Human cognition is not solitary, it is shaped by collective learning and memory. Unlike swarms or herds, human social networks have diverse topologies, serving diverse modes of collective cognition and behaviour. Here, we review research that combines network structure with psychological and neural experiments and modelling to understand how the topology of social networks shapes collective cognition. First, we review graph-theoretical approaches to behavioural experiments on collective memory, belief propagation and problem solving. These results show that different topologies of communication networks synchronize or integrate knowledge differently, serving diverse collective goals. Second, we discuss neuroimaging studies showing that human brains encode the topology of one's larger social network and show similar neural patterns to neural patterns of our friends and community ties (e.g. when watching movies). Third, we discuss cognitive similarities between learning social and non-social topologies, e.g. in spatial and associative learning, as well as common brain regions involved in processing social and non-social topologies. Finally, we discuss recent machine learning approaches to collective communication and cooperation in multi-agent artificial networks. Combining network science with cognitive, neural and computational approaches empowers investigating how social structures shape collective cognition, which can in turn help design goal-directed social network topologies.This article is part of a discussion meeting issue ‘The emergence of collective knowledge and cumulative culture in animals, humans and machines’. From tool use, language and mathematics to beliefs about the world and morality, human cognition is shaped by learning and memory in social networks. Unlike swarms or herds, human social networks have diverse structures comprising strong, weak, clustered and sometimes hierarchical ties that serve different roles. Networks of humans pass and share information in order to synchronize their collective memories, knowledge and beliefs, or to discover and integrate diverse information and knowledge. This review focuses on empirical and computational investigations of how the structures of communication networks  shape collective cognition. Specifically, we ask how social network topology interacts with psychological, neural and computational principles of learning and memory to synchronize collective memory and knowledge.While a number of prominent papers and books over the past decades have addressed the role of cooperation, and social networks on collective outcomes, a review with the particular synthesis of social network topology with psychological and neural computation seems lacking. Thus, this review narrows the focus to notable research on the interaction of network structures (macro level) with psychology and cognition (micro level) in behavioural studies of collective memory ,2, colleBefore returning to the focus of the review, it is noteworthy that over the past decades diverse disciplines have investigated different faces of collective cognition. Philosophers such as Bratman –14, DaviStudying the topology of human communication networks empowers us to understand, explain, model and predict the emergence and dynamics of collective knowledge in large networks. Decades of seminal research by renowned mathematicians, physicists, neuroscientists, computer scientists, sociologists and economists have established the science of complex networks that are brilliantly reviewed in earlier publications –33.This manuscript specifically focuses on the combination of network topology research with the methods of computational and cognitive sciences. A graph-theoretic understanding enables us to study how communication networks interact with psychological and neural computation to shape collective cognition. Moreover, it enables us to make goal-directed predictions, and design interventions to achieve desired collective cognitive outcomes. Such desired collective outcomes could span from predicting and combating misinformed beliefs about a global pandemic to facilitating optimal structure of classrooms for learning, synchronizing memories prior to elections, optimally connecting scientific task forces working on rapid vaccine discovery, studies of human collective cognition empowering researchers and designing effective multi-agent machine intelligence.This paper reviews recent directions of studying collective human cognition within the scope established above and concludes with a brief discussion of current and future directions in multi-agent machine intelligence. We review how network topology aligns collective memories (§2), collective beliefs and behaviour (§3), cultural accumulation and collective intelligence (§4). We then discuss how the brain's neural responses capture the topology of one's social network (§5) and then discuss common neural findings in cognition of social and non-social topologies (§6). We close with applications in multi-agent machine learning (§7) and a summary of the topology of social networks in humans and machines (§8).. 2convergence of memories among the members of a social network or community [A key question in understanding collective cognition is how the structures of communication networks  align coommunity ,2. Howevommunity ,35, e.g.In a number of studies, Coman, Momennejad and colleagues investigated collective memory using graph theory, behavioural experiments, complex and temporal network analysis, and agent-based simulations ,2,36. ToEvery experimental session consisted of a number of individuals (e.g. 10 or 16), each facing a computer screen and later interacting with a pre-assigned number of other participants virtually through a text chat window. All experiments followed a three-phase design : in phasmnemonic similarity  became more similar after conversations. Mnemonic alignments of all pairs were averaged to measure the collective memory of the network.The authors first coded the behavioural memory recall responses from phase 1 and phase 3 as vectors of recall items. For instance, one study had 16 recall questions [milarity  was comphe items . SubtracUsing the experimental paradigm described above , the autnetwork diameter, or a longer path between the most distant members of the network, than the non-clustered network. The results show that the collective memory of networks with a smaller diameter (non-clustered topology) converged more than the networks with a clustered graph structure or topology.The hypothesis was that pairwise participants' memories would align according to their degree of separation, with the most alignment in those with a direct conversation and the least alignments with those with the further geodesic distance . This hybridge ties exchanged information first. These were individuals who had a direct tie but did not have any ties to other individuals in common .In another experiment , MomenneThe studies above show that the topological structure and temporal order of communication networks determine the mnemonic alignment among individuals in a network, even if they did not directly interact. In a recent computational study , we combThese recent advances carve the way for theoretical and experimental approaches to studying the ties that bind the micro, meso and macro scales of human cognition and behaviour. Graph-theoretic approaches to collective experiments, and simulation of institutions  with par. 3Collective memories often form the foundations of shared systems of beliefs, and beliefs shape how we remember . ReligioVlasceanu and Coman conducted a belief synchronization version of the study described in The authors also studied how belief endorsement by a public speaker affects belief alignment in 12-person laboratory-created networks . During homophily between two individuals, i.e. the extent to which their social contacts are similar to one another, increases their dyadic-level influence on each other's behaviour. However, the broader consequence of this pattern is that in large clustered networks less healthy individuals are more likely to have close ties and influence one another, reducing their probability of interactions with, and being influenced by, healthier individuals [The present manuscript focuses on the role of social network topology in collective cognition rather than behaviour broadly defined. However, beliefs about health, education and politics govern large-scale patterns of collective human behaviour. Thus, it is reasonable to hypothesize that the topology of communication networks shape behaviour. Centola has provided evidence for this hypothesis in a series of seminal studies, establishing a link between network topology and collective behaviour ,4. They While the present manuscript is a review of the role of network topology in collective cognition with a focus on cognitive neuroscience and machine learning, a series of recent papers have addressed how topology affects health behaviour, resource sharing and inequality, and wisdom of the crowds  –39. ThesTaken together, these studies clarify the role of network topology in the mechanisms by which beliefs, norms and behaviour propagate in networks, and how centralized interventions—such as collective exposure to public endorsement and endorsement by influential members—can change collective beliefs and norms. These findings, together with findings on collective memory and belief formation, offer the important potential for designing interventions to combat misinformation  or harmful polarization in larger networks. Mapping network topology of misinformation networks makes it possible to devise a number of intervention tools that can synchronize memories and beliefs in larger communities at times of crisis. These tools could span from affecting the topology of communication networks, when possible, to targeting bridge ties and isolated clusters (information bubbles) for intervention and centralized public speeches.. 4Consider the Brooklyn bridge, your smart phone, or the international space station. Achieving any of these complex technologies required generations of cumulative inventions, leading to levels of problem-solving ability that go far beyond what is possible at the individual intelligence level. It has been suggested that the capacity and success of cumulative cultural achievements, such as complex technologies, depend on the size and connectivity of collaborative networks .full connectivity), while in the second condition, they worked in three teams of two and exchanged members twice throughout the experiment . The results suggest that participants in the partial connectivity condition achieved further levels of the hierarchical invention compared to the full connectivity condition.In an inventive study, Derex & Boyd  investigThus, while full connectivity may serve the convergence of memories and beliefs, as discussed earlier, partial connectivity may increase cultural accumulation required for complex and cumulative invention. These findings provide compelling support for the core thesis of the present paper: that different social network topologies can serve different collective outcomes. Further hypothesis-driven investigations could lead to insight for intervention design: designing goal-directed network structures or targeted interventions on specific parts of a network towards a desired outcome. Examples of desired collective outcomes span from predicting and combating misinformation about a global pandemic to designing optimal communication among scientific research networks for rapid vaccine discovery.Wooley and colleagues define collective intelligence as the above-mentioned collective's ability to solve a diverse set of tasks and problems beyond the ability of the most intelligent members of the collective ,51. Theythe collective intelligence of a collaboration network may depend on the network's flexibility in reorganizing its collaborative connectivity to adapt to diverse task demands.The study by Derex and Boyd discussed earlier provides preliminary evidence for the hypothesis that network topology and connectivity can impact the collective intelligence of a community. Other studies have established collaborative learning in social networks  and inveAnother future direction is to investigate whether collective intelligence merely relies on sensitivity to social cues, or whether it is also related to the ability of community members to perceive the network status of others, and the broader topology of their social network. Such a study can benefit from the methods developed in recent neuroimaging studies (discussed in the following section) showing that the brain spontaneously encodes the social network status of one's community members.. 5Previous sections reviewed behavioural evidence that human memories and beliefs become similar to one's community members, and the extent of this similarity tracks one's geodesic distance, or degree of separation, to any other community member. Given these behavioural findings, a hypothesis naturally follows: social network topology should also impact similarities in the brain signals of community members. A recent study considered whether human brains are sensitive to the network status of other individuals . The auteigenvector centrality to analyse an academic cohort of 275 students and scanned 21 members in a functional magnetic resonance imaging (fMRI) study. Eigenvector centrality measures how influential a member is and how many influential members they are connected to  and medial temporal lobe regions of the brain . This paThe similarity of social topological learning to navigating spatial topologies, finding shortcuts and learning non-spatial associative topologies calls for more comparative studies of common mechanisms. Two particular brain regions involved in social, spatial and other modes of topological learning are the medial PFC (mPFC) and the hippocampal-entorhinal complex ,81–84. ONotably, these studies largely draw from expertise and diverse tools from neuroscience, mathematics, graph theory and physics . Identif. 7A thriving direction in contemporary machine learning regards multi-agent learning and collaborative artificial intelligence (AI). Research and innovation in these directions span from AI-AI and AI-human interactions, including communication via natural language processing , to builoptimal network topologies tailored to fulfilling particular tasks or goals in a multi-agent setting. The goals of such a system could vary from collaboration to competition (e.g. as in Xbox games) or assisting humans. Second, combining principles of evolving network architecture with multi-agent problem settings can offer insights into the coevolution of neural architecture  and the topologies of social and ecological multi-agent networks. These directions are especially timely given recent advances in graph learning [A forward-looking computational direction is to compare the emergence of different social structures dependent upon the neural architecture of individual agents in a multi-agent system. It is possible to envision at least two related directions. First, the emergence of learning .Advances in these directions could offer theoretical insight into the correspondence and coevolution of neural architectures in individual brains and species with the demands of navigating large and complex social, spatial and environmental networks. Which structures of social networks emerge from multi-agent systems with different goals? Which neural network or brain architectures can afford the multi-agent behaviour observed in a given species? This direction offers exciting prospects for studying how neural networks and social networks co-evolve in biological and AI.. 8Human brains and cultures are embedded in large social and ecological systems. Unlike swarms and herds, human social networks have diverse composition and topologies. Here we have reviewed research backing the hypothesis that social network topology shapes collective cognition and behaviour. We narrowed the scope predominantly to psychological and neuroscientific studies that ground this proposal in micro–macro interactions.The integration of these studies shows that: (i) human memories, beliefs and behaviours synchronize with their social ties, and with members of the community they never directly communicate with –5; (ii) The body of research reviewed here uses diverse interdisciplinary methods developed in graph theory, statistics, mathematics, physics and neuroscience for clustering and characterizing community structures in complex networks ,106, temGraph-theoretic tools for analysing the architecture of complex networks apply to brains and social networks alike. Just as neural networks with different architectures share and integrate information differently, specific structures or topologies of social networks synchronize or integrate knowledge in different ways. Future studies can combine experimental and computational approaches to study the coevolution of neural networks capable of processing large social network topologies, and the emergence of topologies that serve different collective functions and outcomes.Combining experimental and computational approaches empowers researchers to investigate how the topology of social networks shapes collective cognition and behaviour and help design goal-directed social network topologies toward desired outcomes . Comparative studies on social and non-social graph learning across species could offer insight into the evolution of neural and social mechanisms in humans, other species and machines. Such an interdisciplinary approach empowers researchers to design effective multi-agent machine intelligence inspired by knowledge of human collective cognition. In turn, multi-agent machine learning models of collective intelligence can help theorize and test hypotheses about the coevolution of complex neural architectures and complex social networks.


Looking ahead to 2030 and beyond, the United States will be both older and more multicultural than presently. To explore the impacts and characteristics of an increasingly diverse population beginning to age, the MIT AgeLab conducted online focus groups in August 2020 (n=92) with ethnically diverse participants ages 40-69 on topics related to household composition, use of technology and digital engagement. Regarding household composition, Black and Latinx participants were more likely to report living with grandchild(ren), and Asian, Latinx, and White participants were more likely to report living with a parent(s) or parent(s)-in- law. Latinx participants often described ways in which caregiving for aging parents was a cultural value, but many participants who had raised children in the United States but who were not born in the United States themselves described cultural gaps in family attitudes that had sometimes widened across the generations. While all participants were using some technology, due to the coronavirus pandemic, digital tools were being used more widely than ever before. Racial/ethnic identity groups were more similar than different in terms of their responses to questions around consumer digital engagement. There were notable differences in overall trust in technology across racial/ethnic groups, with Asian participants reporting the highest average overall level of trust in technology and Multiracial participants reporting the lowest. Looking ahead, the intersection of aging and growing racial/ethnic diversity in the United States will yield a wider array of consumer needs and expectations.


Monascus strains, also called Hongqu, red fermented rice (RFR), and red yeast rice (RYR), has been used as a food coloring agent, food preservative, and traditional medicine for about 2,000 years in China , monacolin K (MK), and citrinin. Genomic information mining shows that Monascus spp. have great potential to produce multiple secondary metabolites , the fermented product of Monascus strains containing the active β-hydroxy acid form that exerts pharmacological effects, as well as an inactive lactone form, which makes the side effects of MK less than currently reported statin-like drugs , functional RMR (FRMR), and brewing RMR (BRMR)  the classification and identification of Monascus strains; (2) the methods to improve useful metabolites but inhibit citrinin; (3) the isolation and identification of new metabolites; (4) the exploration of the functional activity of metabolites; (5) the biosynthetic pathway and genetic regulation of secondary metabolites and developmental process; and (6) genomic information mining. These studies have brought new life to the RMR. However, many issues about RMR and the Monascus species still need to be further discussed, which are summarized as followed.Given large-scale utilization and economic importance of RMR, scholars make more efforts to study the Cylindrocarpon sp. LL-Cyan426 and Acremonium sp. LL-Cyan416, which was attributed to the interface of SSF providing various exceptional habitations, such as the gradient of pH, O2, and substrate concentrations as well as product concentrations for mycelia growth  has continued from ancient times to today in China (Chen et al., Monascus purpureus, Monascus ruber, and Monascus pilosus are widely used as the producers of various types of RMR (Patel, Monascus strains from RMR (Tieghem, Monascus have been recorded (Li and Guo, Monascus species come from a wide range of ecological environments, such as sand pine (Barnard and Cannon, Monascus strains for fermentation usually grow slowly and are easily contaminated. However, how do these Monascus strains survive in such a diverse natural environment? What is the ecological role of a Monascus strain in nature? There is no doubt that different environments should influence the genetic regulation and cell development even influence the secondary metabolites. So the exploration of these issues will help us to better understand and utilize Monascus resources.Generally, R Patel, . In factTieghem, , more thMonascus strains, and their biosynthetic pathways had been explained by several research groups (Fu et al., Currently, MonAzPs, MK, and citrinin are the most well-known secondary metabolites produced by It was proposed that the initial synthesis of citrinin shared the same precursor and biosynthetic steps with MonAzPs (Hajjaj et al., The biosynthesis of secondary metabolites are regulated by multiple levels. It is well-known that certain regulatory factors, such as global regulator MrLaeA (Liu et al., Monascus strains have played important regulatory roles in the production of MonAzPs and citrinin, and usually affected their growth, sexual, and asexual development (Yang et al., Secondary metabolism is always coupled with developmental processes (Chen et al., Monascus species at the genetic level. With the application of genome information mining and modern biotechnology, the genetic information of Monascus species will be continuously deciphered, which will help us make better use of Monascus resources.Although RMR has been used as a traditional fermented food for nearly 2,000 years, we still lack a deep understanding of JW and YH collected data and drafted part of the manuscript. YS drafted the manuscript and revised it. All authors commented on the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Trees are generally long-lived and are therefore exposed to numerous episodes of external stimuli and adverse environmental conditions. In certain trees e.g., oaks, taproots evolved to increase the tree’s ability to acquire water from deeper soil layers. Despite the significant role of taproots, little is known about the growth regulation through internal factors , regulating taproot formation and growth, or the effect of external factors, e.g., drought. The interaction of internal and external stimuli, involving complex signaling pathways, regulates taproot growth during tip formation and the regulation of cell division in the root apical meristem (RAM). Assuming that the RAM is the primary regulatory center responsible for taproot growth, factors affecting the RAM function provide fundamental information on the mechanisms affecting taproot development. Roots, functionally and structurally diverse, form an integrated system allowing for water and nutrient acquisition . Many asDespite the important functions of taproots in many woody plants, significant questions remain on how internal and external factors control the growth and development of taproots. Genes, hormones, and microRNAs regulate every stage of root development . HoweverOur present objective is to determine individual and composite factors that affect and regulate taproot development and growth, and the influence of environmental stimuli on these factors. Such knowledge could contribute to the development of seedlings cultivation strategies, which further enabling taproot restoration in container-grown trees, e.g., oaks, in which taproots are typically rendered non-functional by air pruning. For example, long-term taproot pruning reduces the access of planted oaks to water during drought periods , 2021. FCommonly, the classification of roots is based on the position of emergence, and the recognition that most of the functional traits of root systems as a whole are directly related to this location . PrimaryA comprehensive understanding of the root growth potential arises from the apical configuration of a primary root – a synonym of taproot root . The abiThere are three unanswered questions remaining in the regard to the taproot root meristems: (1) how does organization and cellular signaling enable a taproot to grow and penetrate deep soil layers, (2) what internal factors enable taproots to grow rapidly and penetrate deep soil layers, and (3) how does soil water limitation induce the vertical growth of taproots. Aside from the unanswered questions above, how much does the genetic control the cell division explain the continued maintenance of root growth and apical dominance of taproot meristems . CurrentInsufficient water availability and associated reduced water uptake by absorptive roots are the main factors contributing to global forest decline . Countervia signal transduction pathways, including complex, environmental-sensing networks. The signaling pathways regulate plant root elongation, radial growth, branching, and overall architecture , and concomitantly water and nutrient uptake , spruce (Picea abies), and pear (Pyrus), have reported a broader and more unique role for these proteins in auxin-controlled root development in trees  mutants that exhibit enhanced ethylene biosynthesis, relative to wild-type plants, which produce long primary roots (ETHYLENE RESISTANT 1 (etr1), ETHYLENE INSENSITIVE2 (ein2), and ETHYLENE INSENSITIVE3 (ein3) mutants also provided evidence that ethylene inhibits root growth , abscisic acid (ABA), and brassinosteroids (BR) are classes of hormones that can affect root development. Gibberellins act mainly on endodermal cells in root tissues, inducing an expansion of endodermal cells in the root elongation zone, which consequently limits the elongation rate of other root tissues . The effabi1 (abscisic acid insensitive1) exhibit an ABA insensitive phenotype, allowing plants exposed to a short-term water shortage an induction of primary root elongation  expression by AUXIN RESPONSE FACTOR (ARF), which negatively regulates WUSCHEL RELATED HOMEOBOX 5 (WOX5) transcripts – the driver of stem cell formation – leads to distal stem cell differentiation in RAM , along with other growth regulators, form networks controlling gene expressions at a developmental and tissue level, being key for the regulation of root development , also inifoliate . Particuifoliate . The mulifoliate . Little ifoliate . MicroRNifoliate . A compaifoliate .miR390–TAS3–AUXIN RESPONSE FACTOR 2/ARF3/ARF4 regulatory pathway, which is involved in auxin signaling, and miR393 represses auxin signaling mediated by its downstream F-box auxin receptor targets, namely, TRANSPORT INHIBITOR RESPONSE 1 (TIR1), as well as AUXIN SIGNALING F-BOX PROTEINS 2 (AFB2) and AFB3   . The modd ARF19) .The regulatory function of miRNAs may also affect drought resistance in roots enabling through the expression of drought-responsive genes. In this regard, some miRNAs, such as ABA responsive genes, auxin signaling genes, genes encoding osmolytes, and antioxidant defense-related genes, can promote an accumulation of target mRNAs associated with enhanced stress tolerance . NotablyThe interaction of external and internal factors influences the growth and physiology of the taproot. The tips of a taproot consist of meristematic cells in the RAM. Assuming that the RAM is the main regulatory center responsible for taproot growth and cessation, a better understanding of the factors regulating the function of the RAM in taproots will provide fundamental information on the mechanisms that influence the development of the taproot. It is therefore necessary to understand the interactions between internal factors in the regulation of taproot growth and development, and to determine how these factors are related to external factors, e.g., drought. This raises the question of whether water restriction regulates and/or induces root growth in plants not only to maintain but also to accelerate root growth into deeper soil layers in response to water stress, and what internal factors are responsible for taproot development under drought stress. However, it is difficult to determine which one of these factors has a dominant effect on root growth, because the paths of dependence between external and internal factors are closely related and dependent on each other.In the long term, understanding the regulatory role of genes, hormones, and microRNAs will help to improve the quality of nursery seedling production, including the development of effective management strategies that will allow the restoration of taproots in container cuttings. Unfortunately, the selection of specific strategies to improve the elongation of taproots in tree seedlings is challenging due to the variability of the reactions of roots to multiple internal and external influences. Under changing climate, manifested by high temperatures and reduced precipitation, the formation of a deep root system is crucial for the survival of seedlings, saplings and maturing tree.PK drafted the manuscript. MZ sought funding for it. All authors contributed to the article review and editing, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Nepal, in recent years, is witnessing an increasing problem of type 2 diabetes that has resulted significant premature deaths and disability. Prevention and management of non-communicable diseases (NCDs) including diabetes have been prioritized in the national policies and guidelines of the Nepal Government. However, research looking at the overview of the implementation of the existing policies and guidelines for diabetes prevention and control is scarce. Hence, this study reviewed diabetes related existing policies and its implementation process at the primary health care level in Nepal.This study involved two phases: Phase I: situation analyses through review of documents and Phase II: qualitative exploratory study. In phase I, four databases  were systematically searched using key search terms related to diabetes care and policies between January 2000 and June 2021. Also, relevant gray literature was reviewed to understand the trajectory of policy development and its translation with regards to diabetes prevention and management at primary health care level in Nepal. Following the phase I, we conducted in-depth interviews (IDI) and key informant interviews (KII) with health care providers, policy makers, and managers  at peripheral and central levels in Kavrepalanchowk and Nuwakot districts of Nepal. The in-depth interviews were audio recorded, transcribed, and coded. The triangulation of data from document review and interviews was done and presented in themes.Four key themes were identified through triangulating findings from the document review and interviews including (i) limited implementation of policies into practices; (ii) lack of coordination among the different levels of service providers; (iii) lack of trained human resources for health and inadequate quality services at the primary health care level, and (iv) inadequate access and utilization of diabetes care services at primary health care level. Specifically, this study identified some key pertinent challenges to the implementation of policies and programs including inadequate resources, limited engagement of stakeholders in service design and delivery, lack of trained health care providers, lack of financial resources to strengthen peripheral health services, fragmented health governance, and weak reporting and monitoring systems.This study revealed that the policies, plans, and strategies for prevention and management of NCDs in Nepal recognized the importance of diabetes prevention and control. However, a major gap remains with adequate and lack of clarity in terms of implementation of available policies, plans, strategies, and programs to address the problem of diabetes. We suggest the need for multisectoral approach  at central as well as peripheral levels to strengthen the policies implementation process, building capacity of health care providers, ensuring adequate financial and non-financial resources, and improving quality of services at primary health care levels. Diabetes mellitus is one of the most prevalent chronic conditions associated with increasing morbidity, mortality, and economic burden worldwide . In 2019South Asia, where a quarter of the world population resides, has a majority of all global diabetes cases . Nepal, Being cognizant of the impacts of NCDs including diabetes, the Government of Nepal (GoN), in recent years, has developed some policies, guidelines, and manuals to guide the prevention and management of NCDs including diabetes. The Government of Nepal annual report shows that different level of NCDs related services are being provided at local health facilities, such as services for hypertension and diabetes detection, counseling, referral, follow up services for NCDs patients including diabetes, drugs refilling, and health promotion related services . This inDespite the development of policies and strategies on NCDs including diabetes prevention and control in the country, the evidence on the implementation of these policies remained largely unexplored. Therefore, in this study, we systematically reviewed the existing literature that included both academic literature and policies specific to diabetes in Nepal and then conducted a qualitative study, to explore the implementation aspects of policies and strategies related to diabetes prevention and management in Nepal. The study aimed to answer two research questions: (i) What are the policies and guidelines being developed to prevent and control type 2 diabetes in Nepal (ii) what is the implementation status of the existing policies and guidelines for diabetes prevention and control in Nepal?This study adopted an approach of combining documents review and in-depth interviews (IDI) and key informant interviews (KII) to answer the research questions. This approach has been widely adopted in the previous studies to identify the factors in the inclusion and prioritization of NCDs in polices, guidelines, and actions plans –15. In pIn this phase, a systematic search was conducted in four key electronic databases including Medline, Web of Science, Embase, and PubMed to identify peer-reviewed journal articles and government documents . Also, gray literature was searched through google and webpage of the Ministry of Health and Population, Government of Nepal. The literature search was limited to the academic and gray literature published between 01 January 2000 and 31 June 2021. Most policies for NCDs prevention and control in Nepal have been formulated in recent decades . The NatWe considered search of literatures by using combinations of different keywords, namely “diabetes,” “people with diabetes,” “diabetes mellitus,” “sugar,” “guidelines,” “protocol,” “policy,” “guide,” standard practice,” “strategy,” “implementation,” “intervention,” “Nepal,” “health post,” “primary health care center,” “peripheral health system,” “facilitators,” “Barriers,” and “community health workers.”The inclusion criteria of this study is:(i) The primary or secondary studies  focused on diabetes prevention only, or management or prevention and management in Nepal; (ii) programs that cover health promotion, prevention, treatment, or rehabilitation activities for people with diabetes at the primary health care center or health post or community level (iii) Primary or secondary studies that focused on barriers and facilitators for management of diabetes in Nepal, and (iv) policies and plans documents focusing on NCDs in Nepal.The exclusion criteria is: (i) studies including Gestational Diabetes Mellitus or Diabetes Insipidus (ii) studies that solely focused on estimating prevalence of diabetes in Nepal, (iii) clinical interventions studies of diabetes prevention or management, and (iv) studies based on hospital settings.The data extraction and synthesis process as recommended and by Heller et al.  and otheThe results of document review guided the development of interview guide and inform the identification of the potential participants needed for the study to explore the implementation process of the existing policies and guidelines for diabetes management from the perspective of health care workers working with peripheral health system of Nepal.2 (539 sq mi). Kavrepalanchok with an area of 1,396 sq.ft. is situated at a mid-hilly area majorly, having the subtropical climate with an elevation range of 280–3,018 m, bordered to the east by Ramechhap and Dolakha, west by Kathmandu valley, north by Sindhupalchok, and south by Sindhuli and Makawanpur. According to CBS, 2068, the total number of households is 80,720 with a total population of 381,937 including the number of men 182,936 (47.90%) and women 199,001 (52.10%). The adult literacy percentage is 62.77% and per capita income is $1399  and KIIs (n = 7) were conducted in two districts namely Kavrepalanchowk (n = 13) and Nuwakot (n = 7). These two districts were chosen due to the convenience for the researchers to access, where the study team has been implementing diabetes management intervention using the Randomized Controlled Trial. The interviews included 13 IDIs with health care providers at community level and 7 KIIs with health policy makers and program managers at central and district levels. The general characteristics of the participants involved in in-depth and key informant interviews are presented in In this phase, IDIs (We adopted purposive sampling to recruit the participants. A semistructured interview guide was used to obtain the data. The focus areas included in the interview schedule were (i) access, availability, and utilization of services for prevention and management of diabetes; (ii) facilitators and barriers to the prevention and management of diabetes; (iii) potentials to developing culturally appropriate and context specific intervention approaches to prevention and management of diabetes. Telephone interviews were conducted due to the COVID-19 restrictions. All the interviews were conducted in the Nepali language by two members of the research team (RS and DM). All in depth interviews and key informant interviews were audio recorded and were transcribed verbatim. The transcripts were then translated into English by a research team member (RS) and checked for accuracy by another team member (UNY). Three interview transcripts were randomly selected and checked by additional team members (UNY and LR) to ensure reliability of the transcription.The transcripts were individually read and re-read several times in order to become familiar with the data and to record initial ideas then organized into a coding framework, informed by the interview topic guide. A thematic analysis using an inductive approach was used to identify the emerging patterns and themes within the data (2017) . Themes The reporting of this qualitative research adhered to the Standards for Reporting Qualitative Research (SRQR) . SeveralThis study is a part of an ongoing larger research project in Nepal, which uses a randomized controlled trial for diabetes self-management in Nepal. Ethics approval of the main study has been obtained from the Ethics Review Committees of Nepal Health Research Council, Nepal, Tokyo Women's Medical University and Central Queensland University Australia. Informed verbal consent was obtained from all participants prior to audio recordings of the interview.The systematic search of different databases yielded 4,048 studies. A total of 1,012 (not duplicated) publications were screened. The titles and abstracts were screened for 232 studies and after removing the publications/ reports that did not meet inclusion criteria, 45 studies met full-text review criteria. The full text records/documents were reviewed and further assessed for eligibility and finally, 11 records met the inclusion criteria and were included in this review. In addition, a total of 9 records were retrieved from the gray literature search and review of citations/reference lists. Altogether, 20 relevant studies and policy documents were included in the review see . We haveThe findings from the document review and IDIs and KIIs were triangulated. Four major themes emerged that were directly relevant to the implementation process of the existing policies and guidelines for diabetes management in the peripheral health system in Nepal. The key themes identified are: (i) limited implementation of policies into practice, (ii) lack of coordination among the different level of provider, (iii) lack of human resources for health and comprehensive quality services at the primary health care level, and (iv) boundaries for the people with diabetes to access diabetes care at primary health care and engagement to promote diabetes self-management.In recent years, Nepal has developed policies for NCDs prevention and control. However, to date, no specific policies exist for the diabetes prevention and control. Some of the policies related to NCDs include (i) National Health Policy 2019, (ii) Multisectoral Action Plan for the Prevention and Control of Non-communicable Diseases (2014–2020), (iii) Nepal Health Sector Strategy (NHSS) Implementation Plan 2016–21, (iv) WHO's Package of Essential NCDs (PEN) Intervention at PHC setting, (v) Nepal Tobacco Products Control and Regulatory Act, 2011 (Smoke free zones/Tobacco Advertising), (vi) Food (Fifth Amendment) Rules, 2064 (2007) 2064.6.14 (1 Oct. 2007)  Food Adulteration Act/), (viii) Alcohol Regulation and Control Policy, 2017, and (ix) The Public Health Service Act, 2018 see .The qualitative findings showed that most of the community health workers reported not using any protocol or guidelines in the management of diabetes. The understanding of package of essential NCDs (PEN) protocols was limited to few health care providers who received training on the PEN package in Nuwakot and Kavrepalanchowk districts. Most interviewed health care providers mentioned that they were unaware about any guidelines for diabetes management at the primary health care level, while few expressed that they had received basic training on PEN 2–3 years back in other districts. Some of the senior peripheral health care providers mentioned that there is a lack of guidelines for engaging community health workers for diabetes care in Nepal.We do not have such type of guidelines, protocols; however, we have heard from others or based on our own experiences, we have been providing some kind of diabetes relates services in particularly diabetes screening and distribution of basic medication” .One of the participants said, “Two to three people have training on PEN package but there is no translation of learnings from training. I would say it's crucial to strengthen primary health system while providing training to the community health workers.” .Few health care providers mentioned that training for management of non-communicable disease including diabetes should focus on skill development rather than educating them on disease prevention and control and improving healthy behavior. Some participants expressed that the selection criteria for sending people for any training is not as per the guidelines for training and capacity building, rather selection of participant done solely based on nepotism and favoritism. This reflected the lack of implementation of National Health Training Center protocols. One health care provider reported- “Two studies suggested the need to improve the coordination among the different levels of the stakeholders , 25 withEngaging Management committee, health management committee, political representatives, teachers, health worker, FCHVs, etc. from the inception to delivery of the program will create ownership and trust toward the program activities. But unfortunately, INGOs/NGOs just collaborate with some powerful political leader or government representative and implement the program.” “Though such programs are being carried out by many INGOs/NGOs, I think it should be carried out mobilizing employee by Nepal Government. If those programs can be conducted in collaboration with the Nepal government, INGOs, and NGOs it would be more fruitful and achievable.” “In community level we need to coordinate with FCHVs, our management committee which we have here, likewise health management committee, representatives, teachers, health workers etc. to make sustainable programs” “We have the PEN program, but nobody knows what we are doing. Focal person for NCDs does not have enough idea on NCDs. Honestly speaking, I think there isn't any monitoring done specifically for NCDs.” .Some health care providers from the Nuwakot district mentioned that there is a lack of monitoring and supervision of program related to NCDs. As such, one expressed- “Few participants also cited lack of sensitization of issues related to NCDs, along with lack of technical and economic resources as major problems to deal with growing problem of diabetes and other NCDs.All the included studies discussed the challenges that are prevalent with health care system in delivering diabetes care at primary health care level. Five out of eight studies mainly discussed the unavailability of the health resources and human resources at the primary health care system , 25–27. Moreover, WHO PEN program is the only nationwide robust program implemented in Nepal till date, however, it's implementation across the country is taking longer . AwareneSimilarly, the findings of our study also noted the inadequate human resources for health and supplies of glucometers and strips required for screening of the diabetes cases. Likewise, higher proportion of the study participants reported the diabetes medicine, metformin, are unavailable in most of the health centers. However, few reported a limited stock of metformin in PHC level.Metformin was supplied by province government since last year, but not now and I don't know the reason” .One health care provider said, “- “We used to do glucometer testing previously but now we are out of strips.” .Similarly, another health care provider expressed We envisioned the recruitment of human resources for health, such as doctor and health assistants but we cannot do anything because of lack of resources from federal and provincial government. District health office does not have budget to tackle NCDs specifically.” .Majority of the health care providers expressed dissatisfaction with supply chain management system. Participants cited lack of co-ordination between health care coordinator and logistic division representative of district, inability of officials to forecast demand of medicines, inadequate funding and an inefficient purchasing system as the major reasons for inefficient supply chain management system. Most of the senior level health care professionals mentioned the lack of trained doctor or health care providers to manage Diabetes and other NCDs. One senior health care provider mentioned that- “Three studies highlighted that people had low level of awareness on diabetes and its management , 10, 26.One said “NCDs are a major health problem globally. Lack of recognition of these problems by them , not realizing that it's a major problem and design programs accordingly.” Similarly, barriers to engage in diabetes self-management practices included modifying the dietary habits that are deep rooted to cultural practices, unavailability of space for physical activity, lack of motivation toward lifestyle management, poor adherence to lifelong medication for diabetes and lack of family support in changing the behavior .The major challenge is to change people's behavior. Most of the people are aware about the consequences and knowledgeable but they don't implement in their life. The main problem is the negligence or not prioritizing diabetes as a major health problem” .One participant expressed “Some participants perceived a lower trust in the medicines supplied by the government because they believed that free medicines will not be effective on disease management. Few participants also perceived poor health literacy as a major challenge for diabetes prevention and management at the primary health care (PHC) level. One said:Limited health literacy on diabetes among people is unaddressed issues. There is greater need of transforming the community through health literacy program. This could develop trust among people for government health facilities among those who do not feel so.” “This study identified several key policies, strategies, and plans that have been formulated by the Government of Nepal and have aimed at addressing the problem of NCDs including diabetes in Nepal. The Government of Nepal has launched multisectoral Action Plan for the prevention and control of NCDs and implemented PEN package in selected districts of Nepal, there is still a lack of programs that emphasize screening, diagnosis of diabetes, and providing comprehensive self-management and care.Given the increasing problem of NCDs including diabetes in Nepal, there has been a critical need for developing and implementing effective policies and strategies into affordable and feasible programs that can detect individuals at risk of developing diabetes, provide health services at the local level and can support people with diabetes in self-management of conditions. Examining available public health policies with regard to diabetes prevention and control is crucial, given the social and economic burden that diabetes creates for the individuals, communities and the health system as a whole. At present, Nepal has introduced a range of NCDs related policies, however they lack the specifics for diabetes prevention and control and the implementation of existing policies is weak.Impact of some policies such as graphic warnings on tobacco packaging and alcohol products, diabetes risk factors survey, ban of alcohol advertisement and promotion and sponsorship are laudable but the implementation of policies for the prevention and management of type 2 diabetes at primary health care level is not yet well-organized. The poor implementation of policies for preventing and managing diabetes at the primary health care level have been largely reflected in recently published studies from Nepal , 29. TheStudies have shown that delivery of diabetes care through strong PHC has resulted in lower health costs, better health outcomes, higher satisfaction of people with diabetes, fewer hospitalization rate, and greater socioeconomic equity –35. WhilLack of trained or poor retention of human resources for health is a pertinent issue in LMICs including Nepal, that needs to be addressed effectively in order to delivering diabetes prevention and care services in low-income settings , 39. ThePrevious studies have identified that importance of health literacy in improving behavioral, clinical, patient–provider communication, and other outcomes among people with diabetes , 43. It The findings of this study are useful for the policy makers in Nepal to map the gaps in formulation and implementation of NCDs related policies in Nepal, particularly diabetes prevention and control at the peripheral level. The findings are also helpful to strengthen the ongoing implementation of PEN package at the peripheral level. The lack of screening and awareness at the community level implies the greater need of people centered health literacy intervention  requiredThe primary health care has a significant role to play for the prevention and management of NCDs  includinAs like other studies, this study does have strengths and some limitation. The strengths include: (i) study triangulated the findings from both literature review and a qualitative study conducted with health care providers and policy makers, (ii) findings gathered add to the literature on policy translation research on diabetes, and (iii) the gaps identified in the current study might guide the decision makers to take appropriate steps for diabetes prevention and management at primary health care setting of Nepal. Our study had some key limitations. First, search of literature was done in selected databases which may not have captured all the evidence. Second, some studies may have been missed to be included because of language bias as we did not include articles or policies available in Nepali language. Thirdly, the findings from a qualitative study cannot be generalized to other study settings of Nepal as they each constitute a small number of respondents.Our findings suggests that despite the formulation of a range of policies and strategies for the prevention and control of NCDs including diabetes in Nepal, there has been a poor translation of these policies into practices. Integrating NCDs including diabetes related programs within the current health care systems and revitalizing primary health care systems along with effective implementation of such programs are essential to achieving SDG-3, health, and wellbeing and ensuring universal access to health services by 2030. There is also a need for developing and implementing effective, context specific, and cost-effective intervention required for prevention and control of NCDs including diabetes in Nepal. In order to improve and strengthen implementation aspect of policies and strategies to NCDs and diabetes prevention and control in Nepal, there is a need for engaging wider stakeholders such as government, health care professionals, local community leaders, political leaders, private sectors etc.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 Human research Ethics Committee of Nepal Health Research Council Nepal. The patients/participants provided their written informed consent to participate in this study.RS, UY, AbS, GP, and LR contributed conceptualizing the study, drafting the manuscript, and finalization. RS, AbS, DM, GP, BK, HI, UY, LR, and RK contributed to data collection, processing, analyses, and results' write up. UY, PP, YH, AbS, ArS, YH, BK, RK, TS, and LR thoroughly reviewed the manuscript and contributed substantially for necessary revision. RS, UY, AbS, GP, and LR final reviewed the manuscript and prepared for submission. All authors contributed to the article and approved the submitted version.RS, DM, and HI are regular project staff of the project funded by Japan Agency for Medical Research and Development (AMED). LR, TS, BK, AbS, ArS and RK are research investigators of the ongoing project funded by AMED Japan (Grant Number JP21jk0110020) under the Global Alliance for Chronic Disease (GACD) Call and funding mechanism.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cephalopod Research Across Scales - Molecules to Ecosystems.” Along with this Research Topic there are two other companion special issues in Bulletin of Marine Science .This Research Topic aims to draw a picture on recent advances in cephalopod research inspired by selected papers from the Cephalopod International Advisory Council Conference—CIAC 2018 held in Saint Petersburg, Florida, USA, during 12–16 November, 2018, but also includes papers on topics encompassing the theme of the conference, “Overall, this Research Topic consists of 12 contributions. Nine of the papers are primary research articles, one of them is a hypothesis theory driven paper and, there are two review articles. The overarching topics that are being addressed by the contributions in this Research Topic reflect several key issues that provide a comprehensive and integrative view on cephalopod physiology and related subthemes, including sexual selection, behavior, climate change, feeding and metabolism, and welfare.Ibáñez et al. tested this hypothesis by studying the evolution and diversification of several reproductive traits  across benthic octopuses (including 87 species), employing phylogenetic analytical methods. The results point out that male reproductive traits have evolved in a correlated way with body size and exhibited accelerated rates of evolution  presumably due to sexual selection. Morse and Huffard presented a riveted and comprehensive review summarizing the current knowledge of reproductive behavior within the Cephalopoda. The authors have combined existing information on pre- and post-copulatory behaviors to build novel insights, relating to cephalopod mate choice, sensory ecology, and the proliferation of polyandry among the class. They have concluded that sperm competition and possibly cryptic female choice are likely to be critical determinants of which individuals' alleles get transferred to subsequent generations in cephalopod mating systems. Gaps within the current knowledge of how sexual selection operates are also uncovered and highlighted, valuably indicating areas of interest for new research on the elaborated mating systems of cephalopods.Intra-sexual selection includes processes such as sperm competition and cryptic female choice, and one of the consequences of intra-sexual selection is that male reproductive traits tend to evolve and diverge at high rates. Marian et al. provide a rich review on male alternative reproductive tactics in loliginids. The authors argue that loliginid squid provide unique models to explore sexual selection as they have two distinct fertilization environments in the female body that differ in aspects such as fertilization timing and success and, are associated with male alternative reproductive tactics, namely “sneaker” and “consort.” Large consort males fight other males to gain access to females and deposit spermatophores within the female mantle cavity, while small sneaker males, engage in furtive mating and deposit spermatophores near the female buccal seminal receptacle. These results lead to the conclusion that several ejaculate traits  have unique features that may have evolved in response to the fertilization environment faced by each temporary or permanent male morph.Further exploring the sexual selection topic, but addressing the perspective of squids, Apostólico and Marian contribution deals with an unexplored sexual selection topic in cephalopods: the underlying mechanisms responsible for the expression of male alternative reproductive phenotypes. Based on observations made in captivity they described, first-time, males of the loliginid squid Dorytheuthis pleii of intermediate size and age displaying behaviors of both sneakers and consorts males simultaneously, leading to the hypothesis of them being a transitional stage between these both phenotypes. The result corroborates the ontogenetic hypothesis, indicating that small young males adopt sneaker tactics to mate instead of competing with large consort males for females, but as they grow, they modify the morphology of their ejaculates and mating behavior, going through an “intermediate” stage, before becoming large consort males.Vidal and Salvador documented the ontogeny of predatory behaviors in Doryteuthis opalescens looking closely at the specialized tentacular strike behavior of squids. Loliginid paralarvae do not capture prey as adults, they use progressive predatory behaviors in which the tentacles function as arms, because important morphological and structural features are not yet formed, namely, clubs, stalks, and muscle fibers. By examining the relationship between overall morphology and predatory behaviors, the authors were able to uncover the interconnected morphological and behavior traits that enabled squid to perform the tentacular strike behavior , leading to the conclusion that the expression of the tentacular strike involves different levels of development and thus represents a major developmental milestone.Evaluation of the ontogenetic underlying factors responsible for the expression of a particular behavior provide valuable insights into developmental constraints  the great adaptability of cuttlefish to highly dynamic coastal and estuarine zones, and (ii) the fact that the embryos already face harsh conditions (hypoxia and hypercapnia) inside their eggs during early development. Zakroff and Mooney report the results of their experimental study exposing Doryteuthis pealeii embryos and paralarvae to the combined effects of OA and warming. They found that when reared under severe, chronic acidification and warming these early stages show a range of responses from sensitive to resistant. For example, time to hatching, which increased with acidification, decreased drastically under warming and, further, removed delays caused by acidification driven by between clutch differences. Noticeably, their study strongly aligns with the theme of this Research Topic, showing how global processes (OA and warming) interact across biological  and temporal (across the breeding season) scales to affect squid development.Cephalopods are highly diverse and thrive in a wide range of marine habitats, from coastal waters to the deep-sea, reflecting their successful adaptations to distinct habitats and motivate the need to learn more about the interrelationships between their life-cycles and environmental conditions  of the gonad, hepatopancreas and muscle of Octopus maya relative to sex and season. Such findings may serve as reference values for several physiological indicators in O. maya, useful for programs monitoring wild populations, as well as to design diets and management protocols to produce octopus under controlled conditions. Regarding cephalopod growth patterns, it is known that young juvenile Sepia officinalis can grow up to 12% body weight per day, but how the metabolic costs associated with such substantial growth rate impacts muscle performance is unknown. Lamarre et al. integrated several aspects of contractility, protein synthesis, and energy metabolism in mantle of juvenile cuttlefish to provide a comprehensive insight into these biochemical processes.Abiotic conditions are known to affect processes of growth and sexual development, and biochemical composition of cephalopods. Maiole et al. tackle this topic by characterizing Octopus vulgaris mTOR functional domains through designing and testing an in vitro protocol of resistance exercise and inducing fatigue in arm samples. They found a high level of homology with vertebrates' mTOR and revealed the activation of the mTORC1 pathway in the exercise paradigm, which suggests that mTORC1 activity can be used as a marker to assess cephalopod response to changes in physiological and ecological conditions and, thus improve their maintenance and welfare.Considering that cephalopods high metabolism is fueled by a protein-based diet in a muscular body, muscle physiology studies  and cold seawater (11 and 13°C) on growth and mortality of Octopus maya juveniles. Based on the adopted criteria, metabolic (oxygen consumption) and behavioral (prey capture) responses to anesthesia were evaluated. Exposure to all concentrations tested of magnesium chloride, cold seawater (13°C), and clove oil reduced or inhibited the incidence of attacks to prey after recovery from anesthesia. Only clove oil proved to have a long-term effect on growth. Based on the results, the authors propose that anesthesia can be suppressed during short-term handling (<180 s), when no pain, distress, or suffering are involved. But when handling requires an anesthetized animal, the use of ethanol (3.0%) or cold sea water (11°C) were recommended to improve octopus welfare.Cephalopod welfare has become a timely topic that attracts great interest recently  in marine food webs, with the ultimate goal to provide a comprehensive and integrative review paper on the topic.The workshop “Hard structures of cephalopods and their application in your field of study” was led by Alexander Arkhipkin, Catalina Perales-Raya, and Fedor Lishchenko, with the main goal to have the most recent update on use of recording structures in studies of cephalopod taxonomy, age, growth, and population structure. The workshop was attended by 23 participants (scientists as well as students) from eight countries around the Globe. Theoretical sessions included general introduction on the recording structures of cephalopods, specific methodologies dedicated to processing of statoliths, cephalopod beaks, and gladii, as well as their shape analysis. Additionally, Kathleen Ritterbush gave a talk on the shell hydrodynamics of ammonoid cephalopods. Practical sessions took place with participants having first-hand experience in extraction of recording structures  from cephalopod bodies, their sectioning and examination. At the final part of the workshop a broad discussion on the key knowledge gaps and promising fields for future studies took place. The most important subjects for future studies included (a) Terminology-related issues; (b) Physiology of increment deposition; (c) Problems with aging accuracy and precision; (d) Validation methods and associated problems; (e) The best aging methods for each group of species; (f) Species in which hard structures provide reliable tools for age estimation and, (g) Species for future research.The workshop “Genetic Tools and Live Imaging in Cephalopods” led by Eric Edsinger had a hands on approach with computer software interaction to cover several practical issues on implementing genetic and live imaging tools for cephalopods, namely: (1) Identifying genes of interest in annotated genomes, (2) Designing transgenic reporters, biosensors, and CRISPR-Cas9 guide RNAs, (3) Injection of mRNA/constructs/CRISPR-Cas9, (4) Live imaging approaches for light-based genetic tools and, (5) Applications of genomic resources and genetic tools to cephalopod biology, emerging genetic models, among others future prospects. During the workshop, embryos, and hatchlings were produced and used for expressing injected mRNAs, transgenic constructs, or genome edited genes, allowing a practical, interactive and also first-hand experience among the participants.The workshop: “Cephalopod Science: the direction of future research and the relevance of new policies” led by Giovanna Ponte, Ian Gleadall, and Graziano Fiorito provide the ground for a brainstorming session to identify likely avenues for novel ground-breaking cephalopod research areas and their potential effects on and benefits to human society. A discussion on the changes in policy for experimentation and fisheries of cephalopods occurring in different regions of the world and the potential effects of these changes on cephalopod research in both global and local contexts were also addressed, with the aim to prepare a white paper to summarize and report on these topics.The workshop “All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Cardiovascular disease is the leading cause of human death worldwide. Drug thrombolysis, percutaneous coronary intervention, coronary artery bypass grafting and other methods are used to restore blood perfusion for coronary artery stenosis and blockage. The treatments listed prolong lifespan, however, rate of mortality ultimately remains the same. This is due to the irreversible damage sustained by myocardium, in which millions of heart cells are lost during myocardial infarction. The lack of pragmatic methods of myocardial restoration remains the greatest challenge for effective treatment. Exosomes are small extracellular vesicles (EVs) actively secreted by all cell types that act as effective transmitters of biological signals which contribute to both reparative and pathological processes within the heart. Exosomes have become the focus of many researchers as a novel drug delivery system due to the advantages of low toxicity, little immunogenicity and good permeability. In this review, we discuss the progress and challenges of EVs in myocardial repair, and review the recent development of extracellular vesicle-loading systems based on their unique nanostructures and physiological functions, as well as the application of engineering modifications in the diagnosis and treatment of myocardial repair. About 16.5 million people die of cardiovascular disease every year and is still the leading cause of death according to the Global Burden of Disease (GBD) study . The damExtracellular vesicles (EVs) are a group of membranous vesicles released by all cell types. These vesicles can range in diameter from 30 to 1,000 nm , 5. ExosEVs play an important role in intercellular communication, providing a new acellular therapy –19. Althin vivo distribution of EVs may also play a role in cardiac protection  involves injury of endothelial cell function and structure in a number of ways, including mass release of reactive oxygen species (ROS), direct injury of white blood cells, calcium overload, and reduced secretion of NO. EVs derived from cardiomyocytes were initially discovered under hypoxia and re-oxygenation conditions –8. CardiImmune cells play an important regulatory role in the development of myocardial ischemia, I/R injury, septic cardiomyopathy and chemotherapy-related cardiomyopathy –34. EVs In the process of myocardial injury, macrophages are recruited to the damaged area to initiate release EVs into the peripheral tissue. Macrophage-derived EVs aggravate myocardial injury, inflammation, and promote myocardial fibrosis. Studies demonstrate that in the process of myocardial ischemia, macrophage derived exosomes deliver miR-155 to cardiac fibroblasts, which inhibit proliferation and promoted inflammation, suggesting that macrophage derived EVs containing miR-155 aggravate myocardial injury . MacrophAntigen presenting T cells have the ability to release specific EVs. Treg cells can improve the healing and remodeling after myocardial infarction , 39 and Different types of stem cell (SC) derived EVs can convey different biological information. EVs with cardioprotective function may come from marrow mesenchymal stem cell (MSC), embryonic stem cells, and hematopoietic stem cells. Various strategies have been tried for the treatment of cardiovascular disease with SC transplantation therapy. Studies have found that the paracrine factors of transplanted cells, not the transplanted cells themselves, play a major role in repairing damaged tissue.2O2-induced oxidative stress by inhibiting caspase 3/7 activation, and alleviated IR injury in mouse myocardium by delivering cardiac protective miRs such as miR-21 and miR-210  in cultured CPCs increase the number of EVs released while maintaining basal cell gene expression and cell morphology as opposed to hypoxic conditions  can specifically target the myocardial cells of MIRI . Xu Wang+ and lectin immune-active cells in myocardial infarction rats and promoted angiogenic activity in the infarct area.In addition to peptides, binding targeted proteins such as nanosomic and signal regulatory protein α to exosome surfaces has also become an effective targeting strategy . For carAlthough exosomes have shown promising in the field of drug delivery, it is not easy to achieve specific targeting of exosomes through surface modification, and the reaction conditions need to be strictly controlled to avoid the destruction and aggregation of exosomes caused by improper temperature, pressure and osmotic pressure. At present, the efficiency of exosome targeted drug delivery is not ideal as modifications result in clearing by the immune system.EVs have favorable biocompatibility, non-immunogenicity and non-tumorigenesis. They are physiologically more stable than graphted cells, circulate throughout the body, and can cross the blood-brain barrier, and are more resistant to freezing and thawing than cells, have the advantage of long-term storage , and havThe most common EVs separation technique is differential centrifugation, however, EVs obtained by this technique often contain aggregates of cell culture medium, cell proteins and particles . In addiThe lack of appropriate preservation methods is another major problem that limits the clinical use of EVs. Generally, EVs are stored at −80°C, become unstable under long term storage . Studiesin vivo dynamics of EVs have not been studied in detail. EVs have irreplaceable advantages in the treatment of cardiovascular diseases, including those diseases that lack effective drug therapy  20–100 nm, large vesicles (LUV) 100–1,000 nm and large vesicle (GUV) 1–200 μm . Enginee−/− mice. Gene modification in exosome donor cells can greatly improve the stability of functional exosomes, but it is expensive and time-consuming to perform gene manipulation in donor cells.The exosomal donor cells are genetically modified to express the targeted peptide, effectively expressing the targeted peptide on secreted exosomes . Kim et At present, there are two chemical modification methods for artificial vesicles: wet chemistry method and microfluidic technology . The wetCurrently, the reassembly of phospholipid membranes with different functions has become a new direction of engineered EVs, which makes it possible for EVs to have specificity, enabling repair and anti-inflammatory functions at the same time. However, there are few related studies, and they are mainly used in cardiac ischemia and ischemia reperfusion injury in cardiovascular diseases.in vivo remains a problem. As early as 2002, Lestini et al.  have shown potential to attenuate ischemic injury and restore cardiac function in preclinical myocardial infarction models. At present, cell transplantation poses a variety of risks to the recipient. However, the collection and administration of EV's from patient autologous cells could become an effective personalized treatment method.The conventional diagnostic methods of heart failure include echocardiography, MRI imaging and identification of myocardial necrosis markers. Exosomes show great diagnostic potential as biomarkers of AMI, and we focus on the diagnostic value of miRNAs and proteins carried by exosomes , 125.miRNAs found in serum and plasma are characterized by stability, time, and tissue specificity. Exosomes, as effective carriers of miRNAs, may provide a new possibility for the diagnosis of AMI. Beg et al. studied the plasma exosome miRNA in patients with heart failure and normal controls with average LVEF of (22.2 ± 7.2) %, and found that the ratio of miR-146a/miR-16 in peripheral blood of patients with heart failure was significantly higher . StudiesEVs contain a variety of proteins, nucleic acids, and lipids, as carriers of intercellular material and information, they can play an important role in influencing the course of disease by regulating interactions between heterogeneous cell microenvironments. EV cargo is effected by disease states, which give circulating EVs the potential as a diagnostic biomarker, which earlier and more accurately reflect the clinical progress of certain diseases, treatment response and prognosis judgement. The study of EVs provides an option for acellular therapy for regeneration and improvement of cardiac function. A large number of experiments have shown that EVs have great therapeutic potential in the treatment of myocardial injury and are also ideal drug delivery tools.in vivo safety remain to be confirmed. In vivo pharmacokinetic properties, mode of administration, safety, and industrialization must be fully evaluated before clinical transformation can be achieved. The current studies on exosomes as biomarkers in cardiovascular diseases are mostly based on small samples of patients. Moreover, the therapeutic effect of exosomes has only been confirmed in animal experiments and multiple heart-related cells, and no systematic human experiments have been conducted. Despite the above challenges, with the continuous development of cell drug delivery systems, clinical transformation of nano-biomimetic drug delivery systems, the field demonstrates a promising future.Although many advances have been made in basic research on extracellular vesicle myocardial repair, many challenges remain and some key questions need to be answered in depth before clinical transformation can occur. For example, which cell-derived EVs are most effective at repairing the heart muscle; What are the exact mechanisms of selection and packaging of extracellular vesicle contents; How to regulate the process of extracellular vesicle production; How to efficiently prepare and purify exosomes. How to maximize the retention of EVs in the body so that they can function properly. In addition, allogeneic cells are often used in current studies because of the convenience of obtaining them, but their immunogenicity, individual rejection and CL and NB were responsible for writing the main body of the article. TD and HC retrieved the literature. JT and XL modified the format. DH and YD made charts. PY, JL, ZF, and LW provided ideas and guidance for the writing of the article. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China , Macao Youth Scholars Program (AM2021023), Scientific research projects of Guangdong Bureau of traditional Chinese Medicine (No. 20200513093851), Guangdong Basic and Applied Basic Research Foundation (2021A1515012573 and 2019A1515111108), Science and Technology Foundation of Guangzhou City (202102010257), State Key Laboratory of Dampness Syndrome of Chinese Medicine Research Foundation (SZ2021ZZ21), the TCM Research Fund of Guangdong Provincial Hospital of Chinese Medicine (YN2019MJ15), and the Fund of Science and Technology Innovation Strategy of Guangdong Province (191900105).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.