As a result, new information is emerging about how flying, swimming and running animals rapidly and efficiently generate media-based forces, process multi-modal sensory information and make use of intrinsic neuromechanical mechanisms to achieve robust control of motor behaviours over short time scales. In parallel, new computational approaches provide powerful tools for modelling the neuro-musculoskeletal control of complex body systems with many degrees of freedom. These experimental and modelling approaches, in turn, are driving the development and implementation of diverse bioinspired robots based on abstracted biological concepts, leading to new insights for the rehabilitation of human neuromotor deficits.Stability and manoeuvrability in animal movement: lessons from biology, modelling and robotics. The assembled topics cover modes of animal locomotion in water, in air and over ground, highlighting novel interdisciplinary approaches that integrate neuroscience, biomechanics and physics with computational methods and engineering design.Agile locomotion is fundamental to successful biological performance, such as predator–prey interactions, mating, obstacle traversal and avoidance, and navigation, as well as engineering designs that emulate such performance. By including perspectives of locomotion over and through different media, commonalities of approaches across animals emerge that may reflect convergent evolutionary pathways, as well as commonalities of approaches taken by researchers working in these related fields. We summarize below the main results and approaches taken by the authors of the papers published in this theme issue on . 2et al. [Aurelia aurita produces a stopping vortex (that is absent when swimming from rest), which interacts with the opposite sign starting vortex generated by contraction of its bell. The resulting vortex–vortex interaction beneath the bell's subumbrellar surface results in an effective ‘virtual wall’ created by the convergence of fluid at the vortex interface, which produces significantly greater pressure and thrust leading to a greater swimming speed, without the need to alter swimming kinematics. The presence of a ‘virtual wall’, combined with earlier evidence of ‘passive energy recapture’ [In their paper ‘The most efficient metazoan swimmer creates a “virtual wall” to enhance performance’, Gemmell et al.  show thacapture’ , enablescapture’ . It seemet al. [In contrast with the moon jellyfish, fast, pelagic, predatory fish such as tuna have a broad ‘kinematospace’ that facilitates impressive agility. While the hydrodynamics of steady-state, cruising swimming in fish can now be measured routinely, it is a greater challenge to determine the fluid forces underpinning unsteady manoeuvring because animal behaviour ensures variation of kinematics and a lack of repeatability. In ‘Tuna robotics: hydrodynamics of rapid linear accelerations', Thandiackal et al.  sidestep. 3et al. [Drosophila, oscillate their halteres while walking and also use them to control fast take-off behaviour. Using ablation experiments to deprive flies of their halteres, the authors showed diminished take-off speed and body stability in calyptrate flies during and just after leg extension, yet this observation does not apply to non-calyptrate flies. More generally, the paper presents an example of how mechanosensation can be used for stabilization and locomotor control even when key sensors  are placed some distance from the principal actuators (the rapidly extending legs during jumping).In Diptera (the true flies), the erstwhile hindwings of ancestral forms have been reduced to specialized mechanosensory organs called halteres. Halteres have slender shafts and bulbous tips, and when they oscillate, they bend out of plane under Coriolis forces if the body rotates. Monitoring the strains provides information about movement that is important for flight control. Halteres also play a role in maintaining the timing of the wingbeat. In their paper, ‘Takeoff diversity in Diptera’, Yarger et al.  show thaDrosophila’, Rauscher & Fox [As insects fly, sensory information is gathered from a suite of sensor types known to be useful for guidance, navigation and control tasks. Each receptor and neuron has its own properties , and these may be dependent on anatomical location. At some point in the sensorimotor control system, incoming information from different modes is fused before motor commands are sent to the muscles responsible for power, stabilization or steering. Therefore, single-input, single-output experimental methods are gradually being replaced by experimental frameworks that include multiple inputs. In their paper, ‘Haltere and visual inputs sum linearly to predict wing (but not gaze) motor output in tethered flying er & Fox  devise scontrol loop hypothesis, visual commands modulate the feedback strength by activating haltere muscles, which results in changes of flight direction. Evidence from the blowfly Calliphora vicina and the fruit fly Drosophila melanogaster support that hypothesis. Hence the haltere should be viewed as a multifunctional sensory organ that is involved both in maintaining stability in the face of external perturbations but also in visually guided voluntary manoeuvres. The nested control loop design Dickerson [Insect flight involves extremely fast reactions to perturbations during wing beats. In ‘Timing precision in fly flight control: integrating mechanosensory input with muscle physiology’, Dickerson  reviews ickerson  proposesickerson , which iet al. [The compound eyes of insects are, of course, multifunctional themselves. Alongside image formation, target tracking, obstacle avoidance and a number of other tasks, the lobula complex of the insect brain functions to process delays in spatial patterns of contrasts moving across the ommatidia in order to estimate self-motion using optic flow. The ventral visual field can be used to determine ground speed or relative changes in altitude for a given spatial pattern, although these two variables are entwined; the angular rate of the visual texture passing beneath a flying insect is sensitive to both, because either reducing airspeed or increasing altitude both slow the rate of optic flow. While bees appear to show an innate preference for a particular angular rate, this can be limited by maximum airspeed (in the case of headwinds) or make flight control problematic (in the case of tailwinds where the airspeed may become negative). This paradigm was elucidated by Baird et al.  in theirManduca sexta), flight downstroke is powered by the synchronous dorso-longitudinal muscles, which typically operate at a consistent frequency to maintain a constant wingbeat frequency. It had previously been hypothesized [et al. [Insect flight is energetically demanding and requires precision control to maintain stability. In hawkmoths  to investigate how lateral stability may be compromised due to dynamic effects resulting from changes in centre of mass (CoM) position of the trunk and body relative to the location of the centre of pressure (CoP), exerted by the ground reaction force on the base of the foot. This affects the margin of stability (MoS), defined by the authors as the lateral horizontal distance of the CoM relative to the CoP during each step. Past work had examined human walking at faster and self-selected speeds, but had not focused on very slow speeds, which are more typical of the speeds that elderly subjects use as they age and are associated with increased fall risk owing to improper shifting of body weight support during step transitions. Best & Wu show that minimum MoS decreased with gait speed due to increased lateral excursions of the CoM that were not compensated by lateral shifts in CoP. As a result, ankle eversion and hip abduction torques also increased with slower walking. Changing step width, which is a main strategy of healthy subjects walking at faster speeds, was not observed during slow speed walking. Consequently, increased ankle eversion and hip abduction torque appear to be the key strategies used during very slow walking. Future studies need to examine active versus passive mechanisms based on muscle activity recordings (EMG) as well as control of fore-aft pitch torque, which can also contribute to fall risk.In their paper ‘Upper body and ankle strategies compensate for reduced lateral stability at very slow walking speeds', Best & Wu  analyse In her field perspective paper, ‘Human biomechanics perspective on robotics for gait assistance: challenges and potential solutions’, Wu  reviews In their paper ‘Perspective on musculoskeletal modelling and predictive simulations of human movement’, De Groote & Falisse  provide . 5We are living in exciting times with fast progress on both scientific and engineering fronts. This special issue highlights the beautiful diversity and agility of animal locomotion in different movement modes and through different environmental media. The papers within this issue reveal common principles underlying movement among different animals, including control loops running in parallel, the interplay of feedforward and feedback mechanisms, and the fundamental importance of biomechanics underlying agile and robust behaviour of moving animals. Engineering tools have enabled exciting progress in innovative experimental set-ups, more realistic modelling and improved analysis to help decipher principles of animal locomotion. This theme issue provides a glimpse of how these tools and improved understanding might lead to better robots and more effective assistive devices, such as actuated exoskeletons and prostheses. Despite these advances, many challenges remain. Specifically, future studies will need to address non-steady-state locomotory behaviour and locomotion through a wider range of environmental contexts. Additionally, it is essential to consider movement throughout ontogeny because animals must move throughout growth. Finally, there is a need for greater understanding of motor learning and planning, particularly in the context of unsteady manoeuvring and agility behaviours—animals appear to have the ability to learn quickly from one or a few attempts at a novel behaviour , yet thi


About 2.3 billion people (mainly from upper and lower middle income countries) suffer from untreated dental caries (affecting permanent teeth) while 530 million children have caries involving primary teeth, according to the Global Burden of Disease 2017. This makes dental caries one of the most common global public health concerns , 5. TreaThe COVID-19 pandemic has sharply brought into focus the need to re-examine oral health systems given that virtually every aspect of healthcare delivery has been impacted by the outbreak including oral health care delivery. It can be argued that COVID-19 has completely altered the care landscape with not only new challenges and threats, but also new opportunities. Likewise dentistry and oral care delivery should not be left behind as the entire health delivery systems morphs and evolves along with the times. This paper advocates a review of public oral health systems (both in developed and developing countries) with a renewed focus on improving oral health related outcomes, as a response to the COVID-19 pandemic. A SWOT analysis framework is used to examine strengths, weaknesses, opportunities, and threats related to the current delivery of oral health services. The strengths and weaknesses of oral health systems will first be examined, followed by opportunities to improve oral health care delivery. Possible threats to achieving improved service delivery will also be explored. This analysis is intended to create greater awareness among oral health and health practitioners, oral health planners, policy makers, health decision-makers, researchers, and academics on the value of oral health within general health care. Additionally, this analysis could be used to guide oral health related “decision-making as it is crucial during the current pandemic to work on weaknesses, avoid threats, and utilize all future opportunities” Oral health systems (both public and private) have been in existence but the challenges of delivering effective oral health care remains a challenge in many parts of the world , especiaOther weaknesses of the health system became more apparent during COVID-19. The pre-COVID inequities in access to optimal health care have been exacerbated during the pandemic where underserved populations and uninsured as those in the US, have been disproportionately affected by the disease . SimilarA review and re-organization of oral health systems is thus overdue. There is need to ensure equitable and improved access to oral health care with a focus on improving population health outcomes . There iWhile there is currently no natural immunity against SARS-CoV-2 infection, studies show that people more at risk of developing COVID-19 related complications include those with diabetes and obesity , 15. WhiHence a more committed focus is needed on prevention of commonly occurring oral diseases and the promotion of healthier behavioral practices. Isolated individual interventions directed toward modifying specific oral health-related behaviors have not been successful in achieving long-term changes in behavioral practices . A populDespite the highlighted challenges, several opportunities exist to optimize a more seamless delivery of oral health services, as outlined below:Promotion of oral health care should not be the responsibility of just the health system. From an organizational perspective this requires a shift from health practitioner focus to oral health promotion within a social setting , 23. It Further investments in oral health could include engagement with technologies to improve the digital interface in health communication . ModalitLikewise, stronger collaboration is required between the health system and community based settings for the safe delivery of oral health promotion services . These sOral health interventions directed at the intrapersonal and interpersonal level should focus on unhealthy behavioral practices such as diet, smoking and alcohol consumption. Smoking has been shown to be linked to a number of health complications such as diminished lung capacity, cardiac complications, and periodontal disease . FurtherStudies have shown that early clinical signs of COVID-19 include a loss of taste and smell , 35. COVDespite these opportunities some of the possible threats to implementing these strategies could include lack of practitioner skills. There is thus a need for continuing professional and skills development for the oral health care worker as well as a review of undergraduate dental curricula so that appropriate training can provided to better equip the individual practitioner.Although the notion of integrated oral health care through a multi-disciplinary team approach has been touted as a key strategy to broaden the delivery of oral health promotion services , this seThis highlights the need for greater dialogue both within and outside of the health system to explore ways of integrating oral health messages and care within a broader scope of overall community health. This should be supported by ongoing opportunities for health workers to develop skills in oral health promotion activities through training programmes. Further research is required to unpack the barriers and delays in integrated health action.The COVID-19 pandemic has provided opportunities for renewed interest in the oral health agenda. A re-organization of oral health systems with a focus on social orientation of oral health self-care, could see improved oral health gains in the long term. Concurrently, the role of oral health care workers and their preparedness for a public health emergency should be reviewed and addressed through appropriate training platforms.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Zika virus (ZIKV) is a vectorborne infectious agent of global public health significance due to its potential to cause severe teratogenic outcomes. The question of whether health systems should consider adopting screening programmes for ZIKV infections during pregnancy warrants consideration. In this analysis, we apply the Wilson-Jungner framework to appraise the potential utility of a prenatal ZIKV screening programme, outline potential screening strategies within the case-finding pathway, and consider other epidemiological factors that may influence the planning of such a screening programme. Our evaluation of a potential prenatal ZIKV screening programme highlights factors affirming its usefulness, including the importance of Congenital Zika Syndrome as a public health problem and the existence of analogous congenital prenatal screening programmes for STORCH agents , rubella, cytomegalovirus, and herpes simplex virus). However, our assessment also reveals key barriers to implementation, such as the need for more accurate diagnostic tests, effective antiviral treatments, increased social service capacity, and surveillance. Given that the reemergence of ZIKV is likely, we provide a guiding framework for policymakers and public health leaders that can be further elaborated and adapted to different contexts in order to reduce the burden of adverse ZIKV-related birth outcomes during future outbreaks. While it is well established that Zika virus (ZIKV) infections during pregnancy can have deleterious impacts on the health and well-being of congenitally infected offspring and their families, the question of whether prenatal screening for ZIKV may be warranted during epidemics remains open.Our analysis of a potential prenatal ZIKV screening programme using the Wilson-Jungner framework highlights factors affirming the utility of screening, such as the importance of Congenital Zika Syndrome as a public health problem, a growing understanding of the natural history of the disease, and the likely acceptability of a programme.However, our assessment also reveals key barriers to implementation, especially related to diagnostics, antiviral treatments, social service capacity, and surveillance.Adopting prenatal screening for ZIKV during an epidemic would enable pregnant persons to make more informed decisions about their pregnancy and facilitate the early identification of exposed newborns for specialised follow-up care, which may be of particular importance for children who present asymptomatically at birth but develop ZIKV-related sequelae in later childhood.Nevertheless, to be most impactful, prenatal screening programmes require cheaper and more precise ZIKV screening tests, as well as continued investment in the development of efficacious and safe therapeutics.Screening programmes are a core public health service and can be a valuable tool in improving a population’s health outcomes.1Aedes spp. mosquitoesAedes spp. vectors without yet having documented ZIKV transmission.6Similar to other STORCH  agents, ZIKV can be vertically transmitted across the placenta during pregnancy with potentially deleterious consequences for fetal development. Unlike other STORCH agents, ZIKV is vectorborne, and its transmission by competent Given the severity of outcomes associated with congenital ZIKV infection and the threat of ZIKV reemergence in areas with prior outbreaks or emergence in new settings,Whereas maternal ZIKV infections are generally mild and self-limiting, a subset of congenital ZIKV infections may disrupt fetal development and result in structural malformations and functional neurodevelopmental impairments, which are collectively recognised as CZS.13ZIKV infections during pregnancy are primarily identified using nucleic acid amplification and serological tests. Nucleic acid amplification tests detect the presence of ZIKV RNA  by reverse transcription-polymerase chain reaction (RT-PCR) in maternal whole blood, serum, plasma, urine and amniotic fluid in patients presenting, in general, <7 days from onset of symptoms, and serological tests detect binding and neutralising antibodies  against specific ZIKV antigens  in whole blood, serum and plasma in patients presenting ≥7 days from symptom onset.The generally mild clinical presentation and the co-circulation of other immunologically cross-reactive flaviviruses in ZIKV-endemic areas has made establishing a case definition for ZIKV infection in pregnant persons challenging.26While highly sensitive and specific laboratory diagnostic assays will improve the identification of maternal ZIKV infection before the onset of severe fetal anomalies, there is currently no available antiviral for impeding vertical transmission of ZIKV in humans29While further research on attitudes of expectant families in relation to ZIKV screening is needed, non-invasive prenatal screening tests for congenital infections are generally well accepted.Due to the potential for vertical transmission of ZIKV infection during pregnancy, both the pregnant person and offspring would be considered as patients. While evaluations, clinical decision making and treatment after birth are mainly focused on the offspring, it is crucial to recognise the unique vulnerabilities of parents of CZS patients, such as the increased risk of developing anxiety and depression.33At present, there are no available vaccines to prevent maternal infections or approved antiviral treatments to limit ZIKV infection or block vertical transmission and acute clinical care for ZIKV infection in pregnancy is mainly focused on treating maternal symptoms with analgesics and antipyretics.Of note, access to unrestricted legal abortion remains rare in Latin America, with the majority of countries having complete prohibition or restrictive laws. Thus, termination is not an option for many pregnant individuals with ZIKV infection, even if microcephaly and/or brain abnormality are detected at ultrasound examination or ZIKV is detected early in the pregnancy. However, there are other interventions that can be offered to pregnant persons and their families, such as supportive measures to mitigate the emotional impact of the potential adverse outcomes.37For newborns with CZS, anticipatory guidance to caregivers and early referrals to appropriate specialists and support groups is crucial. Although confirmatory research is ongoing, early intervention programmes addressing CZS are well accepted and expected to result in an overall improved functional performance.38In the absence of authorised point-of-care rapid tests,The cost of a prenatal infection screening programme depends on the annual number of pregnancies, whereas the preventable costs depend on the maternal infection rate. Thus, if the screening costs are less than the preventable costs, then a screening programme will be cost-effective and should be adopted.in utero exposure to ZIKV infection and presentation of CZS at birth,44Continuing examinations allow a programme to become more efficient and economical, and regular offers of examination are likely to gradually cover more and more of the population at risk. In addition to or in lieu of laboratory testing, continued monitoring and case finding of at-risk pregnant individuals can be done using ultrasound. Although microcephaly was initially described as the hallmark feature of Given reports of late-onset ZIKV-associated anomalies among children with a normal HC at birth,46A major challenge in implementing a screening programmes is balancing the benefits with the harms of screening.49As there will always be false positives and false negatives, a screening programme may introduce unintended harms.Another factor that complicates the benefit–harm analysis is the current uncertainty in the estimated risk of adverse outcomes following detection of a ZIKV infection during pregnancy, which may challenge the clinical decision-making process and be a source of significant anxiety to expectant parents. Given that only limited quantities of new data are likely to become accessible before the next reemergence of ZIKV, large-scale individual participant data meta-analyses of existing cohort studies, such as those proposed by the Zika Brazilian Cohorts Consortium,Ultimately, the decision to implement a prenatal ZIKV screening programme is highly dependent on the context of a country’s health system, resources available and guiding ethical principles. Screening criteria that incorporate the values and priorities of a country and its population may help balance the benefits and harms of a screening programme. Anticipated benefits and harms can be tested using pilot projects, which will also generate important data about cost-effectiveness and efficiency. Additional research that more precisely defines risk estimates of adverse fetal outcomes or leads to the development of lower cost and/or more accurate diagnostics or of novel therapeutics will also likely tip the scale.To help illustrate population-based prenatal screening for ZIKV, here, we present a general flow-diagram with recommended components that can be further elaborated to fit each settings’ needs and available resources. In settings with a history of recent ZIKV circulation and a high seroprevalence, a universal screening strategy based on serological testing at the first antenatal visit could be adopted to identify seronaive individuals who may be at heightened risk of ZIKV infections and would benefit from repeated testing during pregnancy (58Modification to the diagram may be warranted in settings with mostly travel-related infections. ZIKV seroprevalence varies hugely among traveller populations compared with resident populations living in areas with active transmission (<2% in travellers vs up to 60% in the local population,Following a positive screening result, an ultrasound should be obtained as evidence suggests a normal HC to femur length ratio in fetuses without microcephaly is associated with an 87% NPV for the postnatal detection of congenital ZIKV-associated injuries.62A crucial prerequisite to the effective implementation of a screening programme is surveillance. By systematically monitoring the incidence of infections and associated disease, such as congenital anomalies, surveillance helps to inform the timing and type of screening programme adopted by providing information on the rate of community-wide transmission. In addition, long-term surveillance may also yield information on the likely proportion of the pregnant population with pre-existing protective immunity to ZIKV. Although there is limited evidence on the duration of neutralising antibodies following a ZIKV infection,Designing a screening programme for ZIKV during pregnancy is a complex process that requires careful consideration. Maternal infection is often asymptomatic or consists of only mild, non-specific symptoms and vertical transmission rates are variable but have potentially life-altering consequences. Normally, screening provides medical benefits from early treatment. However, while early intervention allows for anticipatory support of newborns and families affected by CZS, there are no treatments currently available to prevent the vertical transmission of ZIKV or to minimise the risk of potential congenital anomalies, and termination of pregnancy is not always a legal option. This initial assessment of the feasibility and utility of a prenatal ZIKV screening programme using the Wilson and Jungner criteria highlights affirmative factors such as acceptability and potential positive impact of such a programme, even in the absence of curative treatment and accurate diagnostics. In addition, consideration of the timing, as well as the overall benefits and harms of implementing a prenatal ZIKV screening programme are necessary foundations for more context-dependent decision making. Moving forward, research should be directed into the natural history of CZS, especially the long-term prognosis of ZIKV-exposed children who present with defects before or at birth and those who present asymptomatically at birth but develop clinical manifestations later on. The development of screening tests with enhanced precision and decreased costs and the introduction of efficacious, safe treatment will further improve the benefit-to-risk balance.


The gut microbiota of animals displays a high degree of plasticity with respect to environmental or dietary adaptations and is shaped by factors like social interactions, diet diversity or the local environment. But the contribution of these drivers varies across host taxa and our ability to explain microbiome variability within wild populations remains limited. Terrestrial animals have divergent mobility ranges and can either crawl, walk or fly, from a couple of centimeters toward thousands of kilometers. Animal movement has been little regarded in host microbiota frameworks, though it can directly influence major drivers of the host microbiota: (1) Aggregation movement can enhance social transmissions, (2) foraging movement can extend range of diet diversity, and (3) dispersal movement determines the local environment of a host. Here, I would like to outline how movement behaviors of different host taxa matter for microbial acquisition across mammals, birds as well as insects. Host movement can have contrasting effects and either reduce or enlarge spatial scale. Increased dispersal movement could dissolve local effects of sampling location, while aggregation could enhance inter-host transmissions and uniformity among social groups. Host movement can also extend the boundaries of microbial dispersal limitations and connect habitat patches across plant-pollinator networks, while the microbiota of wild populations could converge toward a uniform pattern when mobility is interrupted in captivity or laboratory settings. Hence, the implementation of host movement would be a valuable addition to the metacommunity concept, to comprehend microbial dispersal within and across trophic levels. Microbial associations with animal hosts are ubiquitous and increasingly recognized as important factor for the understanding of host ecology and evolution . The gutVarious studies applied a metacommunity concept for an eco-evolutionary understanding of host microbiome associations, including environmental microbes as a regional species pool . Host moWhile insects have  relatively simple and species poor gut microbiotas , most maWith this manuscript I would like to highlight the role of host “movement” and mobility range as a neglected parameter explaining patterns in the microbiota of mammals, birds and insects and the potential transfer across host taxa.acquisition and dispersal are often combined and hard to disentangle , which promotes the dispersal of a hymenopteran gut parasite by contaminations of flower tissue with copious defecations , the tracking of individual movement patterns revealed, that social connectivity and encounters with conspecifics explains microbiota similarity better than spatial distances or genetic relatedness  the medium foraging range indicated a positive correlation with microbial diversity  or the painted lady (Vanessa cardui), migration abilities are not uncommon for other butterflies or nocturnal moth, but remain often unnoticed as they fly in lower numbers or at night   . But to Crocidura spp.) showed the second highest proportions of Proteobacteria and a less mammal-specific microbiota than Chiroptera (bats), directly followed by Pholidota (ant-eating Pangolins). If the observed pattern would be explained by a physiological adaptation to flight, this raises the question why terrestrial shrews have the most “bird-like” microbiota of all mammals.A recent comparative study concludes that a convergent physiological adaption to “flight” (reduced dependence on microbes to reduce weight of the digestive system) shapes the bird as well as the bat microbiota . ParticuTadarida brasiliensis) preys on high altitude flying insects, which includes several migrating species, and noctuid moth make on average 77% of their diet  turned out to be an important aspect of host microbiota associations within aquatic systems , host moThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.AW conceived, designed, and wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Acute and chronic administration of intranasal oxytocin and vasopressin have been extensively utilized in both animal models and human preclinical and clinical studies over the last few decades to modulate various aspects of social cognition and their underlying neural mechanisms, although effects are not always consistent. The use of an intranasal route of administration is largely driven by evidence that it permits neuropeptides to penetrate directly into the brain by circumventing the blood–brain barrier, which has been considered relatively impermeable to them. However, this interpretation has been the subject of considerable debate. In this review, we will focus on research in both animal models and humans, which investigates the different potential routes via which these intranasally administered neuropeptides may be producing their various effects on social cognition. We will also consider the contribution of different methods of intranasal application and additionally the importance of dose magnitude and frequency for influencing G protein-coupled receptor signaling and subsequent functional outcomes. Overall, we conclude that while some functional effects of intranasal oxytocin and vasopressin in the domain of social cognition may result from direct penetration into the brain following intranasal administration, others may be contributed by the neuropeptides either entering the peripheral circulation and crossing the blood–brain barrier and/or producing vagal stimulation via peripheral receptors. Furthermore, to complicate matters, functional effects via these routes may differ, and both dose magnitude and frequency can produce very different functional outcomes and therefore need to be optimized to produce desired effects. Over the last few decades, acute and chronic administration of intranasal oxytocin (OXT) and vasopressin (AVP) has been extensively utilized in both animal and human studies to modulate various aspects of social cognition and their underlying neural mechanisms. Functional effects of these neuropeptides vary from basic emotional recognition and social reward to complex social behaviors such as altruistic behavior and moral decision making, although some effects have been inconsistent ,2,3. GivThe blood–brain barrier (BBB) has long been recognized as a significant impediment for therapeutic drug development , and an The precise mechanism whereby neuropeptides such as OXT and AVP can enter the brain via the olfactory and trigeminal nerve routes is not fully established. There are several steps required before an intranasally administered substance can be delivered to the brain: it must first be transported across the olfactory or respiratory epithelial barriers in the nasal passages and then from the nasal mucosa to sites of brain entry via peripheral olfactory or trigeminal nerve components, and finally be transported from these initial brain entry sites to other regions within the brain . In . In 29])Although researchers have mainly focused on demonstrating that intranasally administered OXT and AVP can produce functional effects via direct entry into the brain  occur following intranasal administration in both rhesus macaques  or nebulizer) ,32) and While, as already mentioned above, research on intranasal neuropeptide administration has primarily focused on functional effects produced via direct entry into the brain, the original pharmaceutical application for both synthetic OXT  and AVP  was to produce effects on peripheral organs via absorption into nasal blood vessels and entry into the peripheral circulation . Thus, intranasal administration of OXT, either via a standard nasal spray or a nebulizer, increases concentrations in peripheral blood across species, although with a slower temporal profile (increases occur within 10–15 min proceedings of the end of administration) compared with intravenous administration (occurs immediately at the end of administration) ,37,40,43While it had widely been assumed that the BBB was almost impermeable to OXT and AVP and that consequently, any effects on the brain and behavioral functions were unlikely to be influenced by increased concentrations in blood, this assumption is no longer tenable. A key recent finding from animal studies is that OXT in the peripheral blood can cross the BBB by binding to the receptor for advanced glycation end products (RAGE) . The funFurther indirect support for peripherally mediated effects of OXT has come from an increasing number of studies reporting functional effects when it is given by other peripheral administration routes that, unlike the intranasal route, would not permit direct entry into the brain . For example, high doses of intraperitoneal-administered OXT can still modulate the social behaviors of mice, although findings are less consistent and differ in some respects compared to central administration ,53. In hIn addition to peripheral OXT entering into the brain via binding to RAGE, peripheral OXT can influence brain function indirectly via the autonomic nervous system, particularly sympathetic and vagal pathways, by acting on its widespread receptors in peripheral organs  . There iAs reviewed above, functional effects of OXT can be exerted by direct entry into the brain via the olfactory and trigeminal nerves ,26 see aA straightforward, but coarse strategy, for distinguishing the contribution of these different routes to functional effects of intranasal AVP or OXT administration is by conducting direct comparisons based on the same paradigms. Findings in animal models have been somewhat inconsistent. In rats, for example, OXT concentrations in the brain were much higher following intranasal relative to intravenous administration, with >95% of OXT in the brain being directly transported from the nasal cavity. In contrast, blood concentrations were much higher following intravenous compared to intranasal administration, but only intranasal OXT produced an anxiolytic effect by decreasing corticosterone concentrations . This suIn humans, intranasal and intravenous administration of OXT can induce different profiles of plasma concentrations, with intravenous OXT reaching the peak level immediately after dosing whereas increased concentrations of intranasal OXT being observed 10–15 min following application ,43. ThesMost recently, direct comparisons between intranasal and oral  administration have also been conducted in humans. One study demonstrated that orally 24 IU OXT increased neural activity of the reward system and amygdala in response to emotional faces, whereas 24 IU intranasal OXT had no effects on neural responses in the reward system and, in contrast, decreased the amygdala activation in response to emotional faces . FurtherIt should be noted that at this point, it is difficult to disentangle whether OXT indirectly entering the brain via binding to RAGE or causing vagal stimulation are responsible for peripherally mediated effects. In this respect, animal models offer the greatest promise, with RAGE-knockout rodents providing a method for preventing functional effects of OXT crossing the BBB and influencing the brain, as already demonstrated in the context of maternal behavior and hyperactivity . For detBoth OXT and AVP have classical seven-transmembrane domain G protein-coupled receptors, with to date OXT having only a single identified receptor and AVP having three . Additionally, both OXT and AVP can also bind to each other’s receptors, although with a much-reduced affinity (around a 10-fold reduced affinity) .Although OXT only has a single receptor, it recruits three different intracellular G protein-coupled pathways  in a concentration-dependent manner which can result in opposite effects on neuronal activity, with increasing OXT bioavailability shifting coupling away from the excitatory Gq-protein to the inhibitory Gi- or Go- ones . It woulA variety of different methods have been used for the intranasal administration of OXT or AVP. In small animals, a small volume of liquid is deposited into the nostrils for the animal to inhale naturally ,88. In mThe vast majority of intranasal OXT and AVP administration have used the standard nasal spray device, and relatively few have used the more efficient nebulizer type. One study in macaques has compared differential effects of the two devices for intranasal administration and demonstrated that while both produced similar increases in cerebrospinal concentrations 40 min after administration, the increases produced by the nebulizer were more robust. On the other hand, increased blood concentrations only occurred with the standard nasal spray device from 10–40 min after administration . This woAlthough intranasal OXT studies using conventional and nebulizer administration devices have suggested that the latter can achieve similar functional effects at lower doses, to date for social cognition tasks, there is no evidence that at these optimal doses they differ in terms of the nature of functional effects produced, although there are still relatively few studies using nebulizer devices. Furthermore, in contrast to the study on monkeys mentioned above , a studyIn conclusion, evidence from both animal and human studies suggests that while functional effects of intranasally administered OXT and AVP in the domain of social cognition may result from direct penetration into the brain, observed effects may also be contributed to by the peptides either entering the peripheral circulation and crossing the BBB via binding to the RAGE and/or producing vagal stimulation via peripheral receptors. However, based on current methodologies, especially in humans, a distinction of the relative contributions of these different routes to observed functional effects is still unclear. Indeed, inconsistent findings from intranasal administration studies in the domain of social cognition may be influenced by the relative contributions of the different routes, especially given some evidence that there may be opposing functional effects of direct vs. peripheral routes ,52,53. F


Genetic testing through a variety of methods is a fundamental but underutilized approach for establishing the precise genetic diagnosis in patients with heritable forms of dystonia. Our knowledge of numerous dystonia-related genes, variants that they may contain, associated clinical presentations, and molecular disease mechanism may have significant translational potential for patients with genetically confirmed dystonia or their family members. Importantly, genetic testing permits the assembly of patient cohorts pertinent for dystonia-related research and developing therapeutics. Here we review the genetic testing approaches relevant to dystonia patients, and summarize and illustrate the multifold benefits of establishing an accurate molecular diagnosis for patients imminently or for translational research in the long run. The term dystonia refers to a large group of etiologically heterogeneous disorders, some of which are undoubtedly genetically determined. The latter is obvious not only from numerous dystonia families described to date but also from a multitude of currently known genes, the pathogenic variants in which elicit dystonic symptoms. Indeed, since the discovery of the first dystonia gene almost 30 years ago -based approaches such as NGS gene panels, clinical exome sequencing (CES), whole-exome sequencing (WES), or whole-genome sequencing (WGS). In some instances, copy number variation (CNV) analysis may also be required. Which approach or technology will be used for genetic testing should be decided on a patient-by-patient basis as it relies on the clinical presentation at onset and at the latest examination, family history, availability of the specific diagnostic test, and the expertise in neurogenetics and experience of the physician.Single-variant testing can be applied for diagnostic genetic testing in hereditary dystonia forms in which all patients are expected to carry the same variant. This is frequently due to the founder effect, i.e., the occurrence of a novel pathogenic variant in an early member (ancestor) of the specific patient population. At least two different genetic dystonia forms are currently known to be caused solely or primarily by such single founder variants: X-linked dystonia–parkinsonism    in the fifth exon of the TOR1A gene . Similarly, a childhood-onset foot dystonia, spreading cranially to become generalized dystonia with concomitant mild parkinsonism, diurnal fluctuations of symptoms, and excellent response to l-dopa, is highly indicative of dopa-responsive dystonia  resulting from pathogenic variants in the GCH1 gene  represents a variant of WES, i.e., a sequencing analysis directed only to the coding regions of > 4000 genes reported to harbor variants hitherto associated with human genetic disorders  but even more carefully chosen group of early-onset dystonia patients , WES focusing on 225 dystonia-related candidate genes identified clinically relevant variants in 37.5% of screened individuals  of large segments of DNA that may encompass single exons, groups of exons, entire genes, or even two or more adjacent genes. When choosing a test and/or analyzing the data, the potential existence of pathogenic CNVs should be considered. Namely, NGS-based genetic testing can and should also be examined for evidence of CNVs , does not harbor small sequence changes in the SGCE (or KCTD17) gene, analysis of CNVs in SGCE would be warranted. Large deletions within chromosome 7 encompassing SGCE and a few neighboring genes, one of which is COL1A2, have been reported in myoclonus dystonia patients  diagnostic testing, (2) carrier testing, (3) predictive/presymptomatic testing, and (4) prenatal testing. Of these,  diagnostCarrier genetic testing is important for the individuals suspected to carry a pathogenic variant in a single copy of a gene related to autosomal recessive dystonia forms. Such individuals are unaffected but have a family history of dystonia and, if tested positive, have an increased chance of having an affected child  in a fetus before birth  in addition to the personal approach that is an intrinsic part of the patient–physician relationship  that is responsible for the entry of glucose into the brain, may cause a complex phenotype including paroxysmal dystonia due to the reduced levels of glucose in the CNS  develops due to pathogenic variants in the GCH1 gene, which codes for one of the enzymes in the dopamine synthesis pathway (GTP-cyclohydrolase 1). The reduction of dopamine can be effectively mended by dopaminergic medication resulting in a life-long alleviation of motor symptoms. In some cases, upon positive prenatal genetic testing, even prenatal replacement therapy with levodopa may be indicated   may be corelated with an underlying genetic cause  unaffected individuals with disease-causing variants may provide important clues and resources for studies aiming to understand “the genetics of health” or to develop and implement therapies in the prodromal or early disease stages  represents an important initiative with the goal of providing a systematic and comprehensive overview of published data on movement disorder patients reported to carry disease-causative genetic variants. It currently contains information on patients harboring mutations in > 20 isolated or combined dystonia genes and several other genes that may present with dystonia. All MDSGene data are obtained and curated, utilizing a standardized data extraction protocol with predefined inclusion and exclusion criteria, from relevant scientific articles identified through PubMed literature searches. Application of this resource has already resulted in important genotype–phenotype relations for dystonia genes  as well as for the prediction of dystonia outcome and monitoring of disease progression or response to treatment. Ideally, biomarkers should be developed in well-defined disease subgroups , in contrast to the heterogeneous patient populations that are typically recruited into clinical studies  selected for positive findings in a certain dystonia gene may be timely enrolled into gene-tailored clinical trials of potential disease-modifying therapies, underscoring the necessity of systematic testing in dystonia.Genetic testing is the only way to establish a genetic diagnosis in dystonia patients. Which approach or technology will be used depends on the availability and purpose of the genetic test , clinical presentation , and the experience of the physician. A positive genetic test is crucial for appropriate genetic counseling and has the potential to improve or resolve at least some of the worrisome disease aspects for patients and their caregivers. In particularly fortunate cases, it may even indicate a life-changing treatment option. Elucidating the genetic basis of dystonia in patients also indicates the individuals who may contribute to translational research aiming to identify disease modifiers or biomarkers or participate in gene-tailored clinical trials of potential disease-modifying therapies.


A recent meeting at Cold Spring Harbor Laboratory focused on emerging nucleic acid therapies and the essential academic research that has enabled them. The program encompassed everything from chemical innovations to preclinical and clinical progress, and provided a glimpse of the breakthroughs yet to come. With the rapid approval of the mRNA-based vaccine for emergency use in the fight against COVID-19 there is an increased public awareness in the potential of RNA-based medicines. Thus the recent Cold Spring Harbor Laboratory meeting on Nucleic Acid Therapies convening many of the world’s leaders could not have been more timely, or exciting.Beyond COVID-19, the delivery of mRNA vaccines against other diseases, including cancer, seems now poised to achieve great success.The importance of fundamental advances in chemistry and biology to development of cutting-edge pharmaceuticals was a key theme of the meeting. RNA being perhaps one of the least biologically stable of the macromolecules, it is uniquely versatile in its application to novel therapies. RNA can be modified in the base, backbone and sugar to increase target affinity, to thwart nuclease digestion and to maintain the drug’s chemical integrity once administered in vivo. Shulin Gao at Ionis Pharmaceuticals provided an overview of the progress made in RNA modifications and their impact on drug development since the late 1980s, when first generation chemistries—phosphorothioates (PS) modified with a sulfur on their phosphate backbone—were developed. Further innovations on this theme have led to significant improvements in therapies. For example, replacing the 2′-hydroxyl group on the ribose sugar of the PS backbone with a methoxyethoxy group improves target affinity and hence therapeutic activity. A talk from Muthiah (Mano) Manoharan at Alnylam Pharmaceuticals highlighted more recent developments, such as LICA  that improve tissue uptake and biodistribution, showing particular promise against liver diseases.An iconic example of fundamental research in RNA biology driving innovation in therapeutics is the development of CRISPR-Cas gene editing. Although already of great interest to researchers and pharmaceutical companies alike, the recent Nobel Prize in Chemistry awarded to Jennifer Doudna and Emmanuelle Charpentier for CRISPR technology has accelerated both research and drug development. Among the many highlights were three talks illustrating different avenues of current research. Samuel Sternberg at Columbia University presented a talk entitled, “Targeted DNA integration without double-strand breaks using CRISPR RNA-guided transposons,” describing a bacterially derived system—essentially an RNA-guided integrase enabling large-scale sequence changes without requiring double-strand DNA breaks and homologous recombination. Keith Gagnon and his group at Southern Illinois University focused on structure–function relationships in CRISPR-Cas12 and how varying the chemistry of the sgRNA pseudoknot affects the activity of this system. And finally, Briana Wilson at the University of Virginia demonstrated how blocking a specific cellular RNase stabilizes ultra-fast decaying small RNAs, thus promoting entry of small RNAs into the RNA-induced silencing complex (or RISC) as well as target repression. From the pharmaceuticals industry perspective, Christian Dombrowski and Kate Zhang from Intellia Therapeutics and Editas Medicine, respectively, provided insight into how companies are harnessing these discoveries. For example, cytosine base editing screening and optimization or engineering of AsCas12a to achieve high level on-target editing in hematopoietic stem cells, induced pluripotent stem cells, and natural killer (NK) cells, with promising results against sickle cell disease and antitumor activity.Fittingly, the program ended with exciting preclinical and clinical progress. Anastasia Khvorova at the University of Massachusetts Medical School gave a beautiful talk demonstrating the efficacy of RNAi targeting against Alzheimer’s disease, achieving results in the brains of experimental mice where the plaques associated with this disease were clearly abrogated. We also heard from Arthur A. Levin at Avidity Biosciences Inc., who in his talk entitled, “Antibody oligonucleotide conjugates—Progressing towards the clinic”, showed that by conjugating ASO to antibody, the pharmacokinetics in monkeys could be greatly improved with pronounced increase in tissue distribution and prolonged gene silencing activity in multiple tissues. And lest we forget about the most important recent development in RNA-based therapies, Philip Dormitzer from Pfizer gave the keynote fireside chat entitled “COVID-19 Vaccine Development”.Of course, a limitation to RNA-based therapies is that the targets are invariably within cells. Thus, much of the meeting focused on how to engineer RNA drugs that can overcome two main barriers to reaching its intended target within the cell. First, the RNA must be able to penetrate the cell membrane. On this point, Cosmin Mihai at Moderna, Inc. presented an elegant talk entitled, “Dissecting cytosolic mRNA delivery with single molecule resolution enables rational LNP design”, highlighting methods he developed to quantify mRNA in cells in order to evaluate lipids within the lipid nanoparticle (LNP) that might release more free RNA into the cytosol. Once inside the cell, the RNA needs to escape endosomal entrapment. Rudy Juliano—formerly at the University of North Carolina Chapel Hill—has now formed a company in the North Carolina Research Triangle Park called Initos Pharmaceuticals focused on exactly this problem. They aim to produce small molecular compounds that can be co-delivered with therapeutic nucleic acids and assist antisense and splice switching oligomers in endosomal escape.The astounding speed with which vaccines were produced to battle COVID-19 has no doubt re-energized the community of researchers working on RNA biology and therapies. The promise of this field lies in combining all of the technologies discussed above and knowledge yet to be uncovered to develop novel therapies. Beyond COVID-19, the delivery of mRNA vaccines against other diseases, including cancer, seems now poised to achieve great success. We hope that in the aftermath of the pandemic, research effort (and funding) for both basic research and clinical applications of RNA biology will continue to advance with the aim of tackling traditionally intractable or rare diseases for which patients at the moment have little hope.


For over two decades, digital food retail services have been emerging alongside advances in mobile technology and improved access to wi-fi. Digitalization has driven changes within the food environment, complicating an already complex system that influences food-related behaviors and eating practices. Digital food retail services support an infrastructure that enhances commercial food systems by extending access to and availability of highly processed foods, further escalating poor dietary intakes. However, digital food retail services are heterogeneous–food delivery apps, online groceries, and meal kits–and can be feasibly adapted to nutrition interventions and personalized to individual needs. Although sparse, new evidence indicates great potential for digital food retail services to address food insecurity in urban areas and to support healthy eating by making it easier to select, plan, and prepare meals. Digital food retail services are a product of the digital transformation that reflect consumers’ constant need for convenience, which must be addressed in future research and interventions. This paper will discuss public health opportunities that are emerging from the global uptake of digital food retail services, with a focus on online groceries, food delivery apps, and meal kits. Consumer trends have changed rapidly along with technology, creating a market for online retail services, which extends to food . ExpandiThough digital food retail has become ubiquitous in a relatively short time, it is not a new or recent concept for the food retail industry . The firThe digitalization of the food environment has enabled new forms of selling and purchasing food  and has Digital food retail services were burgeoning prior to the COVID-19 pandemic. Restrictions to in-person activities transformed digital food retail from an e-commerce innovation into an essential service that altered food shopping behaviors further bolstering online food purchasing . The COVMost online food purchasing services have been studied as business opportunities to maintain or increase the food market share, and not in relation to health or nutrition ,15. EarlPerceived time scarcity is not only a common reason for using digital food retail services but is also a reason for consuming highly processed foods and can be a substantial barrier to healthy eating ,22,23,24Public health professionals must not underestimate the power of consumers’ need for convenient and timely food preparation. Leveraging existing innovations within the digital food retail sector can be a valuable strategy to support healthy diets in ways that respond to longstanding consumer needs–convenience and saving time. E-commerce and O2O business models have advanced the web-based technology, order/delivery infrastructure, and consumer experience to a degree that can be adapted to fit with public health objectives in most urban and suburban dwelling areas worldwide. Introducing health aspects as an added value to already existing or new digital food retail services is not only feasible but timely.In 2000, Morganosky et al. observed that populations who may find grocery shopping physically or logistically challenging  could benefit considerably from online groceries, packing, and/or delivery services . FurtherDigital food retail services provide cost-effective platforms to implement behavioral interventions at the point of purchase . VirtualThe notion that online groceries dissuade impulse purchases has been cited in multiple studies since 2000 ,33,35,36In addition to behavioral interventions that promote healthy food purchasing, online grocery services could supply healthy food to areas with poor access (food availability or affordability) and address transportation barriers . PolicymIn 2014, the U.S. Department of Agriculture (USDA) Farm Bill included provisions to pilot Supplemental Nutrition Assistance Program (SNAP) benefits to pay for groceries online as a potential solution to neighborhoods with limited access to healthy foods and grocery stores . A pilotThe inability to physically examine products has been a major challenge limiting the adoption of online groceries . ConsumeThere is evidence that online shoppers seek familiar items by focusing on pictures and are less likely to read detailed product information . Brand lThe use of food delivery apps continues to rise, and global revenue is projected to increase by an average of 12.6% a year for the next five years .Regardless of the type of service or their specific attributes, food delivery apps respond to an ever-increasing consumer demand for convenience  and can Though food delivery apps offer a wide range of foods, the items purchased, like most out-of-home meals, are likely large portions of foods that contain excess saturated fat, sugar, and sodium . 87% of Food delivery apps are an expensive service  and healYoung adults are the age group with the highest proportion of food retail app use ,68,69 anOnline food delivery business models, order processing, and delivery logistics are currently being leveraged and adapted by community groups and the charitable food sector to provide local food assistance. It would be valuable to investigate the scalability of successful programs such as Meals on Wheels that have changed over time to provide online food ordering and local delivery of ready-to-heat meals customized to dietary restrictions and are available to all community members regardless of age, income, or health . The digMeal kits, the newest online food shopping innovation to gain popularity, offer fresh packages of raw ingredients with cooking instructions that save time and remove the burden of meal planning . Meal kiTwo separate Australian studies published in 2019 and 2020, respectively, found that meal kits provided a sufficient amount of vegetables but could be high in sodium, and macronutrient content varied considerably from recipe to recipe ,83. ResuCooking and home food preparation are determinants of healthy eating ; howeverThe cost of a computer or mobile phone with Internet is one of the main barriers to not using the Internet . LimitedAs consumer data and tracking information is collected, the digital food retail sector will continue to pivot to meet customer demands for seamless services that grant multiple ways to order, purchase, and obtain food, all while maximizing revenue . We can The fundamental public health challenge within the digital food environment is to develop solutions (programs and policies) within a constantly evolving commercial food system. Adding to this challenge, digital food environments are not fully understood, making it a blurry target to address. We simply do not know the extent to which the digitalization of the food environment will impact consumer food purchasing behaviors and thereby health. Thus, we are left with substantial knowledge gaps regarding the impacts of the ongoing uptake and normalized use of digital food retail services on diet-related health outcomes . HoweverThe digitalization of food environments  generateExploring the influence that online food purchasing has on meal choices, eating practices, and diet quality is a necessary step to deepen our understanding of digital food retail environments. Online food purchasing services are likely to have an impact on the nutritional health of individuals who utilize these services regularly through mechanisms that are linked to changes in home-based food preparation, eating practices, and diet quality. Understanding what matters to consumers is key to developing appropriate interventions that involve emerging digital food retail services. Given the rapid evolution of online food purchasing and the massive knowledge gap about the impacts of new digital food retail environments on eating practices, consumer behavior and policy research are urgently needed.


Such a correlation makes sense because a higher protection from exogenous damage, like that inflicted by UV radiation, is necessary in order for the already superior longevity potential of slowly aging animals to be phenotypically expressed. Long-lived animals can reach many decades of age only if the many different causes of early death due to extrinsic mortality (including UV-induced DNA damage and skin cancer) are avoided. That comparison can also be strongly biased by the much lower need of excision repair for removal of UV-induced lesions in rodents than in humans due to their fur and nocturnal habits.Positive correlation between genomic DNA repair and longevity has been classically described (reviewed in ). Howeve2O2 to the cytosol, they would also need less total cell endogenous antioxidants and less nuclear DNA repair systems. Endogenous total cell antioxidants and DNA repair enzymes are transitorily induced, when needed, to come back again to low levels when episodic increases in oxidative stress have been overcome. In this way, cells save much energy, which otherwise would be invested in the protein synthesis needed to continuously maintain high levels of cellular antioxidants and nuclear DNA repair enzymes when they are not needed at such high levels.Aging is an endogenous process that occurs in internal organs, most importantly in tissues containing postmitotic cells. Is the DNA repair of endogenous damage higher in long-lived animals? When base excision repair (BER) of genomic DNA was measured in four organs including heart and brain it was found not significantly changed or even decreased (instead of increased) in longer-lived caloric restricted mice . MoreoveThat is the situation concerning BER in nuclear DNA, but what occurs in the case of mitochondrial BER (mitBER)? MitBER had never been measured in species with different longevities, and we hypothesized that mitochondrial, instead of nuclear, BER is higher in long-lived than in short-lived mammals. We have thus recently measured activities and/or protein levels of various mitBER enzymes including DNA glycosylases, NTHL1 and NEIL2, and APE endonuclease in mitochondrial liver and heart fractions from eight mammalian species differing by 13-fold in longevity . Our res


Food safety and food quality are two closely related aspects of the food management system. The difference between the two is that one keeps consumers safe while the other keeps consumers satisfied. This study examined the differences in how consumers value food safety and food quality with a focus on the influence of loss aversion on one’s psychological level and of income effect on one’s socio-demographic level. Our findings indicate that loss aversion and income effect significantly influence the way consumers value food safety vs. quality labels when considering potential health risks and food price. High risk-averse and low-income consumers with strong loss aversion and a weak income effect show a higher demand for food safety labels as a way to ensure easy access to safety indications. Low risk-averse and high-income consumers with weak loss aversion and a strong income effect show a higher demand for food quality labels because they hope to gain more health benefits from high-quality food at good prices. This study provides insights that will assist public authorities and food industry in balancing food safety control and food quality improvement in order to meet the heterogeneous market demand changing alongside the transition of China’s food consumption and production. Since the food safety scandal of excess melamine residues broke out in China in 2008, the overwhelming majority of consumers with high risk aversion have been in a panic over the issue of food safety . CompeteFood safety and food quality are two of the most important aspects of the food management system. Although closely related, there are differences between food safety and food quality regarding the requirements in a food-handling environment . Food saHowever, much of the previous literature confused the distinction between the concepts of food safety and food quality, and others primarily focused on consumers’ food demand choice for either food safety or food quality. To the best of our knowledge, no published study has integrated food safety and food quality into a comprehensive framework, compared the differences of how consumers value food safety vs. quality labels, and even evaluated how socio-demographic and psychological characteristics influence consumers’ food demand choice. This study addresses the knowledge gap that exists in the current literature of behavioral economics and psychology. Our empirical analysis aims to (1) estimate whether consumers’ food demand choice differs significantly when it comes to food safety vs. quality labels and to compare the extent of those differences in their food choices, and to (2) investigate how loss aversion  and incThe major objective of this study is to estimate the differences in consumers’ food choice for food safety vs. quality labels. Specifically, we first use the mixed logit model to explore the heterogeneities in consumers’ valuations of food safety vs. quality labels. Second, we categorize respondents into subsamples based on different levels of risk aversion and income in order to identify the differences in their valuations of food safety vs. quality labels. Third, we examine the impacts of loss aversion and income effect when making food choices based on food safety vs. quality labels. The results will provide valuable information to help the food industry decide whether to increase the publicity of safety or quality information labels, help distributors develop effective marketing strategies to meet consumer demand for food safety and quality, and assist policymakers in setting attribute priorities on food safety vs. quality when formulating food policies.Utility is a term in economics that refers to the total satisfaction or dissatisfaction that consumers experience when consuming a good or service. Economic theories based on rational choice usually assume that consumers will strive to maximize their utility, from the perspective of psychological expectations. Utility is also a subjective measure of satisfaction or dissatisfaction that varies from person to person according to each personal preference. Although consumer utility is impossible to quantify, utility losses or gains that a consumer obtains from different goods and services can be compared . ConsumeH1: Consumers with varying levels of risk aversion and income place heterogeneous valuations for food safety and quality information labels.For consumers with a high safety concern and strong budget constraint, the potential health risk of consuming food without official or third-party safety-certified labels would significantly reduce consumer utility. At the same time, the cost savings that come with relatively low prices of safe food would increase consumer utility. Loss aversion, whereby the impact of losses overweighs gains, is typically examined in relation to decisions about anticipated outcomes . In geneH2: When the utility losses from loss aversion outweighs the utility gains from income effect, consumers with high risk aversion and low income prefer safe food with safety information labels.In another case, for consumers with low safety concern and weak budget constraint, the potential health benefit from consuming more nutritious and healthier food with higher quality would certainly increase consumer utility, while the relatively higher food prices would reduce consumer utility. However, because consumers have a low risk aversion for food safety, the loss aversion regarding potential health risks related to unsafe food would be weakened and the negative utility of loss aversion approaches 0. Similarly, the high price – which includes the labeling cost of high-quality food – has no apparent negative impact on high-income consumers’ utility. Here, the negative utility of income effect is also close to 0. In general, utility gains in health benefit have a larger positive impact on consumer well-being than the minimal utility losses in high food price and health risk. This implies that the positive utility created by high-quality food with sufficient quality information is the main factor driving low risk-averse and high-income consumers’ demand for food quality labels. Under this condition, the income effect for potential health benefit from high-quality food with high price far outweighs the loss aversion for potential health risk. Accordingly, we propose and validate hypothesis H3 about the influence of loss aversion and income effect on consumers’ valuations of food quality labels, as indicated by the bottom half of H3: When the utility losses from loss aversion is less than the utility gains from income effect, consumers with low risk aversion and high income prefer high-quality food with quality information labels.Choice experiment is a quantitative technique that is used to elicit consumer preferences. It helps researchers to uncover how consumers value selected attributes of food products by asking them to state their preferences among a series of choice sets of hypothetical alternatives. Each alternative is described by several attributes, and consumers’ responses are used to infer the value placed on each attribute. Comparing with other standard contingent valuation techniques that require respondents to rank or rate alternatives, choice experiment presents a reasonably straightforward task, which more closely resembles a real-world decision. The theoretical foundation of choice experiment is conceptually based on Lancaster’s consumer utility theory, which postulates that consumers obtain utility from the attributes of a product rather than from the product itself .Our choice experiment was carefully designed to specify five product attributes, including two food safety attributes (certification and traceability system), two food quality attributes (brand reputation and grading system), and the prices of rice products. The five specifications of food-specific attributes are summarized in 2 × 23) combinations under a full factorial design. To minimize respondents’ response difficulties, a fractional factorial design orthogonally generated 16 combinations, each two of which were randomly split into one group. A respondent was presented with 8 simulated choice scenarios that each contained two alternatives characterized by the combinations of different levels of five attributes. The “do not buy” alternative was included to simulate a real shopping market where respondents were allowed not to purchase rice products. A choice scenario is illustrated in The five selected attributes can produce as many as 72 , an objective cheap talk , and honesty priming treatment . Overall, ex ante methods, would result in reasonable and robust valuation measures.Since the choice experiment does not provide incentives for respondents to invest sufficient cognitive effort when thinking about their valuation decisions, the WTP values may be overstated in the hypothetical situation because of the lack of real economic commitment. At the beginning of our survey, we use some Our choice experiment was carried out across China’s western, middle, and eastern regions from May to July 2018. A group of well-trained enumerators were recruited to investigate three major capital cities: Chongqing , Changsha  and Nanjing , and six developing cites: Xinyang (Henan province), Luan and Bengbu (Anhui province), Xuzhou, Changzhou and Suzhou (Jiangsu province). These nine cities covered in our survey were selected from major Chinese rice consumption areas. In all, approximately 41% of experimental observations were derived from fresh markets, 46% from domestic supermarkets, and 13% from international supermarkets. This was done to better capture the heterogeneity of consumers’ purchasing behaviors in various purchasing contexts.n obtains from choosing alternative j in choice situation t is given byMixed logit is a highly flexible model that can approximate any random utility model . GeneralUnjt is a function of observable attributes of the alternatives, xnjt, and of the decision maker n. The random term μnjt is assumed to be iid type I extreme value distributed. The mixed logit model extends the standard conditional logit model by allowing heterogeneous coefficients βn in the model to vary across decision makers. The decision maker n knows the value of his own βn for all alternatives J and will choose the alternative i that provides the highest level of utility, if and only if Unit > Unjt,∀j ≠ i.where n, the choice probability of mixed logit model under density function f(βn) can be expressed in the form ofTo estimate consumers’ unobserved heterogeneous preferences for informational attributes, we select the mixed logit model, which is specified to include a combination of non-random coefficients and multivariate normal random coefficients . The mixk is represented byThe WTP for an attribute is interpreted as the level of compensation or discount for consumers relative to the utility without that attribute, which would be needed to make them indifferent to the two situations. To calculate mean WTP values for all consumers, a ratio is taken in which the numerator is the parameter on that attribute and the denominator is the negative price coefficient, which can be perceived as the marginal utility of money. The WTP for attribute k and βprice are all decision makers’ mean coefficients for attribute k and for the price of rice product, respectively.where βk, the Monte Carlo method developed by For the statistical properties of the WTP for attribute For the analysis, the coefficients of food safety and quality labels were assumed as random and normally distributed. As shown in The estimated WTP for food safety vs. quality labels within and between subsamples are compared in t-test statistics indicated in The WTP differences between subsamples are statistically significant, as the t-test statistics of WTP differences significantly validate the hypotheses H2 and H3 at the 1% level. It was expected that loss aversion and income effect would jointly influence differences in consumer reactions to the availability of food safety vs. quality labels. In terms of loss aversion, high risk-averse consumers experience a greater loss aversion when posed with potential health risks, making them more willing to pay a premium price to ensure that the rice product is safe enough. Low risk-averse consumers who present a weakening loss aversion correlated with psychologically perceived health risks tend to prefer food quality labels over food safety labels. In terms of income effect, high-income consumers show a strong willingness-to-pay when it comes to the cost of food quality labels in order to achieve more health benefits from high-quality food at a good price. For low-income consumers with a strong budget constraint, they are more likely to choose safe food that is above the minimum quality standard and with a relatively low price as opposed to higher priced high-quality food.Such WTP differences show that stronger loss aversion would produce a higher demand for food safety labels and a stronger income effect would produce a higher demand for food quality labels. The China is now at a critical juncture in the transformation of food consumption and production. The decision on the part of public authorities and the food industry to prioritize food safety control or food quality improvement should center on market demand for either safe food that is above the minimum quality standard, or high-quality food held to a high quality standard. Although food safety and food quality are closely related in the food management system, there are significant differences between the two in that the former keeps consumers safe and the latter keeps consumers satisfied. However, to our knowledge there is no study in the current literature that integrates food safety and food quality into a comprehensive framework while evaluating the influence of consumers’ socio-demographic and psychological characteristics on preferences for food safety and food quality. Taking rice as a case study, this study employs choice experiment survey data and the mixed logit model in order to estimate the differences in consumers’ food choice for food safety vs. quality labels, and to uncover the influence of loss aversion and income effect on their valuations of food safety vs. quality labels.The mixed logit model results show that Chinese consumers have heterogeneous preferences and WTP for a price premium to cover the cost of food safety and quality labels, with more divergent valuations of food safety labels on governmental-certified and traceable information, and food quality label on brand reputation. The density estimates of WTP differences indicate that although high-risk averse consumers express a higher WTP both for food safety and quality labels than low risk-averse consumers, the density distributions of high-risk averse consumers’ WTP for food safety labels and that of low risk-averse consumers’ WTP for food quality labels both exhibit a high degree of convergence. Similarly, although high-income consumers have a nearly equivalent WTP for food safety labels as low-income consumers, they have a higher WTP for food quality labels on average.The WTP differences between subsamples indicate that loss aversion would produce a high demand for food safety labels and that income effect would produce a high demand for food quality labels. It was expected that consumers with various socio-demographic and psychological characteristics would react differently to the availability of food safety vs. quality labels in the food market. For high risk-averse and low-income consumers, they experience a greater loss aversion regarding potential health risks and a weaker income effect for high food prices, so that they tend to pay a price premium for easy access to safety indications assuring the safety of food. For low risk-averse and high-income consumers, the weaker loss aversion and greater income effect would result in a stronger willingness-to-pay for food quality labels that will bring them many health benefits from high-quality food at a good price.Overall, our findings indicate that consumers with varying levels of risk aversion and income would be influenced by the loss aversion and income effects on their food choice for food safety vs. quality labels. This finding strongly suggests that the Chinese government and food industry should implement a multilevel food labeling scheme that integrates food safety and quality management systems. From the perspective of public policy, although ensuring food safety and improving food quality are two different policy objectives, with the government and food industry as the driving forces behind each, respectively, the two objectives should coexist within the common framework of China’s food management system. The modified food labeling scheme implemented jointly by the government and food industry would provide consumers more useful information to help them identify the inherent food safety and quality attributes, which cannot be easily identified otherwise. Such a fully information-asymmetric market can facilitate well-informed food choices and maximize consumer welfare.Ensuring food safety is an important task that forms an integral part of the national planning strategy for building a healthy China and enhancing people’s well-being. The primary purpose of governmental food management is to guarantee that the food available to the public on the market meets the minimum quality standards, which is now being achieved over the last decade through a variety of initiatives including a modified food labeling scheme, rigorous random food inspection, and enhanced penalty severity. As governmental regulatory capacity is continuously strengthened, food safety risk will be effectively kept to an acceptable level, and consumers’ safety concern and their loss aversion regarding potential health risks will be weakened in terms of psychological expectations. Meanwhile, with the rapidly rising income levels, the current food market and policy climate overly focused on food safety control would not provide more valuable food quality information, nor would it satisfy the growing market demand for high-quality food among high-income consumers. Thus, the original policy objective of prioritizing food safety control over food quality improvement should be revised accordingly to keep up with the changing market demand for food safety vs. food quality. On the contrary, if the revised policy objective of food quality improvement is placed ahead of food safety control, an overemphasis on food quality improvement by the food industry would not only result in a sufficient safe food supply that far exceeds safety requirements, it would also result in increased production costs, higher food prices, and heavy expenditure burdens on low-income consumers who can hardly afford high-quality food at good prices and have a higher demand for safe food with relatively low prices.Therefore, in the transition process from safe to high-quality food production and consumption, the government and food industry should balance the tradeoff between food safety control and food quality improvement. A multilevel labeling system contributes to a good market containing different levels of food quality with competitive prices, where consumers with varying levels of risk aversion and income would make appropriate food choices for safe food or high-quality food. Our findings provide the government with an effective labeling strategy for ensuring the safety of public diet, especially for the health interest of low-income and high risk-concerned groups. It also provides policy incentives for producers, processors, and distributors to collaborate and create a quality-differentiated food market with comprehensive food information in order to enhance the food industry’s competitiveness and to meet heterogeneous market demand for food safety vs. food quality.This study identifies the dual effects of loss aversion and income on consumer food choice for food safety and food quality, but it is unclear whether the effects of education, cognitive performance, and other variables, particularly those affecting consumers’ valuations and choices, are at least as important for their food choices. Because the costs of promoting a modified labeling system are partially covered by food prices, the level at which the price increase should be limited relative to the current price in order to gurantee consumers’ benefit is of interest for future research. Furthermore, a further study comparing consumers’ valuations of mandatory vs. voluntary labeling systems could also establish valuable findings.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Nanjing Agricultural University. The patients/participants provided their written informed consent to participate in this study.WN: conceptualization, methodology, writing original draft. HB: methodology and data collection. JL: manuscript preparation, supervision, and editing. TL: conceptualization, writing original draft and editing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Science1 demonstrates a shutdown mechanism in neutrophils that limits their aggregation dynamics while enhancing bacterial killing.1All biological systems rely on regulatory networks of positive and negative feedback that enable targeted and rapid adaptations, while negative autosignals limit overstimulation and enable self-shutdown. A recent publication in 2 So, while the initial steps and molecular pathways become increasingly clear, observing a swarm event in full swing almost immediately raises the question: when and how does it stop? Such an important and potentially harmful process must be regulated at multiple levels. Both intrinsic and extrinsic cellular mechanisms operate in parallel, depending on the actual in vivo context. The different fates of neutrophils are shown in Fig. The inflammatory cascade is a highly conserved process that allows for the orderly activation and deactivation of immune cells in response to challenges from within or the outside. One of its most numerous and powerful effectors are neutrophil granulocytes. Neutrophils exert their inflammatory functions as functional collective through a highly dynamic behavior called swarming. Swarming dynamics are a universal feature of neutrophil activation and their early recruitment in response to a variety of inflammatory stimuli and perturbations, including sterile tissue damage. The molecular mechanisms of swarming enable the targeted and incredibly rapid recruitment of inflammatory effectors to sites of potential barrier breach or pathogen invasion. In particular, the initial self-amplifying mechanisms are extremely effective. In situ activation of an individual sentinel is sufficient to initiate a feedforward circuit based on the secretion of the chemokines LTB4 and CCL2. This leads to the recruitment and targeted attraction of hundreds of activated neutrophils from circulation—like the feeding frenzy of piranhas. However, the activity of neutrophils comes at a price. Neutrophils carry powerful molecular weapons that cannot distinguish between invading bacteria and the body’s own cells. While swarming is essential for fighting pathogens, it inevitably also inflicts collateral damage on healthy tissue, which has been implicated in the pathogenesis of various inflammatory and degenerative diseases.3 These cells were shown to closely follow the first wave of infiltrating neutrophils. Here, degradation of neutrophil chemoattractants or even their molecular conversion to neutrophil-deactivating mediators could limit swarm growth and keep the inflammatory process in check. In addition, upon activation, neutrophils undergo neutrophil extracellular trap (NET) formation—a particular form of cell death associated with the release of neutrophil-derived chromatin associated with various enzymes and proteins. NETs have been shown to be enriched in proteases that actively degrade proinflammatory mediators as well as various chemokines.5 Although NETs are difficult to detect in the core of an active swarm cluster, we speculate that they would represent a powerful negative feedback mechanism that self-limits neutrophil activation by providing a temporary (pop-up) chemokine-degrading scaffold.For instance, monocytes have been implicated in controlling the population dynamics of swarming neutrophils. In vivo, the cessation of swarm progression and further recruitment of neutrophils is associated with secondary shielding of the focus by recruited anti-inflammatory monocytes.1 now present a novel intrinsic feedback control at the level of regulation of individual cell dynamics. Their finding is based on the observation that once neutrophils have swarmed and cluster, they exhibit dynamic arrest, whereas cells at the periphery exhibit intermittent exploratory behavior. They show that this arrest is mediated by active desensitization of the LTB4/CCL2-driven signaling pathways in activated neutrophils. GRK2-mediated phosphorylation of the respective surface receptors leads to reduced receptivity of clustering neutrophils even and especially at increasing chemokine concentrations—a shift from initial positive (swarming) to subsequent negative temporal sensing (swarm aggregation). While GRK2 signaling has previously been implicated in chemotaxis of immune cells, in extravascular neutrophils GRK2-mediated arrest limits dynamic aggregation and thus the progression of cluster formation, which may be important in limiting collateral tissue damage and pathological inflammation in response to sterile disruptions.3 However, in the case of bacterial infection, this arrest is of even greater functional significance. The spatiotemporal dynamics of neutrophils in response to infections and sterile tissue damage are strikingly similar and rely on the same positive feedback loops. While the direct benefit of swarming in sterile lesions remains speculative, their role in the containment and control of bacterial infections is evident. In a mouse model of lymph node infection, the authors found that although non-arresting neutrophils exhibited increased aggregation and exploratory dynamics throughout the tissue, bacterial clearance was diminished. They conclude that dynamic arrest of neutrophils is a prerequisite for the formation of stable clusters and thus for the effective killing of bacteria. Without GRK2-mediated arrest, neutrophils do not commit to cluster stability, rendering cluster functionality less effective. Instead, the cells tend to engage in exploratory behavior or constantly migrate between different clusters. However, at the functional level, exploration alone is not sufficient to eliminate the threat. Instead, swarm-driven formation and maintenance of functional clusters are essential for killing bacteria. Turning off their responsiveness to the chemokine that actually attracted them there, exactly where its concentration is highest, ensures that they are present where they are needed most, at the center of the swarm.However, because it is so critical to effectively regulate the neutrophil activity, each cell has its own control mechanisms in the form of molecular circuit breakers. For example, it has long been known that circulating neutrophils are programmed for constitutive cell death. Their inherently limited lifespan can be considered a safety measure to limit their destructive potential, which is why the temporal extent of a neutrophil-driven inflammatory activity is primarily regulated by sustained replenishment from the bone marrow. Kienle et al.Overall, mechanisms for (self-)limiting neutrophil dynamics are crucial for the prevention of collateral tissue damages and chronic inflammatory diseases. In addition, however, they also enable a more targeted use of their powerful effector functions by actively directing their focus to the task at hand. In summary, neutrophil activation and deactivation are dynamic processes that are regulated at multiple levels, both cell-intrinsic and -extrinsic. All mechanisms must be closely coordinated and effectively interact to enable the delicate balance between self-destruction and the main purpose of inflammation—protection from the outside world.