Samoa and American Samoa are two island groups in the South Pacific inundated with the physiological consequences of swift westernization of diet and lifestyle. These polities face the singular theme of lifestyle-related problems seen in other countries. This paper aims to discuss the current demographics in Samoa and American Samoa and examine the origin and impact of lifestyle-related chronic diseases within a subset of its populace. This review will highlight the prominent nutrition transition that these polities have undergone in their development and examine the pathogenesis and pathophysiology of lifestyle-related diseases, primarily type 2 diabetes and obesity, in the context of a prominent cultural shift. Samoa and American Samoa face a litany of public health concerns as a result of the rising prevalence of lifestyle-related chronic diseases and the persistent threat of obesity. Lifestyle medicine is proposed as the optimal treatment solution for the currently devastating disease states and is adapted to the vibrant agricultural resources and healing roots of the Samoan culture. The prevalence and rising incidence of lifestyle-driven chronic diseases plague the globe, topping the charts as the leading cause of death and a primary source of the global burden of healthcare costs . The incData used for this review included searches conducted in academic scientific databases, including PubMed, ScienceDirect, Google Scholar, Scopus, EBSCOHost, and data from the Samoa Bureau of Statistics and the American Samoa Department of Commerce. The following search terms were used: “American Samoa,” “chronic diseases,” “climates,” “demographics; social, economic, and health,” “diabetes,” “GDP,” “lifestyle,” “nutrition transition,” and “Samoa.” Additional articles were selected from the reference sections of articles that were reviewed. To procure sources regarding the science and pathophysiology of lifestyle-related chronic diseases, the reference section of the book “How Not to Diet” by Michael Greger M.D. FACLM was utilized. Lastly, to establish evidence-based recommendations, the American College of Lifestyle Medicine and the Samoa Ministry of Health were sourced. Figure Geography, economy, and agricultureAmerican Samoa and Samoa constitute a group of islands located south of the equator in the Pacific Ocean. American Samoa, lying just east of the international date line, includes seven islands with a total area of 77 square miles and a recently reported population of 55,519 (mostly residing on the island of Tutuila) . Samoa lIn American Samoa, the two primary employment sources are the government sector and the tuna canning industry, yielding an estimated annual per-capita income of $14,000 . The priThe archipelago experiences tropical weather year-round, with the hot, rainy season extending from December to April and the cool, dry season lasting from May to November . Samoa aWith access to rich agriculture, the traditional Samoan diet was largely plant-based. Coconut products, starchy vegetables, leafy greens, fresh fruit, and saltwater fish were staples of the traditional Samoan diet, with chicken and pork present in lesser proportion and reserved for celebrations . Other vNutrition transition and physical activityAs low- and middle-income countries develop economically, a characteristic nutrition transition accompanies this growth. This transition is marked by the sharp increase in “consumption of vegetable oils, animal fats, and added sugars ... while the consumption of starchy staples declines” . ImporteIn the last several decades, these polities have transitioned towards the replacement of subsistence agriculture with paid employment and have experienced an associated influx of imported foods . ProcessChronic disease ratesIn American Samoa and Samoa, the leading causes of mortality and morbidity are heart disease, diabetes, cancer, and stroke ,28. In SIt is no secret that these chronic diseases are largely preventable, yet the science behind targeting exact lifestyle behaviors, in reference to the physiological origin of chronic diseases, has previously been convoluted and neglected. As understanding of the human body’s reaction to diet, physical activity, and environmental exposure has progressed, the connection has become irrefutable. The consumption of animal products , refined carbohydrates, increased added sugar and salt, and the lack of fiber from decreased fruit and vegetable intake lead to an inflammatory diet that is responsible for creating and accelerating the pathogenesis of chronic diseases, especially diabetes and obesity ,32.Nutrition and the pathophysiology of type 2 diabetes and obesityInsulin and Leptin InsensitivityThe pathogenesis of type 2 diabetes is multifactorial. Increased consumption of processed sugars can lead to insulin resistance and dysfunction. Foods such as white rice, soda, candy, bread, and pastries are quickly digestible and easily accessible forms of carbohydrates, causing sharp spikes in blood glucose which demand insulin . In the Obesity is an inflammatory condition . Just asObesogensAnother culprit for the rise of obesity rates in these islands may be the increased exposure to obesogenic pollutants from canning and packaging processes, antifouling paint, and cooking meats. Globalization has fostered increased import of, and contact with, obesogens in the islands . BisphenInfluence of the MicrobiomePrevotella species (fiber-feeders) to Bacteroides species  [The microbiome of individuals has also been found to contribute to the development of obesity. The trillions of bacteria that make up the gut microbiome are largely influenced by diet and play an active role in digestion and metabolism . When diroducts) ,73. Whenroducts) .The rise in obesity and diabetes has had a far-reaching impact on the development of nearly all leading causes of chronic diseases and mortality in Samoa and American Samoa, including cancer and cardiovascular diseases . To imprRecommendations: Lifestyle medicineLifestyle diseases are difficult to address because of the subtle normalization of toxic lifestyle behaviors over time. These behaviors become so deeply rooted in a society, that in the attempt at prescribing lifestyle modifications as a treatment for the disease, health professionals may be asking individuals to address their culture, customs, and habits ,75. HowePlans put in motion by the government, private institutions, and global organizations, including the Samoa Ministry of Health Sector Plan from 2008-2018, the WHO’s Package of Essential NCD interventions adapted to Samoa (PEN Fa’a Samoa), and the Samoa-WHO Country Cooperation Strategy 2018-2022, have unified goals in reducing NCD burden, increasing accessible education on chronic diseases, and encouraging sustainable community accountability for health and well-being -82. WithSamoa and American Samoa suffer from profound obesity and chronic NCDs. With morbidity and mortality from chronic diseases on the rise, it is critical that lifestyle factors be addressed. The roles of insulin and leptin insensitivity, obesogens, and the microbiome analyzed in this review are only a few of the many physiological connections between lifestyle decisions and the state of public health. From this analysis, it is suggested that prescribing lifestyle modifications to address the health emergency in these islands is the optimal treatment approach. Individual action by physicians and collective efforts by public health officials is necessary to educate themselves and the public on the impact of their diet decisions and the accessible solution of a whole-food, plant-based diet to prevent and reverse chronic diseases. These lifestyle modifications encourage wellness and foster a return to the vibrant and health-promoting roots of Samoan society.


Wound healing is a dynamic and highly regulated process that can be separated into three overlapping and interdependent phases: inflammation, proliferation, and remodelling. This review focuses on the inflammation stage, as it is the key stage of wound healing and plays a vital role in the local immune response and determines the progression of wound healing. Inflammatory cells, the main effector cells of the inflammatory response, have been widely studied, but little attention has been paid to the immunomodulatory effects of wound healing in non-inflammatory cells and the extracellular matrix. In this review, we attempt to deepen our understanding of the wound-healing microenvironment in the inflammatory stage by focusing on the interactions between cells and the extracellular matrix, as well as their role in regulating the immune response during the inflammatory stage. We hope our findings will provide new ideas for promoting tissue regeneration through immune regulation. Wound healing involves the cooperation between several different cell types and the involvement of various growth factors, cytokines, and the extracellular matrix (ECM), which together contribute to three overlapping phases: inflammation, proliferation, and remodelling . InflammCrosstalk activation between the platelet cascade reaction and the complement system initiates the wound repair process. As the first circulating cells are recruited to the inflammatory microenvironment, neutrophils play a role in the resistance to bacterial invasion . SubsequIn this review, we provide an up-to-date and detailed overview of the contribution of inflammatory cells, non-inflammatory cells, and the ECM to the wound microenvironment. We will focus on the non-inflammatory cells and the ECM in our review, which are two topics that have not received as much attention from a clinical perspective. Finally, we discuss how cell-cell and cell-ECM interactions regulate immune response in the wound microenvironment.The inflammatory cascade is activated after haemostasis and coagulation. Neutrophils, macrophages, and lymphocytes respond to injury signals and are recruited from circulation to the wound microenvironment in a specific spatiotemporal order . AdditioNeutrophils are the first circulating immune cells that are recruited to the wound microenvironment. They can remove bacteria and necrotic tissue by releasing protease-containing particles or by degrading microorganisms in phagocytic cups. In addition, the inflammatory cascade depends on the hydrogen peroxide gradient formed by the neutrophil-releasing enzyme complex nicotinamide adenine dinucleotide phosphate oxidase (NADPH) and reactive oxygen species (ROS) . ROS parNeutrophils undergo apoptosis or necrosis after the removal of bacteria and necrotic tissue and are engulfed by macrophages through efferocytosis. A subset of neutrophils leave the injured site and return to the circulatory system by neutrophil reverse migration . HoweverAfter neutrophils are established, circulating monocytes quickly enter the tissue in response to injury signals and transform into macrophages after exposure to the local inflammatory microenvironment , 8. At tde novo mediators into the inflammatory microenvironment, such as histamine, serotonin, and secretory granules   –30. Amontrypsin) . The comtrypsin) . Inflammtrypsin) . Studiestrypsin) . In sometrypsin) . McS-01,trypsin) . Howevertrypsin) , 37. Scatrypsin) . Notablytrypsin) .Different subsets of DCs in the skin are recruited after tissue injury, including epidermal Langerhans cells (LCs), dermal DCs, and plasmacytoid DCs (pDCs). LCs are anchored to adjacent keratinocytes by the adhesion molecule E-cadherin . LCs maiThere are many different types of T lymphocytes in the epidermis and dermis. Dendritic epidermal T cells (DETCs) are the main type of T cells in the epidermis and form a cross-network with LCs by extending dendrites to the basal layer . DETCs avia integrins β1, β2, and β3 on the cell surface. TLR4 and CD40L mediate the formation of NETs and the production of ROS  in the wound microenvironment are mainly involved in neovascularisation, granulation tissue, and re-epithelialisation during proliferation and reconstruction . Thus faTLRs are transmembrane proteins that consist of leucine-rich repeats. Thirteen members of the TLR family have been identified and 10 of these are expressed in humans . As pattIn intact skin, keratinocytes are closely connected to adjacent epithelial cells through desmosomes and to the extra cellular matrix of the underlying basement membrane through semi-desmosomes . After eFibroblasts, as dermal interstitial cells, repair wounds, mainly through cell proliferation and collagen deposition after tissue injury. The transcriptional analysis of fibroblasts has shown that many immune gene loci have transcriptional potential . Under t® has been approved as an allograft in several countries for the treatment of acute wounds  to form adherent plaque (FAs) to drive cell migration  also regulate immune responses. Winter et al. proposed the concept of treating wounds with a moist microenvironment in 1962 . This isAfter tissue injury, the platelet cascade reaction activates hemostasis and the complement system, which eventually leads to wound healing in the inflammatory phase. When circulating immune cells migrate to the inflammatory microenvironment, they must first adhere to vascular endothelial cells and bind to selectins, integrins, or adhesion molecules , 99. ThiThe ECM constitutes a place for tissue repair following trauma, and its macromolecules and their derivatives can regulate the activation and migration of inflammatory cells as well as the proliferation and differentiation of repair cells. The ECM component HS participates in immune cell migration and regulates the secretion of cytokines, chemokines, and growth factors . HA is iActive wound healing depends on an orderly and moderate immune response regulated by inflammatory cells, non-inflammatory cells, and the ECM. Disruption of any of these links can lead to persistent inflammation and prevent the repair process, leading to the occurrence of chronic wounds such as chronic venous ulcers, diabetic foot ulcers, and pressure sores. These chronic wounds occur in the context of venous hypertension, diabetes, or angiopathy caused by prolonged tissue pressure . The desin vivo . For example, before circulating macrophages arrive, some tissue resident macrophages are already involved in the inflammatory response . Althougin vivo .Correct and coordinated actions in the inflammatory microenvironment ensure proper wound healing. However, when this process is disrupted, skin healing is delayed, which eventually leads to chronic wounds. Compared with acute wounds, marrow-like cells (neutrophils and macrophages) in chronic wounds exist in large numbers for a long time, accompanied by the degranulation of mast cells and high expression of inflammatory T cell subtypes . The sigUnderstanding the inflammatory microenvironment of skin wounds will help to develop a comprehensive understanding of the processes affecting wound healing. This information can provide personalised guidance for the strict control of wound immune response. In particular, research on the immune function of non-inflammatory cells and the ECM in wounds may reveal new strategies for the clinical development of innovative wound treatments.Several studies have shown that the inflammatory microenvironment is composed of inflammatory cells, non-inflammatory cells, and the ECM, which collaborate to scavenge necrotic cell fragments and prevent infection. The activation of repair-related cells promotes wound healing through the secretion of cytokines that lead to the proliferation stage. However, there is a need for further evidence to support the interactions between non-inflammatory cells and the ECM, which are involved in the immune regulation of the inflammatory microenvironment. Additionally, the functional advantages of all the inflammatory factors that control the inflammatory response needs to be elucidated. As the evidence that the reduction of inflammation can promote wound healing comes from the study of inflammatory cells, it is not clear whether the regulation of non-inflammatory cells and ECM can achieve the same or perhaps even a better immunomodulatory effect.Literature search and manuscript drafting, ZW and GX. Figures, ZW and HL. Manuscript editing and revision, GX, FQ, and DW. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China [grant numbers 81871570 and 82072195], the Science and Technology Plan Project of Guizhou Province [grant numbers (2020)4Y148], the PhD Fund of Scientific Research Foundation of Affiliated Hospital of Zunyi Medical University[grant numbers (2020-03)], and the Chinese Ministry of Education [grant numbers 2020-39].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.


Mycobacterium tuberculosis (TB) and Streptococcus pneumoniae (pneumococcus).Platelets, best known as essential effector cells in coagulation and hemostasis, are increasingly recognized as major inflammatory cells that play a role in the innate and adaptive arms of the immune system. The interaction of platelets with various cell types of the innate immune system, particularly neutrophils, as well as with structural cells of the vascular endothelium, induces the release of platelet-derived mediators, thus exerting a protective effect in the physiologic response to diseases and control of invading microorganisms . HoweverFeldman and Anderson is a review article, concentrating primarily on the role of platelets in the host defense against infection, particularly pneumococcal infection, and describes the current evidence in the literature for how platelet activation may contribute to cardiovascular complications in patients with community-acquired pneumonia. This includes a review of work from the authors’ own laboratory, which uniquely showed that the pneumococcal toxin, pneumolysin, considered by many to be the most important virulence factor of the pneumococcus bacterium, activated platelets, activated formation of neutrophil extracellular traps, and mediated heterotypic aggregation of neutrophils and platelets in vitro. It is thought that the cytolytic action of pneumolysin itself, together with its activation of platelets, plays a major role in the occurrence of cardiac complications in pneumococcal pneumonia.The article entitled “Platelets and their role in the pathogenesis of cardiovascular events in patients with community-acquired pneumonia” by Kirwan et al. is a review article that describes the emerging evidence that platelets play a significant role in TB immunopathology. Patients with TB disease often have thrombocytosis, which correlates with disease severity  and is associated with a hypercoagulable profile. It is thought that platelets drive the pathology of TB through their effects on other immune cells, especially monocytes, leading to upregulation of activation, increased matrix metalloproteinase secretion, and enhanced phagocytosis. Patients with TB exhibit changes in platelet structure and function. Similar to what was described for pneumococcal infections, activated platelets interact with leukocytes, which facilitates the recruitment of these cells to the site of infection, and is associated with the formation of platelet-monocyte and platelet-neutrophil aggregates and the release of neutrophil extracellular traps, the latter being associated with severe TB-associated lung damage and long-term sequelae.The article entitled “Platelet activation and the immune response to tuberculosis” by Interestingly, both these manuscripts discuss the emerging concept, although still largely unexplored, of the use of platelet-targeted interventions in both conditions. For community-acquired pneumonia, these include pharmacological strategies that directly target platelet activation and their mediators of thrombosis and inflammation, as well as additional indirect adjunctive therapies, such as macrolide antibiotic therapy, that largely target pneumolysin-induced platelet activation. For TB, these have been repurposed anti-platelet and anti-inflammatory non-steroidal anti-inflammatory drugs. The authors of both these manuscripts are to be commended for their cutting-edge contributions to this Research Topic of the Journal.in vitro via interference with phosphatidylinositol 3-kinase” by Tintinger et al. shows the results of in-vitro experiments that examined the impact of bedaquiline, an anti-TB agent used for the treatment of multidrug-resistant TB, on human platelets. The authors demonstrated dose-related reduction of calcium mobilization, CD62P expression and aggregation of ADP-activated platelets, seemingly via inhibition of phosphatidylinositol 3-kinase-mediated phosphorylation of the serine/ threonine kinase, Akt1, an important facilitator of alpha granule release from platelets. They speculate that this anti-platelet effect could be secondary to the cationic amphiphilic properties of this agent and could play a role in ameliorating the risk of TB-associated cardiovascular disease. Further investigation of this finding in the clinical setting is clearly needed.Further to exploring the role of platelets in the pathophysiology of TB disease, the article entitled “Bedaquiline suppresses ADP-mediated activation of human platelets Steel et al. entitled “Differential responsiveness of the platelet biomarkers, systemic CD40 ligand, CD62P, and platelet-derived growth factor-BB, to virally-suppressive antiretroviral therapy” compares three circulating biomarkers of platelet activation between treatment-naive and virally suppressed participants. The authors found that sCD40L and sCD62P were significantly elevated in the treatment-naive group and identified sCD40L, in particular, as a potential biomarker of successful HIV treatment. If confirmed in the clinical setting, this biomarker could augment current monitoring strategies.The third pathogen of interest, HIV, is discussed in two reviews and one research article. The latter authored by Madzime et al. reviewed the “Interactions of HIV and antiretroviral therapy with neutrophils and platelets”. The authors describe the role of platelets in harboring and disseminating HIV, as well as the contribution of persistent platelet activation and dysfunction in the development of systemic immune activation and an inflamed vasculature, both of which could increase the risk for cardiovascular disease. They highlight the fact that certain antiretroviral medications, most notably abacavir, as well as ritonavir-boosted lopinavir and darunavir, have all been linked to an increased risk of CVD.E Pretorius is a review entitled “Platelets in HIV: A guardian of host defense or transient reservoir of the virus?”. Apart from detailing the inhibitory action of platelets with regards to HIV, this review delves deeper into the findings of recent studies that demonstrated that the virus can temporarily hide from the immune system inside platelets. Such platelet reservoirs may be of particular significance during treatment interruption. Finally, the risk of platelet hypercoagulation secondary to platelet complex formation with immune cells and erythrocytes, is highlighted, a theme that has been recurrent throughout this Research Topic.The final article in this Research Topic by TR and CF contributed equally to this editorial. CF wrote the summary of the articles covering pneumococcus and tuberculosis and TR wrote the section about HIV and made the figure. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Toxoplasma gondii, are realized much more slowly. The protozoan parasite Plasmodium falciparum can cause acute fatal cerebral complications without extravasating into brain tissue.Many infectious agents are capable of disrupting the normal functioning of the central nervous system (CNS) by invading the brain parenchyma. Some of these pathogens, for example encephalitic viruses and meningitis bacteria, cause acute perturbations, whilst the effects of others, such as prions and During the last few years, evidence has gradually accumulated suggesting that certain pathogens may interfere with the normal functioning of the brain, over extended periods, without entering the CNS. Likely mechanisms include releasing soluble factors that can cross the blood-brain barrier, or inducing their production by the host immune system, or both. It has been hypothesized that these sorts of mechanisms may contribute to the neurodegeneration that is central to dementias, including Alzheimer's disease.Frontiers in Cellular Neuroscience—Cellular Neuropathology brings together several review and original research articles that explore these topics. The authors have evaluated from different standpoints the etiology of neuroinflammation, whether acute or chronic, and have critically examined the evidence concerning the mechanisms through which CNS or peripheral infection may relate to the development of dementia in some cases.This Special Issue of Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae, bacterial meningitis in general is an acute condition with a high fatality rate. However, it also can cause long-lasting neurological sequelae in survivors. Two mini-review articles address the link between bacterial meningitis and neurodegenerative disorders from different perspectives, each providing original insights on the mechanisms through which blood-borne bacteria may cause neurodegeneration. Neuroinflammation is identified as an important common mechanism. Potential therapeutic approaches and future research directions are also suggested.Bacterial meningitis is an inflammation of the meninges, the membranous coverings of the CNS. Mostly caused by blood-borne bacteria, such as Farmen et al. describe the molecular mechanisms by which bacterial pathogens can enter the brain parenchyma and cause neurodegeneration. Several molecular mechanisms potentially leading to neuronal cell death are explained, including direct neurotoxic effects of bacterial products and indirect routes mediated by microglial activation and neuroinflammation. They suggest therapeutic approaches through targeting host molecules that are involved in bacterial entry into the brain, by enhancing neuroprotection, and also through modulating immune responses. The authors point out the importance of identifying virulence factors responsible for the processes leading to neuronal loss. They conclude that, whilst treatments targeting neuroinflammation may prove useful for preventing neurodegeneration, more epidemiological studies are needed to understand the molecular mechanisms behind the short-term and long-term impacts of bacterial infection on cognitive ability, in order to effectively prevent neurological sequelae.In their mini-review, Too et al. suggest common mechanistic pathways at the cellular and molecular levels, particularly focused on neuroinflammation. They identify several immune components as key players in bacterial meningitis and the two neurodegenerative disorders, supporting their views on the link between bacterial meningitis and neurodegeneration. Further, they outline the current treatment options for bacterial meningitis and discuss their potential for the therapy and prevention of Alzheimer's disease/age-related macular degeneration. They also suggest possible alternative scenarios for the infectious etiology of neurodegeneration and point out unresolved issues that must be addressed for the development of safe and effective therapeutic strategies.Alzheimer's disease and age-related macular degeneration are neurodegenerative disorders with distinct pathologies, but the two diseases share a number of common risk factors. Whilst an infectious etiology for Alzheimer's disease has gained considerable recognition in recent years, any link between infection and age-related macular degeneration is less recognized. By providing comparative reviews of Alzheimer's disease and age-related macular degeneration, Shinjyo et al. provide a comprehensive overview and evaluation of the significance for the development of dementia and other brain disorders of pathogen-induced complement activation within the CNS. Complement proteins are synthesized within the brain and have numerous non-immune roles, for example regulating some aspects of neuronal development and responses to injury. The authors point out that both over- and under-expression, or activation, of some components of the complement cascade are associated with brain disorders in experimental models and human disease. They also consider the association between complement activation and prion diseases. The authors bring together numerous strands of evidence concerning the potentially beneficial and deleterious effects of complement activation in the CNS response to pathogens. Finally, they consider the possible significance of these processes in the insidious development of neurodegeneration and dementia, pointing out that the outcomes of complement system activation in the CNS may be context-dependent and influenced by numerous regulatory factors.Complement system activation is a keystone of the host anti-microbial response. Bacterial meningitis is a prominent example of the importance of this system for eliminating pathogens within the CNS. However, the neuroinflammatory response to the presence of the pathogens is a major cause of neuronal damage and dysfunction, which may be fatal or have deleterious long-term impacts on cognitive performance in survivors. A wide range of other pathogens—viruses, fungi and parasites—also activate the complement system within the CNS. Hosseini et al. study the important concept that infection with common respiratory viruses might promote Alzheimer's disease through inducing microglial activation and, thereby, neuroinflammation. They report on work that builds on their previous finding that non-neurotropic influenza virus infection leads to prolonged cognitive impairment in mice. Microglial activation, neuroinflammation and the loss or functional impairment of neurons were suggested to mediate those effects. They now have gone on to show that sub-lethal inocula of a non-neurotropic strain of influenza virus exacerbated the progressive CNS changes occurring in a transgenic mouse model of Alzheimer disease. Among the neuropathological features that were studied, microglial activation, amyloid-β plaque load, onset of synapse loss and decreased synaptic plasticity were all more prominent in the virus-infected animals than in their sham-infected counterparts. These factors likely explain the greater degree of cognitive impairment in the transgenic mice infected with the non-neurotrophic influenza virus.Turning now to viruses, Narengaowa et al. reviewed the bi- and tri-directional oral-gut-brain interactions that might underlie the pathogenesis of Alzheimer's disease. By evaluating evidence from various sources, the authors postulate links between the oral/gut microbiota and the incidence of Alzheimer's disease. These might be the consequence of microbial pathogens entering the CNS through the breach of a protective barrier during a disease, e.g., gingivitis, or via microbial secretions that permeabilize the blood-brain barrier. In either case, the neuropathologies of Alzheimer's disease could be triggered. Alternatively, the oral/gut microbiota may indirectly lead to the development of Alzheimer's disease through the release into the bloodstream of neuroactive agents that subsequently enter the CNS, initiating a cascade of neuroinflammatory processes.Several historical lines of evidence have supported a link between infectious agents and the development of neurodegenerative diseases, especially Alzheimer's disease. Taking advantage of advances in high-throughput research technologies in the last few decades, multiple research groups have progressively explored the composition of the microbial fauna within the human body system that is associated with health and disease. Given that the gut and oral cavity are two important homes for the large diversity of microbiota, Shinjyo and Kita discuss in their review how interactions between infectious agents and metabolism in the brain and periphery might contribute to neurodegeneration. Specifically, two metabolic hormones, insulin and leptin, that are key players both in energy homeostasis and neurocognitive development are comprehensively explored. The review brings together numerous lines of evidence that potentially link two factors: first, the bidirectional relationship between the sustained inflammation and metabolic disturbance caused by pathogens and, second, chronic inflammation and increased risk of neurodegenerative disorders. The authors go on to analyze evidence that supports a possible contribution of dysregulated leptin/insulin signaling pathways to neurological disorders caused by various central and peripheral infectious agents. These include West Nile virus, Porphyromonas gingivalis, human immunodeficiency virus, Borna disease virus, and Canine distemper virus. They conclude their review by identifying key questions that remain to be answered before any therapeutic benefits of targeting immunometabolic pathways might be harnessed.Growing evidence suggests an association of metabolic disorders with neurodegenerative maladies, such as Alzheimer's disease. In general, energy metabolism and the immune system are tightly related. The articles in this Special Issue highlight the pivotal role of neuroinflammation in disrupting the normal operations of the CNS across a spectrum of different initiating agents. In the case of some viral and bacterial pathogens that invade and replicate within the intracranial space, the inflammatory response is acute, brutal, and makes a major contribution to neuronal damage. In contrast, other pathogens may perturb brain function through systemic actions that induce insidious neuroinflammatory processes which smolder over prolonged timeframes. Classic inflammatory mediators such as complement proteins and immune mediators seem to be implicated in both the acute and chronic neuroinflammatory etiologies. Anti-microbial agents are established front-line treatments for neuroinvasive pathogens, but complementary therapeutics that dampen neuroinflammation might be beneficial, by lessening cellular damage, if they do not interfere with the host immune response. The recent findings considered in the Special Issue suggest new approaches to preventing or slowing the onset of dementias by ameliorating the long-term effects of infectious diseases, but much more detail is needed about the key pathways that are involved.LKT, NH, and NS wrote and critically reviewed the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Backfill mining is the only way to realize no-waste mining and create green mines, but complicated backfill mining technology, high mining costs, and low-production capacity greatly restrict its application in low-quality iron mines. To reduce the cost of iron ore backfill mining, a large number of low-cost green backfill cementing materials have been developed in China over the past 10 years. This paper first introduces the research and development of green cementitious materials using solid waste. Then, it points out the key technologies in the development of green filling cementing materials, reveals the hydration mechanism of green cementing materials through microscopic analysis and research, and optimizes the ratio of green cementing materials based on an orthogonal test. Finally, the development direction of green filling cementing materials is put forward: combining technology development with the filling mining method and filling process; taking the development route from technology to products and from products to commodities. To reduce the cost of filling mining and pursue the economic benefits of filling mining, a demonstration mine of tailings and green cementing materials is taken as the breakthrough point to comprehensively promote the development of iron ore full solid-waste filling mining technology and achieve its large-scale promotion and application. With China paying increasing attention to environmental protection and facing the development and utilization of more complex and difficult-to-mine mineral resources, not only is the number of nonferrous, gold, and precious metal mines using the filling mining method increasing year by year, but the filling mining method is also gradually expanding to iron ore and coal mines ,2,3. EspThe cement filling material is mixed with the underground filling material through the mixing and filling method. The filling slurry coagulates and solidifies in the stope to form a filling body with a certain strength to support the surrounding rock in the goaf, limit the deformation of the surrounding rock, and control the surface settlement to achieve the purpose of safe mining and disaster control. At the same time, the beneficiation tailings are backfilled into the underground goaf to avoid the environmental pollution caused by the stacking of tailings on the surface. At the same time, it also reduces the land acquisition, construction, and maintenance costs of the tailings pond and fundamentally solves the problem of geological disasters such as the breaking of a tailings dam and debris flow. Filling mining also reduces ore dilution and loss as well as realizing the full recovery and low-cost utilization of valuable resources. It can be seen that iron ore filling mining can “control harm with waste” and achieve the dual purposes of safe production and environmental protection.At present, cement cementitious materials are still widely used in iron ore filling mining in China. Due to the poor adaptability of cement to the aggregate containing mud tailings, the strength of cemented backfill is low. The finer the tailings, the lower the strength of cemented backfill. At the same time, the viscosity of the tailing filling slurry increases with the smaller particle size of the tailing sand, increasing the pipeline transportation resistance of tailing filling slurry, decreasing the pipeline transportation concentration, and further reducing the strength of the cemented filling body. Therefore, the amount of cementitious material must be increased to further improve the cost of filling and mining.To solve the problem of the poor economic benefits faced by cement tailings cemented filling mining, most filling mines mostly use graded tailings filling, and the particle size of filling tailings is increased by removing fine mud tailings from tailings. However, graded tailings filling not only reduces the utilization rate of tailings  but also causes it to be difficult for the graded discharged fine mud tailings to be stacked on the surface, which has the potential of more severe geological disaster risk. It can be seen that the research and exploration of low-cost filling cementitious materials suitable for tailings filling aggregates are not only necessary but also imminent for iron ore mountain filling mining. In the past 10 years, some progress has been made in the development of low-cost green filling cementitious materials with metallurgical slag. Among them, new filling cementitious materials—such as cementation powders—have been industrialized in some mines in China. This paper summarizes the research and development of filling cementitious materials and their application in iron ore, puts forward the key technologies for the development and utilization of new filling cementitious materials, and finally points out the development direction of the application of green filling cementitious materials in tailings filling mining.Cement used for tailings filling cementitious material has the advantages of low strength, large dosage, high mining cost, and poor economic benefit. Therefore, using metallurgical solid waste resources to develop low-cost cement substitutes is an important research topic of filling mining.Blast furnace slag is a type of solid-waste slag discharged from a blast furnace utilized for smelting pig iron . After t2) is approximately 0.1. The activity of fly ash depends on its fineness. The finer the fly ash, the higher its activity [2 is added, the 7 and 28 d strengths of the cemented filling block increase by approximately 45%, respectively, and the later strength is also increased by 17–32%. Through experimental research, Gou Mifeng et al. [Fly ash is the fine ash recovered from the flue gas in coal combustion, also known as fly ash. It is the solid waste discharged from coal-fired power plants. Its mineral composition is similar to that of high-alumina clay. Most of the fly ash is glass phase with a small amount of unburned carbon and some crystalline minerals of quartz and mullite. The ratio of calcium oxide (CaO) to silicon dioxide 2. The water in the mixture is continuously supplied, and an alkaline film is continuously formed on the surface of the slag; through the gaps between the hydration products on the slag surface, it penetrates inward to corrode the slag until all the slag is hydrated. Gypsum can stimulate the salt of slag-based cementitious materials and promote the reaction between Al2O3 and Ca(OH)2 in slag to produce calcium aluminate hydrate, namely, ettringite. Since the formation of ettringite consumes the main hydration product, calcium aluminate, after slag hydration, the slag hydration process is accelerated. At the same time, the newly formed hydrated calcium sulfoaluminate increases the compactness of the structure. The product has a high water content, which greatly reduces the free water and causes the structure to become increasingly compact to improve the strength of the cemented backfill.An activator is used to stimulate the potential activity of blast furnace slag to produce a hydration reaction and produce ettringite with the cementitious property. The cementitious material prepared from this is called slag-based cementitious material. The Changsha Institute of Mining Research Co., Ltd., Changsha, China, used lime and other activators to research filling cementing agents, which greatly improved the strength of tailings cemented filling bodies. The results showed that the 28 d strength of tailings cement with a cement–sand ratio of 1:8 can reach more than 2 MPa, and its cost is only 40–60% of the cost of cement. The Jiaojia gold mine in Shandong Province carried out experimental research on slag-based cementitious material and developed cementitious powder green filling cementitious material in 2003. The test results showed that the cementitious powder cementitious material meets the technical requirements of tailings filling, and its material performance and price are better than that of cement. It has been popularized and applied in Shandong Jiaojia, Xincheng, and other gold-filling mines . Gao QiaFly-ash-based filling cementitious material is one of the research contents of filling mining technology . The XinCementitious materials were prepared from fly ash, silicate gel C–S–H seeds, composite sulphates, and sulfoaluminates and admixtures. The cementitious materials were mixed according to a 40–80% fly ash, 10–30% silicate gel C–S–H seed, 5–15% composite sulfate and sulfoaluminate, and 1–5% additive mixture. When the content of a +45 μm powder is zero, a fly-ash-based gelling agent can be prepared to replace cement. Feng Juen et al. used cement, gypsum, lime, admixture, and fly ash to research filling cementitious materials . The resIn conclusion, fly ash in fly-ash-based cementitious materials has the dual effects of potential activity and a microaggregate effect. Low-strength filling cementitious materials can be prepared by optimizing the proportion and proper grinding. However, due to the low early strength, it has not been popularized and applied.Red mud is the waste residue discharged from the aluminum industry. Its main minerals include dicalcium silicate, tricalcium aluminate, calcium carbonate, hydrated calcium aluminosilicate, and hematite. Therefore, it has a certain potential activity, but its activity varies with the production methods of alumina, its origin, and the grade of bauxite . Due to In conclusion, compared with slag- and fly-ash-based cementitious materials, red mud has low potential activity and high technical difficulty in development. For fine tailings filling aggregates, the strength of cemented filling bodies is very low; thus, red-mud-based filling cementitious material is still in the research stage.2, Fe2O3, MnO, Al2O3, and a small amount of TiO2 and P2O5. The main mineral composition is tricalcium silicate, dicalcium silicate, calcium magnesium olivine, calcium merwinite, dicalcium ferrite, RO , free lime (f—CaO), etc. Therefore, steel slag has certain potential activities. With the gradual increase in filling mines in China, the demand for filling cementitious materials is increasing year by year, and the demand for filling cementitious materials is increasing. According to the characteristics of filling cementitious materials, research on green filling cementitious materials using low-quality solid waste can not only significantly reduce filling mining costs and alleviate the shortage of high-quality slag resources but also explore a method for the modeling of low-quality solid waste and the utilization of high added value.Usually, new filling cementitious materials use lime, cement clinker, and admixture to prepare an activator that can stimulate the potential activity of blast furnace slag and produce a hydration reaction to form a stone body. At present, slag-based cementitious materials, such as cementitious powder, have consolidation agents, and consolidation powders have been developed. In recent years, with the strict management of China’s environmental protection and the restrictions on the production and energy reduction of iron, steel, and cement enterprises, the output of blast furnace slag is decreasing, and its application in building materials is increasing. Not only is the utilization cost of blast furnace slag increasing year by year, but the demand is also in short supply in some areas. Therefore, with the increase in the cost of slag-based cementitious materials, it is close to ordinary Portland 42.5 cement. On the other hand, the metallurgical industry discharges a large number of low-quality solid wastes, such as steel slag, white slag, magnesium slag, and industrial by-product gypsum, every year. Due to the fact of its poor quality, low activity, and adverse mineral components, such as toxic and harmful substances, the utilization of low-quality solid wastes is difficult, has a high cost, and has a low utilization rate. In 2016, the output of steel slag in China was approximately 65–120 million tons, while the utilization rate was only approximately 20% and the storage volume of steel slag was as high as 1 billion tons. The main chemical components of steel slag are CaO, MgO, SiOAs the name suggests, green filling cementitious material is a low-cost green filling cementitious material developed entirely from solid waste. Alkaline or salt solid waste is used to develop activators instead of lime and clinker to stimulate the hydration reaction of potentially active solid waste to form a stone body. Therefore, green filling cementitious materials are more different than slag-based cementitious materials in excitation mechanisms, material ratios, and water-hardening reactions. To develop green filling cementitious materials with reliable technology and reasonable economy, technical developments and research are put forward.Developing technology is an important step in the research of green filling cementitious material. It mainly uses alkali and salt solid wastes to develop activators as well as proportion testing and the optimization of cementitious materials:(1) Firstly, the mineral composition and characteristics of the available solid waste are analyzed, and then the alkalinity and salinity of the solid waste are quantitatively classified and comprehensively evaluated. The same is the case for the pretreatment and safety evaluation of the available solid waste;(2) Research on green filling cementitious material tests and proportions is conducted, and then strength tests on the cementitious block according to different proportions of green activators are conducted. On this basis, the proportion of composite activators is optimized; finally, the economy, environmental protection, and safety of cementitious materials are analyzed;(3) According to different tailings filling materials, carry out the test of the cement strength and pipeline transportation characteristics of green filling cementitious materials, study the relationship between tailings fineness, cement–sand ratio, slurry concentration, cement strength, and slurry pipeline transportation characteristics, and evaluate the safety and reliability of green filling cementitious materials.The production process is a key step in the transformation of green filling cementitious materials from technology to products. The grinding process of cementitious materials and product quality analysis as well as evaluation is mainly designed as follows:(1) The production technology of green filling cementitious material is studied. According to the physicochemical characteristics, hardness, and grindability of green filling cementitious materials, the appropriate grinding equipment, production process, and quality indices are selected. On this basis, considering comprehensive factors, such as equipment investment, production scale, and economic benefits, the investment, operation cost analysis, and decision making on green filling cementitious materials are carried out;(2) The quality index of green filling cementitious material is studied. According to the grinding equipment and production process, the quality indices of green filling cementitious materials are determined including the physicochemical characteristics, quality and activity, powder fineness, and ratio control accuracy of raw materials.The commercialization of products is based on the industrialized production of green filling cementitious materials. This is to popularize and apply the products as commodities in filling mines. It mainly involves products’ technical indicators, application conditions, and detection methods:(1) Technical indices of green filling cementitious materials including the particle size parameters and particle size gradation, powder density, and fluidity of cementitious materials;(2) Quality index of green filling cementitious materials including product storage conditions, shelf life, comparative analysis with cement in terms of technology and economy, and precautions for product application.Green filling cementitious material is prepared by using solid wastes, such as alkali and sulfate, to prepare composite activators and stimulate the activity of slag powder. The activity of raw materials is related to the performance of green filling cementitious materials. Therefore, mineral composition analysis, acid–base classification, and the toxic as well as harmful treatment of the used solid waste is one of the important research contents of green filling cementitious materials.The key to the development of green filling cementitious materials lies in the optimization and decision making of the activator ratio. The physicochemical properties and utilization cost of cementitious materials are closely related to their grinding fineness and production technology; therefore, it is necessary to carry out a strength test of cemented backfill according to different fineness and ratios as well as optimize the ratio of green filling cementitious material on this basis.The application of green filling cementitious material as a product in filling mining depends on the material production process. To this end, the following research contents are involved:(1) Composite activator grinding and mixing homogenization process. Generally, activator materials are different in hardness, moisture content, particle size, and particle size gradation; therefore, it is necessary to study the grinding and preparation processes of composite activators;(2) Mixing the homogenization processes of the activator and active material. For green filling cementitious materials produced by different grinding processes, a mixing system needs to be used to mix and homogenize different powder materials to produce green filling cementitious materials. Therefore, mixing equipment and production processes affect the homogenization effect and quality of green filling cementitious materials.2− and silicon  solute was low, and the later concentration increased. Under the combined excitation of desulphurized gypsum, slag and slag promoted hydration. The hydration products were mainly ettringite (AFt) and calcium silicate hydrate (C–S–H) gel, and the number of hydration products increased rapidly. The needle-like AFt crystals interspersed in C–S–H gel caused the hardened paste structure to become more compact. Li Litao et al. [With the wide application of filling mining and facing the problems of a shortage of slag resources in addition to high utilization costs, the development of green filling cementitious material using low-quality solid waste is another research hotspot of filling mining in recent years. Du Huihui et al.  used vano et al.  researcho et al.  carried Green filling cementitious material is still in the stage of research and exploration. With the support of a special fund for major technology transformation from the Department of Science and Technology of Hebei Province, the researchers in this paper developed steel-slag-based consolidated powder cementitious material, which was successful in the industrial filling test of the Zhongguan iron mine and realized its industrial application. To popularize the application of green filling cementitious materials in filling mines, further research and development directions are put forward.At present, green filling cementitious material uses steel slag and desulfurized gypsum to prepare a composite activator to stimulate the activity of slag powder and develop steel-slag-based green filling cementitious material. As is known, industrial solid wastes include white slag, nickel slag, magnesium slag, calcium carbide slag, and other alkaline solid wastes, in addition to steel slag and desulfurization gypsum. At the same time, the chemical industry also discharges phosphogypsum, fluorine gypsum, and other salt wastes. The characteristics of industrial solid waste are not only scattered sources, large output, and complex composition, but some solid wastes also have the characteristics of toxicity, radioactivity, and corrosivity. According to the development experience of steel-slag-based consolidated powder cementitious materials, the development of green filling cementitious materials by using a variety of alkali and salt solid wastes is the research and development direction of green filling cementitious materials. Liu Quan and Huang Xuquan researched fluorine–gypsum-based cementitious materials ,53. Li GThe core technology of the development of green filling cementitious materials is to develop composite activators by using alkali and salt solid wastes to stimulate potential activity and prepare green filling cementitious materials. Obviously, due to the different mineral compositions and salinity of different solid wastes, the hydration mechanisms of activators are different. Therefore, research on the hydration mechanisms of a variety of green filling cementitious materials is the basis of optimizing the proportion of cementitious materials and the research direction of developing green filling cementitious materials. Ni Wen et al.  studied Cementitious materials suitable for mining methods and the production conditions of filling mines are the basis for industrial application in mines. As is well established, different mining materials have different methods, technical conditions, and mining processes, and there are great differences in the requirements for the characteristics of cementitious materials. Therefore, the development of green filling cementitious materials must be closely combined with mines; according to the filling aggregate, strength requirements of filling bodies, slurry pipeline transportation conditions, preparation methods, and transportation technology, it is the only way to carry out the research and development of green filling cementitious materials. At the same time, the characteristics of green filling cementitious material research are to use a variety of solid wastes according to local conditions and carry out the development and application of research on new cementitious materials.The industrial application of green filling cementitious materials lies not only in transforming technology into products but also in transforming products into commodities. From technology to products, and from products to commodities, is an important development direction of green filling cementitious materials. The research includes the following: according to the optimized formula of green filling cementitious material, combined with the mining method and production technology of mine filling, carry out industrial tests on the strength and pipeline transportation characteristics of the cemented filling body, test and verify the reliability, feasibility, economy, and environmental protection of filling cementitious material, and finally obtain approval for filling mines as a green filling cementitious material recognized in the market, thus achieving circulation in the market.As a low-cost filling cementitious material, it is necessary to establish a demonstration project for its popularization and application in filling mines. It not only provides filling mines that can visit and exchange technology for tailings filling but also plays an exemplary role in the development and popularization of green filling cementitious materials. The contents involved in the construction of the demonstration project: select typical tailings filling mines and carry out the development of green filling cementitious materials and industrial filling tests according to the mining methods, mining technical conditions, filling aggregate, filling system, filling multiple lines, and the requirements of the filling stope for filling body strength and slurry pipeline transportation. Through a large-scale industrial filling test, the corresponding tailings filling cementitious material is developed, and the filling process, technical specifications, and quality standards of new cementitious materials are formulated. On this basis, the technical specification and safety production plan for tailings filling are prepared to lay a foundation for the popularization and application of low-cost green filling cementitious materials in mines.


Spalax ehrenbergi and the Iberian mole, Talpa occidentalis) are discussed in relation to a changing world where increasing exposure to artificial light at night (ALAN) is becoming a challenge for humans and animals in the modern society.The mammalian eye contains two systems for light perception: an image detecting system constituted primarily of the classical photoreceptors, rods and cones, and a non-image forming system (NIF) constituted of a small group of intrinsically photosensitive retinal ganglion cells driven by melanopsin (mRGCs). The mRGCs receive input from the outer retina and NIF mediates light entrainment of circadian rhythms, masking behavior, light induced inhibition of nocturnal melatonin secretion, pupillary reflex (PLR), and affect the sleep/wake cycle. This review focuses on the mammalian NIF and its anatomy in the eye as well as its neuronal projection to the brain. This pathway is known as the retinohypothalamic tract (RHT). The development and functions of the NIF as well as the knowledge gained from studying gene modified mice is highlighted. Furthermore, the similarities of the NIF between sighted  and naturally blind mammals (blind mole rats  The daily shift between day and night due to the rotation of the earth toward the sun defines the astronomical day of 24 h, which has shaped almost all life forms on the planet. In mammals, light is perceived through the retina and used for image formation primarily based on the classical photoreceptors, rods and cones, and a non-image forming (NIF) system using the photoreceptor, melanopsin . The cirWithin the last 20 years, studies of anatomy and physiology using different mammalian species and, in particular, gene modified mice, have shed light on NIF. Through the discovery of specific neurotransmitters (glutamate and pituitary adenylate cyclase activating polypeptide (PACAP)  and the Spalax ehrenbergi and the Iberian mole, Talpa occidentalis) will be discussed.This review will focus on NIF and studies in the circadian photoentrainment, masking behavior and pupillary light reflex in animal models, neuroanatomy, and physiology in gene modified mice lacking elements of the NIF pathway to the brain such as photoreceptors, neurotransmitters, and their receptors. Furthermore, the different aspects of the effects of light on the physiology between sighted  and blind mammals  . FurtherLight has a profound effect on the phase of the circadian clock which is fundamental for the ability of the species to stay entrained with the solar cycle. This phase shifting capacity is time dependent which means that light stimulation during daytime in normal feed animals have a little effect on the clock phase while light stimulation during the early part of the subjective night slows down the clock speed by inducing phase delays . Light sLight can also directly influence the rhythmic physiology and behavior, and this effect is called masking . While nAs early as the late 1920s, Clyde Keeler described a strain of blind house mice which, despite lacking the outer retina, still had light perception and an intact PLR . This NIIn 1972, a distinct monosynaptic neuronal pathway to the SCN was described in mammals for the first time . These pArvicantis niloticus)  , and as loticus) . Interesloticus) , althougloticus) .In the 1990s, Russel Foster and colleagues described two mouse models, the rd/rd (rodless/rodless) and the rd/cl (rodless/coneless) mice, characterized by the loss of all rods or both rods and cones during early development , 1993. Btau-lacZ gene, which codes for the β-galactosidase enzyme fused to a sequence of tau protein and promotes axonal transport of the marker enzyme, Cre/+; Z/AP) mouse in which CRE-recombinase were combined with an enhanced placental alkaline phosphatase that increases the sensitivity of visualization of melanopsin expressing cells and their projections in the brain, the number of mouse mRGCs were found to be more than twice the number of mRGCs which were initially visualized by immunostaining in mice (Using the melanopsin promoter and knockin of the  in mice . Brain a in mice . These o in mice .The melanopsin expressing RGCs (mRGCs) were a more heterogeneous group of mRGCs than what was initially suggested and represented by 5–7 subtypes of mRGCs in both rodents and primates, including humans . The totIn addition to being directly responsive to light, the mRGCs receive light information from the rods and cones as well . The infSpalax ehrenbergi, which is a blind subterranean mole rat with rudimentary eyes (diameter less than 1 mm) located under the skin, responds to light stimulation and adapts behavior and physiology to both circadian and annual lightnings  are innervated as found in sighted animals  expressing Brn3a and calretinin, but not melanopsin , several questions were asked. Is melanopsin the only photoreceptor for the NIF functions? Rod- and cone-less mice had an intact NIF such as photoentrainment, negative masking behavior, and suppression of nocturnal melatonin . GeneratThe initial discovery of melanopsin in one subtype of RGCs was modified based on the morphology, expression of melanopsin, dendritic projections/connections, and electrophysical properties. Today, 6–7 subtypes of melanopsin have been identified . These dIn mice, melanopsin can be found in a long form (OPN4L) and a short form (OPN4S), both encoding an active photopigment  see abo. The obsNerve fiber terminals of the RHT are found in the retino-recipient areas of the brain including the SCN, IGL, ventrolateral preoptic nucleus (VLPO) regulating sleep, subparaventicular zone of the PVN, lateral hypothalamic area dorsal to the SON , and sevIn vivo and in vitro studies of the behavior and gene expression using PACAP and PAC1 deficient mice have increased our understanding of the role of PACAP and the PAC1 receptor in NIF . In vitro electrophysiological studies indicate that PACAP can potentiate glutamate induced phase delay during early night and decrease glutamate induced phase advance at late night  . This fintration . PACAP Kntration . A thirdntration . Howeverntration . In addintration . These rin vivo and in vitro studies in mice lacking either PACAP or the PAC1 receptor show that PACAP plays an important role in light regulation of the SCN activity especially at low light intensities.PACAP receptor 1 (PAC1) deficient mice showed a normal photoentrainment as the PACAP KO mice, indicating that both genotypes have a stable biological clock , 2008. PLight stimulation at early night induces, in mice, large phase delays of the circadian rhythm see  and smalThe VGLUT2 transporter is important for the process that packs glutamate into synaptic vesicles . The VGLin vitro and in vivo (reviewed in The investigations of mice lacking PACAP (PACAP and PAC1 KO mice) and glutamate signaling (VGLUT2 KO mice) confirm the behavior, physiologically and gene expression studies Different subtypes of mRGCs are involved in the different NIF functions . In a reAll NIF functions including the circadian timing system have evolved in mammals long before the occurrence of modern society. While many people on earth still lives in rural areas where light is coming primarily from daylight, people in most parts of the industrial world are exposed to artificial white light at night (ALAN) . ElectriPhotoentrainment of the circadian clock is fundamental for the stable regulation of neuroendocrine systems leading to the secretion of hormones into the temporal niche controlling physiological functions such as metabolism, sleep, immune systems, and reproduction. Light directly suppresses melatonin secretion independent of the circadian system with an impact on several neuroendocrine axes. In modern societies, ALAN seems to affect NIF including the circadian and neuroendocrine systems. Therefore, it should be taken into serious consideration when trying to gain a better understanding of health problems in the industrialized human population.JH 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.


Cancer kills millions of people around the world every year. Surgery is a mainstay for the cure of solid organ cancer. As a modern principle of surgical oncology, surgery should not only remove the complete locoregional tumor, but also aim to minimize surgical trauma to the patient in order to reduce postoperative morbidity and to improve and guarantee postoperative quality of life.Compared to open surgery, minimally invasive surgical techniques can provide benefits in the form of reduced blood loss, faster recovery, less pain, less wound-related complications and a reduced hospital stay for the patient. Therefore, minimally invasive surgery techniques with instrumentation by a video camera and special surgical instruments, which are inserted through small incisions in the patient’s skin, are used in surgical oncology.Robotic surgery is one of the most recent innovations in the spectrum of minimally invasive surgery. After introduction of the robotic platform for surgical procedures in the beginning of the current millennium, the first operations were conducted for a variety of benign diseases. Nowadays, robotic surgery is also increasingly applied in complex cancer surgery. Robotic-assisted surgical techniques, especially for tumors at solid organs located in visceral cavities, were developed, approved and distributed within the last decade.Current technology in the field of robotic surgery can improve surgical outcomes in treating cancer through improved and highly magnified 3DHD-visualization and intra operative near-infrared fluorescence imaging with visual assessment of tumor tissue and related tissue perfusion. Complex anatomical areas can be visualized through high-resolution and three-dimensional (3D) vision with high magnification options and a very stable operating field. The preparation under this view can separate tissue structures from one another very precisely and, thus, minimize intraoperative injuries to critical surrounding anatomical structures.Besides the improved visualization, high-precision instrument control and movement is a major improvement obtained by robotic instrumentation. Robotic instruments allow endo-wristed movements and improve surgical dexterity and expand the options for minimally invasive tumor resectability and surgical reconstruction. The scaling of motion in the movement of robotic instruments can improve the precision and safety of surgical procedures. All of these factors contribute to minimizing surgical trauma, increasing the precision and safety of the tumor resection and increasing the safety of reconstruction procedures. This improves the functional but, in some cases, also the oncological results of tumor operations.Today, robotic operations are performed on tumor diseases of the lung, prostate, esophagus, pancreas, kidney, intestine, cervix and other organs. In particular, the feasibility and safety of the application of surgical robots have been largely proven “in field” for various cancer entities and surgical approaches. However, surgical, technical and scientific challenges remain. Clear long-term evidence of the superior results of curative robotic surgery over traditional open and especially conventional laparoscopic approaches is controversial.Despite all these experiences and possibilities, the use of robotic systems in surgical oncology must always be critically questioned. In particular, the question of whether real evidence exists for these postulated advantages must be asked. The definitively more cost-intensive robotic method can only be economically justified, compared to the traditional approaches, with proof of its superiority for the relevant functional and oncologic endpoints. Obtaining this evidence will be one of the greatest challenges in surgical oncology over the next few years. Up-to-date, available, prospective randomized therapy comparison trials are very rare and mostly show no or only marginal advantages for the use of robotic systems in surgical oncology. Corresponding individual studies are available, e.g., for rectal cancer and bladder cancer ,2. Many Cancers shows the current results of robotic cancer surgery and broadens the evidence for the application of the technique in surgical oncology. It also discusses the limits and shows future possibilities for improving the surgical results of cancer treatment through the use of surgical robots.This special edition of


For each group, cognitive networks were created reflective of test-to-test covariance, in which nodes represented cognitive tests and edges reflected statistical inter-nodal significance (p < 0.05). Network metrics were derived using the Brain Connectivity Toolbox. Network-wide clustering, local efficiency and global efficiency of nodes showed linear differences across the stages of aging, being significantly higher among older adults when compared with younger groups. Among patients, these metrics were significantly higher again when compared with healthy older controls. Conversely, average betweenness centralities were highest in middle-aged participants and lower among older adults and patients. In particular, compared with controls, patients demonstrated a distinct lack of centrality in the domains of semantic processing and abstract reasoning. Network composition in the amnestic mild cognitive impairment group was similar to the network of Alzheimer’s dementia patients. Using graph theoretical methods, this study demonstrates that the composition of cognitive networks may be measurably altered by the aging process and differentially impacted by pathological cognitive impairment. Network alterations characteristic of Alzheimer’s disease in particular may occur early and be distinct from alterations associated with differing types of cognitive impairment. A shift in centrality between domains may be particularly relevant in identifying cognitive profiles indicative of underlying disease. Such techniques may contribute to the future development of more sophisticated diagnostic tools for neurodegenerative disease.In accordance with the physiological networks that underlie it, human cognition is characterized by both the segregation and interdependence of a number of cognitive domains. Cognition itself, therefore, can be conceptualized as a network of functions. A network approach to cognition has previously revealed topological differences in cognitive profiles between healthy and disease populations. The present study, therefore, used graph theory to determine variation in cognitive profiles across healthy aging and cognitive impairment. A comprehensive neuropsychological test battery was administered to 415 participants. This included three groups of healthy adults aged 18–39 ( The integrity of our cognitive functions is heavily influenced by a number of factors including, but not limited to, our educational background , age Gl, and theDespite recent advances in biomarker identification , clinicaAlthough the traditional reductionist approach toward the study of cognitive functioning is clinically helpful and provides a valuable theoretical avenue for the formulation of inter-disciplinary research hypotheses , a more cognitive dedifferentiation hypothesis remains a central concept within the study of aging and cognition, due largely to the assumption that the well-established dedifferentiation in neural function and response to cognitive tasks in older individuals  included in this study were identified retrospectively from a large database coordinated by the University of Sheffield’s Department of Neuroscience. Healthy adults (n = 220) were approached using multiple recruitment strategies, with a proportion being carers of patients and others obtained via opportunity sampling and assigned to one of three groups according to their age: a younger group aged 18–39 (n = 75), a middle-aged group aged 40–64 (n = 75) and an older group aged 65+ (n = 70). All patients were recruited through a memory clinic after neurological examination and were split according to clinical diagnosis. Of the 195 patients, 60 had a clinical diagnosis of probable Alzheimer’s disease dementia, in adherence to the NINCDS-ADRDA criteria (n = 75) and those with a non-amnestic profile (naMCI) (n = 60) according to neuropsychological assessment. All procedures were carried out following the Declaration of Helsinki. This study received ethical approval from the West of Scotland Regional Ethics Committee 5, Ref. No.: 19/WS/0177. Written informed consent was obtained from all participants.The participant sample  and level of education (in years). The covariates age and education were chosen to reflect two demographic factors that have been found to mediate cognitive functioning most strongly among healthy populations and as such are the basis of the majority of normative studies , and a number of binary bidirectional links, or edges, between the nodes, representing significant positive correlations. Due to the use of the absolute threshold of as edges . As one as edges , the useIn order to visualize the structure of each cognitive network, the binary adjacency matrices for each group were exported to the Gephi software , where tTo quantify network structure further, the community conformation of each graph was calculated with the Louvain community detection algorithm applied to each node using the Brain Connectivity Toolbox within MATLAB . Nodes wwiring cost, simply refers to the fraction of edges that are present in the graph in relation to the number of possible edges that may be available, given the number of nodes. In the present study connection density was calculated on a node-by-node basis as the fraction of edges connected to a given node, out of the possible number of edges available if it were connected to all other nodes in the network. Please refer to Quantification of node-level network parameters was then performed on each adjacency matrix using the Brain Connectivity Toolbox run in a MATLAB environment. The specific parameters assessed included betweenness centrality, clustering coefficient and both the local and global efficiency of each individual node. Whole-network connection density was also computed for each graph. Together, these parameters function to quantify the integration and segregation of the network. Specifically, betweenness centrality represents a measure of how integral a node is to the efficient communication of the overall network and is calculated as the fraction of shortest paths  between any two nodes that include the given node . ClusterFurther assessment of how network parameters differed between cognitive domains was conducted through the use of mean network metrics derived from select nodes. The values of network metrics derived from sub-sets of nodes, chosen according to their cognitive domain, were averaged to give a mean value for each metric for four different cognitive domains. Tests reflective of memory function, abstract reasoning, semantic processing, and executive functioning were grouped, in the first instance, on a theoretical basis so that metrics relating to memory function were calculated using a mean score derived for each group from the nodes corresponding to recall of the Rey-Osterrieth Complex Figure, both Prose Memory measures and the Verbal Paired Associates Learning Test of the Wechsler Memory Scale . Mean meU tests. Differences in categorical variables were assessed using chi-square tests  and this appeared particularly relevant for tests of semantic processing/abstract reasoning and memory.Since network structure can be influenced by both age and education, U tests, can be seen in Among healthy adults, measures of both network segregation and network integration showed linear differences across groups with average global and local efficiency measures, clustering coefficients and connection density being lowest in the youngest group and highest in the older control group. Betweenness centrality, however, demonstrated a different pattern. This measure was lowest among the youngest controls and highest in the middle-aged group, with older controls showing a decrease in this measure compared with middle aged adults. Significant differences, calculated by Mann–Whitney The analysis on the graphs of the healthy groups was repeated including the three negative correlations. The findings confirmed that the inclusion of these negative correlations had very little impact on the results . The resulting graphs were very similar to those of the original aMCI group.Finally, we examined in more detail the profile of multi-domain aMCI patients  and middle age, a change that may occur in a similar manner to the age-related dedifferentiation of the neural response .differentiation–dedifferentiation hypothesis of intellectual ability across the lifespan (dedifferentiation hypothesis of aging, the differentiation hypothesis of human intelligence, originally introduced by A further indication of age-related cognitive dedifferentiation is reflected by the results relating to modularity. As in previous studies reporting similar age-related decreases in network modularity within brain systems , the numlifespan . In addiUnlike factor analysis, however, modularity, in this case, is calculated as part of a wider, complex set of metrics and therefore functions as a contributing factor to the thorough description of the entire cognitive scaffold. Graph theory parameters assessing both the segregation and integration of the overall network, also showed significant differences between the stages of healthy aging. Differences tended to present in a linear manner, with older adults demonstrating significantly higher levels of both efficiency measures and clustering coefficients than the youngest controls and the middle-aged group having averages that were intermediate between the two. As measures of network segregation, both differences in clustering coefficient and local efficiency indicate a difference in the local interconnectivity between neighboring nodes, suggesting higher levels of cognitive network segregation in older adults. Conversely, as a measure of network integration, significantly higher levels of global efficiency among both the older groups, when compared with young controls, is an indication of greater network-wide interconnectivity . A netwodifferentiation–dedifferentiation hypothesis (Despite the controversies surrounding the pothesis , the usepothesis  that undAcross individual domains, the linear pattern of differences in clustering coefficient, as well as in global and local efficiency, was relatively well preserved among the three healthy groups and the levels of each parameter were relatively similar for each domain within groups. Betweenness centrality of individual domains, however, revealed notable differences depending on age group. Young adults demonstrated similarly low levels of betweenness centrality across domains whereas middle aged and older adults showed a much greater variance in betweenness centrality, with both groups showing the highest levels of this measure in the domains of abstract reasoning and semantic processing. In particular, when compared with the middle-aged group, the oldest group of healthy adults demonstrated much higher levels of betweenness centrality in the domain of abstract reasoning, while showing much lower levels in the memory domain. Such findings may reflect changes in the reliance on differing domain-specific functions across the lifespan. High levels of betweenness centrality in the domains of semantic processing and abstract reasoning, in both the middle-aged and older groups, support the hypothesis that there is an increased reliance on this type of crystallized intelligence, which is developed throughout the lifetime , to suppSignificant differences in cognitive network topology were further established between healthy groups and those with pathological cognitive impairment. Firstly, all patient groups presented with significantly greater levels of connection density than healthy adults, a finding reflected by previous network analyses of cognitive profiles in healthy aging and Alzheimer’s disease . Higher Regarding modularity, of particular interest was the finding that the discernible modules in the graphs of the aMCI and dementia groups were clearly separated by their relation to language and memory function, a characteristic identified in Alzheimer’s disease in the study by Network segregation appeared significantly affected by the presence of disease, with both local efficiency and clustering coefficients being significantly higher among patient groups when compared with healthy older controls. Furthermore, all patient groups demonstrated significantly higher connection densities when compared with controls and dementia patients further presented with significantly higher global efficiencies, suggesting an alteration to network integration. Previously, neuroimaging studies assessing the topology of both structural and functional neural networks have demonstrated significant alterations in the small-world properties of such networks in Alzheimer’s disease patients, at varying disease stages, including patients with prodromal and even preclinical manifestations of disease . Though Average network parameters for particular cognitive domains allowed for more nuanced insight into domain-specific differences between the groups. In general, network parameters in each domain revealed a similar pattern of differences between patients and controls as findings relating to the overall graph, with measures of clustering coefficient, local efficiency and global efficiency tending to be lowest in young healthy adults and highest in patients. However, measures of betweenness centrality indicated some notable differences between patients and controls in how integral differing domains were to the efficient communication of the network. In particular, betweenness centralities in the domains of abstract reasoning and semantic processing were distinctly lower among patient groups when compared with healthy adults, with the relative levels of this metric in abstract reasoning being the greatest difference seen between MCI patients and healthy older adults. Contrastingly, betweenness centralities in the domain of memory were very similar between older healthy adults and the patient groups, where both had distinctly lower averages when compared with middle-aged adults. A diminished role of memory function in the cognitive network, reflected here by low betweenness centralities, therefore, appears to be a property of both healthy and pathological aging, likely resultant of declines in episodic memory, that are a well-established characteristic of both the healthy aging process  and of ALow levels of betweenness centrality in semantic and abstract reasoning domains among the patient groups, when compared with controls, however, may reflect a disease-related decrease in the reliance on such functions to facilitate cognition. This finding is supported by studies showing that significant declines in semantic processing tend to occur in concomitance with the earliest pathological stages of Alzheimer’s disease  and, thepost hoc analysis, education was excluded from the set of regressors in order to compare education-corrected and education-uncorrected coefficients of correlation. Except for the youngest controls, education had some influence over the significance of correlation coefficients seen between cognitive tests. As such, the number and conformation of edges that are moderated by education attainment differ across diagnoses, and appear to be particularly relevant among the middle aged and naMCI groups. The percentage of coefficient of correlations altered by inclusion/exclusion of education, was however small. These findings, therefore, suggest that education does indeed play a role in the formation of cognitive networks and suggests that cognitive reserve, a concept heavily linked to educational attainment (A possible limitation of this study was the exclusion of extraneous factors, such as education and imaging features from the analytical process of cognitive network formation. In a tainment , may be A second potential limitation might be related to lack of inclusion of imaging features in the analysis. While the inclusion of neuroimaging is certainly important, the current literature already includes many studies that have investigated the utility of graph theoretical methods in assessing alterations in neural networks at varying stages of Alzheimer’s disease . While pIn conclusion, the present study outlines a new approach to the modeling of age- and disease-related cognitive decline. Quantification of the structure of cognitive networks within both patients and healthy controls revealed compelling evidence for the existence of measurable alterations in neuropsychological profiles throughout healthy aging that are distinct from alterations associated with underlying pathological change. Furthermore, topological distinctions between the cognitive networks of differing diagnostic groups suggests some potential for the further exploitation of graph theory methods for the differentiation of cognitive profiles associated with varying disease etiologies. Finally, network parameters in specific cognitive domains highlighted a prominent role of crystallized abilities in the network connectivity of healthy older adults that appeared greatly diminished among patient groups, a defining feature that may serve to inform future investigations into novel diagnostic approaches to pathological cognitive impairment.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 West of Scotland Regional Ethics Committee 5, Ref. No.: 19/WS/0177. The patients/participants provided their written informed consent to participate in this study.AV and MDM conceived this study and contributed to study design. AV contributed to data collection. LW contributed to study design, carried out data analysis, and drafted this manuscript. MDM and AV provided critical review of the manuscript. AV finalized this manuscript. All authors approved the final version of this manuscript.The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.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. The handling editor declared a past collaboration with one of the authors AV.


Stroke is currently the second leading cause of death worldwide, and results in significant morbidity, and poorer quality of life for those affected . Stroke Although stroke incidence has declined in high-income countries, it remains a prevalent issue amongst low and middle-income countries, disproportionately affecting a younger, working age population in these areas . The treA related concept to CA is the physiological mechanism of neurovascular coupling (NVC). Under healthy conditions, neuronal activity is tightly coupled to cerebral blood flow (CBF), such that increases in neuronal activity will result in increases in CBF to ensure the metabolic demands of the brain are met. Intact NVC is integral to maintain optimal cognitive function, and thus may be an important physiological mechanism in the chronic or rehabilitation phase of stroke. The following sections consider the evidence to support a role for CA and NVC as important mechanistic factors in the acute and chronic phases of stroke, and the key clinical and research implications going forward.2 (PaCO2), cerebral blood flow and dynamic cerebral autoregulation  is of significant interest (2 levels) associated with poor prognosis  has now been carefully characterised at rest in AIS , acute igulation , 17. Hypgulation , 17. Metgulation . Unfortugulation . Specifigulation . Whilst gulation , 20, endgulation  and modegulation —their beinterest . In ICH,rognosis . Further imaging . These d imaging  and neur imaging . Unfortu imaging .2 were independent predictors of diffusion-restricted lesion incidence  and CO2 reactivity were not related to white matter lesions—however, relationships with duration of hypertension and nocturnal BP dipping were shown  and resistance  is less well-understood. There is debate as to the sensitivity of CrCP to variation in intracranial pressure (ICP) . HoweverTo date, the majority of studies have focussed on changes in CA in the acute, subacute, and chronic phases of stroke, with fewer studies investigating the effects on NVC . Animal In a systematic review, sixteen studies investigated changes in brain activation using transcranial Doppler or positron emission tomography based imaging . The revTo date, the majority of human studies have been cross-sectional, and longitudinal studies investigating the temporal evolution of NVC changes post-stroke are lacking. In particular, the role of NVC in the pathogenesis and outcome in haemorrhagic stroke has not been researched. Available evidence suggests NVC disruption in the early phases is predictive of functional outcome in ischaemic stroke , 37, 43,Given the evolution of the field and the desire to utilise haemodynamic studies to deduce treatment response, prognostic indices and optimise physiological profiles—there is an ever-increasing individualised approach. However, gaps have emerged across both NVC and CA lines of investigation, offering an opportunity to highlight necessary short- and medium-term study recommendations:What is the longitudinal behaviour of NVC beyond sub-acute stroke and into chronic stroke states?Does NVC behaviour differ post ICH as compared to AIS?Can NVC be modulated to enhance functional and cognitive recovery in patients post stroke?2 change post stroke and development of white matter lesions?Is there a longitudinal relationship between COTo what extent does BP lowering cause harm due to its interaction with hypocapnia in AIS and ICH?In order to address these pending research questions, multi-modality and inter-disciplinary studies are necessary. In addition, pooling of existing datasets to minimise research data waste and to maximise validity and statistical power is essential. There already exist multi-centre efforts to this effect, across cerebrovascular  and non-LB and JM prepared and wrote this manuscript through equal contribution to all aspects of its delivery.The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health, or the authors' respective organisations.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.