Arsenic is one of the most potent carcinogens in the biosphere, jeopardizing the health of millions of people due to its entrance into the human food chain through arsenic-contaminated waters and staple crops, particularly rice. Although the mechanisms of arsenic sensing are widely known in yeast and bacteria, scientific evidence concerning arsenic sensors or components of early arsenic signaling in plants is still in its infancy. However, in recent years, we have gained understanding of the mechanisms involved in arsenic uptake and detoxification in different plant species and started to get insights into arsenic perception and signaling, which allows us to glimpse the possibility to design effective strategies to prevent arsenic accumulation in edible crops or to increase plant arsenic extraction for phytoremediation purposes. In this context, it has been recently described a mechanism according to which arsenite, the reduced form of arsenic, regulates the arsenate/phosphate transporter, consistent with the idea that arsenite functions as a selective signal that coordinates arsenate uptake with detoxification mechanisms. Additionally, several transcriptional and post-translational regulators, miRNAs and phytohormones involved in arsenic signaling and tolerance have been identified. On the other hand, studies concerning the developmental programs triggered to adapt root architecture in order to cope with arsenic toxicity are just starting to be disclosed. In this review, we compile and analyze the latest advances toward understanding how plants perceive arsenic and coordinate its acquisition with detoxification mechanisms and root developmental programs. Plants are constantly scouting their surrounding environment in the search for nutrients and water. However, soils contain multiple toxic metals and metalloids, some of them essential for plant growth in low amounts. Therefore, plants must display a battery of tightly regulated perception mechanisms that allow them to distinguish between beneficial or harmful elements, finely tuning their nutrient intake and metabolism or detoxifying through sequestering or extrusion. Roots are the first organs to sense soil composition and texture and consequently plants are constantly adapting root growth to the prevailing environment, reshaping its architecture to address a highly efficient nutrient capture mode but in parallel controlling the entry of toxic elements ] and the reduced chemical form, arsenite [As(III)]. Among these two chemical species, the presence of As(III) in soils and subterranean waters is a global environmental problem. That is particularly serious in rice, being the most important gateway for arsenic to the human food chain  tolerance depends on its reduction to As(III), despite the fact that As(III) is more toxic than As(V). One possible explanation is that at the beginning of the history of Earth, As(III) was the prevalent chemical species in a reducing atmosphere which forced all living organisms to evolve strategies to cope with this chemical species. However, when the great oxygenation event occurred, As(V) became the most prevalent form in the biosphere  transporter shows higher affinity for As(V) than for Pi, leading to increased As(V) uptake and contributing to the extraordinary capacity of this fern to accumulate arsenic , it has been shown that some bacterial strains, isolated from highly arsenic-contaminated waters, exhibit increased preferential affinity for phosphate than for As(V)  is a key regulatory signal that regulates the arsenic response, even controlling the expression of the Pi/As(V) transporter in response to arsenic -transceptors, the potential nature of the arsenic sensor in plants can only be speculated based on the information obtained from other organisms, specially bacteria and yeast.In plants, several metal sensors have been described, mostly nutrient transporters, named “transceptors,” that sense their substrates  to ArsR triggers a conformational change in the DNA-binding site of the repressor that results in the dissociation from the ars promoters, allowing the transcription of the operon  concentrations, improving the sensitivity of the arsenic sensor to perceive the amount of arsenic inside the cell.In bacteria, the sensor is the ArsR repressor protein that negatively regulates the bona fide arsenic sensor or some other molecular mechanisms involved in arsenic sensing in plants.In yeast, the transcriptional activator Yap8 is a key regulatory protein of arsenic detoxification responses. Yap8 is a bZIP protein that in the absence of arsenic is constantly being degraded by the ubiquitin proteasome pathway  competes with sulfur (S), As(V) with Pi, or As(III) with silicon (Si)  and its degradation by low Pi provides a fine-tuned regulatory loop to modulate As(V) uptake, maintaining the regulatory machinery ready to activate the expression of the Pi-transporter as soon as As(V) disappears from the medium.The first transcription factor involved in arsenic signaling has been WRKY6  uptake through the exodermis and endodermis  uptake  binds thiol groups of proteins, inhibiting their enzymatic activities, which provokes the generation of reactive oxygen species  transporter PHT1;1, similar to wrky6 mutants  targeting diverse genes, several CBF transcription factors have been identified as negative regulators of arsenic tolerance, probably through direct regulation of Pi transporters,  transporters Lsi1 and Lsi2, is regulated by ABA. Similarly, Cd uptake is also regulated by ABA which is mediated by phosphorylation-dephosphorylation of the ABA-responsive transcription factor ABI5  are also essential components for stress survival across different species  stress  transporters compared to the wildtype, highlighting the importance of F-box proteins-mediated ubiquitination for dealing with arsenic toxicity. Therefore, it can be hypothesized that in response to arsenic, ASRF mediates the degradation of transcription factors involved in the activation of Pi/As(V) transporters, leading to the suppression of As(V) uptake. In addition, a second study showed that another F-box, named PHIF1, targets PHR1, the key activator of Pi/As(V) transporters, for ubiquitination and subsequent degradation in response to arsenic  or As(III) species, led to the identification of tens of differentially-expressed miRNA  transporter  have an emerging role as regulatory components, post-transcriptionally modulating gene activity to cope with heavy metal stress  uptake due to a suppression of the high-affinity Pi uptake system, but displayed increased arsenic accumulation  transport throughout the endodermis, increasing arsenic accumulation in the above ground tissue, further supporting its role in arsenic tolerance  transporters, probably coordinating As(V) uptake with root elongation, being a major factor in the coordination of arsenic uptake and detoxification with uptake  and other rhizospheric microorganisms to attenuate arsenic phytotoxicity and promote root development. Indeed, these microorganisms promote nutrient  uptake, and modulate arsenic bioavailability and phytohormone levels. Indeed, they increase auxin levels by the production of indole-3-acetic acid (IAA), and reduce ethylene content by the production of 1-aminocyclopropane-1-carboxylate (ACC) deaminase, thus resulting in increased root growth  as a key signal that controls transcriptional regulation of the arsenic response prepares the ground for the identification of sensors and regulatory factors involved in arsenic perception and signaling. In addition, an important aspect of arsenic tolerance response that must be approached is the characterization of root growth adaptation to the presence of the metalloid. Roots are the first organs to sense arsenic, which may be present in different concentration gradients, leading to the activation of local and systemic arsenic responses in the root that must be characterized. Therefore, it is an urgent matter to study how roots transduce arsenic perception into root morphological responses integrated with tolerance mechanisms. In addition, further characterization of the root microbiota that modulates arsenic bioavailability and root growth adaptation to the presence of arsenic will be crucial to develop arsenic resistant crops and to aid phytoremediation strategies. Moreover, due to climate change prediction, it is also imperative to characterize the effect of light intensity, temperature, drought and salt, as essential factors that will have a dramatic impact on plant arsenic accumulation. All these actions will provide an integral overview of plant arsenic tolerance.In conclusion, the characterization of the mechanisms involved in arsenic sensing and signaling is currently in a very preliminary stage and further in-depth studies are needed. However, the new genome-wide techniques for transcriptome and proteome profiling and gene editing techniques allow the exploitation of natural variation at an unprecedented scale, thereby predicting a thriving future in the comprehension of the molecular basis underpinning arsenic response in plants.AL conceived and wrote the manuscript with contributions for writing and reviewing from MAN and CN. All authors contributed to the article and approved the submitted version.This work was supported by fellowships from the Spanish Ministry of Science and Innovation (MICINN) and Severo Ochoa Centers of Excellence Grant Programme to CN, and by fellowships from Fulbright and FPU Ph.D. fellowship to MAN. This work was funded by Grants BIO2014-55741-R and BIO2017-87524-R, PID2021-125289OB-100 funded by MCIN/AEI/10.13039/501100011033, and Grant 2020AEP013 funded by the Spanish National Research Council (CSIC).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.


Aging is an intricate and unavoidable phenomenon characterized by progressive accumulation of damage to cellular structural components with consequent decline in physiological functions and development of different pathological conditions, which lead to increase in frailty and mortality risk and bring a huge economic burden in our society. Aging is considered the number one risk factor for the development and progression of many chronic disorders ranging from cardiovascular diseases and diabetes to different types of cancer and neurodegenerative disorders. Genetic and environmental factors concurrently shape aging and age-associated diseases. A variety of genetically regulated mechanisms affecting aging have been identified in the past 50 years, also as a result of the exploitation of multicellular genetically tractable model organisms. A growing body of evidence indicates that environmental factors, including diet, impact human health and aging. On the one hand, external factors such as pesticides, radiation or dietary components as well as products of endogenous metabolism may negatively impact disease development and progression and may accelerate the aging process. On the other hand, several food components and supplements have been described or proposed to promote health and longevity. Nonetheless, these observations originate primarily from epidemiological or correlative studies, and while some molecular mechanisms have been involved in the modulation of cell and organism homeostasis in response to a wide range of external toxicants and insults, more mechanistic investigations are necessary to establish beneficial causal effect role of dietary interventions.A number of aging theories have been proposed, and the “mitochondrial free radical theory of aging” (MFRTA) has taken center stage in this area of research for several decades. According to this theory, reactive oxygen species (ROS) generated by the mitochondrial respiratory chain (MRC) are the main cause of molecular damages. This theory has been questioned in recent years by the growing body of evidence showing mild increase in ROS and mild suppression of mitochondrial activity can actually promote health and lifespan across species. Nonetheless, there is no doubt that mitochondria play a pivotal role in cell homeostasis, e.g., through the regulation of energy metabolism, cellular redox status and cell death pathways. Accordingly, a wide spectrum of structural and functional mitochondria alterations, as well as the imbalance redox status, are characteristic features of the aging process and play an important role in the pathogenesis of different age-associated diseases. Environmental factors such as pesticides, radiation, cigarette smoke, and exposure to metals may also exert mitochondrial toxicity in different ways, e.g., by altering mtDNA integrity, inhibiting MRC complexes, or activating pro-apoptotic signaling. Moreover, as mitochondria are key players of cellular energy metabolism, they also represent central hubs in sensing and usage of dietary factors.With this Special Issue, we aimed to highlight some of the current knowledge on the important role of mitochondria in environmentally- and dietary-modulated aging and associated diseases.In this context, the review by Bortoli, Coumal and colleagues provides a comprehensive summary of the literature describing the role of mitochondrial dysfunction as a hallmark of environmental injury . The autAltschmied, Haendeler and colleagues, in turn, present a neat review of the current knowledge on the protective effects of curcumin, a polyphenolic compound naturally found in the Curcuma longa (tumeric), on treatment of cardiovascular diseases, with a special focus on its impact on oxidative stress and mitochondria . The autTwo additional reviews describe very important mitochondrial functions, namely one-carbon metabolism and mitochondrial protein import in the context of aging and age-associated diseases. Tavernarakis and colleagues  first prThe review from Borshchevskiy and colleagues  present C. elegans, a powerful genetically tractable model organisms for aging and intervention studies, for an in vivo phenotype-based screening in search of interventions acting through mitochondria with beneficial effects on healthspan. To this aim, the authors exploit a high-content microscopy platform to search for natural compounds able to induce phenotypes  associated with mild mitochondrial stress, which is known to promote animal health- and lifespan across species. The screen led to the identification of four compounds i.e., isobavachalcone, manzamine A, kahalalide F and lutein consistently affecting different nematode phenotypes, which were subsequently validated in Drosophila cells for their effects on mitochondria activity and lipid content. Out of the four, kahalalide F and lutein were chosen for further age-related analysis, and were shown to promote resistance to stress, health- and lifespan. Interestingly, initial mechanistic investigation reveals that the C. elegans ortholog of the synaptic regulatory protein neuroligins, nlg-1, was induced by the two compounds and mediated lutein healthspan effects.Finally, the original research work of Ventura and colleagues  exploitsOverall, the five papers offer an interesting overview of the possible opposite impact that environmental and dietary factors can have on aging and associated diseases via modulation of different mitochondrial-associated activities and metabolic pathways, the former in most cases acting as mitochondrial toxicants while the latter functioning as beneficial agents or nutraceuticals.


Astrocytes, despite some shared features as glial cells supporting neuronal function in gray and white matter, participate and adapt their morphology and neurochemistry in a plethora of distinct regulatory tasks in specific neural environments. In the white matter, a large proportion of the processes branching from the astrocytes’ cell bodies establish contacts with oligodendrocytes and the myelin they form, while the tips of many astrocyte branches closely associate with nodes of Ranvier. Stability of myelin has been shown to greatly depend on astrocyte-to-oligodendrocyte communication, while the integrity of action potentials that regenerate at nodes of Ranvier has been shown to depend on extracellular matrix components heavily contributed by astrocytes. Several lines of evidence are starting to show that in human subjects with affective disorders and in animal models of chronic stress there are significant changes in myelin components, white matter astrocytes and nodes of Ranvier that have direct relevance to connectivity alterations in those disorders. Some of these changes involve the expression of connexins supporting astrocyte-to-oligodendrocyte gap junctions, extracellular matrix components produced by astrocytes around nodes of Ranvier, specific types of astrocyte glutamate transporters, and neurotrophic factors secreted by astrocytes that are involved in the development and plasticity of myelin. Future studies should further examine the mechanisms responsible for those changes in white matter astrocytes, their putative contribution to pathological connectivity in affective disorders, and the possibility of leveraging that knowledge to design new therapies for psychiatric disorders. There is a solid body of experimental and human postmortem brain evidence demonstrating that astrocytes play fundamental roles in supporting neuronal metabolism, survival and communication at synapses, and in the development and maintenance of the white matter. These essential roles and the ability of astrocytes to become reactive when confronted with injury or disease are reflected in their crucial involvement in the neuropathological mechanisms of most neurological and neurodegenerative disorders –3. The rEach astrocyte and its highly branched processes occupy a region of the gray matter that is adjacent to neighboring astrocytes territories with very little overlap  Figure , each asWM astrocytes are morphologically different from the large population of protoplasmic astrocytes in the GM, and are termed fibrous astrocytes ,39. ProcAltered structure and function of astrocytes and oligodendrocytes, and disturbed interactions between them have been proposed to play a major role in the pathophysiology of mood disorders, particularly MDD ,50, whilNRs), which are stretches of bare axon carrying ion channels for action potential regeneration and propagation. This closeness to NRs , ws to NRs  appears vs) at NRs during NR formation and maintenance [vs’ clustering [Interaction between astrocyte processes and axons at NRs is mediated by those extracellular matrix (ECM) components, which include the proteoglycans brevican, phosphacan, versican-2, and BRAL-1, as well as the glycoprotein tenascin-R, and the axonal adhesion molecules neurofascin-186 (NF186) and contactin ,71. Despntenance ,74. As sntenance . Astrocyustering . AccordiAlthough neuron-to-neuron synapses supporting neurotransmitter-based communication are mostly absent in the white matter, substantial glutamate release in the white matter has been detected . This rev aggregation. These features are crucial for adequate propagation of action potentials. Thus, if glial processes, associated ECMMs and EAAT1s are altered in depression they could critically participate in pathophysiological mechanisms involving disturbances of connectivity among brain centers in MDD.Recent findings on the molecular composition of astrocyte processes suggest a role for ECMMs and EAAT1 transporters in regulating extracellular glutamate actions in the WM ,79,80. BThe processes of astrocytes associated with NRs, in conjunction with the myelin of oligodendrocytes, regulate the speed of saltatory conduction, thus allowing optimal communication between neurons ,81. AlteNTRK2), but only in subjects diagnosed with depression [The importance of astrocytes to the maintenance of adequate signal conduction along axons also includes their role as providers of neurotrophic factors to facilitate oligodendrogenesis and myelination after damage to the white matter ,93. Othepression , while spression ,103.Morphological and neurochemical differences of WM astrocytes as compared to most GM astrocytes, their ubiquitous involvement in myelin formation and maintenance, and their crucial association with nodes of Ranvier to support the regeneration of action potentials, suggest a critical contribution of those aspects of astrocyte biology to the integrity and fidelity of nervous signals carried along WM axons, and thus to normal brain connectivity. Accordingly, disturbances in brain connectivity that have been described in depression and other psychiatric disorders may be at least partially a consequence of disturbances in astrocyte interactions with oligodendrocyte membranes and nodes of Ranvier in the involved cortical brain regions. An argument could be made that targeting astrocyte-related pathology in the white matter may provide new or complementary approaches to better therapies that improve connectivity in the brain of patients with affective and other psychiatric disorders.


Harnessing the human immune system as a foundation for therapeutic technologies capable of recognizing and killing tumor cells has been the central objective of anti-cancer immunotherapy. In recent years, there has been an increasing interest in improving the effectiveness and accessibility of this technology to make it widely applicable for adoptive cell therapies (ACTs) such as chimeric antigen receptor T (CAR-T) cells, tumor infiltrating lymphocytes (TILs), dendritic cells (DCs), natural killer (NK) cells, and many other. Automated, scalable, cost-effective, and GMP-compliant bioreactors for production of ACTs are urgently needed. The primary efforts in the field of GMP bioreactors development are focused on closed and fully automated point-of-care (POC) systems. However, their clinical and industrial application has not yet reached full potential, as there are numerous obstacles associated with delicate balancing of the complex and often unpredictable cell biology with the need for precision and full process control. Here we provide a brief overview of the existing and most advanced systems for ACT manufacturing, including cell culture bags, G-Rex flasks, and bioreactors , as well as semi- and fully-automated closed bioreactor systems. A wide range of immunotherapeutic products have found extensive use in modern science and medicine. From various cell products to antibodies and cytokines, they are produced worldwide on an industrial scale. Therefore, scaling up of the biotechnological processes to meet the growing needs represents a serious challenge. Multiple optimization approaches exist for scaling up the production of immunotherapeutic products. The main principles are based on closed systems and automation. The more autonomous the process becomes, the cheaper and more efficient it gets for large-scale manufacturing. The use of closed systems can significantly reduce the risk of contamination, thereby increasing the quality of the product and lowering the infrastructural requirements.The production of most immunological products is based on the patient’s own immune cells. Therefore, any biotechnological process related to cell cultivation, when scaled up and automated, will have to end up with bioreactor systems of some kind. In this regard, given the wide range of practical issues to be addressed, the development of modern bioreactors for industrial production of immunotherapeutics is extremely important. Industrial use of cell culture bioreactors is carried out after careful development and optimization of the protocol, since methodology and used materials can have a significant impact on the efficiency of the whole process .Primary parameters to consider for biotechnology processes include pH, temperature, dissolved oxygen levels that can be controlled by medium oxygenation and replenishment , mixing of cell suspension to achieve uniform distribution of cells inside the bioreactor, etc. Bioreactor systems may use different basic principles and therefore may vary in performance and specific application. In addition, certain mechanical features may be advantageous for the efficient cultivation of one cell type while leading to low proliferation or even cell death in other cases. Thus, there is no universal solution to enhance throughput and achieve the required product quality, however, with careful selection of the appropriate system, high yields of quality cell products can be achieved. Below we describe various cultivation systems that are currently used in both academia and industry for the manufacturing of a wide range of cell products .Cell culture bags are made of polymeric materials and may have up to several aseptic ports for media input/output, sampling, and harvest. The main advantage of bags compared to T-flasks is a significantly lower risk of contamination. Bags may be manufactured from a wide range of gas-permeable polymers, such as silicone, ethyl vinyl acetate, polyolefins, etc. However, it should be taken into account that the bag material and its shape can significantly affect the cell proliferation and expansion.Li et al. cultured human T cells in bags made of various materials such as silicone, polyolefin/ethyl vinyl acetate (EVA), fluorinated ethylene propylene (FEP) and compared results to regular T-flasks . In polyZuliani et al. performed the cultivation of tumor infiltrating lymphocytes in polyolefin bags and found that cell expansion was reduced by 9.8% compared to regular plates . The autThe mixing option may also be implemented in bags by connecting input and output ports by a continuous tubing accompanied with a magnetic pump. Li et al. incubated human T cells in bags at different conditions: static, with periodic activation of magnetic pump, and with continuous pumping . The useIn general, the main advantages of the bags are a high level of aeration and relatively low cost. Bags of various intricate shapes can be designed for a local increase in intercellular interactions, which is important in the cultivation of lymphocytes. However, due to conflicting data for many types of immune cells, careful selection of bag material is required.2 incubators, which significantly reduces technical requirements for cell culture manipulations in comparison to conventional bags [One of the most popular devices for suspension cell culturing is the G-Rex flask, designed and manufactured by Wilson Wolf Manufacturing. G-Rex is a round cylindrical flask with a special gas-permeable silicone membrane at the bottom . The vesnal bags . This sinal bags ,8,9.Nevertheless, the G-Rex system has some drawbacks with regards to integration with automated GMP protocols for manufacturing of immunotherapeutic cell products, especially at the stages of cell seeding and quality control. The problems arise mainly due to the difficulty of transferring large volumes in a sealed and sterile manner from the flask to other devices, e.g., for washing and buffer exchange. The issues also include problems with sampling and limited maximal volume of the vessel. For example, for TILs manufacturing it may take up to 30 G-Rex flasks to produce the quantity of clinical grade cell product sufficient to effectively treat a single patient. At the same time, some types of perfusion bioreactors allow one-step production of large amounts of therapeutic cell products due to much higher volume of the expansion vessel. For example, in WAVE  rocking, the motion bioreactor volume of the cultivation bag can reach up to 100 L with a possible cell density of up to 10E7 cells/mL [Despite all the drawbacks, G-Rex remains one of the most popular solutions for scaling up biotechnological processes and is widely used in immunotherapy manufacturing. G-Rex is known for particularly efficient cell expansion when scaling up TILs production ,11,12, wOverall, G-Rex flasks have proven to be an affordable and efficient solution for scaling up production without requirements for sophisticated additional equipment. In addition, G-Rex flasks consistently demonstrate high efficiency of cell cultivation due to the technology of medium oxygenation through a gas-permeable silicone membrane.The main feature of the rocking motion bioreactors is a specialized swinging platform with heating elements and temperature sensors. Cells are grown in special plastic bags that are placed on this platform and are equipped with ports for gas injection, fresh medium infusion, waste medium removal, and sampling . Wave-liThe rocking motion type of mixing can be both advantageous and disadvantageous depending on the specific experimental conditions . Meng etIn another study, Spanholtz et al. discovered that rocking motion has a clear positive impact on proliferation of natural killer cells. The NK cells were isolated from 16 donors and expanded in parallel in static Vuelife bags and WAVE bioreactor for 6 weeks. The average fold of expansion in bags was significantly lower than in WAVE at the end of the experiment. As a possible reason for this, authors indicate efficient media oxygenation achieved through rocking or waving of the cell suspension .However, there is a growing body of evidence demonstrating the high efficiency of shaking and wave-like medium movements for TILs cultivation ,19. SadeAltogether, rocking-motion bioreactors represent the most common type of bioreactors used in cell product manufacturing. They have a high efficiency, can be connected to various sensors for monitoring the state of cell culture, but may have limited applicability for cells sensitive to intense medium flows. We believe that such bioreactors represent the optimal solution for clinical or large-scale production of immunological cell products. In comparison with G-Rex flasks, rocking motion bioreactors have a greater degree of automation, and therefore a lower risk of manufacturing human error and higher safety of the finished product.The paddle mixing of cell culture medium was carried out in all stirred flasks and stirred-tank bioreactors. This type of mixing is associated with a high level of medium aeration, as well as a high shear stress of the cells. Stirred flasks are one of the oldest and most well-known cell culture reservoirs, consisting of a flask with a built-in mechanical or magnetic paddle stirrer . StirredThe positive effect of paddle mixing on the growth of various types of immune cells has been known for a long time. Examples include bone marrow mononuclear cells ,23, NK cCarswell and Papoutsakis showed that paddle mixing has no negative effect on the cultivation of T cells at low speeds and that the use of medium additives that provide protection from mechanical stress can positively affect T cell expansion in stirred-tank bioreactors . In addiCostariol et al. cultured T cells in the Ambr 250  stirred-tank bioreactor with various blade rotation modes . Two actFoster et al. investigated the speed of paddle mixing on the expansion of cytomegalovirus-specific T cells using Bellco Glass stirred flask bioreactor and found that in this case expansion was more efficient compared to regular T-flasks . They foStirred flask and stirred-tank bioreactors are also used for manufacturing therapeutic cell products in clinical settings. According to Bohnenkamp et al., stirred flask bioreactors are useful for clinical scale expansion of T cells obtained from donors with cytomegalovirus infection . In addiStirred-tank bioreactors are more commonly used for the production of viral vectors in HEK293 cells, or for the cultivation of mesenchymal stem cells (MSCs) . PreviouHollow-fiber (HF) cartridges represent tubes filled with semi-permeable capillary fibrils and are constructed in such a manner that both intra- and extracapillary space can be utilized . The ranCells can be grown both inside and in between the capillaries within the respective media circuit depending on the system configuration, cell type, membrane permeability, and required outcome . One or Most commonly, hollow-fiber bioreactors (HFBR) are used to produce various types of pharmaceutical protein products, such as antibodies . AnotherThe suspension cultures, such as immune cells, are mostly grown in the extracapillary HFBR circuit in high densities . The freThe intracapillary compartment is rarely used for cultivation of suspension cells, however Nankervis et al. proposed using the Quantum automated system (Terumo) for expansion of T cells . HoweverThe Quantum system has proven to be effective for cultivation of human immune cells ,40. PeriThe main advantage of hollow-fiber bioreactors is flexible configuration that allows for the adjustment of cartridge structure, material, and membrane porosity. However, during cultivation with liquid flow in both compartments (as in the Quantum system ), very cThe CliniMACS Prodigy  is the most widely used semi-automatic device for the manufacturing of various immunotherapeutic cell products . The ranCliniMACS Prodigy is probably the most convenient automated closed system available on the market, and it is frequently used for the purpose of clinical trials ,43,44. TCocoon  is another example of a closed automated system currently entering the market. This system, unlike CliniMACS Prodigy, does not allow cell separation or final product formulation, but it is capable of cell transfection, transduction, and expansion . In addiCliniMACS Prodigy is probably the most popular system for automated manufacturing of adoptive cell immunotherapies. However, in the near future, it may encounter tight market competition with other new devices. Automated point-of-care (POC) systems represent the most advanced technological edge for manufacturing clinical-grade cell products. Only a few such systems are now available for clinical use, suggesting that more companies will be entering the competition very soon.The rapidly expanding global market for all types of bioreactors for cell products makes it a highly lucrative field of science and technology that attracts major investments to accelerate the development of improved manufacturing practices. In recent years, the development of automated and semi-automated bioreactor systems has advanced rapidly to enhance the affordability, efficacy, and quality of various cell products. Expanding the scope of available technological solutions will allow for the manufacturing of a wide range of therapeutic cell products, including CAR-T cells, TILs, DCs, and NK cells .The fast-ever-growing field of immuno-oncology and customized cell therapies requires academic research and clinical facilities to accelerate the development to cover the unmet market needs . HoweverFurther advancements in both cell biology and hardware/software engineering will lead to more sophisticated closed automated POC platforms for rapid and cost-effective manufacturing of personalized cell immunotherapies. The POC systems are normally self-sustained and have lower infrastructural requirements which makes them more usable in various clinical settings. Such platforms are capable of regulating nutrient supply, medium exchange and waste removal. They also often include single-use disposable components and wireless sensors that monitor and record data in real-time.The challenges that lie ahead of the scientific and biotech community, such as scaling up manufacturing of the cell products, automated monitoring, and sophisticated regulation of the whole process, will lead to the emergence of novel manufacturing platforms. Altogether, this eventually will transform the landscape from single institutions and small hospitals to an extensive and interconnected global network of manufacturing centers that will define the future of T cell therapeutics.


Breast cancer has a high mortality rate among malignant tumors, with metastases identified as the main cause of the high mortality. Dysbiosis of the gut microbiota has become a key factor in the development, treatment, and prognosis of breast cancer. The many microorganisms that make up the gut flora have a symbiotic relationship with their host and, through the regulation of host immune responses and metabolic pathways, are involved in important physiologic activities in the human body, posing a significant risk to health. In this review, we build on the interactions between breast tissue  and the microbiota, then explore factors associated with metastatic breast cancer and dysbiosis of the gut flora from multiple perspectives, including enterotoxigenic Bacteroides fragilis, antibiotic use, changes in gut microbial metabolites, changes in the balance of the probiotic environment and diet. These factors highlight the existence of a complex relationship between host-breast cancer progression-gut flora. Suggesting that gut flora dysbiosis may be a host-intrinsic factor affecting breast cancer metastasis and progression not only informs our understanding of the role of microbiota dysbiosis in breast cancer development and metastasis, but also the importance of balancing gut flora dysbiosis and clinical practice. The 2020 Global Cancer Statistics report shows that female breast cancer is the most common cancer worldwide, with the highest number of new cases annually , having overtaken lung cancer 11.4%) . In turn% . In tuWith advances in early diagnosis and comprehensive treatment, the prognosis for patients with breast cancer has improved; however, the incidence of metastasis is also increasing . It has The priority of metastasis varies from organ to organ, resulting in differences in prognosis and treatment response. A widely accepted model of metastasis is the “seed and soil” hypothesis proposed by Paget , which iphyla Firmicutes and Bacteroidetes, followed by the phyla Actinobacteria and Verrucomicrobia , and Bacteroides fragilis , and Gut microbiota may influence estrogen-related diseases in the elderly  levels of estrogen in the body . The metculation . In addi elderly , such as elderly , 110. Du elderly . When th elderly . In addi protein  are asso protein . Karen L protein , Nichola protein , These f protein . It was bacteria . A compabacteria . In contbacteria . Prevotepatients . Furtherpenicillins, streptomycin, chloramphenicol, tetracyclines, erythromycin, cephalosporins and their analogues) decreases plasma levels of lignans-enterolactone, which can increase the risk of breast cancer by affecting the microbiota , maintain their cytotoxicity, and enhance cellular immunity  isolates and a Staphylococcus epidermidis isolate from normal adjacent tissues of breast cancer patients had the ability to induce DNA double-strand breaks, thus causing genomic instability  that does not secrete BFT. The presence of BFT was found to be detected in the mammary glands of ETBF-carrying mice compared to controls, with a 3.9-fold higher tumor volume than 086Mut controls, enhanced lung and liver metastases, and more proliferative tumors forming in the ETBF group, exhibiting a mesenchymal phenotype. Moreover, trichrome staining showing significantly higher stromal infiltration, demonstrating that ETBF intestinal or ductal colonization was associated with breast cancer progression and distant metastasis. Furthermore, significant differences in breast tissue structure were found in the ETBF group compared with the 086Mut control group  breast cancer in a more aggressive and metastatic tumor model, Parida S et al.  evaluatein-situ mouse model of breast cancer, Kirkup et al.  persisted or overgrew. The composition of the gut microbiota was significantly altered in terms of species, abundance and overall diversity following the use of antibiotics, which was associated with accelerated tumor growth and an increase in mast cells in the tumor stroma. To determine whether mast cells affected tumor growth, Kirkup et al. . C57BL/6 mice carrying PyMT-BO1 tumor cells and receiving a cefadroxil dose equivalent to that in human patients experienced a significant acceleration in tumor growth. Analysis of the gut microbiota of the animals showed that the microbiota aggregates in samples from the experimental and control animals were independent and clustered differently before and after treatment. The relative abundance of Lactobacillus decreased over time in the control and experimental groups, and this appeared to be replaced mainly by fecal genera in the control animals, however, this did not occur in the antibiotic-treated animals. The genus with the most significant change in the microbial composition of the animals in the experimental group compared to the pre-treatment samples was Lactobacillus, but there was no significant difference before and after the control group. We presume that the disappearance of Lactobacillus might be driven by tumor cells, tumor–microbiota interactions, or natural maturation of the microbiome rather than by cefadroxil administration. Further analysis revealed differences in the abundance of 11 genera after cefadroxil treatment: Mucispirillum, Marvinbryantia, Parabacteroides, Anaeroplasma, Bacteroides, and Paraprevotella were significantly higher, and Alloprevotella, Alistipes, Odoribacter, Faecalibaculum, and Anaerotruncus were significantly lower. When multiple comparisons were made, 8 genera were significantly altered after antibiotic treatment. the genera that were significantly lesser abundant in treated animals relative to the controls, several are known butyrate-producing bacteria  or genera carrying the genes required for butyric acid production   , consistA major signaling route between the microbiome and the host is the secretion of Microbial metabolites that enter the circulation and reach their target cells –158. micin vitro to affect the functioning of breast cancer and immune cells. Members of the microbiota can digest certain indigestible components of the human diet , and SCFAs—for example, acetate, propionate, and butyrate—are components of metabolized dietary fiber  in terms of LCA abundance is unknown and requires substantial research and continued trials.In the gut, disruption of the microbiota breaches the biologic barrier between it and the underlying tissue, leading to adverse physical contact between microbes and host cells, inducing paracrine production of bacterial metabolites . ChangesShigella felis, Shigella sonnei, Escherichia coli, and Streptococcus are all capable of expressing it , mice fed regular milk and mice not fed any special food, it was found that the group fed FM showed an inhibition of tumor growth and a decrease in tumor vascular filling, tumor cell extravasation and lung metastasis. Khoury et al.  exerted an anti- angiogenic effect on mouse mammary tumors by down-regulating the tumor-promoting invasive interleukin 1β and vascular endothelial growth factor (a key mediator of angiogenesis). In the above model, levels of the pro-angiogenic factor interleukin 6 were found to have declined (Lactobacillus casei CRL431 (probiotic fermented milk (PFM)) reduced the side effects of capecitabine and reduced intestinal mucositis and mortality in a mouse model of breast cancer by modulating the immune response, this suggests the potential of PFM as a probiotic as an immune adjuvant that may reduce tumor growth and metastasis without compromising the anti-tumor/anti-metastatic effects of chemotherapy. They differentially regulate cancer-related signaling pathways in a cell-type-specific manner and play a suppressive role in the pro-tumor microenvironment  and SCFAs in humans  are cited from the relevant references and the data are authentic and publicly available.JZ, ZL, MD, XH and MY contributed to the conception and the drafting of manuscripts. GS, QX and YZ are responsible for coordinating and participating in the article revision. All authors contributed to the article and approved the submitted version.The project was supported by the 2022 Qinghai Province Central Guide to Local Science and Technology Development Fund, the Breast Disease Treatment Centre of the Affiliated Hospital of Qinghai University manages this funding.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.


Vitis vinifera is the most widely cultivated grapevine species. It is highly susceptible to Plasmopara viticola and Erysiphe necator, the causal agents of downy mildew (DM) and powdery mildew (PM), respectively. Current strategies to control DM and PM mainly rely on agrochemical applications that are potentially harmful to humans and the environment. Breeding for resistance to DM and PM in wine grape cultivars by introgressing resistance loci from wild Vitis spp. is a complementary and more sustainable solution to manage these two diseases. During the last two decades, 33 loci of resistance to P. viticola (Rpv) and 15 loci of resistance to E. necator (Ren and Run) have been identified. Phenotyping is salient for QTL characterization and understanding the genetic basis of resistant traits. However, phenotyping remains a major bottleneck for research on Rpv and Ren/Run loci and disease resistance evaluation. A thorough analysis of the literature on phenotyping methods used for DM and PM resistance evaluation highlighted phenotyping performed in the vineyard, greenhouse or laboratory with major sources of variation, such as environmental conditions, plant material (organ physiology and age), pathogen inoculum (genetic and origin), pathogen inoculation , and disease assessment method . All these factors affect resistance assessment and the quality of phenotyping data. We argue that the use of new technologies for disease symptom assessment, and the production and adoption of standardized experimental guidelines should enhance the accuracy and reliability of phenotyping data. This should contribute to a better replicability of resistance evaluation outputs, facilitate QTL identification, and contribute to streamline disease resistance breeding programs. Vitis display susceptibility, partial, or total resistance to Plasmopara viticola Berl. & De Toni, the causal agent of downy mildew (DM), and to Erysiphe necator Sch., the causal agent of powdery mildew (PM). Vitis vinifera L. is the most cultivated grapevine species worldwide, but most of its accessions are highly susceptible to both P. viticola and E. necator. DM and PM have devastating impacts on grapevine cultivation  are obligate, biotrophic and polycyclic pathogens, affecting all green organs of their host  and mild temperatures , and 15 loci of resistance to E. necator (Ren and Run) in American, Asian Vitis spp. and in some V. vinifera cultivars (https://www.vivc.de). Some Rpv and Ren/Run loci are labeled as major if they explain large phenotypic variance . This variability in loci characterization seems to be impacted by the receptivity of the plant material to infection, control of the pathogen inoculum, management of experimental conditions, and resistance variable assessed.In the past 20 years, phenotyping strategies to map E. necator with 12 Ren/Run loci identified, while laboratory (in vitro) assays were more frequently used for P. viticola evaluations with at least 27 Rpv loci identified. Evaluations in the greenhouse have been used to a lower extent with only 3 Rpv and 7 Ren/Run loci characterized  and/or pathogen growth. In the vineyard, P. viticola and E. necator, respectively, refer to a semi-quantitative scoring method. The scales comprise five classes, ranging from 1 for very susceptible phenotypes (with extended and dense pathogen sporulation) to 9 for totally resistant phenotypes   or by different visual scales (disease severity) . The usems) OIV,  Table 3ms) OIV, . This scms) OIV,   produced the most significant QTL identification  and environmental components involved in the experiments and their interactions, the technical difficulties in managing and standardizing the resistance evaluations, and the consequential costs and time associated with the phenotyping practices. Objective and quantitative measures of grapevine mildew resistance using new tools, but also the harmonization of the procedure according to Minimum Information About a Plant Phenotyping Experiment (MIAPPE) would improve future phenotyping protocols.Phenotyping in the vineyard yield resistance data at the whole plant level during natural polycyclic infections and under unstable epidemic pressure. Some studies suggested that the leaves may be a proxy of whole plant resistance  growing and rated in the same environment and experimental design as the candidate plants to be assessed, would validate the phenotyping practices . Finally, due to the possible pathogen genetic variability, the identified resistance QTL should be checked in multi-year and multi-time evaluations, and in different vineyard areas before their introduction into breeding programs  resolution  may hamper the correct interpretation of mapping studies and their application to new phenotyping and genetic investigations. This lack of standards is the result of a large variability of protocols but also of the dependence of the genetic trait on the environment and phenotyping conditions  checklist consists of attributes that can be classified within the following eight categories: (1) general metadata ; (2) location and timing of the experiment; (3) biosource ; (4) environmental descriptors  such as aerial conditions, light, fertilizing and watering; (5) treatments ; (6) experimental design ; (7) samples collection, processing and management protocols; and (8) observed variables described by three basic attributes: trait name, measurement method, and notation scale. Furthermore, authors relied on annotations that agree with publicly available ontologies using proper dataset formats . For grapevine resistance phenotyping, this approach is still new and guidelines are not available yet. Such guidelines need be developed to implement best practices, improve the quality, availability, and usefulness of the data and to associate metadata describing the experiments. The implementation of such standards would facilitate the harmonization of data and metadata resources in a shared format  was proposed to harmonize phenotypic observations and develop precise and repeatable protocols . Additionally, they affect the degree of DM and PM infections, and significance of the QTL analyses. Phenotyping in more controlled environments such as the greenhouse or laboratory is often more effective than in the vineyard because it allows the production of reproducible results that increase the reliability of QTL identification. However, controlled environments generally provide only partial information on the resistance of the genotypes studied, such as leaf resistance under conditions of monocyclic pathogen development. Thus, with an aim of resistance durability, grapevine genotypes identified as resistant to DM and PM under these conditions should be evaluated in the vineyard where natural and diverse pathogen populations occur. Finally, in the search for new resistance loci in grapevine, future phenotyping experiments should follow MIAPPE guidelines to standardize protocols and increase the reliability and reproducibility of QTL mapping results, regardless of the phenotyping environment. Meanwhile, phenomics could provide new tools to increase grapevine-resistance assessment throughput and accuracy.During the past 20 years, effective protocols have been implemented in all the environments of phenotyping  for the identification of several DM and PM resistance TP and SW-M conceived the work, performed the literature search, analyzed the data, drafted, and edited the manuscript. Both 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.


Autism spectrum disorder (ASD) is a neurodevelopmental disorder with onset in early childhood. While highly heterogeneous, the core manifestations always include persistent difficulties in social interaction and communication, as well as a pattern of restricted interests, repetitive behaviours, and abnormal sensory processing . In addiCurrently, psychopharmacological treatment in ASD can improve many comorbid neurodevelopmental disorders, such as attention-deficit/hyperactivity disorder or aggressive behaviour, and the core symptoms of restricted and repetitive behaviours ,9. No phGiven the heterogeneity regarding the ASD phenotype and its underlying etiology, such as diverse genetic variation and additional environmental risks with the related neurobiological mechanisms, discovering new pharmacological treatments for the condition is a huge challenge. This challenge is at the heart of this Special Issue. Here, we have collected a set of contributions providing state-of-the-art coverage, ranging from the theoretical framework, linking genetics to human behaviour and therapy, to initial practical examples of how genetics can provide valuable insights into the personalized clinical management of autistic individuals. To introduce the papers of this Special Issue, a broad summary of the many challenges related to the development of personalised medicine in ASD is given here. In the final statement from the editors, the specific contributions of the articles included in this Special Issue will be summarised.Due to the limitations of comparable clinical outcome measures in ASD, genetic research aiming to describe underlying biological mechanisms has most often taken the gene-to-behaviour approach, as a rule, via intermediary phenotypes. In the case of cell models, morphologocial neural change, differential gene expression and other functional approaches to neural development are used . These oA promising approach in delineating the functional consequences of genetic risk factors aims to study molecular or neural mechanisms, which show overlapping characteristics between species. For example, the role of mutations in the mTOR or RAS signalling pathways show similar neuropathological characteristics in human and rodent models . Gene exTo test new pharmacological compounds related to the specific genetic background of an individual, pharmacological information has to be linked with the individual’s molecular findings . The avaCurrently, clinical trials may either be carried out in individuals with a specific monogenetic disorder or microduplication/-deletion, which is often accompanied by ASD, such as fragile-X syndrome (FraX). This approach has been followed by large consortia and is described in several articles of this Special Issue. A recent comprehensive review has delineated the road to precision psychiatry by translating genetics into disease mechanisms . Still, Recent developments in the design of clinical trials for individuals with ASD have emphasized the strong relevance of change-sensitive and patient-centred outcome measures, which should be used in clinical trials with individuals with ASD. A seminal article implementing qualitative and quantitative methods has reviewed the state of the art on outcome measures in young children with ASD . QualitaPersonalised medicine, especially pharmacotherapeutic approaches, based on individual genetic burden, has made steady progress over recent years. The combination of phenotypically and genetically informed personalised approaches, and in relation to pharmacological and psychosocial intervention, is another area of importance for the clinicians, the affected individuals, and their families.


The hospital environment significantly contributes to the onset of healthcare-associated infections (HAIs), which represent one of the most frequent complications occurring in healthcare facilities worldwide. Moreover, the increased antimicrobial resistance (AMR) characterizing HAI-associated microbes is one of the human health’s main concerns, requiring the characterization of the contaminating microbial population in the hospital environment. The monitoring of surface microbiota in hospitals is generally addressed by microbial cultural isolation. However, this has some important limitations mainly relating to the inability to define the whole drug-resistance profile of the contaminating microbiota and to the long time period required to obtain the results. Hence, there is an urgent need to implement environmental surveillance systems using more effective methods. Molecular approaches, including next-generation sequencing and PCR assays, may be useful and effective tools to monitor microbial contamination, especially the growing AMR of HAI-associated pathogens. Herein, we summarize the results of our recent studies using culture-based and molecular analyses in 12 hospitals for adults and children over a 5-year period, highlighting the advantages and disadvantages of the techniques used. It is generally recognized that built environments (BE) can be considered super-organisms, with their own microbiome that, in more confined environments, show more anthropic origin, less biodiversity, and higher antimicrobial resistance AMR; .In the hospital environment, these features are very important because the hospital microbiome represents the reservoir for the so-called healthcare-associated infections (HAIs), which are a concern worldwide  and are Staphylococcus aureus  and Clostridium difficile are all able to survive for particularly extended periods of time in the healthcare environment  bioluminescence . AlthougMolecular methods, being based on the analysis of the genetic material of the sample, are characterized by high rapidity, sensitivity, and specificity, allowing the detection and quantification of even a very low number of targets in a few hours, and providing an in-depth characterization of the microbial community . These mStaphylococcus spp. was identified as a prevalent contaminant, followed by Gram-positive Enterococcus spp., Gram-negative Enterobacteriaceae, and fungi  in all sampled settings. The high prevalence of mecA was likely due to the high prevalence of S. aureus that was also detected on the sampled surfaces , which is an important virulence factor enabling S. aureus to evade host immune responses (lukF), a toxin leading to trans-membrane pore formation , ermA-B-C , OXA-51 group (conferring resistance against beta-lactams and carbapenems), and QnrS/QnrB-8 group (coding for resistance against quinolones). By using a sanitation procedure able to modulate the stability of the hospital microbiome compositions—based on the competitive exclusion exerted by Bacillus probiotics included in the cleaning system—a significant decrease (80%) in pathogens was observed in the treated environments, accompanied by a halving of the HAI incidence . Short hypervariable regions of <500 base pairs (bp) harbored in conserved genes are amplified by PCR using universal primers targeting bacterial 16S ribosomal RNA (rRNA), fungal 18S rRNA, or Internal Transcribed Spacer (ITS) rRNA. The subsequent sequencing of the amplified fragments can provide the characterization of complex microbial communities, as well as the identification of individual species and detection of microorganisms of interest among many others. Furthermore, besides the identification and tracking of microorganisms of interest, 16S/18S/ITS rRNA sequencing data can be used to describe and compare the diversity of multiple complex environments through Alpha (α) and Beta (β) diversity analyses, providing useful parameters for comparing complex microbial communities.This sequence-based approach, when applied to the study of AMR, can provide information on all AMR genes and their precursors in a microbial species or population, thus profiling the whole resistome . In receIn the shotgun metagenomic approaches, the extracted DNA is first fragmented by shotgun, generating shotgun libraries that are sequenced, thus providing unrestricted sequencing of all the microbial genomes present in a sample. Shotgun metagenome sequencing is currently performed for taxonomic profiling (diversity and abundance), allowing for parallel sequencing of DNA from all organisms within a community, with high coverage for species-level detection. The resultant sequencing reads are then aligned to a reference database to identify taxa. Thus, being independent from amplification, shotgun metagenomics allow the identification—in a unique sample and with improved genus and species level classification—of bacteria, archaea, eukaryotes, and DNA viruses, with broad taxonomic coverage, accurate functional profiling, and the possibility of detecting previously unknown species and strains of microbes.Shotgun metagenomics have also been proposed for the detection of AMR-related genes , since tS. aureus and Enterobacterales, and M. tuberculosis , quinolones, macrolides, erythromycin, lincosamides, and streptogramin . This stMetagenomics may result in low sensitivity due to sequencing all of the DNA present in the sample. By contrast, quantitative PCR methods may provide higher sensitivity. A direct comparison of these methods, with respect to sensitivity and specificity, is needed. Next-generation sequencing represents an invaluable tool for the in-depth characterization of the resistome of hospital surfaces. However, for daily surveillance practice, where it is necessary to have results in a short period of time and at reduced costs, the applications of molecular methods such as qPCR microarray—that identify and quantify selected panels of resistance genes associated with HAIs—have been shown to be effective and may be easier to apply . The higDuring the last decade, metagenomics approaches have significantly improved analysis capacities, and the cost of new options available to scientists and clinicians is constantly decreasing. The high-throughput sequencing of 16S rRNA gene is uniquely able to identify unsearched bacteria and AMR genes, compared to targeted PCR and conventional microbiological methods, rendering it an effective first-step tool for monitoring the hospital microbiome and evaluating the safety of the environment, in terms of associated infectious risk. Next-generation sequencing can identify all the genetic material in a sample even if present in trace amounts. Due to the LGT of AMR among bacteria  and the The presence of traces that do not necessarily belong to viable microbes at the time of sampling may present a bias. This could be overcome by treating the sample with PMA (propidium monoazide) to block the amplification of dead cells’ DNA, for example .Furthermore, 16S rRNA-based NGS cannot detect eukaryotic cells, such as fungi, or distinguish virulent from non-virulent bacterial species. Therefore, the addition of other molecular tools, such as WGS or specifically targeted PCR, should be considered in order to obtain sensitive and accurate identification of pathogens and their AMR.Currently, qPCR microarrays seem to be a useful tool for monitoring the hospital environment, due to their rapid results on the AMR genes of interest, less complex data processing requirement compared to NGS or WGS, and less expensive instruments  and of the resistome of the microbial population, may provide a deeper knowledge of the microbiome contaminating the hospital environment. This will lead to consistent improvements in protocols and interventions to counteract the increasing AMR diffusion. Molecular analyses can be conveniently included in surveillance programs, providing standardization of pipelines and interpretation of the genomic data, which is urgently needed. In the near future, using these molecular investigations, our understanding of the resistome may become sufficiently mature to enable the development of strategies that actively fight resistance mechanisms and stop the spread of AMR.CC, MD’A and EC performed literature search, drafted the manuscript, and prepared the figures. IS, MC, and EC edited and revised the manuscript. EC initiated, supervised, and finalized the work for submission. 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.


The pandemic is aggravating health inequalities, particularly mental health inequalities, while revealing the social determinants of these inequalities, including migration as a social determinant that mediates the interaction of social, economic, cultural, institutional, and structural factors with health indicators. Therefore, it is of most relevance to identify the multiple interconnected factors that influence the mental health and well-being of migrant populations. A scoping review was developed to map the research performed in this area and to identify any gaps in knowledge, following the PRISMA extension for scoping reviews. MEDLINE, Scopus, and WHO Global Health research databases on COVID-19 were searched from January 2020 to October 2021. The review followed the inclusion criteria Population/Concept/Context (PCC): Population-Adult International migrants ; Concept-determinants of (and factors influencing) mental health and well-being; Context-COVID-19 anywhere in the world. Of the sixty-five selected studies, eleven were from European countries and were the focus of this review with special attention to health inequalities experienced by migrants in Europe. The results cover a diversity of themes related to the effects of COVID-19 on the mental health of migrants , responses (such as solidarity and resilience), populations, and study methods. The evidence found can inform recommendations and interventions focused on health promotion and mitigation of the inequalities accentuated by the pandemic. As rapid as the COVID-19 pandemic emerged, it gave rise to a series of disruptive consequences in the economic, health, and educational sectors that contributed to a scenario of disproportional economic and social vulnerability. These effects of the pandemic seem to be greater in socially vulnerable and marginalized groups, more specifically migrant populations. While these groups are overrepresented in COVID-19 cases in terms of laboratory diagnosis, hospital admissions, intensive care, and death statistics in all countries according to the available data ,3,4, theThis research centralizes around the premise that the pandemic is aggravating health inequalities, particularly mental health inequalities, while revealing the social determinants of these inequalities, including migration as a determinant that mediates the interaction of social, economic, cultural, institutional, and structural factors with health indicators, affecting the different spheres of life ,11,12,13Intersectional approaches are needed to analyze the complexity of the pandemic situation and adapt the political responses to deal with this complexity. Intersectionality is a theoretical-methodological powerful tool to reveal processes of interaction between power relations and categories—such as gender, class, race, and ethnicity—in individual, collective, and cultural/institutional contexts, yet still with limited use in mental health. Using an intersectional lens of analysis can help to identify differentials in the mental health effects of the pandemic between individuals and social groups, facilitating the elaboration of political responses tailored to people at the most marginalized intersections  with a focus on equity ,15,16,17This scoping review aims to identify and summarize the existing research on the effects of the COVID-19 pandemic on the mental health of migrants with reflection on the European context  to inform suited recommendations for migrant-sensitive and migrant-inclusive healthcare. The overarching research question was to pinpoint the multiple factors influencing the COVID-19 pandemic’s effects on the mental health of international adult migrants .In early October 2021, we conducted a preliminary search on the Joanna Briggs Institute (JBI) Database of Systematic Reviews and Implementation Reports and the Cochrane Database of Systematic Reviews for identifying existing scoping and systematic reviews on the topic. No studies on the intersections between COVID-19, mental health, and migrants were found. Therefore, a scoping review was developed to map the research carried out in this area and to identify existing knowledge gaps, since scoping reviews provide a comprehensive overview to address broader review questions than traditionally more specific systematic reviews of effectiveness or qualitative evidence .The protocol was registered with the Open Science Framework on 5 November 2021. The review was undertaken following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews—PRISMA-ScR  and the A systematic literature search was performed using the following electronic databases: MEDLINE (via PubMed), Scopus, and WHO Global Health research database on COVID-19, using combinations of the search terms, tailored to the syntax, and functionality of each database. All searches were conducted on 13 October 2021 and tailored to each electronic database  defines a migrant as “any person who is moving or has moved across an international border or within a State away from his/her habitual place of residence, regardless of (1) the person’s legal status; (2) whether the movement is voluntary or involuntary; (3) what the causes for the movement are; or (4) what the length of the stay is”) was considered . So, artThe PCC method (Population (or participants)/Concept/Context) recommended by the JBI to identify the main concepts in the primary review questions was used for the search strategy and the definition of inclusion criteria : P  Author(s) and year of publication, (2) country, (3) population , (4) aim, (5) design, (6) mental health outcome(s), (7) social determinants of health, (8) overall results, (9) overall limitations, (10) and overall recommendations. Bibliometric data regarding the journal’s title, publication quartile, and domain/area of work  were also collected. Methodological quality or risk of bias of the included articles was not appraised because it was not relevant to the scoping review objectives, which is consistent with guidance on scoping review conduct . ResultsA total of 1938 publications were identified from the three searched databases. Once duplicates were removed, 1291 articles remained for screening. Of these, 1226 were excluded because they were not empirical studies, did not focus on mental health outcomes, or were not conducted among migrant populations. As a result, 65 studies could be included. Eleven articles (17%) were conducted in European countries and were specifically selected to be included in this review paper for mapping the research on the effects of the COVID-19 pandemic on the mental health of migrants as well as to identify knowledge gaps in Europe. A flow diagram detailing the number of studies included and excluded at each stage for this review is provided in All of the selected studies were published in journals with impact factor, mainly in journals ranked in the first quartile (7/11). Three studies were published in journals in the second quartile, and one study in the third quartile. In terms of the subject area, four articles were published in the Public health, Environmental and Occupational Health domain, two in Psychiatry and mental health, two in Geography, Planning and Development, and one in Clinical psychology, in Leadership and Management, and Health, Toxicology and Mutagenesis.The studies were conducted in eight European countries and one publication was from a European Consortium, the ApartTogether Consortium, led by the Ghent University in Belgium and the University of Copenhagen in Denmark, and the Migration and Health program of the WHO Regional Office for Europe .Two of the eleven studies were conducted in Italy with migrant patients in mental health outpatient departments, one published in 2020 aiming to evaluate the impact of the COVID-19–related lockdown on the difficulties in the utilization of mental health services and follow-up adherence , and theTwo other studies were conducted in the United Kingdom (UK), one with Black, Asian, and Minority Ethnicity group (BAME) healthcare workers , and anoAdditionally, two studies were related to the Netherlands—more specifically an online survey among Chinese immigrants living in the Netherlands  and a PoFinally, four countries  had one publication each, with different populations and approaches. Research conducted in Spain was centered on the role of resilience for mental health in times of COVID-19 across groups of migration and non-migration individuals . The stuThe studies used a quantitative approach, with online and/or telephone surveys. There is a diversity in the mental health outcomes analyzed, from depression, anxiety, and stress, to sleeping problems and substance use, satisfaction with life, and responses .The COVID-19 pandemic has posed new challenges to societies and their health systems. The included papers mention a series of unprecedented interventions implemented, from minor (mask wearing and hand hygiene) to major readjustments to everyday life, such as the “lockdown” periods that first took place in many countries between March and June 2020 to reduce the spread of SARS-CoV-2 infection , with ItPreventive actions involved a series of escalating restrictions on everyday life, including limitations on gatherings, travel restrictions, and minimization of movement outside of the house, with several services closed and social activities suspended. In addition to the tremendous consequences to the economy, socio-economic inequalities were exacerbated during the lockdown. The United Kingdom is among the countries where pre-existing socioeconomic inequalities have become worse than before the pandemic due to the adopted measures .Switzerland was among the countries most rapidly and severely affected relative to its size, with a peak incidence of new positive tests on 30 March 2020, in Geneva, where undocumented migrants represent about 2.5% of the 500,000 residents. The duration of the public health lockdown measures put migrants, especially undocumented migrants, at increased risk of not being able to meet their basic needs . While sIn addition to social isolation, COVID-19 has demanded people adapt to novel situations and future uncertainty, which represented a great psychological burden. A study conducted in Poland and the Netherlands to explore environmental stress and the quality of life connected with COVID-19 has shown cultural differences between the two countries, that can be linked to the government’s crisis management in these countries . AnxietyEconomic stability Of the 11 articles selected, six presented findings on economic and labor instability in migrant populations during COVID-19 [COVID-19 ,25,29,30Socioeconomic issues linked to unemployment and immigration status uncertainty increased the risk of mental suffering due to the pandemic . COVID-1Socio-demographic characteristics of the migrant populations Most migrants work in jobs (domestic or construction work) requiring their presence, which added to their dense housing conditions, puts them at higher risk of infection than the general population, across several settings ,29,30. FGender differences in health outcomes in the context of COVID-19 were observed in the selected studies. Moran and collaborators concluded that while men have a higher risk of COVID-19 mortality and severity, the indirect consequences of the virus tend to impact more women, due to their greater socioeconomic vulnerability. Impacts range from job and income losses to increasing gender-based violence and mental health. However, men who are marginalized or in disadvantaged positions are also particularly vulnerable .Aragona et al. presented the negative impacts of the COVID-19 lockdown on access to mental health services and illustrated how the pre-pandemic situation of vulnerability put some subgroups of the population more at risk, including people with lower economic status, homelessness, migrants, and patients with mental health disorders. Additionally, some individuals fall into several of these subgroups, thus facing a significantly higher risk of negative mental health consequences. In Italy, there are increasing cases of asylum seekers whose claim has been rejected that are without documents, without jobs, homeless, and living in poverty. Those most vulnerable migrants also often have symptoms of post-traumatic stress disorder (PTSD) due to their migratory experience, as well as depressive and adjustment disorders .Healthcare access and treatment complianceIn the ApartTogether online global survey of refugees and migrants, individuals with citizenship reported the least effect of COVID-19 on their mental health, compared to the most vulnerable groups of migrants . Younger participants also reported a less negative effect of COVID-19 on their anxiety and depression, indicating an age effect .HealthcMigrants more frequently face limited access to medical care, diminishing the odds of seeking medical treatment early enough to reduce the number of undetected cases and self-isolate at home, which may accelerate the transmission of the disease. In addition, during the COVID-19 pandemic, access to public hospitals has been controlled by security staff, with the likely consequence to repel undocumented migrants. Data since the beginning of the COVID-19 crisis indicates that undocumented migrants have lower utilization of healthcare, compared to regularized migrants. Additionally, poor mental health was related to the avoidance of health care .During the lockdown, patients reported barriers to mental health care access . This perceived unavailability of services due to the COVID-19 emergency is not only related to a reduction in the number of patients and follow-up visits but also influenced treatment discontinuation ,23. AragAdditionally, the study in France has shown that the specific policy measures implemented by the French government, such as the validity of all residence permits and the State Medical Aid , were only acknowledged by a few migrants. However, regarding strategies to preserve one’s health, a majority mentioned using barrier measures  .Mental and family-related distressAmong individuals already in treatment before the pandemic, there was an increase in the frequency of psychic anxiety, depressive symptoms, feelings of tension/nervousness, and sleep disorders, ranging between 74% and 91%, and including anxiety specifically related to the coronavirus . In terms of the effects of the lockdown, mental symptoms were unchanged or improved in many patients. However, anxiety and nervousness were reported as the most frequently worsened symptoms, but never above 50% [bove 50% .A study of minority ethnic healthcare workers has shown feelings of anxiety about the working condition and about family, particularly living in social isolation during COVID-19, with a significant impact on their mental health .Stigmatization and discrimination of vulnerable groupsA study with female psychiatric patients also has found greater family-related distress, including more household tension, more housework, and more domestic violence, especially among those with a migration background .StigmatSince the earliest cases were reported in China, several studies have drawn attention to the rise of stigmatization and racism against Chinese and Asian immigrants. As the study conducted among Chinese immigrants in the Netherlands has shown, the pandemic and its societal dynamics harmed migrants’ views of their host country. Besides feelings of fear of COVID-19, financial consequences, social isolation, feelings of lost time, missing China, and perceived travel restrictions to China, more experiences of racism were frequently reported .Other results have shown that refugees and migrants with higher perceived discrimination levels since the pandemic also reported worse mental health outcomes .The German study evaluating the experience of the pandemic among a cohort of outpatients at a large psychiatric outpatient institution measured the level of distress concerning COVID-19 lockdown and found increased concern about relatives, anxiety, worse sleep, and more physical symptoms, with a small group also reporting increased drug consumption. Women with a migrant background showed greater lockdown-related stress .Meanwhile, the Spanish study examining the relationship between mental health and resilience across groups of migration and non-migration found a moderating group effect with higher resilience among individual migrants. This may be because migrants have a larger repertoire of coping strategies to deal with stressful situations such as the COVID-19 restrictions .Due to the significant difficulties to fulfill their financial, material, and food needs during the pandemic, migrants engaged in seeking external support, such as using the strategy of requesting a financial loan from the immediate social circle of friends or relatives .During the first wave of the COVID-19 pandemic, a total of 168 countries closed their borders, and resettlement movements were suspended, hence aggravating the need for international protection of migrants and refugees . The panThis review identified eleven publications from European countries, reviewing data on the effects of the COVID-19 pandemic on the mental health of international migrants in those countries. The results show a diversity of themes related to the effects of COVID-19 on the mental health of migrants and societal responses at micro, meso, and macro levels. This variety relates not only to the different sociodemographic needs across countries and regions but also to the characteristics of the healthcare systems and the variations in the COVID-19 management and adoption of measures .Findings from the reviewed publications provide valuable insights and contribute to a better understanding of the condition of migrants in the context of the COVID-19 pandemic. First, this review describes mental health outcomes across different European countries during the COVID-19 global pandemic. Second, it informs about the social determinants as the social, physical, and economic conditions that most affect mental health outcomes and resilience factors. Third, these identified factors can inform future policy measures, focused on supporting the most at-risk-identified populations, that is the most socioeconomic vulnerable groups of migrants (those undocumented and those with employment and housing insecurity), and provide a strategy to mitigate special risks in these subpopulations.Despite the variation in the countries’ response to the coronavirus pandemic, several public health measures focused on the continuity of care for mental health service users and facilitating access to mental health assessment and care for new patients were identified. Retaining existing services while promoting new health equity practices and providing individualized mental health services to patients who already have mental disorders or who have developed them during the pandemic needs to be considered. Telehealth services have been recommended to provide continued mental health care for those with existing mental health conditions, for populations who face barriers to accessing care and to combat the impacts of the pandemic .Health workers at the frontlines in Europe and worldwide were the ones at a greater risk of being infected since the beginning of the outbreak of COVID-19, especially those from migrant and minority ethnic backgrounds, at a higher number and risk because of their migrant and socioeconomic backgrounds . FrontliThere is a need for the implementation of a COVID-19-related mental health monitoring system that includes outcomes related to mental health service use .This review has limitations that should be addressed when interpreting the results. First, only three databases were consulted for identifying papers with no additional search strategy, such as searching references of the included papers or references of literature reviews identified during the screening process. A strong point, nevertheless, is that Scopus is among the largest databases, with a wide global and regional coverage of scientific journals. In addition, the search strategy was comprehensive and followed the recommendations made by the Joanna Briggs Institute (JBI) , such asMost of the studies take place in a specific national context, in which the developments over time, the government measures, the COVID-19 communication, and the populations may have considerable differences, forming eco-systems that may be hard to generalize to other contexts . FurtherNevertheless, the results of this review pointed out the need for more effective comprehensive health coverage in countries that see large populations of undocumented migrants with an emphasis on mental health services to reduce further health consequences and strengthen their capacity for resilience. Additionally, of most importance, findings indicate that regularization policies are relevant to facilitate their access to public social services and healthcare to mitigate the consequences of the COVID-19 crisis ,30.Mental health services and professionals need to be aware of the need to consider the family situation in psychiatric outpatients, with special attention to people with a migrant background . CommuniFinally, findings serve to highlight the need for proper housing as a strategy to prevent both COVID-19 and mental distress by revealing that people who have more difficulties in accessing health care and preventive measures against the infection experience deterioration of their mental health and increased discrimination by the host population .This review summarized the existing research on the multiple factors influencing the COVID-19 pandemic’s effects on the mental health of international adult migrants , reviewing existing data on European countries to advise recommendations for migrant-sensitive and migrant-inclusive healthcare, while identifying existing knowledge gaps. Findings can serve to inform on the socioeconomic, cultural, geopolitical, and legal environment diversity that forms the context for people’s lives in different settings and which influences mental health outcomes, including mental health workforce shortages and geographical maldistribution of providers, problems that the pandemic made more acute . They ca


Resveratrol, a plant-derived polyphenol, is an intensively studied compound with widely documented positive effects on health. Antioxidant activity is the property most often mentioned as responsible for its beneficial effects. Therefore, since the adverse effect of ionizing radiation is primarily related to the induction of oxidative stress, the question arises of whether the use of resveratrol could have a radioprotective effect. This paper summarizes the data on the cytoprotective activity of resveratrol and pieces of evidence for the potential interplay between response to radiation and resveratrol activity. The paper focuses on changes in the metabolic profile of cells and organisms induced by ionizing radiation and exposure to resveratrol. The comparison of metabolic changes induced by both factors provides a rationale for the potential mechanism of the radioprotective effects of resveratrol. Research on new substances that may have beneficial effects on human health is the objective of numerous studies. Natural compounds, commonly present in certain amounts in the standard diet, are a frequent subject of studies focused on their use in the prevention or treatment of various diseases. Among numerous plant-derived compounds, polyphenolic compounds are of great interest. (Poly)phenolic compounds have various functions in plants: they can be fragrances and colorants, poisons and feeding deterrents, allelopathic compounds, signaling molecules, structural components, and finally antifungal and antimicrobial agents . ExtensiResveratrol naturally found in fruits, especially grapes, is probably the most-explored plant secondary metabolite ever. It belongs to the stilbene class and, like most stilbenes, is a phytoalexin synthesized by plants in response to damage or pathogens ,5,6. NumVarious cellular mechanisms putatively contribute to the beneficial effects of resveratrol. This includes antioxidant activity with an increase in the activity of enzymes responsible for counteracting oxidative stress  ,11,12. RThe primary mechanism of toxicity of ionizing radiation is its ability to induce oxidative stress in tissues, which directly and indirectly leads to damage to cell structures resulting in their improper functions ,23,24. TAt low, “physiological” concentrations, reactive oxygen species (ROS) serve multiple functions: they act as signaling molecules, regulate physiological processes, participate in signal transduction, and activate ion channels and pathways involved in the acquisition of stress-induced resilience . HoweverBecause one of resveratrol’s mechanisms of action is its antioxidant activity, researchers seek to answer the question of whether it may also have radioprotective properties. In a study on bone marrow cells isolated from irradiated mice, Carsten et al., showed that administration of resveratrol reduces the number of chromosomal lesions induced by radiation . A similNoteworthy, the potential cardioprotective activity of resveratrol is also addressed. Questions related to the putative radioprotective activity of resveratrol in cardiac tissue may be of great importance since even low doses of radiation, though considered harmless for decades, may have adverse health effects due to increased risk of cardiovascular malfunction . HoweverMetabolomics is a technique that allows the identification and quantitative measurement of metabolites in biological systems. It is one of the most effective methods to detect cellular response to various endogenous and exogenous  factors, including ionizing radiation . SeveralThe analysis of radiation-altered metabolites allows the identification of specific metabolic pathways affected by radiation exposure. The vital importance of radiation-affected metabolic pathways it is important to address the question: what is the influence of resveratrol on cellular metabolism? However, the actual effect of resveratrol on the metabolism of cells and tissues remains a poorly studied field. The knowledge of mechanisms of radiation injury suggests that the potential radioprotective effect of resveratrol would likely involve the protection of mitochondrial function and energy metabolism. Hence, one might expect that the resveratrol administration would affect the metabolites associated with increased efficiency of energy production or improved antioxidative mechanisms since such changes will potentially antagonize the toxic effects of radiation. The few papers addressing this topic focus primarily on rodents. Mass spectrometry of plasma from rats subjected to trauma-hemorrhage (TH) revealed that resveratrol administration improves energy metabolism and reduces protein degradation. The specific changes included an increase in carnitine and a decrease in acetylcarnitine, butyrylcarnitine, trimethyl lysine, pipecolic acid, 3-ketobutyrate, 3-hydroxybutyrate, lactate, and citrate levels in TH with resveratrol supplementation group when compared to TH only group . AnotherA particularly interesting human study explored the effects of resveratrol on metabolic profile in men with metabolic syndrome . After 4The influence of resveratrol on cellular metabolism was also analyzed using in vitro models. The study on fibroblasts with mitochondrial Complex I disorder revealed that resveratrol administration resulted in a reduction in polyunsaturated fatty acids, phosphocholine, lactate, myo-inositol, and taurine levels, while the content of glutamate/glutamine, glycine, alanine, and BCAA increases . AnotherThere is only one report yet that addressed the influence of resveratrol administration on the metabolic profile of murine heart irradiated in vivo. The authors documented by NMR profiling that resveratrol supplementation changed levels of several metabolites in murine hearts 20 weeks after irradiation with a single 2 Gy dose. The administration of resveratrol mitigated the radiation-induced decline in the content of choline-containing compounds and unsaturated lipids, which might reflect the stabilization of cell membrane structure against radiation-related damage. Moreover, resveratrol itself affected metabolites associated with maintaining the balance of energy production—increased glycine and hypotaurine and decreased lactate levels. Obtained results fit the concept that resveratrol supplementation may prevent metabolic changes related to radiation-induced damage to the heart .Nevertheless, when the comparative analysis of metabolic pathways altered by exposure to radiation and resveratrol was performed, several common pathways could be identified that are illustrated in Resveratrol, a well-recognized dietary compound, possesses numerous beneficial health properties. An important area of its possible application is radioprotection, that is, counteracting and protecting against the negative effects of radiation exposure. To date, resveratrol has been shown to have radioprotective effects on bone marrow and germ cells, as well as on neuronal cells. There are also single reports of radioprotective effects of resveratrol in the context of the heart muscle. However, molecular mechanisms of radioprotective activity of resveratrol remain to be identified. The use of metabolic profiling techniques—NMR spectroscopy and mass spectrometry—enables the detection of molecular changes induced either by radiation or natural products. Therefore, a metabolomics approach could be implemented to explore the detailed mechanisms of resveratrol bioactivity. The results of available metabolomic studies indicate that the beneficial effects of resveratrol could be associated, at least in part, with the “counteracting” metabolic effects of radiation (which is schematically presented in