients/participants provided their written informed consent to participate in this study.YH drafted and edited this manuscript, assisted in the surgery, and analyzed patient data. XC, SR, CZ, LW, PX, and FY analyzed patient data. WL performed the surgery, edited this manuscript, and analyzed patient data. All authors read and approved the final manuscript.This work was supported by National Natural Science Foundation of China , the Natural Science Foundation of Hunan Province, China (2019JJ30038), the Hunan Provincial Key Area R&D Program (2019SK2253), the Scientific Research Program of Hunan Provincial Health Commission (20201047), and the Clinical Medical Technology Innovation Guide Project of Hunan Province (S2020SFYLJS0311).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This article discusses the fracture modelling accuracy of strain-driven ductile fracture models when introducing damage of high strength sheet steel. Numerical modelling of well-known fracture mechanical tests was conducted using a failure and damage model to control damage and fracture evolution. A thorough validation of the simulation results was conducted against results from laboratory testing. Such validations show that the damage and failure model is suited for modelling of material failure and fracture evolution of specimens without damage. However, pre-damaged specimens show less correlation as the damage and failure model over-predicts the displacement at crack initiation with an average of 28%. Consequently, the results in this article show the need for an extension of the damage and failure model that accounts for the fracture mechanisms at the crack tip. Such extension would aid in the improvement of fracture mechanical testing procedures and the modelling of high strength sheet metal manufacturing, as several sheet manufacturing processes are defined by material fracture. Over the past decades, the automotive industry has continuously strived to reduce the product development time in order to increase their competitiveness and profit. By the use of numerical modelling with the Finite Element method (FEM), it is now possible to perform virtual testing of components with high accuracy, thus reducing the amount of costly experiments and prototyping. However, with extended use of computer aided engineering in the product development process comes new challenges and demands on the numerical FE-modelling. One of the challenges of numerical FE-modelling is how to accurately describe damage generation in terms of micro-cracks, sharp notches and voids. Damage markedly affects sheet formability and part performance of high strength metallic sheets, such as Advanced High Strength Steels (AHSS) or high strength aluminium alloys. Most manufacturing defects in such materials are related to the edge cracking phenomenon, that is, the generation of small cracks at sheared (damaged) edges during stretching or bending. Regarding part performance, crash resistance involves the generalized cracking (damage) prior to final fracture. High strength metallic sheets are widely used for automotive lightweight constructions. Thus, FE-analysis of sheet metal forming and crash modelling requires numerical models that accurately handle damage, that is, the formation and propagation of cracks.Shear cutting of high strength sheet metals is such process where the material separation involves the formation of cracks, and inherited damage from the cut affects the formability of the part. Publications by Konieczny and Henderson , DykemanCasellas et al.  showed ta et al.  proposeda et al.  proposedNumerical modelling of the shear cutting process is a challenging forming operation to simulate, as shear cutting involves both large material deformation, shear failure and duplex crack initiation. In addition, the numerical failure model should be able to handle a large range of stress states. The complex failure assessment is conventionally managed by strain-driven ductile failure models with stress state dependency. This was done by Hambli and Potiron , who impIt is clear that the intended area of usage differs between strain-driven ductile failure models and fracture mechanics, but for the numerical analysis of the shear cutting process there is an apparent need for both a failure assessment of undamaged material and crack tip analysis. To investigate the applicability of using only strain-driven ductile failure models for processes involving cracks, such as shear cutting, the authors of this article perform numerical modelling of cracked high strength sheet steel without taking notch effects or crack-tip singularities into account. The current work focuses on well-known fracture mechanical lab tests in order to ensure controlled crack initiation and propagation. Results from the laboratory tests were compared with corresponding simulation results using the Generalised Incremental Stress State Dependent Damage Model (GISSMO) as a ductile failure model in order to investigate how cracks limit the modelling accuracy. The laboratory tests experience Mode I crack opening with a minimum of uncertain details such as friction, dynamics or joints. The simplicity of the validation cases makes them suitable when evaluating the numerical modelling as every assumption made for the model can cause deviation from the actual load case. The material investigated is a complex phase steel with an ultimate tensile strength of 1000 MPa approximately and high ductility (named as CP1000HD from now). It is an AHSS grade with 1.5 mm thickness, commonly used for automotive crash components due to its high strain hardening rate and ductility.In this work, the Generalised Incremental Stress State Dependent Damage Model (GISSMO) was used for damage and failure modelling. GISSMO was developed by Neukamm et al.  and exten is the damage exponent.The damage accumulation rule is defined by Neukamm et al.  accordinD and the damage value at material instability m controls the non-linearity and the exponential damage coupling.When the accumulated damage value reaches Equation , where iF controls when damage/stress coupling is initiated and accumulates in a similar way as the damage value D, as shown in Equation  was investigated by tensile testing of four different notched specimen geometries shown in . The tenThe true plastic strain–true stress curve of the CP1000HD material is shown in Digital image correlation (DIC) and strain field evaluation provided the possibility of measuring the local strain field of the necked specimen at crack initiation. The Stepwise Modelling Method developed by Marth et al.  enabled Equation . SjöbergWith the stress-triaxiality and failure strain data from the four tensile testing specimen geometries in erzbicki  and the As plane stress conditions are assumed for sheet metal, the lode angle parameter in Equation  can be eThe calibrated MMC curve for plane stress is shown in For solid elements, it is necessary to include lode angle parameter dependency for the fracture locus, thus obtaining a surface of failure strain values that spans the full ranges of triaxialities and lode parameter values. With the the MMC parameters Equation . The MMCThe experimental triaxiality testing data presented in m and damage exponent n were also calibrated along with the failure strain-trixiality curves. The damage and failure model calibration flowchart is shown in m and n in Through the use of the optimisation software LS-OPT, the failure strain-trixiality curves were scaled in order for the numerical modelling results from the R3.75 FE-model to better match the force displacement tensile testing response of the R3.75 specimen. The fading exponent ECRIT data for the damage and failure model model.The characteristic element length of the R3.75 specimen mesh used throughout the damage and failure model calibration was 0.1 mm. No mesh regularisation was performed as the damage and failure model model was intended to use on models with the same element size. The authors of this article defined the instability point for this particular CP1000HD material as the Validation of the numerical models was done by experimental testing of the standardised VDA 238-100 bending test and by double edge notched tensile (DENT) testing. In both tests, the cracks initiate and propagate under Mode I, that is, constantly under tensile loading. The bending test specimens have been machined and do not present cracks or surface defects. Meanwhile, two types of specimens were prepared for DENT; with and without fatigue pre-cracks, that is, with and without damage. The presence of the fatigue cracks in the DENT specimen provided the opportunity to investigate the effect of crack tip stress concentration and compare the results to uncracked (undamaged) material loaded in bending and tension. The isotropic piecewise plasticity model presented in The VDA 238-100 bending test widely used in the automotive industry to characterise the local formability of metal sheets. It is described with the VDA 238-100  standardMeasurements of the elastic deformation of the tool accounted for the vertical stiffness of the bending punch. One exception from the VDA 238-100 recommendation was made during the testing presented in this article. Instead of using rollers mounted on bearing, the rollers were fixed and lubricated by teflon paper. The modification of the experimental setup was not considered to influence the validity of the results.The double edge notched tensile (DENT) test is increasingly used for measuring fracture toughness of thin sheets according to Casellas et al. and Frómeta et al. ,12,13. TResults from notched and cracked DENT specimens are used to evaluate how accurately the ductile failure model can mimic the failure behaviour of AHSS thin sheets with and without the presence of cracks. In notched DENT specimen, the notch root endures substantial plastic work and necking before fracture, whereas for cracked DENT specimens, the pre-existent cracks imposes high stress concentrations at the crack tip and the plastic deformation is limited to a more narrow plastic zone.The experimental testing of the DENT specimen was conducted following the essential work of fracture methodology described in the work of Casellas et al. . Both foLS-Dyna was used to perform numerical models of the triaxiality tensile testing, VDA 238-100 and DENT testing of the CP1000HD sheet metal. Discretization of the various sheet metal geometries was done with fully integrated 8-nodes solid hexahedral elements. The characteristic element length at the area of localisation and the failure of the specimens was Simulations of the triaxiality testing specimens in The modelling of the DENT testing resembled the tensile testing models presented in Since the CP1000HD damage and failure model was calibrated for matching the force-displacement results from the R3.75 tensile testing, the correlating results between simulation and experiment in The comparison between experimental and simulation results for notched DENT specimens are shown in Comparing the equivalent strain field of the DENT ligament for both cracked and notched DENT specimen right before crack initiation is a supplementary indication of the modelling accuracy. The good correlation between experiments and simulation for VDA 238-100 and notched DENT in However, the study of cracked DENT specimens in z et al. , Wang anz et al.  and Zhanz et al.  in interThis work shows that strain-driven ductile failure modelling of crack-tip analysis cannot be used to predict the crack initiation of cracked high strength sheet metal. The results show an over-prediction of roughly 28%, which consequently causes the following crack propagation to be invalid as well. This holds even if the failure model accurately describes the large scale failure of undamaged material. As the numerical modelling presented in this article fails to describe the fracture initiation at the crack tip, it sets the basis for further development of fracture models to overcome the identified limitation.The experimental and numerical results presented in this article identify the need for a damage and failure model that extends strain-driven ductile failure models such as GISSMO with the capabilities of treat cracked materials with a triaxiality dependent ductile fracture. This extension enables the refinement of fracture mechanical testing procedures, such as the EWF methodology, if the numerical modelling can provide insight into crack nucleation occurring at positions hidden from the DIC camera.Furthermore, an extended strain-driven ductile failure model is required to enhance the accuracy when modelling sheet manufacturing processes involving crack propagation phenomena. This is the case of many forming processes, where the sheet is fractured and separated, such as trimming, blanking, punching, and so forth. When high strength materials, such as AHSS or high strength Al alloys, are manufactured, the part quality is largely affected by the crack propagation resistance exhibited by the material. Such behaviour implies that material models should accurately account for the crack initiation and propagation.Additionally, improved capabilities of modelling crack initiation and propagation will consequently aid in rationalising cracking behaviour in metallic sheets. It will definitively help to predict and minimize the edge cracking phenomenon that originates from sheared edges and is a great concern for part manufacturers when using high strength materials.In this study, the capabilities of predicting crack initiation and propagation using a strain-driven damage and failure model were evaluated through correlation with experiments consisting of both cracked and un-cracked specimens. The following conclusions were drawn:


Anxiety disorders are globally one of the most prevalent and disabling forms of psychopathology in adults and children. Having a parent with an anxiety disorder multiplies the risk of anxiety disorders in the offspring, although the specific mechanisms and processes that play a role in this intergenerational transmission remain largely unknown. According to information processing theories, threat-related biases in cognitive processing are a causal mechanism in the development and maintenance of anxiety. These theories propose that individuals with anxiety are more likely to cognitively process novel stimuli in their environment as threatening. Creswell and colleagues proposed a theoretical model that highlighted the role of these cognitive biases as a mechanism in the intergenerational transmission of anxiety  Information processing biases and anxiety: a developmental perspective, Wiley, pp 279–295, 2010). This model postulated significant associations between (1) parents’ and children’s threat-related cognitive biases (2) parents’ threat-related cognitive biases in their own and their child’s environment, (3) parents’ threat-related cognitive biases and parenting behaviors that convey anxiety risk to the offspring , and (4) parenting behaviors and child threat-related biases. This theoretical review collated the recent empirical work testing these four core hypotheses of the model. Building on the reviewed empirical work, an updated conceptual model focusing on threat-related attention and interpretation is proposed. This updated model incorporates the links between cognition and anxiety in parents and children and addresses the potential bidirectional nature of parent–child influences. Anxiety disorders are among the most prevalent and disabling forms of psychopathology in adults and children across the globe  were incorporated per section if available. Earlier empirical studies reviewed by Creswell et al.  were briThe model by Creswell et al.  postulatThe first empirical studies addressing the similarities in the threat interpretations of parents and children used the ambiguous scenarios task in 7-to-15-year-old children and their parents  using the visual probe task relied on a clinical sample of mothers with (versus without) lifetime panic disorder and their 9-to-14-year-old daughters  and child negative search bias in a sample of 8-to-13-year-olds in two experiments. In the first experiment, child search bias about novel animals was measured before and after children listened to the descriptions of the novel animals from their parents who were instructed to display a negative (versus positive) search bias about these animals during an information search task  are needed to investigate a potential moderation of this link by anxiety diagnosis. Moreover, in view of the current variability in instruments used to measure anxiety and information processing biases, future empirical studies should consider integrating two or more of these instruments in a single design. Ultimately, it will be important to consider the effects of the current variability in the sample characteristics, in the instruments, and the operationalization of the constructs of anxiety and the biases in information processing in future meta-analytic studies.Another important question that awaits further investigation is whether the hypothesized association may be more clearly captured across different stages of information processing of parents and children, rather than at corresponding stages. De Lijster and colleagues measured attention biases of mothers, fathers, and their 8-to-17-year-old children in the visual probe paradigm with threatening versus neutral faces and child interpretations of threat using ambiguous scenarios task in a single design  revealed significant links between parents’ interpretation of ambiguous situations involving themselves and their 4-to-10-year-old children  mothers  would allow the study of change and stability of these associations over time.d = 0.25, van der Bruggen et al., The available evidence indicates that anxious versus non-anxious parents are more likely to perceive ambiguous situations involving themselves or the child as more threatening, and less controllable, and hold more negative expectations of their own and their child’s experience of distress and threat in these situations  anxiety/worry and fear-enhancing parenting behaviors at the start of schooling as a real-life ambiguous situation. The findings reveal that parental social anxiety or worry alters parents’ verbal information in a way that resembles the negative information manipulation by the two experimental studies  children measured before and after they engaged in a family discussion of these scenarios , or in the measurement of child attention. No studies, however, have yet investigated the links between parenting and child attention in experimental designs. Thus, the idea that decreased levels of parental autonomy granting during child confrontations with novel situations trigger child attention bias to threat remains to be investigated.The link between parental overcontrol and child perceptions of distress, coping, and performance was investigated in a sample of 6-to-14-year-olds and their anxious (versus non-anxious) mothers in the study by Becker and colleagues  on child reactions studied the effect of parental modeling and threat information transmission on child behavioral reactions in the lab. Despite consistent evidence of a significant effect of anxious parents’ modeling of non-verbal anxiety displays in novel situations on child observed avoidance as early as in infancy , Fliek and colleagues . For example, providing parents with negative versus positive, or ambiguous information about unknown animals triggered higher levels of parental threat narratives about the animals paired with negative versus positive information  reveal that parents may contribute to the strengthening of initial anxious dispositions in child information processing by encouraging threat interpretations and avoidant solutions to ambiguous scenarios during family discussions. There is also preliminary support for the idea that children whose parents show more controlling parenting show higher levels of threat interpretations. The limited research on the direct link between parental autonomy granting and child attention bias has revealed mixed findings that may be explained by the differences in the parenting constructs studied, as well as in the measurement of attention bias. The reviewed studies also show some support for a link between parental autonomy granting and child negative predictions/perceptions of distress levels and performance in stressful situations.Concerning fear-enhancing parenting, the evidence summarized in this section reveals a significant effect of parental fear-enhancing parenting behaviors  on child cognitive bias towards novel stimuli at the level of fear beliefs. More recent evidence relying on child and parent reports of fear-enhancing parenting revealed a direct link between fear-enhancing parenting and child cognitive biases at the stages of interpretation and confirmation of threat. Moreover, this line of research brings important insights on the mediational role of child cognitive bias in the link between fear-enhancing parenting and child anxiety. This work also highlights the bidirectional nature of the links between child cognitive bias and fear-enhancing parenting. For future research, it will be important to validate questionnaire measures of fear-enhancing parenting in studies that incorporate observations of this construct. There is also some evidence suggesting that maternal fear-enhancing parenting in the form of verbal and non-verbal anxiety expressions prior to a stressful task may be related to child negative perceptions of coping. Future studies will need to further investigate the specificity of this effect across the domains of distress, coping and performance before and after the task. Finally, the lack of empirical studies on the associations of fear-enhancing parenting with child attention marks another important direction for future research.This theoretical review collated recent empirical work testing the four core hypotheses of the model on the intergenerational transmission of anxious information processing biases by Creswell and colleagues . The worFirst, the construct of  cognition was limited to threat interpretations in the original model as there was little or no empirical work at the time testing the hypothesized links at other stages of information processing. Although recent studies have increasingly started to address some of the hypothesized links in attention .Another adjustment concerns the directionality of the postulated associations between parental dimensions and child cognition . These were unidirectional in the original model by Creswell and colleagues , Fig. 1,Moreover, although the causal links between anxiety and information processing of threat in parents and children are at the core of the model on the intergenerational transmission of cognitive biases  on parenting and child cognitions. In addition, the earlier evidence reveals the possibility that parental bias at earlier stages of information processing may impact the bias at later stages of child information processing, whereas the interrelations between different stages of processing are not depicted in the updated model. Developmentally sensitive longitudinal designs that entail bidirectional influences at different stages of information processing in parents and children, together with parent and child anxiety, will be crucial for a better understanding of the shared information processing styles in parents and children.Developmental time frames and mechanisms. The available evidence does not allow any conclusions on the developmental time frames of the hypothesized associations, as the majority of empirical work relied on cross-sectional correlational designs. Future research should adopt a developmental approach to investigating the hypothesized links by testing the associations in longitudinal designs measuring the constructs of interest. This would provide insight into the timeline and the direction of the hypothesized associations. In a related vein, the developmental mechanisms explaining the hypothesized links remain unknown. Future longitudinal studies should incorporate genetic and environmental mechanisms that may account for the emergence and/or the maintenance of the hypothesized links.Threat bias across different stages of information processing. The available empirical work on the hypothesized associations predominantly relies on the investigation of threat interpretations, whereas biases in parents and child information processing have not been simultaneously addressed across different stages of information processing. Future research should consider testing these associations in longitudinal studies that integrate the assessment of child and parent cognitions in two or more stages of information processing.Measurement of threat bias. The methods and instruments used in the measurement of threat-related bias in parents and children not only showed considerable heterogeneity across studies, but were also limited with respect to reliability and ecological validity, and prone to measurement errors (such as single-respondent bias and demand characteristics). Recent advances in mobile eye-tracking technologies provide a unique opportunity to capture child cognitive biases in real-life situations while integrating the measurement of cognitive biases across various stages of information processing  to investigate a potential moderation of the hypothesized associations by parental or child anxiety diagnosis/symptoms.Parental influences. The available evidence does not answer the question of whether the hypothesized links between parental cognitions and parenting and child cognition differ across mothers and fathers, as most studies focused on mothers. In addition to the differential parental influences, the joint effect of maternal and paternal influences in two-parent families is an important area for future research.General limitations characterizing the empirical work addressing the model by Creswell and colleagues (2010) are outlined below to set the main directions for future work.The postulated associations raise the question of whether training parents’ cognitive bias can indirectly contribute to child anxiety interventions. A study that targeted mothers’ child-related cognitions using an interpretation modification program revealed that the beneficial effects of such parental training do not always generalize to child cognition or behavior Benoit, . Thus, i


Fractures of the hamate bone are an unusual clinical entity. Dual fractures involving both the body and the hook of the hamate are even more unique, with only two previous cases described in the literature, to our knowledge. Clinicians are often unfamiliar with the presenting signs of this unusual injury, and subsequently, diagnosis is often delayed or missed entirely. We describe the case of a 19-year-old male who sustained an intra-articular body of hamate fracture with an ipsilateral hook of hamate fracture in his dominant hand. He presented 10 days following the initial injury and was managed with open reduction and internal fixation (ORIF). Isolated carpal fractures are uncommon. Solitary hamate fractures are particularly rare, accounting for 2-4% of all carpal bone fractures . Due to Overlooking this unique bony injury can result in mal- or nonunion and a progressive sequela of osteoarthritis and chronic pain .This report is aimed at increasing awareness of hamate fractures and their patterns of injury. The authors highlight the importance of maintaining a high level of clinical suspicion in the context of traumatic ulnar-sided wrist pain, to ensure timely diagnosis and appropriate management of these uncommon injuries.We, the authors, present the case of a healthy 19-year-old right hand-dominant male who presented to our emergency department (ED) with pain and swelling in his right wrist. His clinical history was significant for trauma to his right hand, having punched a plank of wood whilst intoxicated 10 days prior to presenting to ED. Apart from a 1 pack-year smoking history, our patient had no medical comorbidities and was unemployed.th metacarpophalangeal (MCP) joint which the patient reports as longstanding from a previous injury; examination of the remaining MCP joints and interphalangeal (IP) joints was otherwise normal. There was no tenderness over the anatomical snuffbox, and the proximal limb was unremarkable.On clinical examination, there was generalized tenderness and mild oedema over the right wrist joint, with maximum tenderness over the volar ulnar aspect. Range of motion of the wrist was reduced secondary to pain, with maximum discomfort on wrist flexion. There was no clinical evidence of neurovascular deficit, and grip strength was not compromised. A deformity was noted over the dorsal aspect of the right 5Given the clinical concern for bony injury, an X-ray of the right wrist was performed including posteroanterior and oblique views. Carpal tunnel and specialised lateral views were omitted due to the patient's limited range of motion secondary to pain.Plain films were suggestive of a dual hamate fracture Figures , and a crd-5th metacarpals, and a Futura splint was applied to be worn 24/7 until outpatient review.The following day, the patient underwent open reduction and internal screw fixation of the body and hook of hamate by consultant orthopaedic hand surgeon and senior author RP. A K-wire was used to stabilise the 3Peri- and postoperative films showed satisfactory reduction and alignment Figures . The patThe patient was reviewed 1 week postoperatively at our dressing clinic; his wound was healing well with no evidence of superficial infection. He attended clinic 4 weeks postoperatively; repeat X-rays showed stable fixation and satisfactory alignment of the carpal arch Figures , and theHamate fractures are unusual and pose considerable diagnostic and therapeutic challenges.The hamate is located at the ulnar aspect of the distal carpal row, a wedge-shaped bone with a curved prominence, namely, the hamulus or “hook” . Milch cth and 5th digits [The hook is the most commonly fractured part of the hamate bone . Extendih digits .Mechanism of injury of concurrent fractures of the body and hook is postulated to be a combination of direct and indirect forces resulting in ulnar axial injury –4.th and 5th metacarpals to the body of hamate, followed by indirect traction and avulsion of the hook [Such as in our patient's case, injury to the hamate body commonly occurs when a clenched fist strikes a solid surface. First impact occurs axial to the forearm, encountering the clenched fist which transmits the impact through the 4the hook –4.th and 5th flexor tendons travels through the hamulus and may result in a fracture [Fractures of the hamate bone occur more frequently amongst athletes, particularly racquet games, baseball, and golf . In thisfracture .Physical examination of the hamate bone can be challenging to interpret. Clinicians are often unfamiliar with the anatomy of the carpal arch and superimposed hypothenar tissues, leading to misdiagnoses and a subsequent delay in management .rd metacarpal head [The pisiform bone neighbours the hamate and acts as a useful landmark to guide clinical examination. The hamate can be more clearly palpated along the line extending from the pisiform to the 3pal head .Presentation can be variable, reported cases describe minimal swelling, and point tenderness elicited over the dorsal aspect of the hamate and pain whilst gripping an object or during supination and pronation of the wrist .Radiographic investigations are an essential adjuvant to diagnosing and further characterizing hamate fractures. Plain radiographs are typically the first investigation performed in the emergency department for suspected bony injuries . Hamate Plain film X-ray has a sensitivity of 72.2% and specificity of 88.8%, inferior to that of high-resolution computed tomography (HR-CT) with a reported sensitivity 100% and specificity 94.4% . SubsequComplications of hamate fractures are not uncommon, particularly in cases of delayed diagnosis. Overlooked pathology and misdiagnoses can result in non- or malunion and a progressive sequela of osteoarthritis, chronic pain, and potential dysfunction , 12, 13.Unlike scaphoid fractures, avascular necrosis is fortunately a rare event with hamate fractures, owing to its triple vascular supply .th and 5th CMC joints [Management aims of hamate fractures are stabilisation of the articular surface of the distal hamate and maintaining function of the 4C joints , 17.Stable fractures without articular involvement can be managed by closed reduction and cast immobilisation or splinting, with consideration for any related soft tissue injury .Surgical management is advocated for displaced fractures or articular fractures involving more than 1/3 of the CMC articular surface .Dual fractures involving both the body and hook of hamate are inherently unstable and require surgical fixation . IsolateGiven the intrinsic instability of the fracture configuration in our patient's case, we felt it was optimal to address the hook of hamate fracture concurrently during fixation of the body of hamate fracture. Given the size and orientation of the hook fragment, the authors agreed that it was better suited to compression screw fixation rather than excision.In 2005, Kapickis et al. reported a case of a combined left hook and body of hamate fracture of a left hand-dominant male, who successfully managed with ORIF . In 2012Due to the nature of injury, carpal bone fractures usually occur in the patient's dominant hand, as in our patient's case. Restoring and maintaining function is paramount, particularly given the usual cohort of patients who present with these injuries and young males of working age with a severe injury to their dominant hand.Dual fractures of the body and hook of hamate are exceedingly rare. With increased popularity of racket sports, the incidence of carpal bone fractures is likely to increase. Physician unfamiliarity and discrepancy in presentation are complicated by sophisticated anatomy; this injury is commonly overlooked clinically and underreported radiologically.The authors present to our knowledge the first case of a delayed presentation of a combined intra-articular body and hook of hamate fracture described in the literature.We hope that through reporting our experience, this case will raise awareness of hamate fractures including their presentation and potential mechanism of injury. We encourage other clinicians to report these unusual bony injuries if encountered, to help aid timely diagnosis and appropriate management.