Dear Editor,n = 43) or omnivorous diet (n = 46). The research compared biochemical parameters  and erythrocyte parameters, as well as estimated energy and nutrient intakes, between the two groups. The vegetarian children had a two-fold decrease in serum hepcidin level accompanied by decreased ferritin level and slight but statistically significant increase in concentration of soluble transferrin receptor (sTfR), but no differences in concentration of hemoglobin, mean corpuscular volume, iron, and transferrin compared to the omnivorous group. Moreover, vegetarian children had comparable total iron intake but consumed more (approx. by 30%) ascorbic acid in food [We read with great interest the paper by Ambroszkiewicz et al.  entitled in food . The papOwing to the increasing popularity of vegetarian diets, their clinical consequences are becoming clearer and include such potential health benefits as decreased all-cause mortality and decreased risks of obesity, type 2 diabetes, and coronary heart disease . HoweverMost data on the health effects of vegetarian diets were collected from adults, so the study by Ambroszkiewicz et al. , despiteThe study by Ambroszkiewicz et al.  reportedp < 0.01) and decreased hepcidin level  in lacto-ovo-vegetarian children. Based on these findings, the authors suggest that the vegetarian children may suffer from subclinical iron deficiency. Their view is supported by two references in which similar trends in hepcidin and sTfR levels were found in children diagnosed with iron deficiency [Ambroszkiewicz et al.  noted thficiency , 15. Howficiency . Using tficiency , only foWe would like to suggest that instead of diagnosing a potential disease condition in the lacto-ovo-vegetarian children, the biochemical changes could be considered a form of adaptation wherein a slight increase in sTfR and two-fold decrease in hepcidin as observed by Ambroszkiewicz et al.  are evidFinally, simple measures can be taken to enhance the availability of dietary iron in children or adults who do develop clinical iron deficiency on vegetarian diets. The consumption of diets containing ferritin-rich seeds  provides iron in a more bioavailable form than other vegetables . In someIn summary, there is no evidence that the adaptive changes described by Ambroszkiewicz et al.  in veget


Obesity and metabolic syndrome are considered major public health problems, and their negative impact on cardiovascular disease (CVD) and diabetes mellitus type 2 (DM2) is profound. Targeting modifiable risk factors such as dietary habits is therefore of great importance. Many of today’s health challenges with overweight and obesity may have behavioral roots, and traditional methods such as regulations and campaigns are often insufficient to improve dietary choices. Nudging or choice architecture might be a viable tool to influence people’s everyday choices and behaviors to better outcomes. This paper reviews the current state of the rapidly expanding number of experimental field studies that investigate the effects/associations of nudging on healthy food choices. A systematic literature search was conducted in PubMed, where 142 citations were identified. Based on selection criteria, six randomized controlled trials and 15 non-randomized controlled trials were ultimately included. The results of this systematic review show that many of the studies included traffic-light labeling, which may be a promising strategy. The reviewed findings, however, also highlight the challenges that confront experimental studies examining the impact of nudging on diet.  Metabolic syndrome (MetS) affects public health, and has been associated with a doubling of cardiovascular disease (CVD) risk as well as a five-fold increased risk of diabetes mellitus type 2 (DM2) . To be dThroughout the past decades research in behavioral sciences has revealed that human behavior and decision-making is boundedly rational, and as a result, people make suboptimal, often self-destructive decisions . TherefoTo improve health outcomes nudging or choice architecture (a related term)  might beSeveral systematic reviews have suggested that nudging may be effective in increasing the consumption of healthy food and decreasing the consumption of unhealthy food: Broers et al., 2017   choice architecture and food, and (3) nudging and healthy food. In order to identify published studies examining nudging and/or the related term choice architecture , versus According to Hollands et al., 2013 . The lasThe majority of studies regarding nudging and/or choice architecture consist of multiple nudges and/or interventions. This makes it a challenge to map the different nudges and to evaluate their effects. However, Hollands et al., 2013 [nudge and food choice), 79 in the second search (choice architecture and food), and 32 in the third search . After screening 74 studies , 62 full-text articles were retrieved and assessed for eligibility. After removing duplicates and those not making it through quality assessment, 21 studies were included in this review. The included studies comprise of six RCTs and 15 non RCTs. A matrix was designed to get an overview over all the included articles. The articles were structured according to reference, participants/site, and results. The study characteristics are provided in The literature search identified 142 citations, of which 31 were found in the first search . The participants were blinded to group assignment. The intervention group received placemats featuring two healthy “Kids’ Meals of the Day” upon the restaurant entry, to nudge children toward healthy options. Forty-eight families had looked at the placemat before ordering . After the families finished dining, researchers recorded children’s orders and collected leftovers for quantifying dietary intake via weighed plate waste. Families who were exposed to the study placemats ordered more healthy food compared to controls. However, there were no significant differences in dietary intake when comparing the intervention versus control groups overall. Nevertheless, children who ordered one of the promoted healthy entrées consumed less saturated fat across the total meal compared to those who did not (p = 0.04).Anzman-Frasca et al., 2018  investign = 4) or control (n = 10) for five months. Then, the chef schools were further randomized to chef (n = 2) or chef + smart café (n = 2), and the control schools were further randomized to smart cafe (n = 4) or control (n = 6). In the smart café, vegetables were offered at the beginning of the lunch line. Fruits were placed in attractive containers, or next to the cash registers. Signage and images promoting fruits and vegetables were prominently displayed. White milk selection was placed in front of sugar-sweetened milk . All the modifications were simultaneously present and applied daily by existing food service staff. School food selection was recorded, and food consumption was measured using plate waste methods. The study revealed no association between the smart café intervention alone and food consumption. Fruit selection increased in the chef , smart café , and chef plus smart café  schools compared with the control schools. Vegetable selection increased in the chef , smart café , and chef plus smart café schools  compared with the control schools.Cohen et al., 2015  investign = 4), vegetable (n = 3) or control group (n = 3). However, the paper only focuses on the fruit intervention and control groups. The fruit intervention group made changes to the convenience, visibility, and attractiveness of fruit in their lunchrooms for a period of 6 weeks. The control group made no changes. The selection and plate waste data were assessed. Fruit selection increased overall by 36% (p < 0.001), and fruit consumption increased overall by 23% (p < 0.017) in the fruit intervention group, compared to controls.Greene et al., 2017  conducteHollands et al., 2018  examinedp = 0.044) in energy purchased in the day following the introduction of calorie labeling was found in one site. However, the effect diminished over time. No changes in energy purchased were revealed in the remaining five sites.Vasiljevic et al., 2018  investigVelema et al., 2018  examinedCole et al., 2018  investign = 43, 11–22 years) with intellectual and developmental disabilities were included. The intervention included: (i) prompting by ‘celebrity servers’, (ii) the creation of fruit and vegetable-inspired artwork for the dining hall, (iii) classroom-based taste-testing activities, and (iv) logo naming and branding activities. Selection and plate waste of foods at lunch were assessed. Smarter lunchroom increased selection (whole grains) and consumption  of healthy food, and decreased selection and consumption of unhealthy food (refined grains).Hubbard et al., 2015  investigKroese et al., 2016  investign = 4642) of a large hospital in Boston, MA, US, and regular cafeteria patrons. In the first phase, a traffic-light labeling system was introduced to encourage the patrons to purchase healthy items (labeled green) and avoid unhealthy items (labeled red). In the second phase, certain cafeteria items were rearranged, making green-labeled items more accessible and the red-labeled items less accessible. The main outcome measures were proportion of green or red labeled items purchased. Labeling decreased the red item purchases and increased green purchases. The intervention effects were similar across all race/ethnicity and job types.In a 9 months longitudinal study, Levy et al., 2012  investign = 96, BMI = 29.7 ± 6.0 kg/m2) who regularly ate lunch at their workplace cafeteria, were randomly assigned into one of two intervention groups: (1) Environmental change (low-energy-dens foods and food content labeling) or (2) Environmental change, education and pricing incentives. Food intake and energy intake was assessed with scan card technology coupled with computerized cafeteria cash registers. No difference in total energy intake were revealed between the groups over the study period. However, significant changes in energy intake were observed across the groups from baseline to the intervention period, with an increase in the percentage of energy from carbohydrates and a decrease of energy from fat. Lowe et al., 2010  investigNikolaou et al., 2014  investigp < 0.01).Olstad et al., 2014  investigSeward et al., 2016  investigThorndike et al., 2014  investigThorndike et al., 2012  investign = 291) examined the strength of combinations of toppings and bread type, and the main study consisting of a two (bread type) by two (topping type) between-subjects design. The included participants (n = 226) were given a free sandwich at a university stand with an unhealthy deep-fried snack (croquette) or a healthy topping. About half of the participants were offered a whole wheat bun unless they asked for white bun, and the other half were offered a white bun unless they asked for a whole wheat bun. Regardless of the topping, the whole wheat bun was the default option in 94% of the participants. When the default of bread offered was white, 80% of the participants chose the default option. The study revealed a strong default effect of bread type.Van Kleef et al., 2018  investigVan Kleef et al., 2015  investign = 1113) responded to a survey including questions about the breakfast. Results showed that consumption of fun-shaped whole wheat bread rolls almost doubled consumption of whole wheat bread (p = 0.001). However, consumption of white bread rolls did not differ according to shape.Van Kleef et al., 2014  investigVan Kleef et al., 2012  investign = 24, 86%) of french fries consumers noticed the reduction in portion size during the intervention.Vermote et al., 2018  investigAl-Khudairy et al., 2019  have modNudging or choice architecture interventions aim to improve dietary choices, but empirical evidence to support the effectiveness has been scarce. An important criterion for an intervention to qualify as a nudge is that the targeted audience/participants/customers retain their freedom to make a choice . In thisLabeling is the most frequent used nudge in this review and nineteen of the studies include labeling. Previous studies have shown mixed results and labeling has been debated . DespiteAvailability refers to how accessible an object or stimuli are, and rearranging the positions of food is a common nudge, for instance, in food stores. Seven studies used an availability nudge. Placing healthy food near the cash register increase the sale of these food because people are prone to pick up something in the “last-minute” as done in the study by Van Kleef et al., 2012 . HoweverPriming is, according to Marteau et al. (2012) , a promiThe results of this systematic review show that the majority of the studies include traffic-light labeling, and that may be a promising strategy. The results suggest that the majority of the interventions were effective. Thirteen studies measured effects on purchasing healthier food, and nine of them, plus one site in the study of Vasiljevic et al., 2018 , showed In most of the field experiments, the participants were not aware that they were part of an experiment. This limited social influence regarding desirable behavior and observer reactivity . The fieDespite the tremendous interest and studies on nudging and choice architecture regarding public health, it is still a relatively new and under-explored field. Many of the studies reviewed during this systematic review lacked definitional and conceptual clarity that might lead to poor methodology and unclear effects. A benefit of nudging is that it does not requires any additional actions for the individual or the targeted audience. Furthermore, the interventions are usually no cost or low cost, and that makes it easier to implement. Another important issue is that our environment, whether we like it or not, influences our behavior. Then it makes sense to alter the environment in a way that we make better choices that will be beneficial in the long run . Many ofThis systematic review was executed independently by both authors to minimize errors and bias. When there was discrepancy regarding a study, the study was thoroughly discussed based on the inclusion criteria and the quality check list. We prepared a checklist for measuring study quality based on the Downs and Black validated checklist from 1998 , but resNudging and/or choice architecture alone will not solve the worldwide health challenges caused by poor health choices. Although behavioral economics can provide great benefits if appropriately used, it is still necessary with an underlying political fundament . In otheMoving forward, nudging and choice architecture would benefit from a better conceptual clarity and a more systematic approach. There are no “quick fix” or “magic bullets” when it comes to changing people’s behavior. Additionally, even though it might be challenging, nudging interventions should be compared to more traditional interventions such as information campaigns and educational strategies. Future research should have longer study durations such as Thorndike et al., 2014 , and incThe results of this systematic review show that the effect sizes are very diverse and also low. Many of the studies included traffic-light labeling that might be a promising strategy. Moreover, this study also highlights the challenges that must be addressed when experimental studies concerning nudging are conducted. According to Marteau et al. (2012) , we live


From their discovery in biological systems, reactive oxygen species (ROS) have been considered key players in tissue injury for their capacity to oxidize biological macromolecules. Aerobic organisms possess a system of biochemical defenses to neutralize the oxidative effects of ROS, but the balance between ROS generation and the antioxidant system is slightly in favor of the ROS so that a continuous low level of oxidative damage exists . When thThe papers reported in this Special Issue deal with different aspects of reactive oxygen species (ROS) actions in living organisms. Some papers consider the role of ROS in inducing cellular dysfunction.2O2 to obtain a cell model of oxidative stress to study the role of sphingomyelin synthase 2 (SMS2) in endothelial disease (ED). They found that SMS2 induces the stress of the endoplasmic reticulum (ER) that leads to ED both activating the Wnt/β-catenin pathway and promoting intracellular cholesterol accumulation, both of which contribute to the induction of ER stress and finally lead to ED.Thus, Hua et al.  treated 2O2 or doxorubicin to verify if trimethylamine N-oxide (TMAO), an organic compound derived from dietary choline and L-carnitine, is a factor involved in the progression of atherosclerosis and other cardiovascular diseases. They show that TMAO does not affect the treatment’s effect on cell viability, sarcomere length, intracellular ROS, and mitochondrial membrane potential. Therefore, they conclude that TMAO cannot be considered a direct cause or an exacerbating risk factor of cardiac damage at the cellular level in acute conditions.Querio et al.  used aduAnother work evaluates the role of ROS as agents able to induce cellular protection. Lin et al.  demonstrROS can also be involved in the therapeutic action of some antitumoral drugs. Soltan et al.  evaluate2O2). Artemisinin prevents cell death at clinically relevant doses in a concentration-dependent manner. Artemisinin restored the nuclear morphology, prevented the increased intracellular ROS, and attenuated apoptosis. These data suggested that artemisinin protected neuronal cells. Similar results were obtained in primary cultured hippocampal neurons. Cumulatively, these results indicated that artemisinin protected neuronal cells from oxidative damage, at least in part through the activation of AMPK. These findings support the role of artemisinin as a potential therapeutic agent for neurodegenerative diseases.The antioxidant capacity to protect against oxidative stress-linked disease has been evaluated by Zhao et al. , who stuMoreover, some reviews are presented in this Special Issue. Lévy et al.  reviewedDamiano et al.  examinedXiao and Meierhofer  reviewedSiauciunaite et al.  summarizThe review of Di Meo et al.  analyzedIsmail et al.  collecteIt is our opinion that the articles included in this Special Issue, despite dealing with such different topics, represent an important contribution to the knowledge of the physiological and pathological role of ROS, and give some information on the benefits and limitations of antioxidant treatment.


Growing evidence suggests that the mechanical interaction between the cells and their microenvironment is of critical importance to their behaviors under both normal and diseased conditions, such as migration, differentiation, and proliferation. The study of tissue mechanics in the past two decades, including the assessment of both mechanical properties and mechanical stresses of the extracellular microenvironment, has greatly enriched our knowledge about how cells interact with their mechanical environment. Tissue mechanical properties are often heterogeneous and sometimes anisotropic, which makes them difficult to obtain from macroscale bulk measurements. Mechanical stresses were first measured for cells cultured on two-dimensional (2D) surfaces with well-defined mechanical properties. While 2D measurements are relatively straightforward and efficient, and they have provided us with valuable knowledge on cell-ECM interactions, that knowledge may not be directly applicable to in vivo systems. Hence, the measurement of tissue stresses in a more physiologically relevant three-dimensional (3D) environment is required. In this mini review, we will summarize and discuss recent developments in using optical, magnetic, genetic, and mechanical approaches to interrogate 3D tissue stresses and mechanical properties at the microscale.Cells  Tissues are composed of a large collection of ECM macromolecules (Frantz et al., Tissues and native ECMs are heterogeneous, anisotropic (Jones et al., The microscale tissue or cellular mechanical properties and constitutive relationships can be probed by active microrheology (Wilson and Poon, ex-vivo tissues (Iwashita et al., By laser tracking the deflection of the probing cantilever tip during indentation and retraction , AFM indin vitro and in vivo.Optical tweezer has been used to probe the viscoelasticity of living cells and tissues (Staunton et al., Micro-injected cell-sized ferrofluid microdroplets  can be uECM or tissue deformations provide useful information on the stress states of cells and tissues (Nam and Chaudhuri, TFM is one of the most widely adopted approaches using matrix deformations to compute cell generated traction forces (Dembo and Wang, In principal, TFM can be adapted to 3D (Hall et al., 3D TFM relies mostly on randomly distributed fluorescent beads to compute matrix deformations, which is generally infeasible for tissue deformations. This obstacle can be overcome by monitoring tissue deformations directly after releasing the stored solid stresses (Stylianopoulos et al., in vitro or in vivo (Campàs et al., To overcome the complexities associated with the development of 3D TFM, the dependence of the stress calculation on the local tissue mechanical properties must be eliminated. Hence, several recent studies introduced microbead/droplet-based stress sensors of well-controlled mechanical properties to 3D systems. These types of stress sensors can be introduced to virtually any system, in vitro cell aggregates or living embryonic tissues (Campàs et al., Cell-sized fluorescent oil microdroplets, with defined mechanical properties and coated with adhesion ligands, can be introduced to in vivo (Mohagheghian et al., In addition to the wide application as a compliant substrate in 2D TFM, elastic polyacrylamide hydrogels have also been used to quantify 3D stresses by creating microbeads that are embedded into tissues to act as cell-like pressure sensors (Dolega et al., Unlike the incompressible microdroplet method which measures anisotropic stresses, the elastic microbead method measures the isotropic stresses using volume strain. With more information about bead deformations, either through surface tracking (Lee et al., Stress sensors can also be engineered to be of the molecular size to detect sub-cellular forces with piconewton sensitivity. Unlike the cell-sized sensor described above, the force-induced displacement in the molecular sensor is readily converted to a shift in emitted fluorescence, such as that observed in FRET . Howeverin vivo applications (Cai et al., Cells can be engineered to directly express FRET-based sensors (Cost et al., Molecular tension sensors can also be functionalized to the substrate to detect cell-matrix forces (Liu et al., Tensions within the plasma membrane can be measured by the tether-pulling method, where controlled forces are applied through functionalized AFM cantilevers or optical/magnetic tweezer beads that are tethered to the membrane (Lieber et al., Unlike the stress probing methods discussed earlier, which are based on either the stress-strain constitutive relationship or the displacement-fluorescence relationship, the last collection of approaches discussed here do not rely directly on strain/displacement information.Fluctuation of a freely diffusing Brownian particle has long been used in passive rheology to measure the particle diffusion coefficient and fluid viscosity (Wilson and Poon, in vitro to in vivo (Scarcelli et al., Mechanical properties and states can also directly affect a material's optical properties, which can therefore be used to probe tissue mechanics. One of such approaches with increasing application in mapping tissue mechanical properties is Brillouin light scattering microscopy based on acousto-optic interaction (Scarcelli et al., With the growing interest in exploring the roles of tissue mechanics in physiology and pathology, there are significant recent advancements in developing tools that can map 3D tissue mechanical properties and stresses at the microscale. Future work may be directed at increasing the throughput and/or accuracy of the 3D mapping of tissue mechanics using existing methods such as active microrheology and stress sensors. Opto-mechanical approaches will provide new insights into tissue mechanics due to their non-invasive, label-free and high-throughput nature. Furthermore, simultaneous mapping of local mechanical properties and measurement of 3D deformations will enable accurate 3D TFM. With our developing knowledge of cellular mechanotransduction, it will be possible to utilize and/or engineer some of the cell's intrinsic behaviors as a type of new mechanical probe, as evidenced by the fluctuation-based approaches. However, caution should also be paid to the discrepancies when interrogating tissue mechanics using different approaches (Wu et al., JZ contributed to the conception of the work and wrote the article. NC wrote the article. CR-K supervised the work and wrote the article.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.


In the original article, there was an error. We mistakenly stated that 5-MeO-DMT is part of the ayashuasca brew.Introduction, paragraph one:A correction has been made to the 2A >5-HT2C >5-HT1A receptors (Szabo et al., Ayahuasca, a millenarian decoction used as a sacrament by south American indigenous tribes, known to induce powerful hallucinogenic states when administered with monoamine oxidase inhibitors (MAOI; Araújo et al., Ayahuasca is used by many syncretic churches ritualistically, as a way to heal many physical and mental illnesses with or without scientific knowledge about the effects (Frecska et al., Ayahuasca can potentially treat recurrent depression (Osório Fde et al., “Psychoactive tryptamines are a class of molecules that act as a neurotransmitter in the vertebrate brain (Jacob and Presti, Discussion, paragraph three:Additionally, a correction has been made to the Ayahuasca acute administration to depression diagnosed patients (dos Santos et al., Ayahuasca tea, are composed of several psychoactive substances including DMT analogs and MAOi (Frecska et al., Ayahuasca tea the DMT is administrated with MAOi, in order to avoid tryptamines degradation. Using oral or intraperitoneal administration without MAOi may reduce the availability of 5-MeO-DMT to the central nervous system, since the monoamine oxidase will readily destroy any tryptamine, in the bloodstream, guts and also in the brain (Halberstadt et al., per se can increase neurogenesis, at least in vitro cultured hippocampal cells (Morales-García et al., “The choice of a single dose treatment, was made to address the gap between the molecular mechanisms, subjective and hormonal effects underlying The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.


Dear Mr Editor,Herpesviridae reactivation in patients under veno-venous extracorporeal membrane oxygenation (VV ECMO) for severe acute respiratory distress syndrome (ARDS) and raised some important questions. Data available do not allow to conclude once for all, however, we might provide some pieces of answers.Huang et al. recently commented on our publication concerning Herpesviridae reactivation is so common in ARDS patients under ECMO who often combine sepsis and prolonged mechanical ventilation (MV). It would be of high interest to perform a matched controlled study in order to determine if ECMO occurring during ARDS enhances the frequency of Herpesviridae reactivation.First, the “who?”. In a general population of ARDS patients (without ECMO), Ong et al.  showed tHerpesviridae reactivation or active infection in ICU patients is rather touchy. The positivity of biological samples signs the evidence of viral transition from latency to replication, but end-organ disease symptoms  can be difficult to identify in such complex patients. One key question would be the comparison of performance diagnosis of blood and airway CMV PCR with antigenemia, which is considered as the reference test in end-organ disease diagnosis. Concerning the timing of HSV and CMV reactivation, Heininger et al. [Second, the “how?”. The precise definition of r et al. , compariHerpesviridae reactivation during ARDS [Herpesviridae reactivation with specific markers such as monocytes HLA-DR expression [Finally, the “why?”. Several hypotheses have been stated to explain the poor outcomes of patients exhibiting ing ARDS . Viral ppression .Herpesviridae in ARDS patients, and even more in those under ECMO.To summarize, despite several decades of research, much remains to be done to lighten the role of


Camellia senenisis plant, is the second most consumed beverage worldwide after water, and is consumed by more than two-thirds of the world population  inhibits neuroblastoma cell growth and neurosphere formation in vitro ; the autZhao et al., reported that Fuzhuan brick-tea protects against UVB irradiation-induced photo-aging via MAPKs/Nrf2-mediated down-regulation of MMP-1, and suggested that this tea could be used as not only a functional food but also a good candidate in the development of cosmetic products and medicines for the remedy of UVB-induced skin photo-aging .Annunziata et al., evaluated colon bioaccessibility and antioxidant activity of tea polyphenolic extract by using an in vitro simulated gastrointestinal digestion assay . They foPan et al., report that polyphenols in Liubao tea prevent carbon tetrachloride-induced hepatic damage in mice through their antioxidant function . MoleculShen et al., examined the association between tea consumption and risk of hospitalized fracture in 453,625 Chinese adults. Their study concluded that habitual tea consumption was associated with moderately decreased risk of any fracture hospitalizations, and the participants with decades of tea consumption and those who preferred green tea were also associated with lower risk of hip fracture .Unno et al., determined the stress-reducing function of matcha green tea  in both animal experiments and clinical trials . They foRode et al., determined, in a cross-sectional observational study among a population of 273 hypercalciuric stone-formers, whether daily green tea drinkers experienced increased stone risk factors  compared to non-drinkers, and found no evidence for increased stone risk factors or oxalate-dependent stones in daily green tea drinkers .Furthermore, Khan and Mukhtar extensively reviewed the health-promoting effects of tea polyphenols , by summIlex, including the large-leaved Kudingcha (Ilex latifolia Thunb and Ilex kudingcha C.J. Tseng), Yerba Mate (Ilex paraguariensis A. St.-Hil), Yaupon Holly (Ilex vomitoria), and Guayusa (Ilex guayusa Loes), and suggested their potential applications in the pharmaceutical or nutraceutical industries [In another review article, Gan et al., summarized the distribution, composition, and health benefits of several caffeinated beverages from the genus dustries .Tea consumption is also considered a natural complementary therapy for neurodegenerative diseases such as Alzheimer’s disease that affects an increasing patient population among the elderly. Polito et al., reviewed epidemiological studies on the association between tea consumption and the reduced risk of Alzheimer’s disease, along with the anti-amyloid effects and the role of tea in preventing this neurodegenerative disease .While beneficial effects by tea consumption have been documented in various human disease models as mentioned above, there are major challenges in developing some tea components (such as green tea polyphenols) as therapeutic agents, including how to improve their bioavailabilities, stability, efficacies, and specificity . FurtherI would like to thank all the authors for their exceptional contributions.


Decades ago, Oriental Medicine doctors could use just traditional tools including acupuncture, moxibustion, and herbal medicine despite its long history. However, technology improves and modern medical devices are invented to assist the Oriental Medicine doctors in performing diagnosis and treatment. Now, they can use exclusive medical devices such as pulse meter, tongue diagnosis, and face system with their own sensors and diagnostic skills to get information of body and disease from patients. They also can use modern therapeutic tools including electroacupuncture, pharmacopuncture, and electric-moxibustion as well as traditional ones. Experimental and translational studies on these new tools are underway.For this special issue, we invited manuscripts with the following topics: improvement of tools in oriental medicine, pharmacopuncture (Chinese medicine injection), electroacupuncture and electric-moxibustion, validation of treatment efficacy, development of pulse meter and tongue diagnosis system, and experimental and translational studies on modern device of Oriental Traditional Medicine. We received 105 manuscripts from various labs for six months and 22 manuscripts were accepted for publication. Here we highlight some of the key ongoing challenges published in this special issue.The efficacy of medical devices using radiofrequency is demonstrated in the papers “Moxibustion-Simulating Bipolar Radiofrequency Suppresses Weight Gain and Induces Adipose Tissue Browning via Activation of UCP1 and FGF21 in a Mouse Model of Diet-Induced Obesity” and “Short-Term Efficacy of Pulsed Radiofrequency Thermal Stimulation on Acupoints for Chronic Low Back Pain: A Preliminary Study of a Randomized, Single-Blinded, Placebo-Controlled Trial”.Granule, one of modern forms of herbal medicine, is used in the studies “Study of the Treatment Effects of Compound Tufuling Granules in Hyperuricemic Rats Using Serum Metabolomics” and “Randomized, Double-Blind, Placebo-Controlled Study of Modified Erzhi Granules in the Treatment of Menopause-Related Vulvovaginal Atrophy”.The article “Cinobufacini Injection Improves the Efficacy of Chemotherapy on Advanced Stage Gastric Cancer: A Systemic Review and Meta-Analysis” reviews the literature on the efficacy comparison between Cinobufacini injection (one of Chinese medicine injections) combined with chemotherapy and chemotherapy solely used in advanced gastric cancer treatment.The protective effect of patches on acupoints against electromagnetic fields is shown in “Evaluation of the Effectiveness of Protective Patches on Acupoints to Preserve the Bioenergetic Status against Magnetic Fields”.The clinical application of the low voltage Meridian Energy Detection System is evaluated in assessing the electrodermal activity in the “The Development and Application Evaluation of Meridian Energy Detection System in Traditional Oriental Medicine: A Preliminary Study” and the safety of auto manipulation device for acupuncture which can help Oriental Medicine doctors is shown in the “Safety Assessment of the Auto Manipulation Device for Acupuncture in Sprague-Dawley Rats: Preclinical Evaluation of the Prototype”.Different face diagnosis system is used in “An Herbal Medicine, Yukgunja-Tang is more Effective in a Type of Functional Dyspepsia Categorized by Facial Shape Diagnosis: A Placebo-Controlled, Double-Blind, Randomized Trial” and “Difference between Right and Left Facial Surface Electromyography in Healthy People”.In this special issue, there are more valuable manuscripts besides above. We hope the readers will be interested in improvement of diagnostic and remedial tools of Oriental Medicine.


Vibrio cholerae and downregulate the expression of virulence genes’ by Nicolas Perez-Soto et al., Chem. Sci., 2017, 8, 5291–5298.Correction for ‘Engineering microbial physiology with synthetic polymers: cationic polymers induce biofilm formation in  Vibrio cholerae strain used in this work is A1552The The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


There is a significant gap in our understanding of the molecular and cellular biology of cerebrovascular and neurodegenerative diseases to identify new therapeutic targets and develop diagnostic tools to better understand the disease progression and treatment. The cellular and molecular events linking cerebrovascular pathology and neurodegeneration are also not fully understood. The research articles and review papers published in this topic aim at a multifaceted approach to evaluating recent progress in our understanding some of the underlying molecular mechanisms of disease process and potential therapeutics targeting these diseases. Here we summarize the contributing articles to our topic conveying the aim of the pertaining research. The articles in this Research Topic highlight the challenges inspiring future research to address some of the questions and to exploit new opportunities for development of novel therapeutics for cerebrovascular and neurodegenerative diseases.Smith-Dijak et al. studied the effects of pridopidine, a drug that enhances brain derived neurotrophic factor (BDNF) signaling through stimulation of the sigma-1 receptor (S1R) and S1R agonist, in cortical neurons obtained from a mouse model of Huntington disease (HD). Several pathways implicated in synaptic functions are dysregulated in HD, including BDNF and calcium signaling. The data provide evidence for restoration of synaptic plasticity that maintain the stability of neuronal and synaptic function required for new learning and cognitive function. The results suggest a potential new direction for developing therapy to mitigate cognitive deficits in HD and may provide new avenues for neuroinflammation-related disorders treatment.Agouni et al. provided a comprehensive analysis of circulating extracellular vesicles (EVs) from vascular wall, blood, and immune cells in transient ischemic attacks (TIA) and acute ischemic stroke (AIS) patients from Southeast Asia and the Middle East. This study showed that EVs of various origins, especially those associated with endothelial cell injury and platelet activation, are increased in TIA and AIS patients. The levels of EV continue to be high for up to 30-days post-attacks indicating a sustained cellular activation, which may be associated with an increased risk of recurrence of acute events in this population.D'Angelo et al. carried out a review on antiphospholipid syndrome (APS) and multiple sclerosis (MS). APS and MS are both considered as anti-lipid autoimmune diseases with specific pathophysiological mechanisms and events. Isolated neurological APS represents a significant diagnostic challenge, as epidemiological, clinical, and neuroimaging features may overlap with those of MS. The review draws attention to the clinical relevance of diagnosing isolated neurological APS and suggests that prompt and accurate diagnosis and treatment of APS with anti-aggregant and anticoagulant could be vital to prevent or reduce APS-related morbidity and mortality.Wei et al. examined the cellular mechanisms mediating the neuroprotective effects of Homer1a, a short form of a scaffold protein, which is upregulated in rat cortical neurones following oxygen and glucose deprivation (OGD) mimicking ischemia-reperfusion (I/R) injury. The results showed that overexpression of Homer1a reduced OGD-induced lactate dehydrogenase (LDH) release, cell death, and mitochondrial dysfunctions in cultured cortical neurons. Homer1a also protects against OGD-induced injury by preserving mitochondrial function through inhibiting the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway. In addition, mitochondrial protection of Homer1a was blocked by the ER stress activator tunicamycin (TM) suggesting that Homer1a may be a promising target of protecting neurons from cerebral injury.Yang et al. examined the effect of cyclooxygenase (COX2)/prostaglandin D2 (PGD2)-related autophagy on brain injury in diabetic rats suggesting that the COX2-PGD2 pathway is a potential therapeutic target for diabetic brain injury.Xu et al., reported that low-moderate ethanol consumption may prevent ischemic stroke and reduce brain cerebral ischemia/reperfusion injury (I/R) by suppressing inflammation, whereas heavy alcohol consumption may induce ischemic stroke and worsen brain I/R injury by aggravating inflammation.He et al. found that smilagenin, a steroidal sapogenin from traditional Chinese medicinal herbs, can have neuroprotective effect on dopaminergic neurons in a chronic mouse model of Parkinson's disease (PD) suggesting that this drug could prevent the impairment of dopaminergic neurons in PD.Zhang et al. demonstrated that Naringenin (NAR), a grapefruit flavonoid promoted microglia M1/M2 polarization, thus conferring anti-neuroinflammatory effects via the inhibition of mitogen-activated protein kinase (MAPK) signaling activation. These findings provide new alternative avenues for neuroinflammation-related disorders treatment.Hao et al. showed that heterozygous loss of activin receptor-like kinase 1 (Alk1) can lead to hereditary hemorrhagic telangiectasia, which is a vascular disease characterized by direct connections between arteries and veins leading to arteriovenous malformations (AVMs). The results of the study suggest that Alk1 induces the formation of sporadic human cerebral AVMs through affecting migration and proliferation of endothelial cells combined with vascular endothelial growth factor A.Li et al. developed a flow cytometry protocol to identify microglia and monocyte-derived macrophages from mouse intracerebral hemorrhagic (ICH) stroke model induced by collagenase or blood injection. The authors also combined magnetic-activated cell separation system that allows eight tissue samples to be assessed together. This protocol represents a very important tool for biological functions of microglial and monocyte-derived macrophage in ICH stroke and related brain diseases.Jin et al., showed that glucose-regulated protein (GRP78) a chaperone protein located in the endoplasmic reticulum (ER) is involved in the neuroglial response to neurotoxic insult in rats induced by mitochondrial toxin 3-nitropropionic acid (3-NP), which selectively damages striatal neurons. These data provide novel insights into the phenotypic and functional heterogeneity of GRP78-positive cells within the lesion core and the involvement of GRP78 in the activation/recruitment of activated microglia/macrophages and blood-brain-barrier impairment in response neurotoxic insult.Song et al. reported that the knock down of myosin light chain kinase, a key enzyme in smooth muscle cell contraction, in human brain smooth muscle cells (SMCs) caused effects similar to those observed in cultured SMCs from intracranial aneurysm patients. These results indicate that myosin light chain kinase plays an important role in maintaining smooth muscle contractility, cell survival and inflammation tolerance and is crucial to the normal function of intracranial arteries.Hoyk et al. showed elevated serum triglyceride levels, changes in functional and morphological gene expressions and blood brain barrier dysfunction in transgenic mice overexpressing the human APOB-100 protein, a mouse model of human atherosclerosis suggesting that these transgenic mice could be a useful model to study the link between cerebrovascular pathology and neurodegeneration.Yu et al. reported that injection of hydroxysafflor yellow A (HSYA), a major active chemical component of the safflower via carotid artery improves cognitive impairment and synaptic plasticity in a rat model of stroke induced by middle cerebral artery occlusion.Chen et al. showed that Gap19, a selective Connexin 43 (Cx43) -hemi -channel inhibitor, produces neuroprotective effects in cerebral ischemia/reperfusion injury induced by middle cerebral artery occlusion in mice via suppression of Cx43 and Toll-like receptor 4 (TLR4) mediated signaling pathways.Chang et al. developed a new in vitro cerebral micro-bleed model to study the interactions between brain endothelial cells and red blood cells exposed to oxidative stress. Their findings demonstrate that erythrophagocytosis mediated by the brain endothelial monolayer and the passage of iron-rich hemoglobin and RBC, may be involved in the development of cerebral microbleeds that are not dependent on disruption of the microvasculature.Faustino-Mendes et al. reviewed the current experimental models of immature ischemic brain and highlighted the need for new multifactorial experimental models to attain more efficient therapies to treat this complex vascular condition and related long-term conditions.Chen et al. showed that the compound 22a, a promising neuroprotective compound derived from tetramethylpyrazine and widely used as active ingredient of traditional Chinese medicine, effectively prevented glutamate-induced excitotoxicity in cerebellar granule cells (CGNs) via involvement of the PI3K/Akt and PGC1α/Nrf2 pathways suggesting that this compound might be useful in preventing neuronal death from ischemic stroke.Du et al. tested a hypothesis that chemokine interleukin (IL) eight released by astrocytes and C-X-C motif chemokine receptor 1 (CXCR1) in neurons are involved in neuronal apoptosis induced by methamphetamine (METH), a widely abused illicit drug, which can cause dopaminergic neuron apoptosis and astrocyte-related neuroinflammation. The results suggest that CXCR1 may be a potential target for METH-induced neurotoxicity therapy.Lu et al., aimed to explore the protective effects of rosuvastatin, a 3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, against haemorrhagic transformation (HT) after recombinant tissue plasminogen activator (rt-PA) treatment in a mouse model of experimental stroke. The beneficial effects are related to inhibition of the inflammation-related nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways.Wang et al. showed that mild ER stress (“preconditioning”) induced by tunicamycin (TM), can alleviate LPS-induced astrocytic activation and BBB disruption. Their findings provide a better understanding for the regulatory role of ER stress in neuroinflammation and indicate that mild ER stress might have therapeutic value for the treatment of neurodegenerative diseases.Yang et al., found that adapentpronitrile, a new adamantane-based dipeptidyl peptidase-IV (DPP-IV) inhibitor significantly ameliorated neuronal injury and decreased amyloid precursor protein (APP) and amyloid beta (Aβ) expression in the hippocampus and cortex of rat model of diabetes fed with high fat diet. These authors showed that adapentpronitrile protected against diabetic neuronal injury by inhibiting mitochondrial oxidative stress and the apoptotic pathway.Jang et al. reported intrastriatal injection of adeno-associated viral vector serotype DJ containing N171-82Q mutant huntingtin (HTT) gene to juvenile mice produced Huntington's disease (HD)-like symptoms including mutant HTT aggregation, neurodegeneration, and Neuroinflammation. The authors suggested that this model will a useful tool to better understand neuropathological mechanisms of HD and develop new therapeutics for this disease.Hao et al. established a stable method for the isolation of endothelial cells (ECs) from human cerebral arteriovenous malformation tissues, which play an important role in the manifestation and development of cerebral vascular malformation as well as haemorrhagic stroke and thrombogenesis. The protocol can also be adapted for other vascular diseases.He et al. demonstrated that rosuvastatin treatment significantly increased neurite outgrowth in cortical neurons after oxygen-glucose deprivation (OGD)-induced damage, reduced the generation of reactive oxygen species, protected mitochondrial function and elevated the ATP levels via Notch1 pathway. These findings highlight Notch1 signaling as important player and novel therapeutic target in promoting brain plasticity.In summary, the present Research Topic encompassed several cutting-edge techniques and models for investigating the cellular and molecular mechanisms of cerebrovascular dysfunction and neurodegeneration. Together, they provide a framework for understanding the way some of the diseases progress and potential pathways for therapeutic interventions. We acknowledged that collection of articles in a single topic cannot deal with this extremely vast subject characterized by complex conditions such as cerebrovascular dysfunction and neurodegeneration. The topics addressed, however, help developing clear ideas, not only in terms of recent studies but also the unmet needs for future research in these areas. We trust that the papers assembled in this Research Topic will prove useful in encouraging and stimulating future progress in research related to cerebrovascular and neurodegenerative diseases.SS prepared the editorial and both SK and SS edited the final version. SS and SK made substantial contributions to the review and approved the manuscripts accepted on this topic.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.


Progression from latency to active Tuberculosis (TB) disease is mediated by incompletely understood host immune factors. The definitive characteristic of progressive human immunodeficiency virus (HIV) disease is a severe loss in number and function of T lymphocytes. Among the many possible mediators of T lymphocyte loss and ineffective function is the activity of the immune-modulatory enzyme indoleamine 2,3-dioxygenase (IDO). IDO is the rate-limiting enzyme converting tryptophan to kynurenine. IDO activity was initially recognized to mediate tolerance at the foeto-maternal interface. Recently, IDO activity has also been noted to play a critical role in immune tolerance to pathogens. Studies of host immune and metabolic mediators have found IDO activity significantly elevated in HIV and TB disease. In this review, we explore the link between IDO-mediated tryptophan catabolism and the presence of active TB disease in HIV-infected patients. We draw attention to increased IDO activity as a key factor marking the progression from latent to active TB disease in HIV-infected patients. Recently, the effect of indoleamine 2,3-dioxygenase-1 (IDO) activity in various diseases, including tuberculosis (TB) and human immunodeficiency virus (HIV) disease has generated considerable interest. Tryptophan, an essential amino acid in the body, can either be converted to serotonin or oxidized to kynurenines. IDO is the rate-limiting enzyme in the conversion of tryptophan to kynurenines (Higuchi and Hayaishi, Essential micronutrients are those which cannot be produced endogenously and must be acquired through dietary sources. Humans, like other mammals, cannot synthesize tryptophan, and therefore, must obtain it from their diet and internal protein turn-over Brown, . Foods sIDO1 and IDO2 (Yamazaki et al., de novo pathway for NAD+ synthesis when niacin intake is limited in the diet (Higuchi and Hayaishi, In certain cell types, tryptophan can be converted to serotonin or melatonin by tryptophan hydroxylase (Ruddick et al., Munn and colleagues observed IDO expression and activity at the foeto-maternal interface in pregnant mice (Munn et al., Tryptophan depletion and subsequent generation of kynurenine metabolites have considerable effects on the host's immunity. The IDO pathway plays a significant role in T cell hypofunctionality, a critical concept in immune tolerance to pathogens (Mellor et al., Immune cells, in particular macrophages and dendritic cells, are sites of IDO production. IDO expression and activation creates a local immunosuppressive micro-environment, which allows pathogens to escape sterilizing immunity or containment (Nagamatsu and Schust, Downstream metabolites of the IDO pathway such as quinolinic acid, are neurotoxic and have been implicated in HIV-associated dementia (Gostner et al., in vitro (Byrne et al., in vitro studies have reported that measles, influenza, cytomegalovirus, and herpes simplex viral infections are also susceptible to tryptophan depletion (Obojes et al., Amino acids are critical micronutrients for all pathogens. Microbes either synthesize amino acids or depend on their hosts for amino acids for growing and multiplying. The ability of the host to deprive pathogens of essential micronutrients is a crucial feature of innate defense. Tryptophan, just like carbon, iron, and nitrogen are critical for microbial survival (Rohmer et al., In animal models, increased tryptophan metabolism via the IDO pathway has been associated with poor immune responses to M. TB (O'Connor et al., When co-infecting a host, HIV and M. TB influence each other, accelerating deterioration of immune function. HIV infection causes severe loss of T cells, both in number and function (Douek et al., Werner et al.  reportedin vitro (Blumenthal et al., in vivo (Gautam et al., Despite extensive work in murine and macaque models of TB, only a few studies have investigated IDO-mediated tryptophan catabolism and its metabolites in human TB . M. TB hIDO can be studied quantitatively by measuring mRNA expression or protein levels or enzymatic activity (product-to-substrate ratio; Li et al., A biomarker is defined as any characteristic that can be objectively measured as an indicator of health or disease process or as a response to a therapeutic intervention (Group et al., ex vivo M. TB challenge in cells or tissue from active or latently infected patients to understand TB pathology. Some studies have examined metabolic profiles or genes from active TB patients to identify metabolites or genes that are switched on or off, which may be implicated in the transition from latency to active disease in both HIV-infected and uninfected individuals (Weiner 3rd et al., in vitro (Zhang et al., Most TB studies have relied on animal models or It remains to be determined whether elevated IDO activity is causative of, or only associated with, progressive HIV and TB disease. Some researchers postulate that human co-existence with latent TB infection may be a human evolutionary adaptation to increase host tryptophan in times of low dietary tryptophan availability (Williams and Dunbar, Chlamydia trachomatis, an intra-macrophage pathogen, which can synthesize tryptophan, blocking IDO activity with levo-1-methyl-tryptophan led to improved susceptibility to doxycycline (Ibana et al., in vivo that M. TB induces IDO expression in the lungs of macaques and mice with active TB disease. In the macaque, inhibition of IDO activity led to a reduced M. TB burden, pathology and improved animal survival (Gautam et al., Currently, several clinical trials are exploring blocking IDO activity for therapeutic use. During infection with In summary, IDO-mediated tryptophan catabolism via the kynurenine-nicotinamide pathway represents a common axis upregulated in HIV infection and TB disease. Rather than being uniquely elevated in TB, cumulative elevation of IDO in HIV and TB may explain the extraordinarily high rate of progression to active TB in HIV-infected patients. It is unclear whether elevated IDO is causative of progression to active disease or a compensatory response to the microbe. There is much promise in using metabolites from the IDO-mediated tryptophan pathway to diagnose active TB and monitor anti-TB treatment. IDO holds promise as a TB biomarker in both HIV-positive and negative patients, but further confirmatory studies are urgently needed. Regarding new TB drug targets, it remains speculative whether IDO inhibition would be beneficial. Further exploration of this pathway is necessary to better understand TB pathogenesis and discover novel host biomarkers and potential drug targets for either TB or HIV disease.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Escherichia coli populations. Toxin–antitoxin systems hold a crucial but still elusive part in bacterial response to stress. This perspective highlights how these modules can also serve as a great model system for investigating basic concepts in gene regulation. However, as the genomic background and environmental conditions substantially influence toxin activation, it is important to study (auto)regulation of toxin–antitoxin systems in well-defined setups as well as in conditions that resemble the environmental niche.Autoregulation is the direct modulation of gene expression by the product of the corresponding gene. Autoregulation of bacterial gene expression has been mostly studied at the transcriptional level, when a protein acts as the cognate transcriptional repressor. A recent study investigating dynamics of the bacterial toxin–antitoxin MazEF system has shown how autoregulation at both the transcriptional and post-transcriptional levels affects the heterogeneity of  Escherichia coli K-12 MG1655 strain has at least 37 TA loci in total, with at least 10 toxins characterized as type II toxins with RNA-degrading activity, i.e., endoribonucleases. Type II endoribonucleases can be active independent of ribosomes or in a ribosome-dependent manner, and few of them cleave RNA sequence specifically (Masuda and Inouye Toxin–antitoxin (TA) modules are highly versatile systems, generally widespread in prokaryotic genomes . Overall, the majority of the known type II TA systems are RNA-degrading enzymes, degrading RNA while bound to the ribosome, or in a ribosome-independent manner, such as the MazF toxin regulation in commonly used Measuring toxin and antitoxin levels in single cells in vivo is a challenging task. As toxin and antitoxin proteins form complexes, tagging them with fluorescent reporters would most certainly decrease stability of the complexes and prevent efficient toxin neutralization by the antitoxin. In addition, tagging toxins with fluorescent proteins could interfere with the toxin activity , or as variability in phenotypic traits of the individual cells in time  (Ackermann mazEF transcript induced pulse-like behavior and increased temporal variability in MazF levels during stress (Nikolic et al. Several previous studies indicate that the majority of chromosomally encoded type II TA systems elicit phenotypic heterogeneity in stressed bacterial populations by promoting variation in gene expression, cell size, and growth rate (Klumpp et al. mazEF autoregulation is a complex mechanism attained by several protein–protein, protein–mRNA and protein–DNA interactions. Autoregulation of mazEF expression at the transcriptional and post-transcriptional level is responsible for fluctuations in MazF levels during ectopic stress (Nikolic et al. mazG and relA transcripts are parts of the polycistronic mRNA together with mazE and mazF (Gama-Castro et al. mazEFG transcriptional unit (Goormaghtigh et al. relA-mazEF unit (Gama-Castro et al. mazEF expression, will provide necessary details to obtain a full picture of autoregulatory processes. Stress response mechanisms might additionally regulate mazEF expression (Battesti et al. mazEF expression, and to what extent (Yamaguchi and Inouye mazEF expression during physiological induction of the toxin will further determine the importance and impact on this TA system on the behavior of bacterial cells.The


Sci., 2015, 6, 3242–3247.Correction for ‘Humidity-dependent surface tension measurements of individual inorganic and organic submicrometre liquid particles’ by Holly S. Morris  The corrected figure is shown below.An error in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


The presence of tumor cells in blood vessels, particularly extramural venous invasion (EMVI), is an independent poor prognostic factor in colorectal cancer (CRC).EMVI was present in one-quarter of EC patients after surgery alone, and in 21.6% of patients after nCRT, as confirmed by additional EVG staining.7In future, EMVI should be investigated in a larger group of EC patients undergoing nCRT followed by surgery. Our results in the nCRT group are probably influenced by case mix and less power in a relatively small group with a potential selection bias of non-responders to nCRT.


Background: Space Agencies are planning human missions beyond Low Earth Orbit. Consideration of how physiological system adaptation with microgravity (μG) will be managed during these mission scenarios is required. Exercise countermeasures (CM) could be used more sparingly to decrease limited resource costs, including periods of no exercise. This study provides a complete overview of the current evidence, making recommendations on the length of time humans exposed to simulated μG might safely perform no exercise considering muscles only.Methods: Electronic databases were searched for astronaut or space simulation bed rest studies, as the most valid terrestrial simulation, from start of records to July 2017. Studies were assessed with the Quality in Prognostic Studies and bed rest analog studies assessed for transferability to astronauts using the Aerospace Medicine Systematic Review Group Tool for Assessing Bed Rest Methods. Effect sizes, based on no CM groups, were used to assess muscle outcomes over time. Outcomes included were contractile work capacity, muscle cross sectional area, muscle activity, muscle thickness, muscle volume, maximal voluntary contraction force during one repetition maximum, peak power, performance based outcomes, power, and torque/strength.Results: Seventy-five bed rest μG simulation studies were included, many with high risk of confounding factors and participation bias. Most muscle outcomes deteriorated over time with no countermeasures. Moderate effects were apparent by 7–15 days and large by 28–56 days. Moderate effects (>0.6) became apparent in the following order, power and MVC during one repetition maximum (7 days), followed by volume, cross sectional area, torques and strengths, contractile work capacity, thickness and endurance (14 days), then muscle activity (15 days). Large effects (>1.2) became apparent in the following order, volume, cross sectional area (28 days) torques and strengths, thickness (35 days) and peak power (56 days).Conclusions: Moderate effects on a range of muscle parameters may occur within 7–14 days of unloading, with large effects within 35 days. Combined with muscle performance requirements for mission tasks, these data, may support the design of CM programmes to maximize efficiency without compromising crew safety and mission success when incorporated with data from additional physiological systems that also need consideration. Space Agencies are planning to transition from International Space Station (ISS) missions to Lunar missions including a crewed base from which to test and develop hardware and procedures required for the longer term goal of human Mars missions Foing, . It is wBased on bed rest research and previous spaceflight experience, the ISS provides astronauts with 2.5 h per day for exercise  using a treadmill, cycle ergometer and resistance exercise device designed and adapted for μG  to search the following databases up to July 2017: Pubmed, CINAHL, Web of Science, NASA Technical Reports Server and The Cochrane Collaboration Library. No restrictions on type of bed rest or publication dates were applied, and due to the inability to use “Boolean logic” on the NASA Technical Reports Server, the strategy was adapted to keyword searches. The full search strategy is available in A range of relevant terms grouped by main search terms were constructed using Boolean logic (astronauthttps://rayyan.qcri.org/) , blinded to each other's decisions, using Rayyan  tool was used to assess risk of bias of all the included studies, with “H,” “M,” and “L” showing high, moderate and low risk, respectively, using pre-defined published definitions for each level  were calculated between pre and post-bed rest values for each outcome individually without an overall pooled effect. Hedges' g was used to bias correct for the typically small sample sizes, as only control group data from μG simulation studies were eventually included. The reported data set that was as close to immediate pre and the end of bed rest was used for the analysis. No exclusion or analysis variation was made based on the individual study analysis methods. The pooled standard deviation for Hedges' g was calculated using the root mean square of the pre and post-group standard deviations. This version does not specifically include the sample size (n), preventing any complications that could arise from inflating n when both group means are from the same sample. Results were first sub-grouped by outcome measure type and then by muscle group before being listed in order of ascending days spent in simulated μG. Individual effects sizes were calculated and plotted in figures for each outcome at every time point where data were available. To enable a brief overview of the large data set to also be provided, an unweighted mean effect at each common time point within each muscle group was used to provide a summary result. This was only done when more than one study assessed the same outcome at the same time point. These statistics were chosen due to data being from the same sample rather than a separate intervention and control group, thus making a traditional weighted effects meta-analysis pooling inappropriate. Traditional meta-analysis assumes two different sets of individuals in each group  or 1.2 (large) was highlighted as a time point when a worthwhile mechanistic change had occurred , (3) muscle activity , (4) muscle thickness , (5) muscle volume (cm3), (6) maximal voluntary contraction force during one repetition maximum  (7), peak power (W), (8) performance based outcomes  , (9) power , and (10) torques and strength . Within each subgroup data were further sub-grouped for analysis by major muscle groups. For completeness of reporting, any measures that did not fit within major muscle groupings were grouped for analysis and reported as either “other lower limb,” “other trunk,” or “other upper limb” outcomes, to enable every outcome measure extracted from included studies to be reported in the results. The outcomes included in the “other” groupings are listed in the text.Ten sub groups were created based on the measurement methods units used for each for analysis as follows : (1) contractile work capacity (J), (2) cross sectional area  generally decreased over time, however a transient increase was seen in Plantar Flexor, Dorsi Flexor and Quadriceps muscles and only at 20 days. In Plantar Flexor and Quadriceps muscles, muscle activity decreased again after 20 days, there were no data for Dorsi Flexor muscles beyond 20 days to establish a post 20 day trend. Moderate effects were apparent in upper limb muscle groups by 15 days but not until 90 days for Dorsi and Plantar Flexor muscles which were the only muscles with data at the 90 day point. The breakdown of individual activity effects per muscle is available in Maximal voluntary contraction during one repetition maximum decreased over time except for other upper limb outcomes that remained mostly unchanged as far as data were available up to 45 days. Moderate effects became apparent by 7 days and large effects by 35 days. Other lower limb outcomes that included maximal isometric force during supine squat, hip extensor force and legs total work never reached a large effect, but had no data available beyond 35 days. The breakdown of individual MVC during one repetition maximum effects per muscle is available in Power decreased over time. Moderate effects became apparent by 7 days and large effects by 20 days, although these were only seen in the Quadriceps muscle data. Hamstring, Hip Flexor, and upper limb muscles that included elbow flexors and extensors reached moderate effects by 20 days. Plantar Flexors never reached a moderate effect but data were only available at 14 days. Other trunk muscles included trunk flexors and extensors tested in combination within functional movements. The breakdown of individual power effects per muscle is available in Performance based outcomes all worsened over time, as although sit to stand, balance, and sprint time outcomes all had positive effects, this was considered a worsening effect within these measures. Endurance reached a large effect by 14 days, jumping a moderate effect at 42 days and large by 44 days, sit to stand and balance reached large effects by 60 days and sprint time by 62 days. Data for most outcomes were only available for one time point and so trends over time for individual outcomes are not able to be determined. The breakdown of individual performance based effects per outcome is available in The main finding of the review was that muscle cross-sectional area, volume, shape, size, activity, power, performance, torque, and force-based outcomes, at either regional or global level, all decline over time, based on the current evidence base. Moderate effects became apparent in the following order: power and MVC during one repetition maximum (7 days), followed by volume, cross sectional area, torques and strengths, contractile work capacity, thickness and endurance (14 days), then muscle activity (15 days). Large effects became apparent in the following order: volume, cross sectional area (28 days) torques and strengths, thickness (35 days), and peak power (56 days). No large effects were found for muscle activity. There were limited data for contractile work capacity and no large effects were apparent. In general, lower limb and trunk muscles appeared to decline more rapidly than upper limb muscles. Locomotion muscles such as Plantar Flexor and Quadriceps muscles also generally appeared to decline more rapidly than other muscles groups and with larger effect sizes.Human spaceflight missions differ in duration, so results have to be placed into the context of mission profiles and operationally important considerations. Operationally, performance-related measures such as power, MVC, torques and strengths are considered most critical. In terms of mission profiles, typical ISS missions involve approximately 180 days in μG  level of strength to achieve mission critical tasks such as donning/doffing and standing up/moving whilst wearing a space suit in low gravity, hatch opening, and pulling/dragging a fellow crew member wearing a space suit during an emergency. The absolute level is defined as the precise required strength outcome in raw units to achieve a task, as opposed to considering relative changes with effect size or percentage changes. A relative (%) reduction in strength will make all tasks with an absolute strength requirement more challenging for all individuals, but the biggest impact will be felt by those who have a lower initial level of absolute strength. For example, a strong individual might be able to lose 30% of their pre-flight strength and still comfortably achieve a mission critical task , whereas a weaker individual might already be close to their physical limit during this task without any deconditioning. Operationally, having an estimate of the most rapid possible rate of change in muscle outcomes may be useful in the case of a crew member with low pre-flight absolute strength, or an individual highly susceptible to μG adaptation. In the present study, the most extreme negative value within the confidence interval for each outcome provides an estimate of the most extreme worst likely true value that might be encountered with exposure to μG. Based on this estimation, the results of this analysis suggest that the change experienced by an individual astronaut might reach a large effect size in some muscles within a 7 day lunar transit period for volume, cross sectional area, contractive work capacity, thickness, power, and MVC. However, the confidence intervals are wide due to the small sample sizes across the current evidence base, so this estimate should be treated with caution as it may be exaggerated. Individual effects are difficult to determine in a transferable way to the true population from the data currently available or from individual case studies. Ideally, a population selected for their increased susceptible to unloading/μG-induced muscular adaptation should be studied in a long-duration μG analog to produce a representable average effect that could be transferred to the true population with more reasonable confidence. Until such data are available, estimating the maximum rate of decline in an individual in response to μG exposure of such a duration will remain difficult. In addition, consideration would also be needed should an individual be selected to perform some tasks in a mission that are not considered mission critical, but are essential to other mission goals. It may be that checking for susceptibility to outcomes that are linked more strongly to mission success is checked and made part of astronaut eligibility screening, it could also be any more susceptible mission critical individuals undergo more rigorous preflight and inflight training protocols or consider use of other more removed countermeasures beyond the scope of this review.Exercise countermeasure development may want to consider focusing on those which might best address the more susceptible outcome changes in this review, volume, cross sectional area, contractive work capacity, thickness, power, and MVC while also ensuring any proposed exercises are tailored to tasks considered critical, such as donning/doffing and standing up/moving whilst wearing a space suit in low gravity, hatch opening, and pulling/dragging a fellow crew member wearing a space suit. The impact of any chosen exercise types on future spacecraft exercise hardware would also need further consideration. Future research should consider identifying exercise countermeasures that would best address the more susceptible outcomes and be feasible with any technical constraints of new space vehicles planned for use within Moon and Mars missions.As CM are likely to be needed on the return trip from both Moon and on the journeys to and from Mars, such CM will need developing. Countermeasure devices should support lower limb and trunk muscle exercise as these decline earlier than other body regions and are essential for locomotion and for spinal function on return to G loading Bamman, . Based omuscle changes, additional holistic consideration of other physiological systems will likely be required. Finally, any CM development for exploration missions will also have to consider constraints of space vehicles that will be used, such as available physical space, limited number of devices that can be included in the space craft, consumables, generation of heat, carbon dioxide, and vibration, which are likely to be more restricted than the ISS  ISS Long Duration Mission (LDM) exercise prescriptions  (Dawson et al., Most of the studies scored four on the bed rest tool, with no studies scoring a full seven points, although 13 studies scored six. The reasons for marking studies down was mostly due it being unclear if criteria had been met rather than clearly failing a point. The most common unclear criteria was related to restricted sunlight exposure followed by ensuring a fixed daily routine. The high risk of bias results were most commonly caused by not clearly showing how confounding factors were managed and providing adequate description of participation. The participation domain considers participant eligibility criteria, source of participants, baseline descriptions, description of sampling frame and recruitment, description of period and place of recruitment, and inclusion/exclusion criteria (Hayden et al., There was some asymmetry in the funnel plot showing potential publication bias toward studies reporting a decrease in muscle outcomes. However, there were studies present on the increasing side of the plot, so the risk is not likely to be high. In addition, it is expected that many of the muscle outcomes would decrease during a period of inactivity such as bed rest, therefore, it not surprising most studies reported decreases. Therefore, while it appears a risk of reporting bias may exist, the presence of some studies reporting increases and the expected pattern of more decreases being reporting suggest this finding should be treated with caution and the potential risk is likely to be low.This review only considered muscle outcomes. Spaceflight is known to affect many more human physiological systems including bone, cardiovascular and vestibular (Pavy-Le Traon et al., The results of this review suggest that moderate effects on a range of muscle function parameters may occur within 7–14 days of unloading, with large effects within 35 days. Combined with identification of muscle performance requirements for future exploration mission tasks, these data, may support the design of CM programmes to optimize their efficient use without compromising crew safety and mission success. However, the data suggests CM are likely to still be needed for longer transit/orbital periods of 14–28+ days, such as a prolonged Lunar orbit, deep space exploration, or a Mars mission, as moderate effects occur between 7–14 days and large effects by 28 days for most muscle outcomes. However, if large effect sizes occur only after 28–35 days, to save resources, space agencies might consider short missions without exercise CM, or fixed periods of abstinence during longer μG exposures, if they could be confident that moderate changes in muscle performance could be reversed in-flight. Finally, several research gaps are highlighted for future bed rest studies in which standardized time points for measurements should be used and clear information provided on sunlight exposure control, fixed daily routine, and control of any confounding factors.1Akima et al., 2Akima et al., 3Akima et al., 4Akima et al., 5Alkner and Tesch, 6Alkner et al., 7Arbeille et al., 8Bamman et al., 9Belavy et al., 10Belavy et al., 11Belavy et al., 12Belavy et al., 13Belavy et al., 14Belavy et al., 15Belavy et al., 16Belavy et al., 17Belavy et al., 18Belavy et al., 19Berg et al., 20Berg et al., 21Berry et al., 22Buehring et al., 23Caiozzo et al., 24Cescon and Gazzoni, 25Convertino et al., 26de Boer et al., 27Dudley et al., 28Duvoisin et al., 29Ellis et al., 30English et al., 31English et al., 32Ferrando et al., 33Ferretti et al., 34Fu et al., 35Funato et al., 36Gast et al., 37Germain et al., 38Greenleaf et al., 39Greenleaf et al., 40Greenleaf et al., 41Holguin et al., 42Holt et al., 43Kawashima et al., 44Koryak, 45Koryak, 46Koryak, 47Koryak, 48Koryak, 49Koryak, 50Koryak, 51Koryak, 52Kouzaki et al., 53Krainski et al., 54LeBlanc et al., 55Lee et al., 56Macias et al., 57Miokovic et al., 58Miokovic et al., 59Miokovic et al., 60Muir et al., 61Mulder et al., 62Mulder et al., 63Mulder et al., 64Mulder et al., 65Mulder et al., 66Narici et al., 67Pisot et al., 68Portero et al., 69Reeves et al., 70Rittweger et al., 71Rittweger et al., 72Schneider et al., 73Shinohara et al., 74Trappe et al., 75Trappe et al., 1Belavy et al., 2Belavy et al., 3Belavy et al., 4Biolo et al., 5Cavanagh et al., 6Shenkman et al., 7Amorim et al., 8Rittweger and Felsenberg, 9Koriak Iu, 10Koriak Iu, 11Koriak Iu, 12Koryak, 13Bamman and Caruso, 14Bamman, 15Felsenberg et al., 16Ferretti, 17Greenleaf et al., 18Grogor'eva and Kozlovskaia, 19Guo et al., 20Hargens et al., 21Judith Hayes et al., 22Ito et al., 23Jaweed et al., 24Koryak, 25Kozlovskaia et al., 26LeBlanc et al., 27LeBlanc et al., 28Liu et al., 29Macias et al., 30Meuche et al., 31Meuche et al., 32Milesi et al., 33Miyoshi et al., 34Moriggi et al., 35Mulder et al., 36Netreba et al., 37Scott et al., AW: initial concept ideas, protocol planning and drafting, search screening, analyzing, and drafting all manuscript versions. JS: methods advice, protocol drafting, and approving final draft. NW: data extraction, analysis, and drafting final version. MV: protocol planning, search screening, data analysis, drafting text, and checking final version. NC: protocol planning, search screening, methods advice, manuscript drafting, and approving final 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.


Fusarium mycotoxins. Further, we suggest that understanding how mycotoxin levels are regulated by microbial encounters can offer novel insights for mycotoxin control in food and feed. Microbial degradation of mycotoxins provides a wealth of chemical information that can be harnessed for large-scale mycotoxin detoxification efforts.An important goal of the mycotoxin research community is to develop comprehensive strategies for mycotoxin control and detoxification. Although significant progress has been made in devising such strategies, yet, there are barriers to overcome and gaps to fill in order to design effective mycotoxin management techniques. This is in part due to a lack of understanding of why fungi produce these toxic metabolites. Here we present cumulative evidence from the literature that indicates an important ecological role for mycotoxins, with particular focus on  Aspergillus fumigatus  with the potential to produce a myriad of secondary metabolites. One of the most powerful ways to activate BGCs is by co-cultivation or mixed fermentation of two or more microbes. Microbial interactions that have led to up-regulation of known metabolites or to discovery of novel natural products are numerous benzoic acid and citreoisocoumarinol [ in Trichoderma atroviride  and zearalenone produced by  Chérif, . TrichodF. oxypsorum in both plant and animal hosts (López-Díaz et al., F. avenaceum that lacked the ability to synthesize enniatin showed decreased virulence when infected on potato tubers (Herrmann et al., Fusarium oxysporum f. sp. melonis isolates to synthesize beauvericin or enniatin B does not contribute to virulence in melons (Moretti et al., in vitro cultures in F. graminearum and F. pseudograminearum (Mudge et al., F. culmorum, F. graminearum, and F. pseudograminearum cause fusarium head blight as well as fusarium crown rot. However, the former two pathogens are more aggressive pathogens in head blight while F. pseudograminearum shows enhanced fitness as the pathogen of crown rot. This has been attributed to the differential production of DON in the different tissues (stem base vs. wheat heads; Tunali et al., F. graminearum, DON has been demonstrated to inhibit apoptosis-like programmed cell death in Arabidospis thaliana (Diamond et al., F. graminearum (Voigt et al., F. graminearum has been proposed (Audenaert et al., Burkholderia glumae, a seed-borne bacterium and F. graminearum has been recently identified. Co-cultivation of the two microbes resulted in an increase in sporulation and DON production in F. graminearum, which is at least partially in response to a toxic bacterial metabolite. An overall increase in disease severity was observed upon co-infection of rice with the two pathogens. The two microbes were also found to be physically attached upon microscopic observations after co-cultivation (Jung et al., Fusarium spp. It is necessary to note here that microbial interactions can also reduce the virulence of Fusarium species on their plant hosts, as discussed in section Microbial Interactions in Detoxification and Degradation of Mycotoxins.Although secondary metabolites are not “required” for the growth and development of fungi, they function as fitness factors. Mycotoxins have been shown to contribute to the pathogenicity, aggressiveness and/or virulence of fungi. Fusaric acid has been reported to enhance the virulence of Pseudomonas piscium, from the wheat head microbiome has shown that the bacterium secretes an antifungal agent, phenazine, against F. graminearum. Phenazine, upon entering the fungal cell, inhibits the histone acetyl transferase module of the SAGA complex which subsequently leads to an inhibition of fungal growth and pathogenicity in addition to a complete suppression of DON biosynthesis (Chen et al., Aspergillus nidulans—Streptomyces rapamycinicus association where the bacterium induces histone modification mediated by the SAGA complex which results in production of orsellinic acid and its derivatives by the fungus (Nutzmann et al., Epigenetics has been steadily gaining momentum in the last few decades in the world of transcriptional regulation. There is now growing evidence that microbial communication regulates epigenetic modifiers that in turn control mycotoxin biosynthesis. The SAGA complex, conserved across eukaryotes, induces transcription of genes by mediating histone acetylation of the corresponding promoters. A study that isolated the bacterium, Fusarium mycotoxins mediated by microbes, plants and insects (The literature supports the idea that mycotoxins can be important players in shaping microbial communities and their interaction with hosts. Signaling molecules are regulated “coinage” and need to be recycled—through various chemical transformation processes—to maintain homeostasis in the community. Thus, it is not surprising that there are several examples of degradation of  insects .Fusarium mycotoxin accumulation in grains. Preventative application of Psuedomonas fluorescens strain before inoculation with F. culmorum resulted in a significant reduction in Fusarium head blight as well as DON levels in infected wheat grains (Khan and Doohan, Paenibacillus polymyxa, isolated from wild teosinte, have been shown to produce fusaridins which contribute to the antifungal activity against F. graminearum. Co-existence of these bacteria with F. graminearum in grains during storage at room temperature resulted in a significant decrease in DON accumulation (Mousa et al., Bacteria have been shown to contribute to reduction of Aspergillus tubingenesis NJA-1, a soil isolate, has been shown to convert DON into a less-toxic product that has been speculated to be the result of hydrolysis, based on differences in the mass of the metabolites (He et al., Agrobacterium–Rhizobium strain E3-39 converts DON into 3-keto DON (Shima et al., Nocardioides WSN05-2 forms the non-toxic epimer, 3-epi-DON (Ikunaga et al., Deviosa insulae forms 3-keto-DON (Wang et al., Devosia mutans 17-2-E-8 forms both 3-keto-DON and 3-epi-DON (He et al., Eggerthella spp., isolated from chicken intestine, has been reported to de-epoxify DON over a wide range of temperatures and pH (Gao et al., Tri101, encoding 3-O-acetyltransferase for 3-O-acetylation of the trichothecene ring has been characterized in F. graminearum and has been further identified in other Fusarium species (Kimura et al., Arabidopsis, it has been reported that the UDP-glycosyltransferase catalyzes transfer of glucose from UDP-glucose to the hydroxyl group at the 3-C position in DON (Poppenberger et al., Understanding the mechanisms underlying chemical transformation of mycotoxins could pave the way toward evolving novel techniques for mycotoxin decontamination in food and feed. Several mechanisms of detoxification of DON have been studied as summarized in Clonostachys rosea has been reported to produce a zearalenone-specific lactonase that catalyzes the hydrolysis of the lactone ring, which is followed by spontaneous decarboxylation (Utermark and Karlovsky, C. rosea to zearalenone. Trichosporon mycotoxinivorans has been shown to convert zearalenone into ZOM-1 which is characterized by the opening of the ring structure at the ketone group positioned at C6' (Vekiru et al., Rhizopus arrhizus catalyzes sulfation of the hydroxyl group at the C4 position resulting in the formation of zearalenone-4-O-sulfate conjugate (el-Sharkaway et al., Zearalenone mimics estrogen upon ingestion in animals and humans resulting in sexual and reproductive abnormalities. Microbes possess the ability to degrade and inactivate zearalenone, as reviewed in Ji et al. . ClonostPseudomonas (Altalhi, Bacillus (Cho et al., Rhodoccous, and Streptomyces (De Mets et al., Acinetobacter has been shown to secrete extracellular enzymes that oxidize zearalenone into smaller estrogenic products (Yu et al., Lactobacillus strains with zearalenone although the bacteria removed the mycotoxin from the cultures. The authors were able to recover zearalenone from the bacterial cultures and suggest that the bacteria bind zearalenone in a density-dependent manner (El-Nezami et al., Lysinibacillus sp. isolated from chicken intestine can remove zearalenone from cultures and the process has been shown to be significantly reduced upon heat treatment. The authors suggest a potential enzymatic process that may be involved in the interaction between the bacterium and zearalenone (Wang et al., Pseudomonas putida ZEA-1 utilizes zearalenone as a carbon source (Altalhi, Species of Altalhi, , BacilluAltalhi, .Burkholderia ambifaria, a novel bacterium isolated from barley rhizosphere has been reported to be able to utilize fusaric acid as a sole carbon source (Simonetti et al., Aspergillus tubingensis (Crutcher et al., Colletotrichum sp (Fakhouri et al., Mucor rouxii (Crutcher et al., A significant understanding of the biochemical pathways involved in detoxification processes (Carere et al., The mycotoxigenic fungal species live in complex and nutrient-deficient environments—be it in soil, plant or animal hosts. The soil micro-environment often fluctuates with variations in water availability, air, light, and temperature, among other abiotic factors. Now add to this, a complex cocktail of microbes and hosts that are integral to the environment where survival of microbes heavily depends on active community participation. Mycotoxins play a significant role in the defensive strategies of mycotoxigenic fungi against the resident microbes. Interactions between microbes in such environments may involve competition or compromise where mycotoxins may serve as essential chemical language mediating communication. The host environments are usually unfriendly, thus requiring special adaptations in order for the fungi to thrive in such conditions. Several studies support a view that mycotoxins may act as signaling molecules that modulate host responses and promote successful colonization. Reports of microbes that can metabolize and detoxify mycotoxins are aplenty, highlighting the importance of examining microbial interactions to uncover strategies for mycotoxin detoxification.Fusarium spp. The evolving knowledge on molecular and genetic mechanisms that govern mycotoxin production provides us with valuable tools to study the ecological roles of mycotoxins. This is not only an achievable goal but also has the potential to be highly rewarding. Such knowledge can facilitate development of novel strategies to control infections of mycotoxigenic fungi as well as mycotoxin contamination in food and feed.In this review chapter, we have summarized existing literature that accentuate the ecological significance of mycotoxins with focus on NV along with NK conceptualized and drafted the theme of the review. NV wrote the article and NK reviewed, edited, and refined the manuscript along with NV.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.


Mycobacterium tuberculosis (Mtb) is the bacterial pathogen that causes the majority of human tuberculosis (TB), the leading infectious disease in the world , a well-documented Mtb complex and in a related species Mycobacterium marinum, but absent from the Mycobacterium bovis Bacille Calmette–Guérin (BCG) genome, encodes an ESX-1 type VII secretion system that has been extensively investigated as a major virulence factor  among mycobacterial species have been identified by comparative genomic studies , but their role in Mtb virulence has not been explored. Arora et al. biochemically and functionally characterized the CitE enzymatic subunits. The purified CitE1 and CitE2 proteins degraded acetyl-CoA and propionyl-CoA in vitro and the genes encoding both enzymes were up-regulated when Mtb was exposed to oxidative stress. Moreover, deletion of the citE genes from the Mtb genome reduced the resistance to oxidative stress, intracellular replication in macrophages, and growth in a guinea pig infection model. This study suggests that CitE may be a potential target for TB drug development.Bacterial citrate lyase, which is important for both metabolism and virulence, is composed of three subunits, CitD (γ), CitF (α), and CitE (β)  with a global collection of Mtb genomes and identified a novel phylogenetic clade that share single-nucleotide polymorphisms (SNPs) in key virulence-associated loci, including the mce1 locus and the phoP gene. This clade includes four hypervirulent strains isolated from geographically diverse regions. The common SNPs and structural variations within the clade may be considered as potential genetic determinants of hypervirulence for future studies.Mtb is the most common cause of human TB, M. bovis can cause TB in both humans and cattle, making it a zoonotic threat to both food safety and public health  and folC (encoding FolC-dihydrofolate synthase) genes have been associated with resistance to para-aminosalicylic acid (PAS; Rengarajan et al., Howe et al. found that MetM, a putative amino acid transporter, plays a crucial role in the synthesis of folate precursors, which antagonizes PAS activity.The mutations in the Mtb. In the report done by Ilin et al., FS-1 was used in combination with standard anti-TB antibiotics on guinea pigs infected with an XDR-Mtb strain. The genetic changes in Mtb genomes following infection were analyzed and FS-1 was found to cause a counter-selection of drug-resistant variants that sped up the recovery of the infected animals from XDR-TB. While the drug resistance mutations remained intact in more sensitive isolates, reversion of drug resistance was associated with a general increase in genetic heterogeneity of the Mtb population.Drug induced reversion of antibiotic resistance has drawn recent attention as a prospective approach to combat drug resistance (Baym et al., Mtb virulence, including characterization of new roles for known virulence factors, identification of new virulence factors, and the elucidation of drug-resistance mechanisms and reversion. This Research Topic, together with many recent publications, enhances our understanding of the mechanism of Mtb virulence and pathogenesis.The articles in this Research Topic present new findings regarding the cellular and molecular mechanisms of JS, PC, and FB have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Multimorbidity is widespread, costly, and associated with a range of deleterious outcomes; it affects an estimated 67-80% of older adults. This study tests the validity of a multimorbidity resilience index developed in a Canadian sample of older adults by Wister et al., (2018), with a U.S.-based sample, using National Social Life, Health, and Aging Project (NSHAP) data, and draws upon the index to investigate the effects of resilience on outcomes over time. We mapped Wister et al.’s (2018) index to NSHAP measures, and assessed cross-sectional associations with health outcomes, using logistic regression. To assess the effects of resilience on health outcomes over time, we estimated mixed models of the relationships between resilience on outcomes over a 5-year interval. Total resilience was consistently associated with improved outcomes, including pain level ; reduced utilization ; improved mental health ; self-rated physical health ; and sleep quality . Longitudinal model results indicate change in multimorbidity resilience and number of chronic diseases predict (α=.001) pain level and self-rated physical health. Effects were moderated by socio-demographic factors. Our findings validate Wister et al.’s (2018) resilience index in a U.S. sample, supporting the importance of this measure to capture core components of older adults’ capacity to sustain well-being in the context of living with multiple, chronic conditions. Results from the longitudinal models provide beginning insights into the effects of resilience on symptom experience and perceived health over time, highlighting potential levers for change.