This review focuses on the potential use of SynCom in IBD and its advantages and relative safety over conventional FMT. Additionally, this review reinforces how various technological advances could be combined with SynCom to have a better understanding of the complex microbial interactions in various gut inflammatory diseases including IBD. Some technological advances including the availability of a gut-on-a-chip system, intestinal organoids, ex vivo intestinal cultures, AI-based refining of the microbiome structural and functional data, and multiomic approaches may help in making more practical in vitro models of the human host. Additionally, an increase in the cultured diversity from gut microbiota and the availability of their genomic information would further make the design and utilization of SynCom more feasible. Taken together, the combined use of the available knowledge of the gut microbiota in health and disease and recent technological advances and the development of defined SynCom seem to be a promising, safe, and sustainable alternative to conventional FMT in treating IBD.The human intestine harbors a huge number of diverse microorganisms where a variety of complex interactions take place between the microbes as well as the host and gut microbiota. Significant long-term variations in the gut microbiota (dysbiosis) have been associated with a variety of health conditions including inflammatory bowel disease (IBD). Conventional fecal microbiota transplantations (FMTs) have been utilized to treat IBD and have been proved promising. However, various limitations such as transient results, pathogen transfer, storage, and reproducibility render conventional FMT less safe and less sustainable. Defined synthetic microbial communities (SynCom) have been used to dissect the host-microbiota-associated functions using gnotobiotic animals or  The intestinal tract of the majority of animals including human beings is colonized by complex microbial communities since birth, called the microbiome. The composition of the microbiome differs between individuals, shows unique spatiotemporal organizations, and has a significant role in the host health and disease . Thanks The recent technological advances and utilization of a variety of accurate approaches have further made it possible to monitor and accurately analyze the intestinal microbial community composition and how the functionality and structure of the microbiome vary in healthy and diseased individuals. This has led to remarkable success in correlating the microbiome in health and disease. Currently, the host intestinal microbiome has been associated with a variety of diseases, including various inflammatory diseases of the intestine, cancer, and obesity which are extensively reviewed recently . Other mThere is a gigantic amount of literature supporting the role of microbiota in health and disease. However, various ethical, medical, and microbiological concerns make it hard to establish causal relations between the microbiota and host. The use of fecal microbiome transplantations (FMTs) is an exception though, in which the intestinal microbiota of the healthy donor is transferred to a diseased individual (recipient). FMT-based interventions in humans recently caught the attention of the scientific community. This is because FMT has shown promising results in treating a variety of diseases, indicating that the intestinal microbiota does play a role in influencing the physiology and health of the host.Following the success of FMT in treating ulcerative colitis (UC) and recurrent CDI patients over a prolonged period of 56 years, FMT-based treatments are now making their way to target several other diseases. And it all started with an important case to mention, the one reported in 1989 by Dr. Justin D Bennet , who sufInflammatory bowel disease (IBD) is a worldwide disease in the 21st century . It is aThe exact cause of IBD is unknown. However, an inappropriate mucosal immune response against millions of antigens from food, environment, and microbiome in a genetically and/or immunologically predisposed host is believed to play a role in the pathogenesis of IBD . Mucosalα) antagonists, anti-interleukins, and anti-integrins. These drugs can induce and maintain remission from inflammatory episodes; however, they can cause serious side effects including increased risk of infections and certain cancers [IBD is a public health challenge worldwide for the health professional to treat. Patients with IBD can experience symptoms at a young age , necessi cancers . This mahttps://clinicaltrials.gov/) was conducted using various search terms such as fecal microbiome transplant, Clostridium difficile infection, Ulcerative colitis, IBD, and microbiota transplants to extract information related to trials utilizing FMT in these gut health conditions. A total of 78 clinical trials were enlisted, which were investigating the efficacy of FMT in CD or UC. Among these, 22 trials are completed and only four studies are with results whereas two studies were terminated based on the interim analysis results [P < 0.001). However, RCTs are lacking for CD, and various uncontrolled cohort studies with small sample sizes have revealed mixed results. For instance, using meta-analysis, a 52% remission rate was reported among 71 CD patients who received FMT [Clostridium difficile infection (rCDI), and a meta-analysis revealed that FMT could result in significant outcomes for treating rCDI in IBD patients  compared to non-IBD patients [There is a shred of growing evidence backing the gut microbiome's role in IBD pathogenesis . Diversi results , 35. The results –37. Two  results , 35. In  results . Moreoveived FMT . Howeverived FMT . Furtherived FMT . Becausepatients . AdditioEscherichia coli bacteremia. The source of infection in both patients was tracked back to the same donor stool. One of the two patients expired [FMT-based therapies seem to be a promising treatment option for a variety of diseases including IBD; however, it has a variety of limitations resulting in transient and adverse outcomes . One of  expired . FMT-med expired –45. ThisAnother important concern is the reproducibility and sustainable long-term use of FMT for a stable outcome. Though FMT shows promising results in the case of CDI, in other diseases such as IBD, it usually ends in the transient outcome. This indicates the complexity of the host-microbiome interactions and the low-key technology and poor practices leading to the loss of the major fraction of the original microbiota. Since each individual carries a unique and stable microbiota, it becomes very important to identify a healthy donor microbiome and ensure the reproducibility of the exact replica of that microbiome for long-term sustainable use and stable clinical outcome. Several factors lead to the loss of a major fraction of the fecal microbiota and thus transient results. For instance, majority of the intestinal microbes are strictly anaerobes, and fecal samples are mostly processed under aerobic conditions, which will instantly kill the anaerobes . On the The human gut harbors a diverse array of microorganisms, and it is quite challenging to assess how individual microbes interact with the host and to understand microbiome-mediated functions. Culture-based approaches have been used to decipher host-microbiome interactions; however, various limitations such as only a minute fraction of the total gut microbiota being culturable make these approaches difficult to understand host-microbiome interactions –53. ThisC. botulinum infection, fecal C. botulinum toxin excretion, and colonization pattern [almonella enterica serovar Typhimurium colonization and was even relatively better than ASF-based communities [Helicobacter hepaticus in the presence of normal ASF flora was determined in IBD [The SynCom approach has been widely utilized to determine its safety and functionality in various pathological conditions . Though  pattern . Resultsmunities . So far,d in IBD . This flThough SynCom has a broad range of practical applications in decoding the functional prospects of host-microbiota, still it is unclear whether the SynCom-based outcomes observed in most of the animal models used could be replicated in humans and closely related other hosts as well. The fraction of the organisms cultured so far from the human gut is so small relative to the total microbial diversity of the gut. Therefore, there is a dire need to cultivate more organisms from the gut. Particular emphasis should be on culturing organisms that are abundant in the gut but are still not cultured or with very few cultured members. One such example is the Verrucomicrobia phyla, which are usually present in abundance in the human gut, but so far the cultured members are limited to few representative strains. Once we have enough number of cultured representatives of the gut microbiome, only then will we be able to design better SynCom which could then be of more practical use in human hosts.The recent technological advances in the field of multiomics including but not limited to structural and functional metagenomics, metatranscriptomics, metaproteomics, metabolomics, and the ease of big data analysis have been largely utilized to elucidate the structure and function of the host-associated microbiota . Few bigRecently, the concept of the core microbes has been introduced, suggesting that certain bacterial groups are critical for maintaining the structure and function of the gut microbial community –63. Howein vivo. Also, this approach allows one to test and transfer the outcomes in the laboratory, and the output can ultimately be translated and utilized at a broader scale such as the treatment of various gastrointestinal conditions including IBD via SynCom-based transplants.SynCom comprising of several culturable bacterial isolates of the human gut could be one such alternative to address the limitations of conventionally used FMT as well as those posed by the inherent complexity of the gut microbiota. The use of SynCom may shed light on how the dynamics of gut microbial community composition contribute to IBD development in terms of intermicrobial interactions: physical, chemical, and genetic interactions. Moreover, the use of SynCom in model organisms would further explain the underlying functional mechanisms and intermicrobial as well host-microbiota interactions leading to disease or health. Therefore, defined SynCom stand as the only promising validation tool for host-microbiota-associated function dissection A variety of clinical trials have assessed the efficacy of conventional FMT in various gastrointestinal disorders including IBD . MoreoveVarious human microbiome-related studies have explored the microbial community structure that lives in association within the human gut . Additio


Many studies shown that neurological diseases are associated with neural mitochondrial dysfunctions and microbiome composition alterations. Since mitochondria emerged from bacterial ancestors during endosymbiosis, mitochondria, and bacteria had analogous genomic characteristics, similar bioactive compounds and comparable energy metabolism pathways. Therefore, it is necessary to rationalize the interactions of intestinal microbiota with neural mitochondria. Recent studies have identified neural mitochondrial dysfunction as a critical pathogenic factor for the onset and progress of multiple neurological disorders, in which the non-negligible role of altered gut flora composition was increasingly noticed. Here, we proposed a new perspective of intestinal microbiota – neural mitochondria interaction as a communicating channel from gut to brain, which could help to extend the vision of gut-brain axis regulation and provide additional research directions on treatment and prevention of responsive neurological disorders. Human body is a super organism composed of own cells and resident microorganisms. In the long-term co-evolutionary process, human gut microbes, and the hosts constantly selected and adapted to each other, bringing about a close symbiotic relationship presently . While mBrain is one of the most energy-consuming organ in the body . Neural Alphaproteobacteria, the phylogenetic relationship of the mitochondrial endosymbiont to extant Alphaproteobacteria is yet unclear . However, the relationship between Helicobacter pylori infection and neurological inflammation or AD remains unclear. It has been reported that toxin VacA secreted by Helicobacter pylori can migrate across the blood-brain barrier  in autoimmune CD8 + T cells, which could enter the brain to attack dopamine neurons and cause a sharp decrement in the density of dopaminergic axon expansion in the striatum, leading to movement disorders like Parkinson’s disease (PD) in mice . Effects fission . Helicob barrier , which c barrier . Since i barrier , it coulpression . These sEscherichia coli) could regulate mitochondrial respiration and play an important role in the early development of the nervous system by activating the mammalian target of rapamycin (mTOR) signaling pathway , serotonin (5-HT), and dopamine (DA). These neurotransmitters have been found to be closely in mitochondrial function. For example, GABA can pass through mitochondrial membrane, and regulate citric acid cycle reaction. The distribution mode of GABA is believed to play a critical role in regulating its cytoplasm levels; Conversely, increased mitochondrial activity can reduce GABAergic signaling, resulting in defective social behavior . Recent Escherichia coli (via p38 MAP kinase signaling (Caenorhabditis elegans can induce mitochondrial unfolded protein response in the intestine (Turicibacter sanguinis in the intestine, and Turicibacter sanguinis can affect the expression of multiple pathways including lipid and cholesterol metabolism in intestinal (Reciprocally, mitochondria can also regulate the intestinal microbiota. Studies have shown that mitochondria play an important role in the innate immune response to pathogen infection . In addihia coli . In addihia coli . Moreoveignaling . Clinicaignaling , Parkinsignaling , and Hunignaling , often sntestine . These rtestinal . Combinetestinal , we can The understanding of intestinal system has been revolutionized over the past decades, especially in regarding to its physiological and pathological interconnection with brain function. The crosstalk between gut microbiota and central nervous system, which is also known as the microbiota-gut-brain axis have been well elucidated from numerous studies. Numbers of evidence has confirmed that mitochondria can be regulated by the composition of gut microbiota, and mitochondria are also closely related to the physiological and pathological state of the nervous system. In addition, although there are few studies on how gut microbiota directly regulate the physiological and pathological functions of the brain through the mitochondrial pathway, or how the nervous system regulates the composition of gut microbiota through the mitochondrial pathway, the evidence had been gradually reported in recent years. This perspective proposed a hypothetical model about cross-talk between the intestinal microbiome and the neural mitochondria based on the previously known fact that the mitochondria and the bacteria have the evolutionary homology. Symbiont and pathobiont bacteria have the influence to control the neuronal mitochondrial activity. We highlighted the new role of mitochondria in dialog with gut microbiota across the blood-brain barrier, which is one of the important ways of communicating between the brain and gut . The newThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.YZ performed the statistical analysis. ZZ, LW, YL, QZ, and YS wrote the manuscript. All authors contributed to the article and approved the submitted version.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.


Methods: We systematically searched PubMed, Science Direct and MedRxiv for relevant articles published in English up to March 16, 2021. We included quasi experimental studies, clinical trials, cohort studies, longitudinal studies, case-control studies and interrupted time series. We included the studies that investigated the effect of the implemented public health measures to prevent and control the outbreak of 2019 novel coronavirus disease (COVID-19).In December 2019, a novel coronavirus (2019-nCoV) was recognized in Wuhan, China. It was characterised by rapid spread causing a pandemic. Multiple public health interventions have been implemented worldwide to decrease the transmission of the 2019 novel coronavirus disease (COVID-19). The objective of this systematic review is to evaluate the implemented public health interventions to control the spread of the outbreak of COVID-19. The database search using the predefined combinations of Mesh terms found 13,497 studies of which 3595 in PubMed, 7393 in Science Direct 2509 preprints in MedRxiv. After removal of the duplicates and the critical reading only 18 articles were included in this systematic review and processed for data extraction.Public health interventions and non-pharmaceutical measurements were effective in decreasing the transmission of COVID-19. The included studies showed that travel restrictions, borders measures, quarantine of travellers arriving from affected countries, city lockdown, restrictions of mass gathering, isolation and quarantine of confirmed cases and close contacts, social distancing measures, compulsory mask wearing, contact tracing and testing, school closures and personal protective equipment use among health workers were effective in mitigating the spread of COVID-19. In the twenty-first century, two highly pathogenic human coronaviruses (HCoVs) severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) emerged from animal reservoirs to cause global epidemics. In December 2019, yet another pathogenic HCoV, 2019 novel coronavirus (2019-nCoV), was recognized in Wuhan, China, and has caused serious illness and death  affectinWithin this systematic review we aimed to evaluate the public health interventions and the non-pharmaceutical control measures that have been implemented worldwide to mitigate and control the spread of the outbreak of 2019 novel coronavirus disease (COVID-19).We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . The proWe included articles published only in English language up to March 16, 2021, clinical trials, quasi experimental studies, cohort studies, longitudinal studies, case-control studies, and interrupted time series. The studies that investigated the effect of the non-pharmaceutical interventions such as social distancing, lockdown, quarantine, mobility and travel restrictions, border control measures, contact tracing, isolation of cases that have been implemented to mitigate, prevent and control the outbreak of 2019 novel coronavirus disease (COVID-19). We excluded articles published in a language other than English; narrative literature reviews, policy reviews, case studies, case reports, case series, cross-sectional studies, ecological studies, commentaries, editorials, letters, point of views, simulation studies, modelling studies, prediction studies, qualitative studies,systematic reviews and meta-analysis.The database search was conducted by one author (AI) who did the tiles and abstracts screening in order to identify the eligible studies for full text review with referral to (MJ) and (DW). Both authors  did the full text review of the studies that potentially met eligibility criteria and checked their relevance with referral to a third author (MJ) in case of discordance. Any discrepancy between the reviewers was resolved by discussion.Two authors  did the data extraction using a standardized form to collect the relevant data from each article. The form included study identification features , study characteristics , characteristics of the studied population, public health interventions that has been implemented (description of the intervention(s) and control(s) if applicable), outcomes and authors’ conclusions. The included studies were evaluated for quality and risk of bias using the Effective Public Health Practice Project (EPHPP) quality assessment tool quantitative studies . All stuThe database search in PubMed and Science Direct using the predefined combinations of Mesh terms found 13,497 studies of which 3595 in PubMed, 7393 in Science Direct 2509 preprints in MedRxiv. After removal of the duplicates 12,433 articles remained. During the screening stage one article was excluded as it was retracted and 12,139 records were excluded on basis of title and abstract. After the critical reading of the 293 remaining articles, 275 articles were excluded seeing that they didn’t meet the eligibility criteria and only 18 articles were included in this systematic review and processed for data extraction. Fig. We found that public health interventions and non-pharmaceutical control measures were effective in reducing the transmission of COVID-19 and were associated with reduced epidemic growth. The identified studies showed that travel restrictions, borders measures, quarantine of travellers arriving from affected countries, city lockdown, restrictions of mass gathering, isolation and quarantine of confirmed cases and close contacts, social distancing measures, compulsory mask wearing, contact tracing and testing, school closures and personal protective equipment use among health workers were effective in mitigating the spread of COVID-19 with varying degrees. Our results are in line with the findings of other studies –34 that Travel and entry restrictions, borders measures and quarantine of travellers arriving from affected countries were effective in controlling the spread of infection caused by SARS-CoV 2. Those interventions have been shown to be effective as well in other studies  , 35, whiCity lockdown, restriction of mass gathering physical distancing and stay at home policies has been shown to be effective as well in reducing the spread of SARS-CoV2 in the current study. Further studies support these findings and showed that lockdown measurements and stay at home orders were efficient in controlling and slowing down the spread of the epidemic –39 were Isolation and quarantine measures of contacts and close contacts adding to contact tracing are crucial to control the outbreak of COVID-19 and reduce the human to human transmission. Those results are consistent with the findings of other studies –48 whichCompulsory mask wearing and community wide masking policies are essential in controlling the pandemic of COVID-19. Authors of a rapid systematic review  on the eSchool closures had been found to be effective in reducing the transmission of COVID-19, recently this intervention has been widely discussed; some studies , 56 founFurther studies , 60 founThis systematic review has several limitations, the included studies have heterogeneous methodology and most of them lack a control group and a vigorous study design. Although most of the included studies have moderate quality and for the remaining studies; two studies have low quality and only two studies have strong quality. Also, most of the included studies have moderate level of evidence and low grade of recommendation, six studies have low level of evidence and low grade of recommendation, only one study has moderate level of evidence and grade of recommendation and only one study as well has high level of evidence and grade of recommendation. In addition to that most of the public health interventions are implemented simultaneously or within a short period of time which means that it is difficult to evaluate the effect of each intervention alone accurately, consequently we can either underestimate or overestimate their impact on the COVID-19 pandemic. Future research studies which have rigorous methodology especially experimental and quasi experimental studies are needed to properly evaluate the outcomes of these public health interventions and non-pharmaceutical measures.With no effective treatment and vaccine against SARS-CoV-2, public health measures and non-pharmaceutical interventions are vital to reduce the infection and mortality rate. Some interventions are not efficient enough when implemented alone and could not contain the outbreak, thus, depending on the country and the phase of the epidemic multiple interventions are needed to be applied together in order to bring the outbreak under control.


Hyperspectral reflectance imaging in the short-wave infrared range  has proven to provide enhanced characterization of paint materials. However, the interpretation of the results remains challenging due to the intrinsic complexity of the SWIR spectra, presenting both broad and narrow absorption features with possible overlaps. To cope with the high dimensionality and spectral complexity of such datasets acquired in the SWIR domain, one data treatment approach is tested, inspired by innovative development in the cultural heritage field: the use of a pigment spectral database  combined with a deep neural network (DNN). This approach allows for multi-label pigment classification within each pixel of the data cube. Conventional Spectral Angle Mapping and DNN results obtained on both pigment reference samples and a Buddhist painting (thangka) are discussed. However, for semi-conductor type pigments ruled by electronic transitions with selective absorption in the visible region, the DNN approach also provided efficient labeling and mapping of both pure pigments and pigment mixtures. As such, the reflectance spectra of the chemical compound present characteristic spectral variation apprehended by the model. As an example, the appropriate classification of the pixels containing minium could be explained by a variation of its absorption coefficient in the SWIR domain. For spectra acquired on pellet and mockup samples, a broad decrease in reflectance intensity was observed from 1330 to 1800 nm. Further work should be specifically carried out to determine the origin of such intensity variations and identify the spectral behavior of semi-conductor pigments in mixtures and superimpositions. In the region from 1000 to 2500 nm, the approach was expected to provide efficient mapping of pigments that present overtones and combination bands associated with vibrational transitions of molecular bonds involving mainly hydrogen, carbon, nitrogen, oxygen, and related functional groups. As an example, with characteristic absorption maximum in the NIR region, corresponding to a [νFollowing the results on mockup samples, the mapping of several pigment classes is obtained using the DNN model on a historical Buddhist painting a, previo2(CO3)2(OH)2) pigment, characterized by the presence of absorption bands at 1491, 2285, and 2352 nm (2CO3(OH)2), with characteristic absorption features at 2274 and 2352 nm  is properly identified as the main pigment in the aureole of the central divinity, some clothing parts of the smaller divinities, and in the red decoration surrounding the bottom-right figure. As described previously, a decrease in the reflectance spectrum is observed from 1330 to 1800 nm, and this feature is redundant and characteristic of red areas painted using minium pigment  and vermilion . The DNN-based mapping is consistent with the location proposed in the visible range b,d. MiniFor the yellow area, the presence of As confirmed by p-XRF and the presence of an inflection point located at 500 nm in the VIS-RIS spectra indicate the use of an orpiment pigment. The DNN model allows the mapping of the As-based compound, in accordance with VIS-RIS and p-XRF results b,c, in t2 groups of the animal skin glue, which include features near 2041 nm and 2176 nm, can be differentiated [The SWIR signals in the white and pink areas are similar and present absorption bands at 2275, 2105, and 1930 nm, and a very broad band centered at ca. 1490 nm , are labeled as carmine-rich paint material . The twoThe DNN approach proposed in this study offers new possibilities in the SWIR range to identify and map pigments in complex materials either for unknown mixtures or multi-layered systems. Applied to both mockup and historical paintings, the DNN model has been proven to outperform the most common classification technique in the field known as SAM. DNN allows a more representative mapping of the pigments of interest, which results from the multi-labeling proposed by the approach  and the multiple inputs from mockup and historical paintings used as a training dataset.This study confirms the potential of SWIR for pigments with characteristic absorption features such as malachite and azurite, even when they are mixed and in degraded systems. In the case of semi-conductor-type pigments, more research is needed to understand the overall spectral shape/intensity in the SWIR domain, but it is definitely to be considered as it allows efficient mapping of such pigments and brings complementary information to the VIS-RIS spectra, in particular when multi-layered systems are investigated.As recently outlined in numerous studies, combined access to VIS and SWIR imaging modalities improves pigment classification in historical datasets; it is thus expected that neural network models trained on combined datasets will solve more challenging tasks in the near future.


Single-cell technology is a relatively new and promising way to obtain high-resolution transcriptomic data mostly used for animals during the last decade. However, several scientific groups developed and applied the protocols for some plant tissues. Together with deeply-developed cell-resolution imaging techniques, this achievement opens up new horizons for studying the complex mechanisms of plant tissue architecture formation. While the opportunities for integrating data from transcriptomic to morphogenetic levels in a unified system still present several difficulties, plant tissues have some additional peculiarities. One of the plants’ features is that cell-to-cell communication topology through plasmodesmata forms during tissue growth and morphogenesis and results in mutual regulation of expression between neighboring cells affecting internal processes and cell domain development. Undoubtedly, we must take this fact into account when analyzing single-cell transcriptomic data. Cell-based computational modeling approaches successfully used in plant morphogenesis studies promise to be an efficient way to summarize such novel multiscale data. The inverse problem’s solutions for these models computed on the real tissue templates can shed light on the restoration of individual cells’ spatial localization in the initial plant organ—one of the most ambiguous and challenging stages in single-cell transcriptomic data analysis. This review summarizes new opportunities for advanced plant morphogenesis models, which become possible thanks to single-cell transcriptome data. Besides, we show the prospects of microscopy and cell-resolution imaging techniques to solve several spatial problems in single-cell transcriptomic data analysis and enhance the hybrid modeling framework opportunities. Modern biology is going through the era of big data and omics technologies. Single-cell sequencing (SCS) is one of the breakthroughs and rapidly developing technologies. This technology’s value is difficult to overestimate since it allows one to describe with high accuracy the trajectories of cell development and characterize individual cell types  is complex and includes molecular, hormonal and epigenetic levels of regulation  model formulation; (ii) design experiments to obtain microscopy and scRNA-seq data; (iii) obtaining experimental data; (iv) data analysis; (v) data integration into a hybrid (discrete-continuous) mathematical model of morphogenesis; (vi) model validation and verification.A. thaliana in 2019. For A. thaliana, most of SC studies were conducted on root cells . Unfortunately, it is currently impossible to estimate the effect of these factors and their contribution to genes’ expression. However, their presence makes it possible to identify the main differentiation genes. In general, this fact allows to carry out the procedure for reducing the dimensions of data. Depending on the data set’s complexity, it is proposed to select from 1,000 to 5,000 highly variable genes for clustering and cell classification  can perform dimension reduction, clustering, and visualization; this algorithm is characterized by enhanced performance and better visualization and interpretability compared to t-SNE, PCA, and zero-inflated factor analysis (ZIFA) methods  and regulators which explain a lot of variance/differences between cell types.Searching for novel regulatory genes, which have a spatial distribution of expression between cells of different types.Reconstructing Boolean gene networks using transcriptomic data.Estimation of differences in integral characteristics .For example, SC transcriptome data could provide some indirect estimations of the cell wall’s mechanical properties. The main mechanosensing genes are described in Du and Jiao : receptoSpatial organization plays a significant role in each cell’s fate, affects transport, the direction of division, apoptosis, and the cells’ structural peculiarities. Therefore, this information is the basis for a systemic integrative study of the processes of morphogenesis.The cells of vascular plants form a shared symplast through the cell walls, which determine the fixed position of the cells in the tissue  and growth (isotropic and anisotropic), as well as to detect several mechanical features of the developing tissue .Thus, a large arsenal of available microscopic and imaging techniques allows obtaining high-quality multilevel data integrated into plant morphogenesis models. For example, there is a computational morphodynamics approach that allows formalizing quantitative data from morphometry measurements into a set of rules  according to mechanical constraints of intercellular vertex interactions.To use the first two steps to calculate effective growth and final rate equation.This section will discuss existing mathematical models describing the tissue organization and/or properties of individual cell types. While considering plant growth and developmental processes, researchers often highlight a unique role for the hormone auxin. For instance, in plant roots, auxin triggers cascades of events during development and morphogenesis, while other hormones  interact with auxin  the dependence on intercellular hormonal signaling, (ii) the importance of the intracellular state and individual cellular characteristics, (iii) the relevance of mechanical stresses in intercellular interactions. Therefore, scRNA-seq technologies, microscopy, imaging techniques, and a range of complementary approaches to measuring cell mechanical properties . Three formalisms are most often used to build cell-based models: vertex-based, center-based , and Cellular Potts models. Vertex-based models are often used to simulate plant tissue and make it possible to conveniently describe the dynamics of cell movements in cell ensembles taking into account mechanical constraints . This formalism is implemented in the Cellzilla  is an environment for modeling, analysis, and simulation of cellular processes, and it includes tools for gene network and for the integration of biological images. This package consists of distinct functional modules: rule-based networks, ODE, PDE and kinematics, stochastic simulations, parameter estimation and has the ability to integrate it into hybrid models. Users can define the model structure and the system automatically builds the code and compiles it. A detailed overview of this tool is given in Moraru et al.  was developed specifically to simulate morphogenetic processes in tissues. This tool uses the immersed-boundary concept , coupled with the Lattice Boltzmann method. The model of biased epithelial lung growth was implemented using this tool  allows building models of tissue morphogenesis. This package was used in modeling vascular development in A. thaliana , division, death, and change of cellular state. Individual cells’ metabolic characteristics are influenced by their genotype and developmental stage, which would be described by single-cell transcriptomics approaches. The nature of the proposed framework is hybrid since it combines different mathematical formalisms and modules: (i) ODE/PDE equations for describing the dynamics of substances and morphogens inside the cell and the processes of intercellular transport, (ii) discrete events occurring during the onset of threshold conditions , (iii) the biophysical laws of mechanical interactions between cells , and also to decide whether it is necessary to take into account the biomechanics of cells for the modeled system.Designing experiments to obtain imaging (2.1) and scRNA-seq (2.2) data based on the given aim. For imaging (2.1), it is essential to choose a suitable plant portion and microscopy technology and determine whether it is necessary to track the dynamics of development of a given fragment of tissue and for which interval of time. For scRNA-seq (2.2), it is important to make sure that the process of isolation of protoplasts and their analysis will not be limited due to the structure of the tissue and/or organ of the plant, imperfections, and shortcomings of the available methods, otherwise, this technique will have to be worked out and improved to an acceptable level.Perform the experiments and produce data. (3.1) It is necessary to prepare  a target tissue fragment, get images, process and analyze them , and digitize the resulting patterns to build a structural model of the tissue/organ and identify morphogenetic rules for incorporation into a computational model. (3.2) While obtaining and analyzing scRNA-seq data, special care should be taken to ensure that the research aim is as close as possible to the intended modeling goals. Care should be taken to avoid contamination with cells of those classes that are not needed and so that for most of the required cells, it would be possible to analyze the molecular systems required for the model. Besides, scRNA-seq-based approaches for the reconstruction of gene networks of the corresponding processes have high potential.Analyze experimental data. Experimental results at cell and tissue level have to be analyzed in order to derive key parameters to be used in the model formulation in terms of cellular characteristics (4.1) and molecular processes (4.2) for all the considered cell types.Systematic assembly of the hypotheses, available data and mathematical formalization into a single hybrid model, which consists of the following blocks: (1) ODE / PDE equations for describing the dynamics of substances and morphogens inside the cell and the processes of intercellular transport, (2) discrete events occurring at the onset of threshold conditions , (3) biomechanics interactions between cells (4) agent-based rules describing patterns of divisions and mechanical features of the tissue.Validation and verification of models is based on their success in reproducing the behavior of real biological phenomena that can be evaluated experimentally. In this sense, it can be useful to return to the stage of morphometry and compare the dynamics of tissue development with simulations and study in detail the molecular organization of the subsystems described in the model.In general, the proposed approach is universal for describing any morphogenetic system; however, the pipeline described above may differ in some steps for each specific case, while some of them could be eliminated. In particular, plant tissue morphodynamics is context-dependent due to mechanical interactions inside cell ensembles and the transport of morphogens through plasmodesmata, which is confirmed by numerous studies (Crawford and Zambryski, in silico mechanical modeling has excellent potential for the field and could help obtain a unified understanding of mechanical behavior across different scales.Post-genomic technologies made it possible to obtain detailed information about processes at genomic and transcriptomic levels using SC and whole tissue RNA sequencing technologies. Besides, the existing abundance of microscopy methods allows high-quality characterization of morphology and physiology at the level of extended fragments of tissues and organs. However, microscopy approaches do not allow to perform quantitative assessments of important intracellular characteristics, such as concentrations of substances and metabolites. SC metabolomics approaches for plants, which are beyond this review’s scope, still remain overshadowed, although significant developments have been made in mass spectrometry approaches for such kind of analyses (de Souza et al., To date, the methods and technologies necessary to obtain various experimental data for plant morphogenesis models have reached a balance and are mostly consistent with each other in terms of power, productivity, and spatial resolution. The community of mathematical biologists and programmers faces crucial theoretical challenges and is creating efficient computational frameworks capable of large-scale numerical simulations involving cellular ensembles of several thousands of cells. Such models will provide more accurate resolution and realism in the description of morphogenetic processes. Examples of optimization works are the algorithm of Jeannin-Girardon et al. , and graThe widespread development of SC technologies in the future could serve as a driver for other areas of cellular and developmental biology of plants (Libault et al., in silico biology. In this sense, one of the most urgent problems of SC sequencing is the reverse reconstruction of the spatial position of cells based on corresponding transcriptome expression. Searching for major regulatory genes that characterize certain cell lines will be a critical step to solve this problem. Also, cell-based models of morphogenesis could help interpret and integrate SC and imaging data, making the reasoning more transparent and establishing an understanding of essential parameters and mechanisms for the described systems.On the other hand, it is necessary to verify the emerging issues related to the interpretation and analysis of SC data using advanced microscopy and Summarizing all of the above, we have found the following key features related to SC-technologies that need to be addressed:Some limitations are still present in the phases of integration, analysis, and interpretation of data.Only a limited set of plant species and organs is suitable for obtaining transcriptome and structural data with cellular resolution.There is a need for a more precise reconstruction of scRNA plant atlases.in silico models of morphogenesis, due to the complexity of the studied systems and computational limitations, are non-trivial. Thus, cell-based models, which use a hybrid formalism, could effectively combine our knowledge on different levels and help tackle the complexity of the system. However, the current problem of the large number of dimensions of the initial SC data should be solved by applying preprocessing and filtering algorithms, as well as for the reconstruction of related gene networks. Thereby, model formulation and numerical experiments in silico could be applied using only the essential part of the initial high-dimensional SC data. Such reduction should aim to contain data on gene expression changes and metabolites concentrations, which determine the different cellular states.The task of elaborating and analyzing AB prepared the draft text of the manuscript and figures. UZ and AD developed the concept and edited the manuscript and figures. AB, AD, and UZ finalized the specific parts. FG developed a scheme for single-cell tools describing. FG, FC, and SM participated in discussing the concept of the article, advised writing sections of the manuscript and design of figures. All authors contributed to the manuscript and approved the submitted version.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.


Background. The pulmonary autograft is currently the best valve substitute in terms of longevity and performance. However, there is no agreement about the optimal method of insertion (sub-coronary position or freestanding root).Objectives. We sought to examine the clinical status, detailed imaging and morphometric changes in an explanted pulmonary autograft 22 years after sub-coronary implantation.Methods. A 30-year-old female underwent pulmonary autograft replacement of a severely stenotic valve at the age of 7 years, after presenting to us with signs of moderate to severe heart failure. She underwent clinical examination, detailed imaging including echocardiographic and CT examination with computerised image analysis. The explanted valve was examined by morphometry.Results. Clinical examination showed signs of heart failure (NYHA III). Trans-thoracic and trans-oesophageal 2D echo showed severe malfunction of both the aortic and pulmonary valves associated with dilatation and hypertrophy of both the right and left ventricles. Surgical correction was performed by replacing both the pulmonary and aortic valves with Medtronic 27mm Freestyle valves. The pulmonary autograft showed degeneration of the trilamellar layering of the leaflets, loss and disorganisation of GAGs, increased collagen with fibrotic overgrowth, and markers of fibrosis, inflammation, and calcification. Post-operative imaging showed good correction of the haemodynamic lesions.Conclusion. The pulmonary autograft implanted into the sub-coronary position presented with adverse remodelling, which was detrimental to the functionality and longevity of the valve.Authorship. NL, AM, MN all contributed equally to this paper. This is closely linked to the capacity of the valve substitute to remain viable and adaptive to local and systemic conditions, both in the short and long term8. The original operation was configured in the sub-coronary position by Donald Ross9 and was modified to a freestanding root replacement (previously described for homografts)10.Pulmonary autograft replacement of the aortic valve (Ross operation) is currently the most durable form of aortic valve replacement7.However, varying degrees of degenerative changes, resulting in malfunction of the pulmonary autograft, have been reported. The exact incidence and, importantly, the factors contributing to the degenerative changes, have not been adequately defined. We describe the evolution of long-term severe degeneration of a pulmonary autograft, inserted in the sub-coronary position and discuss the possible role of the method of insertion on this serious complication. In addition, we compare these changes to those seen following the root replacement technique7.Paraffin-embedded sections of valve leaflets were examined with histochemical and immunohistochemical staining as previously describedA 30-year-old female had a sub-coronary root replacement at the age of 7. This patient presented with progressive dyspnea on exertion from the age of 16 (NYHA III). On examination she was found to have mild central cyanosis, congested neck veins, pan-systolic murmur over the pericardium, and marked hepatosplenomegaly.Echocardiography findings  showed sThe ICU course necessitated prolonged mechanical ventilation due to a lung collapse, which gradually improved. Additionally, the patient suffered from atrial fibrillation and atrial flutter attacks, which were successfully cardioverted back to a normal sinus rhythm. The sub-coronary root replacement was explanted 23 years later  after a At follow up, the patient was asymptomatic with normal sinus rhythm, normal LV function and dimensions and no significant gradients across either valve .All 3 leaflets of the pulmonary explant showed thickening, stiffening and an irregular, clumpy surface . LeafletThe amount and distribution of elastin was increased . This waThe central glycosaminoglycan (GAG) layer was disrupted in all leaflets with a random distribution of GAGs and abundant collagen  and 7C. Cellularity was reduced markedly in the central regions of all the thickened leaflets and absent in some regions , 7F. HowOn higher magnification, the native valve interstitial cells, with larger, elongated nuclei, could be discerned from the smaller, infiltrating polymorphonuclear cells  and thesDespite being markedly thicker and stiffer than normal aortic valves , there w10, guarantees an optimal relationship between the component parts of the valve.This manuscript documents the long-term adverse effects of the use of the sub-coronary position for the Ross operation, which can potentially introduce distortion both in the aortic root and components of the valve culminating in late failure. In contrast, the use of the freestanding aortic root, which was introduced for homografts very early on11. There is a continuing concern about the use of the freestanding root for pulmonary autografts because of the reports of dilatation of the root, resulting in malfunction of the valve16. This has stimulated the use of the sub-coronary implantation as the autograft is supported by the native valve preventing dilatation17. However as is illustrated from the current patient, accurate positioning of the pulmonary autograft in the sub-coronary position requires both skill and judgement, particularly when there is a mismatch between the size and shape of the root as compared to the autograft  with the use of an autologous loose jacket (19).


Motivated by the importance of lattice structures in multiple fields, we numerically investigate the propagation of flexural waves in a thin reticulated plate augmented with two classes of metastructures for wave mitigation and guiding, namely metabarriers and metalenses. The cellular architecture of this plate invokes the well-known octet topology, while the metadevices rely on novel customized octets either comprising spherical masses added to the midpoint of their struts or variable node thickness. We numerically determine the dispersion curves of a doubly-periodic array of octets, which produce a broad bandgap whose underlying physics is elucidated and leveraged as a design paradigm, allowing the construction of a metabarrier effective for inhibiting the transmission of waves. More sophisticated effects emerge upon parametric analyses of the added masses and node thickness, leading to graded designs that spatially filter waves through an enlarged bandgap via rainbow trapping. Additionally, Luneburg and Maxwell metalenses are realized using the spatial modulation of the tuning parameters and numerically tested. Wavefronts impinging on these structures are progressively curved within the inhomogeneous media and steered toward a focal point. Our results yield new perspectives for the use of octet-like lattices, paving the way for promising applications in vibration isolation and energy focusing. Lattice materials are engineered periodic structures whose cellular architecture originates from a network of entangled structural elements 1. Their high strength-to-weight ratio, combined with recent progress in additive manufacturing, renders them particularly attractive for the scientific community; their unique mechanical performance has been extensively explored2, with broad application in biomedicine, aerospace and energy absorption. It is only recently that these have drawn attention for their ability to diffract waves and behave as filters3 that forbid energy transmission across selected frequencies, known as bandgaps4. The periodic nature of these reticulated structures is often at the root of their attenuation mechanism, leading to Bragg scattering effects5 that dominate the spectrum of their band structure6. Bragg bandgaps arise through destructive interference, occurring when the wavelength of a wave is comparable to the fundamental period of the media they are propagating through, and typically occur at frequencies too high to be exploited7. Much work has been done to broaden Bragg bandgaps by introducing locally resonant objects, whose resonance coincides with the Bragg frequency10, wherein lattice vectors are carefully chosen such that these frequencies coincide.4 thus, limiting their role. To overcome this limitation, attempts are being made to design lattices with resonance-induced bandgaps that, unlike their phononic counterpart, exploit the coupling between propagating waves and resonating components and offer greater tuning flexibility at subwavelength scale . These structures form a subset of single-phase metamaterials15 that use auxiliary resonators or inborn resonant modes of the lattice to hybridize propagating waves and inhibit their transmission. Common practice for their implementation includes, for instance, embedding stand-alone resonant elements  into an original frame-based topology, similarly to the solution proposed by Li et al.17 A different method, adopted by An et al. in18 uses, instead, the constitutive matrix of a body-centered cubic (BCC) lattice and constructs an integrated resonator via radius jump of its strut cross-section. The BCC cell is only one of the Bravais lattices19 potentially serving as metamaterials. Among the fourteen types known to exist in the three-dimensional space5, the octet design20 is an example of face-centered cubic (FCC) topology with promising attenuation potential. The dispersive behavior of this lattice, already renowned in statics for its high strength combined with a slender lightweight profile21, has been outlined by Arya et al.22 who show that the octet supports a bandgap whose existence depends upon the aspect ratio of the struts, but do not investigate the underlying physics of its generating mechanism; only briefly suggested by Gerard et al.23. In addition, most of the state-of-the-art research on such a FCC cell resort to frequency gaps produced by attached resonators14 or use it as a constitutive matrix of multi-phased materials25, without delving into its inherent resonant modes. The absence of an overarching dynamic assessment of this architecture in the existing literature emphasizes the novelty of our work, which proposes the octet topology as a metamaterial lattice endowed with an energy gap stemming from the bending local resonance of its beam-like members. Moreover, due to the arrangement and behavior of wave propagation through the struts, we show that the octet cells form a medium in which flexural resonances naturally coincide with the Bragg frequency - as observed within the eigenmodes permitted by Floquet-Bloch waves.Despite offering wave control, Bragg-based frame designs suffer from a periodicity requirement that forces their characteristic size to comply with the targeted wavelength1 that, whilst providing lightness to the structure2, are liable to significant vibrations. The propagation of such vibrations in solid thin plates, occurring in the form of Lamb waves with different polarization, has been extensively documented27 resulting in a variety of metamaterial-based solutions. Prominent among these are metabarriers (or metawedges28) encompassing clusters of rods whose longitudinal resonant mode couples with the flexural waves propagating in the plate and triggers the opening of bandgaps30. To enlarge the frequency band of such barriers, that owing to local resonance offer a fairly limited range of applicability, graded designs have been explored, where the spatial variation of the tuning parameter, rod height, yields a wider spectrum of attenuation associated to the so-called Rainbow trapping effect32. The theory underpinning these metastructures can be easily applied to octet-based plates, with the longitudinal resonances replaced by the bending mode of the struts and the rod height by the parameters of the beam-like members. Based on these considerations, a number of parameters exist in the literature to tune the bandgap by tailoring the metamaterials at a micro-structural level34, two of which are of particular interest for the present study, namely auxiliary point masses and joint stiffness. In their pioneering work, Krödel et al.12 were among the first to unfold the effect of added micro-inertial elements on the dispersive behavior of frame-based lattices. By placing added masses at different positions in the constitutive lattice cell, they showed that these lead to either Bragg-type or local resonance bandgaps and that their tuning strongly influences the frequency content of the attenuation zone. Junyi et al.14 proposed equipping the end of cantilever beams, added to primary 3D Bravais lattices, with point masses whose size governs the gap frequency independently of the geometry of the base lattice. Shortly before this, the same spherical masses were attached to the joints of a Kagome lattice by Liu et al.35 to stiffen its connections and open a bandgap tied to the rod-node vibration.In aerospace and aircraft engineering, lattice plates are frequently used as structural components or filling in sandwich panelsgradient-index (GRIN) lenses36. These are effective, aberration-free devices that leverage composite structures to adjust the spatial distribution of the refractive index within a bounded region and ultimately shape the incident wavefronts. The Luneburg lens37 is a type of spherical GRIN lens that diverts any collimated beam colliding at its boundaries to a diametrically opposite focal point. Similarly to this system, underpinned by a refractive index that increases radially from the outer toward the center of the graded area, the Maxwell fish-eye lens, bends the trajectories of rays originated by a point source at its surface and focuses them in a mirrored image point. While building such lenses with ordinary composite materials appears a daunting task, employing phononic crystals40 or metamaterials42 considerably relieves this complexity. From a metamaterial perspective, the cluster of locally resonant rods with graded height, previously discussed, has proven an effective candidate for the design of GRIN lenses45. Its rod-resonance bandgap, besides providing attenuation, serves as tuning variable for the phase velocity of waves traveling in the metastructure and leads to applications at different scales, from acoustics43 to seismology46. In terms of frame structures, the research on wave guiding is still at a primordial state, mainly confined to two-dimensional lattices50 and yielding, only in a handful of cases, to more sophisticated effects. Xie et al.51 and Zhao et al.52 were among the few to design 2D and 3D flattened Luneburg lenses consisting of a three-dimensional truss-based square lattice, to manipulate waves in the ultrasound regime. A recent study53, on the other hand, has explored the propagation of elastic waves in three-dimensional lattices, including specifically the octet cell. Although similar to our investigation with respect to the choice of topology, no bandgap is reported in this case and only the anisotropic character of the structure is emphasized, with no explicit reference to shaping wave trajectories via graded octet lattices. Therefore, the lack of existing literature on gradient-index lenses designed with octet lattices further motivates our work.Beyond widening the bandgaps, graded designs lay the foundation for a multitude of compelling wave control possibilities. One of these dates back to the nineteenth century and the seminal work of Maxwell on so-called flat or Here we take the octet lattice analysis one step further by using this geometry to numerically realize a reticulated plate and two types of integrated devices for flexural wave mitigation and control. Following a dispersion analysis of the proposed standard octet cell, the bandgap and its underlying generation mechanism are revealed, resulting in the identification of two tailoring parameters. Auxiliary masses, embedded in the midpoint of the struts, or variable joint thickness are used to tune the frequency range with forbidden propagation as well as the phase velocity spatially within the lattice. To avoid redundancy of results, only those stemming from the addition of masses to the primary cell are reported here; varying the node thickness produces similar outcomes. Two metabarrier designs are discussed, the first characterized by constant auxiliary masses and the second relying on the grading strategy to trap and hinder wave transmission over a wider frequency band. Finally, Luneburg and Maxwell lenses are built by smoothly increasing the supplementary spherical masses radially from the boundaries to the center of the devices. We find the octet cell and subsequent customizations possess desirable dispersive properties easily coaxed to required frequencies, these properties are readily exploited to create a variety of devices able to manipulate the propagation of waves over a variety of scales, in both a subwavelength (lenses) and Bragg (metabarriers) scattering regime.20. We choose a fundamental cell whose edges coincide with the midpoint of the octet struts, as depicted in Fig. x and y. We consider struts of circular cross-section, of diameter E = 1.7 GPa, density Consider a thin reticulated plate, of infinite extension, constructed from repeating unit cells, each comprising a strut network generating the well-known octet topologyIt is sufficient to consider waves propagating through the fundamental cell as the phase shift from cell-to-cell is completely described by the dispersion relation between eigenfrequencies and Bloch-wavevector, corresponding to the red dotted line reported in Fig. 26. The underlying lattice structure has subwavelength behavior and wave propagation closely resembles an equivalent continuum supporting three propagating waves, respectively two with transverse and one with longitudinal polarization54  beam, geometrically equivalent to the struts in the octet and defined by:13, the bandgap opening frequency can be estimated via Eq.  yield a clamped-clamped behavior of the struts at the nodes. Similarly to Nolde et al.57, our flat bands at et al.8 in which the wavelength of the fundamental clamped-clamped resonance is twice that of the modulus of the primitive lattice vectors; subsequently the Bragg frequency and et al.56 remarks that bandgaps, in this setting, are generated by local resonances and not Bragg scattering; however, in the case where beams are parallel to and of the same length as the primitive lattice vectors, one expects a medium in which the fundamental resonances naturally match the Bragg frequencies, all of which are properties the underlying octet cell possesses. Notice that, a complete bandgap is obtained when computing the band structure over the full two-dimensional Irreducible Brillouin zone, whose lower and upper bounds are still enforced by the two modes in Fig. X, as further explained in the Supplementary section At higher frequencies 2 to 5 kHz), the wavelength reduces rapidly and waves interacting with the detailed geometry of the cell open a  to 5 kHzz, denoted as high-frequency mode in Fig. Beyond the bandgap, approximately from 5 to 8 kHz, additional dispersive modes populate the spectrum of the dispersion relation, mimicking waves that propagate at the strut level accompanied by roto-translations of the nodes . An array of receivers, positioned along this edge, outlines the significant energy localization generated by the lens. A sharp spike emerges in the out-of-plane displacement These designs, engineered via Bloch theory, are validated by means of time-domain numerical simulations of waves traveling in the finite plate of Fig. Similarly, two distinct time instants in Fig. We have demonstrated the potential of octet-based lattice plates for controlling the trajectories of asymmetric Lamb-like waves, be it via attenuation or wave guiding. Starting from the cellular architecture of this structure, we prove the standard octet unit is capable of supporting a Fano-type bandgap (3.85-5.08 kHz) induced by the coalescence of local bending resonances and Bragg frequency, opening the avenue for an easy-to-tune, single-phase material in elastic applications. The design of this reticulated structure is simplified by viewing the struts as Euler-Bernoulli beams clamped at both their ends and leveraging the analytical expression of the fundamental flexural mode as a prediction paradigm for the bandgap opening frequency; furthermore, since the octet contains struts of length and direction identical to that of the primitive lattice vectors, it creates a medium in which the clamped-clamped fundamental resonance exists as a standing wave between nodes, hence it is a medium in which local bending resonances and Bragg frequencies coincide, resulting in destructive interferences and a broadband resonant-based bandgap.The two tuning parameters extrapolated from this analogy, midpoint added masses and joint thickness, are proven to control the frequency content of the attenuation zone as well as the slope of the low and high-frequency bands exhibiting out-of-plane polarization. The opening frequency of the bandgap is inversely correlated with the masses and directly correlated with the node thickness; heavier masses drive the forbidden range to lower frequencies and reduce the phase velocity of waves in the lattice, conversely, thicker nodes shift the content of the attenuation zone to higher values and privilege the transmission of faster waves.Drawing from these intrinsic dynamic behaviors, four devices for controlling ray trajectories are successfully engineered. The devices operate over a range of scales, the metabarriers leverage the bandgap and hence operate within a Bragg-scattering regime; on the other hand, the Luneburg lens is based on spatial variations of the low-frequency The constant metabarrier confirms the existence of a hybridization bandgap (1.8-2.8 kHz) stemming from the interaction between the propagating flexural field and octet units equipped with auxiliary masses. The wave impinging the resonant members is backscattered and prevented from being transmitted within the metastructure. Whilst the bandwidth of the constant metabarrier is broad, the bandgap and frequency range is spatially localized; we introduce a graded design capable of not only tripling the mitigation width (1.14-5.1 kHz), but also spatially filtering the spectrum via a rainbow trapping mechanism, amplifying a large spectrum of frequencies within its resonating struts. The generating mechanism of the stop band, initially exploited by the lattice metabarriers to match the frequency content of incoming fields and inhibit them, serves to also tune the phase velocity within a bounded region and enable wave steering. Two GRIN lenses, the Luneburg and Maxwell fish-eye, are successfully implemented by gradually adjusting the properties of the customized octets according to the theoretical index spatial distribution, thus paving the way for novel applications of this face-centered cubic topology in wave focusing.Although the dynamic assessment of three-dimensional frame lattices is still at a primordial stage compared to the existing knowledge on their static mechanical properties, the outcomes of our work have shed light on the hidden potential of the octet and tuning parameters. The ease of scaling to different wavelengths that characterizes this structure renders it even more attractive for applications in a variety of domains, including vibration isolation or conversion of focused energy. Indeed, the vibration energy trapped and focused, respectively by the struts and metalenses, could be harvested and converted into other forms of energy, e.g., electrical, by attaching piezoeletric components to the lattice. Future steps of our work will address the development of a more sophisticated, yet computationally expensive, numerical model based on solid elements and its comparison with the simplified Euler-Bernoulli beam model proposed in this study. This would then naturally lead to the experimental validation of the octet-based metadevices upon fabrication using 3D printing. Finally, the complicated matter of stress concentration due to dynamic loading, as well as the extension to different lattice unit cells based both on struts and sheets, such as foams, could be tackled.19, which allows us to align the base vectors with the propagation direction of interest. This makes the comparison between the band structure stemming from the FFT analysis performed in the time-transient finite lattice section . External software is employed for both pre- and post-processing; specifically, the geometry and mesh (Fig. 66, for this study, an in-house code, written in Python, was employed to post-process and later visualize the wave field in ParaView.The metadevices Fig.  are testesh Fig. a are genmentclass2pt{miniml. This domain is tested under vertically polarised excitations with unit amplitude that entail flexural Lamb waves propagating along x. Depending on the assessed metastructure, the input may be a line, for metabarriers and Luneburg lens, or punctual source, for Maxwell lens, and its frequency content span from that of a pulse-like Ricker excitation to a monochromatic source (inset of Fig. 60, defined along the five outer cell arrays of the plate, are implemented to mimic an unbounded domain thus, minimizing undesirable reflections from the boundaries. A total of twenty absorbing layers on every edge is considered, each of thickness l/4, and a mass proportional damping with maximum coefficient The in-plane size of the full frame plate is specified by the number of cells, Supplementary Information 1.


Maternal nutritional imbalances, in addition to maternal overweight and obesity, can result in long-term effects on the metabolic health of the offspring, increasing the risk of common non-communicable disorders such as obesity, diabetes and cardiovascular disease. This increased disease risk may also be transmitted across generations. Unfortunately, lifestyle interventions have shown reduced compliancy and limited efficacy. Resveratrol is a natural polyphenolic compound reported to have pleiotropic beneficial actions including a possible protective effect against the metabolic programming induced by poor dietary habits during development. However, studies to date are inconclusive regarding the potential metabolic benefits of maternal resveratrol supplementation during pregnancy and lactation on the offspring. Moreover, the responses to metabolic challenges are suggested to be different in males and females, suggesting that the effectiveness of treatment strategies may also differ, but many studies have been performed only in males. Here we review the current evidence, both in humans and animal models, regarding the possible beneficial effects of maternal resveratrol intake on the metabolic health of the offspring and highlight the different effects of resveratrol depending on the maternal diet, as well as the differential responses of males and females.  The developmental origins of health and disease theory emphasizes the link between fetal and neonatal exposure to environmental factors and the development of metabolic and other disorders later in life ,6,7,8,9.An important area of investigation in the field of nutrition and metabolism is the search for dietary components and supplements that improve metabolic health, and one compound that has received increasing attention in recent years is resveratrol . Resveratrol is a natural polyphenolic compound produced in a variety of plant species  and has been shown to have anti-inflammatory , antioxiHere we review the current evidence, both in humans and animal models, regarding the possible beneficial effects of maternal resveratrol intake on the metabolic health of the offspring. We have highlighted the differential effects of resveratrol depending on the maternal diet, as well as the differences between males and females in response to both dietary challenges and resveratrol.In support of the developmental origins of health and disease theory, animal models and human studies have demonstrated that early environmental influences, including nutritional factors, can affect adult metabolic homeostasis ,35,36,37In experimental animal studies, maternal overnutrition and obesity increase the incidence of obesity in the offspring, with unfavorable programming of the appetite-regulating system in the hypothalamus shown to be involved ,40. ConsOther maternal nutritional imbalances, such as a high-fat/high-sucrose diet during gestation, have been shown to affect the hepatic lipid profile in the offspring at 4 weeks of age, with some sex-specific effects . MoreoveMal-programming of metabolism also occurs with maternal subnutrition. For example, in rodents maternal food restriction  was found to significantly decrease glucose tolerance in adult offspring, as well as to increase lipogenic gene expression in adipose tissue and adipocyte size . FurtherConsistent with animal studies, numerous epidemiological studies in humans have shown that metabolic programming of energy balance can be attributed to events during the very early stages of development ,48. In cIn humans, maternal obesity during pregnancy and lactation is one of the most typical examples of early-life overnutrition that has been linked to increased risks of metabolic disorders in the offspring ,52,53,54There is strong evidence, both in experimental animal models and human studies, supporting the detrimental effects of an unbalanced maternal diet on the offspring’s metabolic health. This emphasizes the fact that the periods of gestation and lactation offer important opportunities to improve metabolic health in the offspring and that strategies against obesity should not only take into consideration interventions in adulthood, but should begin very early in life, including during the fetal and neonatal periods . HoweverThe beneficial effects of specific dietary bioactive compounds such as resveratrol on energy metabolism during postnatal life have been reported by different authors ,35,56,57Given the protective effects of postnatal resveratrol intake and its capacity to cross the placenta, along with its lack of teratogenicity as reported in most studies, the effects of maternal resveratrol supplementation during gestation and/or lactation on the dams and their offspring’s health has become a point of interest ,25,26,59Various studies in experimental animal models support the hypothesis that maternal resveratrol intake exerts beneficial effects on the offspring’s metabolic health ,66,67,68db/+), maternal resveratrol (10 mg/kg/day) was found to reduce gestational diabetes mellitus symptoms in pregnant female mice and improved offspring development, through reducing the enzymatic capacity for glucose production in the fetus, which is most likely related to AMPK activation  was shown to prevent embryonic oxidative stress and apoptosis associated with diabetic embryopathy . These ativation . Other ativation . These sThe effects of maternal resveratrol on metabolic parameters at weaning have also been analyzed. In 2017 Zou et al. reported that resveratrol supplementation (0.2%) in HFD-fed dams (C57BL/6J mice) during pregnancy and lactation protected against the harmful effects of maternal HFD on white adipose browning and thermogenesis in male offspring at weaning, accompanied by persistent beneficial effects in the protection against HFD-induced obesity and metabolic disorders . We usedLong-lasting effects of maternal resveratrol on the offspring have also been reported. In Sprague Dawley rats, Liu Ta-Yu and colleagues investigated the effects of resveratrol, administered in drinking water (50 mg/L), and maternal HFD intake on the progeny and the response to postnatal HFD intake. They reported that on PND140, maternal resveratrol intake reduced lipogenesis and adiposity, increased lipolysis and ameliorated leptin resistance in male progeny . They alMaternal protein restriction during pregnancy is a well-established early life undernutrition model that is known to increase both maternal and offspring oxidative stress, leading to metabolic dysfunction. Vega et al. demonstrated that maternal resveratrol intake (20 mg/kg/day throughout pregnancy) partially prevented low-protein diet-induced maternal, placental and offspring oxidative stress and metabolic dysfunction at PND 110. They also showed sex differences in the modifications of triglyceride levels, liver reactive oxygen species (ROS) and fat depots in the offspring . Taken tStudies in non-human primates have also shown placental and fetal benefits in response to resveratrol supplementation when the mother is on a Western diet  during pregnancy. In an experimental model employing Japanese macaques, Roberts and colleagues  reportedAlthough the evidence in humans is limited, specific effects of resveratrol have been reported in ex vivo human placenta and adipose tissue samples ,72. LappTo our knowledge, limited human studies have analyzed the effects of resveratrol intake during pregnancy and lactation but none of them analyzed the offspring’s health outcome ,74. In tWe know that males and females have metabolically different responses not only to early nutritional changes  but alsoCollectively, these studies indicate an effect of maternal resveratrol intake on the offspring. Although the mechanism of action of resveratrol is not completely understood, it has been hypothesized that it can induce epigenetic modifications. It is important to emphasize that the beneficial effects of resveratrol as a therapeutic intervention may be affected by many factors, such as the baseline health status of the subjects, nutritional habits, resveratrol dose and the intervention period. Although resveratrol is reported to be well tolerated and safe, caution must be exerted as abnormal pancreatic development and vascularization has also been reported in the offspring of non-human primate mothers consuming resveratrol. However, different study designs and objectives, as well the large variability in the dose, route and timetable of resveratrol administration, make it difficult to reach robust conclusions about the health benefits of resveratrol before considering it for human therapeutic use during pregnancy and/or lactation. In addition, the evidence concerning offspring outcome remains scarce even in animal models and some of these studies have been performed only in males. This is of great importance, as we know that the effects of early nutritional modifications can be sex-specific and data to date indicate that the response to early resveratrol also varies according to sex. Therefore, further and more homogeneous studies are needed to determine how resveratrol exposure during gestation and lactation affects long-term health with both the sex-specific responses and the type of diet ingested taken into consideration.


Nanomedicine and plasma medicine are innovative and multidisciplinary research fields aiming to employ nanotechnology and gas plasma to improve health-related treatments. Especially cancer treatment has been in the focus of both approaches because clinical response rates with traditional methods that remain improvable for many types of tumor entities. Here, we discuss the recent progress of nanotechnology and gas plasma independently as well as in the concomitant modality of nanoplasma as multimodal platforms with unique capabilities for addressing various therapeutic issues in oncological research. The main features, delivery vehicles, and nexus between reactivity and therapeutic outcomes of nanoparticles and the processes, efficacy, and mechanisms of gas plasma are examined. Especially that the unique feature of gas plasma technology, the local and temporally controlled deposition of a plethora of reactive oxygen, and nitrogen species released simultaneously might be a suitable additive treatment to the use of systemic nanotechnology therapy approaches. Finally, we focus on the convergence of plasma and nanotechnology to provide a suitable strategy that may lead to the required therapeutic outcomes. Albeit progress continues, cancer remains a devastating disease in millions of patients worldwide. In 2020, over 19 million new cancer cases are projected to occur globally . For insNanotechnology refers to different designs of matter in nanoscale. This technology has emerged as a multidisciplinary scientific field, including physics, chemistry, engineering, and biology. In recent years, nanotechnology has gained much attention, especially in medicine, known as nanomedicine . NanoparGas plasma, produced at body temperature by applying an electric field to one or a set of electrodes, represents a multimodal environment of physical and chemical factors . This teIn pursuit of an innovative oncotherapeutic strategy, the combination of nanoparticles and gas plasma with their main features is presented. Moreover, therapeutic outcomes, efficacy, and implication of each technology are being discussed. To advance cancer treatment modality development, the convergence of plasma and nanotechnology in oncology, especially the nexus between reactivity and therapeutic implications of these therapeutic modalities, is summarized. The future horizons with opportunities and challenges also are presented.Playing a significant role in the COVID-19 vaccine development , nanotecBy their tunable capacity for loading agents and the facilitation and accuracy in drug delivery , nanocarThe surface coating, shapes, size, and elasticity of NPs play crucial roles in their biodistribution and pharmacokinetics in clinical and preclinical experiments –26. BesiNPs can have a positive or negative surface charge based on different components employed during their production. The surface charge has a significant effect on the stability, encapsulation capacity, and biodistribution of NPs. For instance, a slightly negative charge causes a better accumulation of NPs in tumor tissue . SurfaceNPs in drug delivery systems for oncotherapy can be coated with different organic or inorganic substances containing, for instance, metals, polymers, carbon, lipids, and proteins. These NPs, based on their hydrophilic or hydrophobic properties, also can encapsulate different agents. For example, liposomes with their hydrophilic core are suitable for hydrophobic therapeutic compounds . ConcernNPs should have specific properties for the successful delivery of therapeutic agents to tumor tissue. First, NPs require a particular marker or antibody targeted against tumor cells to reduce side effects to nonmalignant tissues. All types of NPs, including micelles, liposomes, and polymeric NPs, can load antibodies on their surface to increase efficacy and improve clinical trials' outcomes . Howeverst century [At the same time, the immunological dimension of cancer therapy is increasingly being recognized, as evident by the advent and success of immunotherapies in the 21 century –50. Ther century . As anot century . Primari century . NPs wer century . Neverth century . By cros century . AgNPs a century .The last factor for drug delivery in oncotherapy is controlled drug release, which some of the elements used for NP generation can regulate. The purpose of the controlled release of drugs from NPs is to preserve the drug coating during the NP journey in the bloodstream and increase its toxic effect once delivered to the purpose destination in the tumor microenvironment (TME) . In geneOne of the essential applications of NPs is their targeted delivery of agents for oncotherapy engineered according to the type of cancer and the therapeutic agents, as well as the unique properties of the nanoparticles . OverallQuantum dots are known as semiconductor NPs, and their characteristics originate from their ability to scatter fluorescent light from the visible to the infrared spectrum after excitation . QuantumLipid-based NPs consist of natural hydrocarbons or are being derived from plants and animal material. They can also be composed of synthetic phospholipids, cholesterol for membrane bilayer, and sphingolipids. For increasing therapy efficacy, lipid-based NPs can be conjugate with polymeric residues such as PEG and PEI (polyethyleneimine). Their form is usually spherical, and by active targeting, they enhance the drug's pharmacodynamics and pharmacokinetic properties , 76. LipThe mainstay of future clinical cancer treatment is combination therapy between novel technologies and conventional strategies. Nanomedicine and gas plasma as documented oncotherapeutic modalities have great potential to potentially improve cancer treatment due to the multifunctional capacity of NPs and the multimodal nature of gas plasmas.Medical gas plasma technology, also known as cold physical plasma, is a partially ionized gas generated at atmospheric pressure and operated at body temperature. It is distinguished for generating a complex physicochemical flux of agents, including ions, electrons, mild thermal radiation, UV light, electric fields, and ROS/RNS . The latGas plasma is generated by electric discharges and represents a partly ionized gas, where all heavy particles except electrons remain cold. The collisions between surrounding air and gas plasma-derived species bring about a physicochemical environment, which comprises the reactive agents including ROS/RNS. Depending on the different device geometries  as well as device configurations and parameters along with individual treatment procedures, different amounts of reactive compounds are being produced, leading to different intensities of the effects observed .Plasma treatment is the process of transferring a set of physical and chemical agents to the target. An important consideration, and perhaps downfall, of the field of plasma medicine is the polypragmasia in the use of plasma devices. Hundreds of different plasma sources for biomedical application have been published, and most work is not necessarily building on top of previous knowledge but is instead reproduced based on methods in physics, chemistry, and cell biology. A clear scheme on optimal plasma source design considerations and technical parameters is not present. However, several sources have been developed in Germany; among them, the first true (cold) medical gas plasma devices intended for medically accredited use in dermatology centers in Europe . NotwithDirect plasma treatment and gas plasma-treated solution (PTS) are two very different plasma treatment procedures. Direct treatment transfers all physical and chemical agents concomitantly on target, especially the short-lived ROS/RNS unique to the gas plasma technology. When treating a liquid, some of the species can be retained in such liquid and stored for later therapeutic use. This concept is called plasma-oxidized liquids (POL) that can be used for clinical application if using solutions certified as medical products such as sodium chloride . AlternaROS/RNS are produced in several stages based on plasma interaction with air, liquid, and matter and appear to play a vital role in the plasma therapy process . The mosApart from identifying the chemistry being critical for biomedical gas plasma effects, the short half-life of generated ROS/RNS  and the The other physiochemical parameters of gas plasma are thought to play a minor role. UV radiation is present but relatively weak . ElectriEven though significant progress has been achieved in recent years, the exact dose definition and optimization of plasma devices remain a debate due to the variety of plasma devices, different therapeutic procedures, and input factors affecting the composition of the produced plasma. Primarily, the concentration of produced ROS/RNS is considered the plasma dose, and based on that, the effect of gas plasma on cancer cells is classified in the majority of cases as programmed cell death as evident in vitro , in vivoAt low doses, gas plasma exposure causes autophagy, senescence, and cell cycle arrest. Concomitant modality of gas plasma and silymarin nanoemulsion (SN) resulted in autophagy activation in human melanoma cells (G-361) . BesidesRegardless of the various affected signaling, apoptosis is the most documented type of cell death that has been evaluated following gas plasma treatment. It can be claimed that the induction of apoptosis has been shown in the majority of cancer types that have been studied yet by gas plasma and POL. For example, we recently indicated that POL with high selectivity induces intrinsic apoptosis in chemotherapy-resistant ovarian cancer cells accompanied by high expression of p53, Bax, and caspase-3 . OverallInterestingly, gas plasma can induce ICD, a type of cell death eliciting an immune response that is highly important in progress on plasma oncology . To overFurther, nonprogrammed cell death might occur under a high dose of ROS/RNS so that both normal and cancer cells are affected and might cause undesirable hallmark effects and tissue damage. Therefore, the concentration of ROS/RNS should be adjusted for acquiring a unique environment for oncotherapy through gas plasma. Besides the abovementioned therapeutic efficacies, selectivity towards cancer and normal cells has been described in some reports –133. TheIt is important to note that several end-stage head and neck cancer patients have benefited from clinical gas plasma treatment using the medically accredited atmospheric pressure argon plasma jet kINPen MED . Tissue Although the combination of nanotechnology and gas plasma is still in preclinical settings, the results show a new strategy that in the future might be able to advance the efficacy of conventional therapies. Here, we emphasize the complementary role of plasma and nanotechnology technologies in improving each other's performance and highlight their main features that led to promising results. In addition, the nexus between reactivity and their therapeutic implications and potential challenges for translating into clinical uses are presented as the basis for a future innovative trend in cancer treatment.Considering the multifunctional and practical properties of nanotechnology platforms and gas plasmas in addressing various cancer hallmarks, the combination or concomitant modality of these technologies arises an emerging strategy towards personalized medicine for cancer patients . Albeit The proposed synergy of gas plasma and NPs is such that in addition to improving each other's strengths, they also cover each other's limitations . NPs havDue to the peroxynitrite production, gas plasma reduces the pH of tissue fluid or tissue in a rapid and reversible process and creates the acidic conditions required for the delivery of NPs , 157. AnRegardless of the types of cancer, NPs, and plasma devices, the combination of NPs and gas plasmas led to encouraging results. Regarding the mechanisms and effectiveness, current research is directed to the production of ROS/RNS and increase of NPs uptake. The currently available studies on combining NPs and gas plasma treatment in vitro and in vivo are summarized in Glioblastoma is the most studied tumor with a combination of gas plasmas and AuNPs, and numerous studies have emphasized the efficacy of concomitant treatments of these technologies compared to each of them. Increased cancer cell death, activation of tumor suppressors, inhibition of tumor growth, reduction of migration and invasion in cancer cells, increased induction of apoptosis, increased E-cadherin in treated tissues, and decreased tumor volume have been presented as a collection of the main findings. The action mechanisms were related to the production of ROS/RNS and enhancement of the uptake of NPs , 159–162Similar results for melanoma were obtained when gas plasmas and NPs were used together. The increase of ROS/RNS resulting from the combination of different configurations of gas plasma with FAK antibody conjugated-AuNPs, silica, silver, iron oxide, cerium oxide, titanium oxide, iron-doped titanium oxide NPs, and Anti-EGFR-AuNPs leads to a significant increase of early apoptosis and secondary necrosis, reduction in G2/M levels, increase in the sub-G1 fraction, FAS externalization, caspase-8 activation, increase of selective cancer cell death, inhibition the viability of cancer cells, and reduction of growth pattern –167.In addition to the antiproliferative effects and induction of cytotoxic effects, decreased metastatic gene expression and increased cellular internalization of NPs have previously been revealed, where fluorouracil-loaded PLGA NPs and gas plasmas concomitantly are utilized as novel solutions for breast cancer oncotherapy . FurtherIron oxide-based magnetic NPs and plasma jet treatment have previously been used to cause cell cycle arrest at the G0/G1 phase, apoptosis induction, condensation of nuclei, restraining tumor growth, intensive necrosis, and reduction of tumor size in lung cancer considering the high-level generation of ROS/RNS .To avoid undesirable effects and target incurable tumors effectively, the mainstay strategy is combination therapies, which aims for cotreatments and integrating novel modalities with traditional methods. To this end, nanomedicine is combined with gas plasma as a multimodal and encouraging platform, as seen in the promising outcomes of preclinical studies. Based on these studies and the properties of gas plasma and NPs, the synergy of these two technologies can become an anticancer treatment strategy in the future. In particular, it is hoped that the synthesis of NPs with gas plasma or processing and subsequent plasma treatment will improve NPs in terms of preventing the degradation of conjugated drugs, delivery of optimum concentration and fluxes in desirable time, and improving the pharmacokinetics of the drug, which is consequently aimed to lead to enhanced cancer cell death and immunogenicity. Importantly, multifunctional and multimodal natures of NPs and gas plasma create a unique environment for cancer treatment.Despite the increasing number of studies on cancer nanomedicine, there is a striking imbalance between preclinical and clinical applications, and the number of approved NPs, which are using for the clinical settings, is relatively limited . RegardiFinally, there are future challenges for NP drug discovery and development in oncology. First, standardized procedures in production for research and commercial applications will help accelerate results translated from bench to bedside . Second,Nanomedicine and gas plasmas have been considered appropriate options for future oncotherapy due to the promising preliminary results. To improve nanomedicine's efficacy, combination with novel therapeutic modalities such as gas plasmas should be taken into account. Cocktail of ROS/RNS and electric fields of gas plasma and the NPs' ability to precisely targeting and penetrating tissues creates a putative oncotherapeutic platform for cancer treatment by enhancing selectivity and targeting chemotherapy resistance. Even though synergistic efficacy of NPs and gas plasmas are reported, more studies are essential to elucidate underlying mechanisms and impact on aggressive cancers.