Cognitive impairment is a shared abnormality between type 2 diabetes mellitus (T2DM) and many neurodegenerative and neuropsychiatric disorders, such as Alzheimer’s disease (AD) and schizophrenia. Emerging evidence suggests that brain insulin resistance plays a significant role in cognitive deficits, which provides the possibility of anti-diabetic agents repositioning to alleviate cognitive deficits. Both preclinical and clinical studies have evaluated the potential cognitive enhancement effects of anti-diabetic agents targeting the insulin pathway. Repurposing of anti-diabetic agents is considered to be promising for cognitive deficits prevention or control in these neurodegenerative and neuropsychiatric disorders. This article reviewed the possible relationship between brain insulin resistance and cognitive deficits. In addition, promising therapeutic interventions, especially current advances in anti-diabetic agents targeting the insulin pathway to alleviate cognitive impairment in AD and schizophrenia were also summarized. Cognitive deficits can be observed in neurodegenerative and neuropsychiatric disorders, such as AD and schizophrenia with demonstratable brain pathology. Brain fAccumulating studies have attracted profound scientific and public attention to the greater metabolic comorbidity of T2DM in schizophrenia patients, which iThis review briefly summarized the mechanisms linking brain insulin resistance and cognitive impairment. In the next section, we provided an overview of preclinical and clinical studies with the aim to explore the potential cognitive enhancement of some anti-diabetic agents in treating AD and schizophrenia.Insulin is a peptide hormone secreted by β cells of pancreatic islets, playing a crucial role in metabolism and cognitive function. Insulin resistance refers to a pathological condition of decreased insulin sensitivity of insulin-targeting cells and issues. In periphery, it has been recognized as a main feature of metabolic syndrome and T2DM. The brain is a further important site of insulin resistance, which is an extremely important organ to regulate energy metabolism, body weight, memory and cognition. Insulin receptor expression and action have also been found in neuronal populations and glial cells, and the disruption of insulin signaling in the brain is related to abnormal neuronal function. In the Neurons are the structural and functional units of nervous system and brain insulin resistance-induced neuronal injury leads to cognitive deficits. Brain insulin resistance is associated with reduced dendritic spines, decreased level of BDNF and impaired synaptic plasticity.Dendritic spines are small postsynaptic protrusive structures from a dendritic, which are essential for synaptic transmission, and ultimately for learning and memory function. HippocaSynaptic plasticity refers to numeral, structural and functional modifications of synapses under various stimulations, leading to the corresponding changes of the transmission efficacy. In addiInflammation is the defensive response to stimuli occurring in the body and brain. In neuropathological disorders, raised inflammatory process (microglia activation and elevated cytokine levels) impairs cognitive performance through disrupting neurobiological mechanism: synaptic plasticity, neurogenesis, neurotrophic factors, the HPA axis and the kynurenine pathway. For insBrain insulin resistance is associated with inflammation. High fat diet (HFD) rodents showed cognitive impairment with elevated Interleukin-1β (IL-1β) and tumoMitochondria are essential for neuronal activity and plasticity, and mitochondrial dysfunction leads to cortical under-connectivity: reduced dendrite, axon and synapse growth. MeanwhiInsulin resistance is related with mitochondrial dysfunction and mitochondria-dependent high level of free radicals also induce insulin resistance. RodentsAlthough the basic pathologies of AD and schizophrenia are diverse, they still have some symptomatic similarities in addition to cognitive deficits, suggestCurrent findings suggest that brain insulin resistance is associated with the development of cognitive deficits and anti-diabetic agents boosting insulin action in the brain present promising cognitive enhancement in T2DM and neurodegenerative diseases. Based on this opinion, targeting brain insulin resistance may have therapeutic potential to alleviate cognitive deficits in individuals with schizophrenia . TherefoThe reductions in the integrity of blood brain barrier may also be a contributing factor to the pathologic cascade leading to cognitive decline in neurodegenerative and neuropsychiatric disorders. Under tFourteen consecutive days of intranasal insulin treatment could prevent the severe memory and learning impairment induced by intracerebroventricular administration of Aβ, which was a rat model of AD. In tranIn healthy subjects, intranasal intake of insulin improved consolidation of words and general mood, indicating intranasal insulin as a potential treatment in patients showing cognitive deficits in conjunction with a lack of insulin. Acute aPrevious research studies have evaluated the cognitive beneficial effect of intranasal insulin therapy in non-schizophrenia patients. Adjunctive intranasal insulin administration was safe, well tolerated, and effective on a measure of executive function in bipolar disorder. SystemaThe cognitive benefit of intranasal insulin in healthy subjects and AD may not generalize to schizophrenia. Single-dose intranasal insulin treatment (40 IU) did not have significant beneficial effect on verbal memory and sustained attention in patients with schizophrenia. This trMetformin, a biguanide anti-diabetic drug, is recommended as first line treatment in T2DM. The main effect of metformin is to acutely decrease hepatic glucose production through the inhibition of mitochondrial respiratory chain complex Ⅰ and subsequent the activation of AMPK. MetformChronic hyperinsulinemia in Neuro2a cells leaded to reduction of phosphorylation of IRS-1, PI3K, translocation of glucose transporter (GLUT) 4 and expression of GLUT3, and metformin could directly reverse such neuron insulin resistance status. MetformAt present, the relationship between metformin and cognitive performance is controversial in clinical studies. In patients with non-dementia vascular cognitive impairment and abnormal glucose metabolism, a year metformin treatment was effective in improving cognitive function, especially in terms of performance function. MetformGLP-1, an incretin hormone from the enteroendocrine L-cells, increases insulin secretion and reduces glucose excursion and glucagon secretion to regulate glucose metabolism. Endogenous GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4) enzyme. Therefore, the DPP-4 inhibitor (vildagliptin or sitagliptin) and the DPP-4 resistant GLP-1 analogues  are developed to overcome the short hart-life of endogenous GLP-1. The act1-42 deposition, alleviating synaptic degradation, and improving hippocampal mitochondrial morphology and dynamics in the mouse model of AD inhibitors are one of the newly developed medications used to treat T2DM. SGLT 2 As a natural pigment, quercetin is a flavonoid with abundant biological activities such as antiviral, anticancer, antioxidation, anti-inflammatory, and antidiabetic activity. The antSulforaphane is a compound with multiple bioactivities such as antidiabetic and antioxidant effects. Sulforaphane could improve glucose tolerance through up-regulation of insulin signaling involving IRS-1/Akt/GLUT 4 pathway in muscle. SulforaCognitive deficits occur in neurodegenerative and neuropsychiatric diseases including AD and schizophrenia. Insulin resistance is a shared metabolic comorbidity of these two chronic diseases. The disruption of insulin action in the brain is considered as a potentially important pathophysiological mechanism of cognitive impairment via deficits in neuronal structure and function, impaired synaptic plasticity, brain mitochondrial dysfunction, increased oxidative stress and inflammation. Intrinsic abnormal glucose metabolism would predispose AD and schizophrenia patients to cognitive deficits and current therapeutic measures cannot achieve expected therapeutic efficacy. Therapeutic interventions may be effective if both the periphery and brain glucose metabolic disruptions are alleviated for effective results. Antidiabetic agents have gained public and scientific attention for its potential as a cognitive enhancement drug and is currently being examined in in vitro experiment, in preclinical animal studies and in clinical trials around the word. The molecular mechanism and preclinical animal models suggest that the repositioning of antidiabetic drugs is a promising opportunity to alleviate cognitive deficits in AD and schizophrenia. However, there may exist some gaps when translate experimental results into application. Drugs specifically designed to target brain insulin resistance may exert beneficial effects on cognition. Furthermore, the pathogenesis and clinical heterogeneity of cognitive impairment remain complex. A better understanding of the relationship between brain insulin resistance and cognitive impairment will help us to design future research. More works are urgent to explore the nature and corelates of brain insulin resistance and cognitive deficits in schizophrenia. For example, preclinical models are expected to discover the molecular and cellular mechanisms of cognitive deficits in schizophrenia, such as cerebral organoids derived from human embryonic stem cells and patient-derived induced pluripotent stem cells from schizophrenia, which are able to clarify the pathogenesis of cognitive deficits and the role of brain insulin resistance to exclude the effects of antipsychotics on this relationship. Additionally, radiotracer or detection methods are expected to clarify the central insulin action in patients with schizophrenia. Some anti-diabetic agents may fail as cognitive enhancement strategies for a number of reasons, such as poor penetrance of the blood–brain barrier and ineffectiveness in reducing brain insulin resistance in vivo. Therefore, works are needed to examine the effect of drugs that are able to increase the sensitivity of insulin receptors in the brain. Besides, multi-site large-scale randomized controlled trails are needed to examine the effects of antidiabetic medications on cognition in schizophrenia. In the future, more works are expected to elucidate the relationship between brain insulin resistance and cognitive dysfunction in schizophrenia leading to the development of novel interventions to alleviate cognitive deficits in schizophrenia to benefit patients.


The COVID-19 pandemic and response has significantly disrupted fishery supply chains, creating shortages of essential foods and constraining livelihoods globally. Small-scale fisheries (SSFs) are responding to the pandemic in a variety of ways. Together, disruptions from and responses to COVID-19 illuminate existing vulnerabilities in the fish distribution paradigm and possible means of reducing system and actor sensitivity and exposure and increasing adaptive capacity. Integrating concepts from literature on supply chain disruptions, social-ecological systems, human wellbeing, vulnerability, and SSFs, we synthesize preliminary lessons from six case studies from Indonesia, the Philippines, Peru, Canada, and the United States. The SSF supply chains examined employ different distribution strategies and operate in different geographic, political, social, economic, and cultural contexts. Specifically, we ask (a) how resilient have different SSF supply chains been to COVID-19 impacts; (b) what do these initial outcomes indicate about the role of distribution strategies in determining the vulnerability of SSF supply chains to macroeconomic shocks; and (c) what key factors have shaped this vulnerability? Based on our findings, systemic changes that may reduce SSF vulnerability to future macroeconomic shocks include: diversification of distribution strategies, livelihoods, and products; development of local and domestic markets and distribution channels; reduced reliance on international markets; establishment of effective communication channels; and preparation for providing aid to directly assist supply chains and support consumer purchasing power. Small-scale fisheries (SSFs) are important contributors to the global seafood system and crucial components of food and nutrition systems. Nearly half of the world’s seafood, the most traded food commodity  have disproportionately felt the impacts caused by COVID-19  how resilient have different SSF supply chains and actors been to COVID-19 impacts; (b) what do these initial outcomes indicate about the role of distribution strategies in determining the vulnerability of SSF supply chains to macroeconomic shocks; and (c) what underlying conditions have shaped this vulnerability? This study builds on an examination of initial responses of SSF supply chains to COVID-19 published by Bassett et al. , which iIn light of COVID-19-related limitations on in-person fieldwork, we adopted a multi-step methodology incorporating ongoing case study research complemented by virtual key informant interviews. Cases were selected based on authors’ pre-existing knowledge of and interactions with SSFs and their supply chains in five countries — Indonesia, the Philippines, Peru, Canada, and the United States. Our focus on these cases studies and applied methods served to minimize burdens on actors, build on existing connections, and cover a diversity of geographies, sociopolitical contexts, and distribution strategies.Authors’ pre-existing knowledge of their respective cases established baseline understandings of each system prior to COVID-19. Information about each study site and SSF supply chain’s experience of and response to the pandemic was gathered from media and governmental reports, websites, newsletters, and semi-structured interviews with key informants. Effort was made to interview actors from several nodes in the supply chains.Interviews with key informants aimed to improve the authors’ understanding of events that transpired since the onset of COVID-19 through September 2020. A collaboratively developed set of questions exploring SSF supply chain vulnerability and resilience were adapted by case due to logistical constraints, cultural and linguistic norms, and knowledge gaps. By taking these steps, we aimed to address limitations to conducting timely research and avoid unnecessary burden to actors in an already stressful period. Additional details concerning data collection for each case are included in Table Case narratives were written by each respective author, then qualitatively assessed to address the questions shown in Table Each case is described in terms of pre-pandemic operations and background and changes since the pandemic onset. Key events since the start of COVID-19 and intra-supply chain ripple effects are shown for each case in Fig. Indonesia is the world’s second largest capture fish–producing country and a major exporter, with the North Sumatra province contributing 11% of volume and 12% of the associated monetary value .Movement restrictions contributed to a seafood glut filling local markets, compounded by the reduced purchasing power of consumers from the palm oil sector Fig. . More seOne crab and snail processor, Rio,Unlike the processors, mobile traders within Langkat continued to work throughout the pandemic; many households still relied on these traders for access to vegetables, tofu, tempeh, and fish. However, many customers were unable to work or took home reduced earnings, particularly those dependent on the palm oil industry . Some families received two or more months of government-distributed food aid, including rice, eggs, and oil, and/or small amounts of financial aid; small portions of dried anchovies used as seasoning were the only fish included in the food aid . Despite reduced fish prices and supplemental financial aid, local households reduced their fish purchases, with food aid potentially displacing demand.Local consumers continued to buy from mobile traders, increasingly by credit, leaving traders with reduced cash flow and even financial losses from both unsold fish and extended credit Fig. . Some moThe Philippines’ fishery sector, ranked 11th in total capture production globally FAO , is valuIn the Tañon Strait, an important Filipino fishing area, small-scale fishers catch several species, including groupers, mackerels, skipjacks, squid, sardines, tuna, rabbit fish, anchovy, and several other reef and pelagic fish . The fishers sell their catch through local consolidators to intermediaries in city markets, such as in Cebu City (PH01), normally fetching decent prices. These intermediaries require capital to purchase fish and transport it into city markets to supply restaurants, hotels, and retailers . Local consolidators may also provide loans or fishing gear to fishers to lock in low selling prices. Commercial fishers have a more formalized system, loading their catch into trucks at the port, or distributing to their regular market retailers. Canning factories own their vessels and directly transport catch from port to factory (PH01).In March, the Philippines’ government enacted COVID-19 mitigation measures for public health through an Enhanced Community Quarantine (ECQ).Fishers were acknowledged as essential workers under the ECQ and exempted from stay at home orders through Resolution 15 of the government’s Inter-Agency Task Force on the pandemic Fig. . The BurThe government has adopted variably effective support mechanisms, including purchasing fish for food relief packages Fig. , financiFishers could receive around USD 100 in government aid through the Social Amelioration Program and were eligible for food aid. Small farmers and fisherfolk also had access to government loans of about USD 500 at zero interest, payable up to 10 years. The aid provided to families was barely enough to cover costs of a single person in a rural area, let alone in cities (PH01). While information about the loans was widely disseminated via radio, complying with requirements was difficult  and fishers in more remote areas were not reached Fig. ; PH01.Tiannge,” an online marketplace connecting 6,000 fishers with buyers from 300,000 households in South Negros, Visayan Sea in the Visayas region, and the Calamianes Group of islands in Palawan , and a stay-at-home order, dependent on relevant ministry recommendations Fig. . Prior tAfter the quarantine declaration, overall fishing effort in Peru dropped approximately 80% Aroni . InformaFishing and product transport activities were considered essential services; however, conflicting means of emergency rule enforcement across scales of government led to confusion and breakdown of supply chain activities . Some fishers attempted direct sale into local markets but attributed their limited success to lack of demand. Formal intermediaries who historically delivered product to processors were unable to work initially due to transit restrictions and lack of COVID-19 control protocols Gonzales . Other iWhile plants and intermediaries developed internal practices to control the spread of COVID-19, fishers and dock workers relied on the National Agency of Seafood Sanitation (SANIPES). Protocol uncertainties led La Tortuga and La Islilla to take contrasting measures Fig. ; La TortDespite the government-mandated quarantine and travel restrictions being lifted in July, the offshore artisanal fleet effort has not recovered Gonzales . InformaIn Canada, British Columbia’s (B.C.) seafood industry relies heavily on export revenue. Seafood worth USD 1.1 billion was exported in 2018, with a third going to China, Japan, and Hong Kong  through their own small-scale independent processor, and then stores frozen seafood at storage facilities or on site. Sales are directly made to members from the Granville Island Fishermen’s Wharf or through food co-ops and socially conscious businesses in Vancouver and domestically. Product labelling informs members who caught their seafood when, where, and with what gear. Such efforts are strategies to strengthen non-market values between fishers and seafood consumers within a seafood supply chain.COVID-19 reduced demand for niche B.C. seafood products like Dungeness crab, geoduck, spot prawns, and herring roe that would normally have been exported to Asian markets for Lunar New Year or sold locally to high-end restaurants Fig. . FisheriSince the pandemic and associated restrictions were introduced prior to the 2020 fishing season , SSFs had time to adapt to the new conditions. Fishers supplying seafood to SO continued operating and received above-market prices for their catch Fig. . Some fiSO also attempted to market and locally process niche seafood like Dungeness crab (SO01). With certain community pick-up locations being closed at the start of the pandemic, SO trialed a home delivery service to members in areas of Vancouver and partnered with new community pick-up locations. Toward the end of the summer, with a surge in new members Fig. , a functThe United States (U.S.) is the top seafood importer and amongst the top five exporters worldwide FAO . Califoruni. Since the collapse of the Japanese market in the 1990s and concurrent burgeoning of sushi restaurants in the U.S., 90–95% of sales are to the domestic market, primarily to restaurants (CA01). Distributors maintain a small supply to Asian and SE Asian markets (ibid), and recently, local and direct-to-consumer operations have emerged. Run by divers or intermediary handlers . Whole urchins are transported to processors, then shipped to distributors in the U.S., Asia, and Southeast Asia (CA01). Divers, processors, or intermediary handlers sell a smaller portion of the harvest as whole urchin to local restaurants or consumers. Some processors handle only uni, while at least one also processes and distributes many locally caught species. Divers tend to operate in more than one fishery or hold other part-time jobs in addition to diving for uni .Currently, there are 262 licensed divers CDFW , with arAt the onset of COVID-19, the RSU fishery lost access to its primary and secondary markets: domestic restaurants and exports Fig. . In mid-uni for the first time (CA03). Capitalizing on the new attention, the Market offered pre-ordering online and curbside pick-up . One multi-species processor was able to maintain operations by adjusting to market demands (CA01). The California Sea Urchin Commission (CSUC), a statewide organization of divers, processors, and managers, provided information on requesting aid and it appears that access has not been an issue .Some divers and processors pursued financial relief aid through Federal or State programs. In addition to enacting policies to mitigate the financial and health impacts of COVID-19 on individuals and families, California expanded unemployment benefits with the addition of USD 600 on top of the weekly benefit received by workers as part of the new Pandemic Additional Compensation initiated by the Federal CARES Act , and indirectly by restrictions on consumers’ ability to purchase seafood, leading to decreased demand, and restrictions on mobility and trade, constricting need for production activities. Direct impacts were reduced in Peru through already distanced activities  or strong sanitary practices , and existing cultural norms or health and sanitation policies helped in Canada, the U.S., and Indonesia. Sadly, the Peruvian case study saw several deaths in the fishing community, leading to fear amongst workers of perceived health risks.Teleconnected vulnerabilities were apparent as some local supply chain actors experienced disturbances due to international market stoppages and restaurant closures. Impacts traveled through and between supply chains, exhibiting the broad reach of ripple effects in highly interconnected food distributions systems , fishery , or product . Fishing in multiple fisheries (RSU), processing multiple species , and employing multiple distribution strategies  have reduced actor sensitivity to market disruptions and increased their capacity to adapt. Actors involved with multiple SSFs and supply chains  have shifted their efforts to nimbly follow markets as COVID-19 disruptions shift spatially and temporally. These findings align with other studies across numerous fields that have highlighted the positive impact of the “portfolio effect” on resilience in social-ecological systems that can experience sudden environmental and market shifts . In the Philippines, self-owned and small businesses reduced purchases, while fishers supplying to tourist-reliant businesses and restaurants reduced their fishing effort. Langkat mobile traders also reduced the frequency of days worked and the amount of fish they bought to sell on their routes, and RSU divers fished only when they had pre-arranged a buyer. Largely, however, upstream-initiated reductions in catch production and sales have been unable to compensate for the reduced demand, with prices significantly decreasing in several cases . This pattern suggests that COVID-19 has presented such a substantial shock that SSF supply chains and actors cannot maintain their core functions by simply coping and must take adaptive actions.uni at home in the RSU fishery), and increased their social media and customer outreach. These adaptive activities are actively shifting their SSF supply chain systems into new regimes.Some actors remaining within their usual supply chains have adapted by adjusting or diversifying their livelihood activities. The most common trend has been for actors to shift to new local distribution strategies, particularly direct-to-consumer sales. Others who already provided direct-to consumer sales have added new means of purchasing  and receiving  products. Some have expanded their offerings , provided tutorials for how to cook unfamiliar species  may initially seem to not support the continued operation of the supply chain. However, the ability of the actor to be flexible and support their livelihood outside of the fishery when demand is low supports the near-term wellbeing of that actor, and their ability to return in accordance with demand, thereby supporting supply chain resilience  aid in reducing supply chain and actor vulnerability was limited by constraints on aid recipients and scale mismatches with COVID-19 shocks; aid has been supplied to some, though not all, domestic recipients, however cannot reach international markets where many of the disruptions are rooted. Without substantial inter-governmental coordination, national governments and organizations have limited ability to mitigate for negative impacts of a supply chain’s reliance on collapsed international markets  with strong unemployment aid and disaster relief infrastructure  had access to consumers who retained more purchasing power than those in the low- and middle-income countries (LMICs) of Indonesia, the Philippines, or Peru. The U.S. and the Philippines provided only one-time stimulus payments, unlikely to change buying power in an ongoing crisis , knowledge sharing (knowledge), and coordination between actors (organization) have been essential dimensions of adaptive capacity employed to manage uncertainties around potential COVID-19 mitigation strategies and maintain supply chain function. Internet and communication technologies (ICTs) were central to the adaptive actions of supply chain actors. Digital tools are increasingly used for coordination and transformation within supply chains Jensen , and in The use of available tools aided mitigation of potential inequities in access to information. If not considered, lack of local infrastructure, individual socioeconomic class, and historical power distributions can inhibit access to ICTs and uniform distribution of information . Otherwise, producer and buyer coordination is the primary means of ensuring harvest will find a market and garner profits. Supply chain actors who were able to coordinate the supply of fish to available buyers  were better able to navigate fluctuations in demand and reduce product waste and effort. Several SSFs saw initial seafood gluts when the markets dropped-off suddenly, with more complex supply chains and distanced nodes taking longer to minimize supply–demand mismatches . Additionally, higher levels of adaptive capacity on the side of all supply chain actors (including consumers) seems to have improved coordination, as these actors were more able to communicate their preferences. For example, wealthier Indonesian clients preferring a higher value product communicated their demand to mobile traders, who did not typically carry them. Similarly, SO, relying on e-commerce and a cooperative business model, was able to effectively communicate with their suppliers to meet the demand of a growing client base and communicate surplus to clients to encourage sales.Market diversification, in particular, has been highlighted as a key factor for SSF resilience to surprise market disruptions, both in our study and others on COVID-19  the type or volume of product traded , (2) the process by which trade occurs , and (3) the groups of actors involved . While the magnitude of disruption associated with COVID-19 has been too great for the SSF supply chains to absorb without necessitating adaptive action and movement into new regimes, their ability to continue performing core functions has varied as a result of disparate vulnerabilities:Three cases  exhibited relatively low resilience and high vulnerability in that supply chain actors could not continue working in their usual roles and the usual consumers did not receive their regular seafood products. All three of these cases were reliant on international markets or tourism (high exposure and sensitivity) and exist in relatively low-income countries and local areas (low adaptive capacity), where they have been unable to establish new markets either due to consumer preference, spending power, or both. With some established domestic market links, the Philippines case fared somewhat better than the other two (lower sensitivity and higher adaptive capacity).Two cases (LKM and RSU) demonstrated moderate resilience and vulnerability as some actors continued in the supply chain and some consumers maintained access to products. Both cases target domestic and local markets primarily, but their usual distribution channels were disrupted by reduced consumer spending power (LKM) and restaurant closures (RSU) (moderate exposure and sensitivity). Adaptive capacity varied amongst actors and allowed some to remain active in the supply chain by modifying the focus of their activities, while others employed their agency and flexibility to pursue other livelihood activities or means of support. Diversification of products (LKM) and distribution strategies (RSU) was key to continued operation of the supply chains (moderate adaptive capacity).One case (SO) showed high resilience and low vulnerability and was able to increase operations, hiring new employees and accessing new consumers. Targeting an affluent domestic market via established diverse distribution strategies and channels , the SO supply chain was able to capitalize on reduced international trade, increasing domestic market demand and reducing local catch price. Their market was further strengthened by ongoing government financial relief provided to Canadian citizens (lower sensitivity).Examining across all case studies, several key factors for reducing SSF supply chain and actor vulnerability to the pandemic have emerged: (1) access to local and domestic markets with purchasing power ; (2) low reliance on international, tourism, and restaurant markets (reduced exposure and sensitivity); (3) access to information and communication (increased adaptive capacity); (4) government aid supporting the SSF supply chain directly or consumer spending ; and (5) diversified distribution channels and strategies, livelihood options, and products .COVID-19 is an unprecedented supply chain disruptor, but will not be the last to transcend geographic boundaries. Climate change, slower moving in its effects, will have similar global reach (Lam et al. The negative impacts experienced by SSF supply chain actors since the onset of COVID-19 have not been limited to direct health impacts. Instead, impacts derived mostly from underlying social conditions that increased the vulnerability of systems and actors to this type of disruption, as has been theorized by conceptual models (Blaikie et al. These case studies suggest several systemic changes that could support reduced vulnerability in SSF supply chains and prepare actors for future shocks. First, development of well-connected local and domestic supply chains reduces reliance on international markets and their associated teleconnected vulnerabilities. While local or domestic distribution may not be economically preferable or culturally viable during “normal” times, efforts to develop the market and diversify distribution strategies may provide valuable alternatives to the globalized trade system, leaving systems and actors less vulnerable to shocks and better able to cope or adapt in times of stress. Second, supporting diversified product portfolios, livelihood activities, and distribution strategies will increase actor and system flexibility and their agency to respond to market fluctuations and logistical limitations. Third, proactive establishment of effective means of equitably distributing aid and information will support both supply chain actors and consumers to continue to operate their respective roles, thereby decreasing supply chain disruption. Providing sufficient and consistent financial aid to households will increase their ability to purchase seafood and either buying fish for food relief packages or directly providing aid to supply chain actors will promote their continued functioning.The case studies presented here suggest that these lessons for supporting invulnerable and resilient SSF supply chains can apply to a broad range of systems and contexts, if appropriately adapted. As is always the case with social-ecological systems, there is a positive feedback loop in which the wellbeing of system actors supports continued provision of wellbeing from the system in which they participate; thus, equity and inclusivity are essential considerations to promote sustainable and resilient systems. The pandemic has highlighted flaws in globalized and integrated seafood systems and its outcomes should inform preparation for similar future shocks.


Together, this will yield important insight into the cell biological mechanisms of microglial impact in the central nervous system, particularly in the development and maintenance of myelin, that will facilitate the development of new, and refinement of existing, therapeutic options for a range of brain diseases.Microglia are highly dynamic cells crucial for developing and maintaining lifelong brain function and health through their many interactions with essentially all cellular components of the central nervous system. The frequent connection of microglia to leukodystrophies, genetic disorders of the white matter, has highlighted their involvement in the maintenance of white matter integrity. However, the mechanisms that underlie their putative roles in these processes remain largely uncharacterized. Microglia have also been gaining attention as possible therapeutic targets for many neurological conditions, increasing the demand to understand their broad spectrum of functions and the impact of their dysregulation. In this Review, we compare the pathological features of two groups of genetic leukodystrophies: those in which microglial dysfunction holds a central role, termed ‘microgliopathies’, and those in which lysosomal or peroxisomal defects are considered to be the primary driver. The latter are suspected to have notable microglia involvement, as some affected individuals benefit from microglia-replenishing therapy. Based on overlapping pathology, we discuss multiple ways through which aberrant microglia could lead to white matter defects and brain dysfunction. We propose that the study of leukodystrophies, and their extensively multicellular pathology, will benefit from complementing analyses of human patient material with the examination of cellular dynamics  Summary: Microglia abnormalities are increasingly linked to white matter diseases. Complementing analyses of leukodystrophy patient material with animal models yields insight into the impact and therapeutic potential of microglia across diverse brain disorders. Macrophages are myeloid-derived cells distributed throughout the vertebrate body that have tissue-specific subsets and functions based on their origin and tissue of residence . Their fin vivo imaging in zebrafish and mouse models, microglia were subsequently found to be highly dynamic in ways previously not imagined. By extending and retracting their ramified processes, microglia constantly scavenge, monitor and modulate the brain environment  are especially suitable for studying early brain development and pediatric disease: the embryos develop rapidly, ex utero, are transparent, and it is now generally accepted that all the major glial cells known in mammals  related to recessive genetic variants in TREM2 and DAP12/TYROBP, and leukodystrophies related to recessive genetic variants in the LRRC33  or USP18 genes. Next, we will address lysosomal and peroxisomal leukodystrophies, including metachromatic leukodystrophy (MLD), X-linked adrenoleukodystrophy (X-ALD) and globoid cell leukodystrophy (GLD), also known as Krabbe disease, that all show beneficial responses to HSCT. Based on the overlapping pathological features of these two groups, we will describe possible mechanisms, supported by circumstantial evidence, through which aberrant microglia could lead to white matter abnormalities and overall disturbance of brain health. We argue that studying these diseases provides a unique opportunity to elucidate the putative roles of microglia in modulating myelin development and maintenance, while expanding our understanding of the detrimental effects caused by aberrant microglia in the human brain.We will compare the cellular pathology of two groups of leukodystrophies to build a case for a more global involvement of microglia in neuropathology and, in doing so, highlight the broad promise of this glial cell type as a therapeutic target. First, we will describe microgliopathies, which are white matter diseases believed to be caused primarily by microglial abnormalities , includiCSF1R, TREM2, TYROBP, LRRC33/NRROS or USP18 can be categorized as primary microgliopathies  and later as hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) . Followi8+ cells . The dev regions , a phenopatients . AltogetCSF1R variants and reminiscent of those observed in Csf1r-deficient zebrafish, mouse and rat models, which may additionally affect brain development  or DNAX activating protein of 12 kDa (DAP12), also known as TYRO protein kinase-binding protein (TYROBP) , was described in the early 1970s by (TYROBP)  Fig. 2)TREM2) or(TYROBP) . Both TR(TYROBP) , NHD is (TYROBP) . Ligands(TYROBP) . TREM2 i(TYROBP) . TREM2 itabolism . Microgllination . TREM2-dlination . Hence, Trem2−/− or Dap12−/− mice, microglia numbers are typically reduced during early development but differences from wild-type mice are largely absent at later stages  at the cell surface and is required for the activation of TGF-β1 in macrophages and microglia  Fig. 2)Fig. 2). icroglia .Lrrc33 knockout mice show increased CD68+ microglia numbers with an altered hypertrophic morphology, along with upregulated cell division and interferon signaling pathways , a type of genetic disorder termed a type I interferonopathy, which causes death within days after birth (+ and HLA-DR+ microglia throughout the brain (Usp18-deficient mice exhibit an elevated number of microglia that appear to have engulfed oligodendrocytes (Ubiquitin specific protease 18 (USP18) is a negative regulator of the type 1 and 3 interferon (IFN-I) pathway by binding to the intracellular domain of interferon alpha and beta receptor subunit 2 (IFNAR2)  Fig. 2)Fig. 2). tivation . Converstivation . Microglf myelin  and presf myelin . These mf myelin  and low f myelin . Homozyger birth . A striker birth . Immunohhe brain . Additiodrocytes .LRRC33/NRROS and USP18-related microgliopathies reveal that deficiencies in key microglial immune signaling pathways, in this instance TGF-β and interferon signaling, lead to phagocytic abnormalities in the brain and a consequent reduction in brain integrity and function, with particular involvement of the white matter.Despite differences in their underlying mechanisms, There is strong evidence indicating that microglial involvement in leukodystrophies is caused by lysosomal or peroxisomal defects. Lysosomes are key metabolic hubs for the recycling of macromolecules and metabolites . ImpairmARSA gene that lead to deficiency of arylsulfatase A (ASA), a lysosomal enzyme that digests sulfatides – glycosphingolipids that are highly enriched in myelin sheaths  half-transporter ALDP, resulting in the failed transport of very long-chain fatty acids (VLCFA) into the peroxisome  disease . The res disease . X-ALD iroxisome  roxisome . This ulroxisome . The estroxisome .Galc−/− mice and in postmortem spinal cord tissue of GLD patients. In mutant mice, Schwann cells, the myelinating cells of the PNS, require lysosomal Galc to maintain myelin and axonal integrity, and are unable to receive enzyme from the surrounding environment, partly due to ineffective uptake. GLD patients who received HSCT showed an improvement in axonal integrity and myelin thickness, as well as a reduction of phagocytic CD68+ microglia, fewer multinucleated phagocyte clumps  and reduced substrate accumulation in macrophages , in which abnormal microglia are typically seen in very early embryogenesis, right at the stages at which they seem to shape brain development , which is characterized by a severe reactive astrocyte phenotype, including hypertrophic GFAP+ processes and astrocytic cytoplasmic inclusions of GFAP called Rosenthal fibers (Drosophila AxD model (+ astrocytes are also abundantly present in microglia-related leukodystrophies, and glutamate toxicity is a known cause of axon pathology, a similar astrocyte phenotype could partly underlie the white matter defects in microglia-related leukodystrophies (Important clues on the impact of aberrant astrocytes on white matter integrity come from astrocyte-related leukodystrophies. Gain-of-function mutations in l fibers . AxD moul fibers , which ixD model . AstrocyxD model . ExcessixD model . As elevtrophies . Deposittrophies . Hyalurotrophies , Fig. 3 trophies . Microgltrophies . Hence, in vivo cell biological observations are still challenging, and developmental processes in particular are relatively obscured. Cerebral organoids derived from iPSCs are improving but are not yet able to effectively model myelination and the native interactions of multiple glial cell types. The zebrafish has repeatedly proven its value as a system for unparalleled developmental observations of in vivo cellular mechanisms, and its many unique advantages readily complement data obtained through other model systems (CSF1R-related leukodystrophy (RNASET2-related leukodystrophy (Looking forward, it will be important to combine and compare data from diverse models, human material and clinical observations of disease to improve insight into the cellular brain. Rare brain diseases can give unique and precious clues into human genetics, physiology and pathology. Nevertheless, high quality postmortem brain tissue is very rare, and studies often allow only limited quantitative analysis. So far, the majority of available leukodystrophy animal models have been mice. Hence, their neuropathological and clinical features are thoroughly characterized. Mouse models allow thorough investigation by highly standardized techniques and reagents in a well-characterized system. Yet, despite the substantial advantages of mouse models, direct  systems . Especia systems . The maj systems  and have systems . Indeed, systems , includiystrophy , 2019 anystrophy , and theystrophy .CSF1R-related leukodystrophies and CSF1R-deficient animal models could assist in deducing the consequences of the absence or local depletion of macrophages and microglia on the human brain.Leukodystrophies involving microglia raise intriguing hypotheses regarding the impact of macrophages and microglia on the developing and adult brain, in particular on myelination. In addition, they may help provide insight regarding the issues of optimal macrophage and microglia enhancement or depletion strategies that, although avoiding detrimental side effects related to macrophage function, could treat human disease. It is now clear that depleting microglia, at least temporarily via CSF1R inhibitors, can be beneficial in mouse models of Alzheimer's disease, and therefore has clinical potential. Conversely, studies of rare human disease complemented by zebrafish and rodent disease models has demonstrated that there are undoubtedly negative effects associated with microglial depletion. Therefore, understanding the breadth of roles microglia have in normal human brain development and in the maintenance of adult brain health would be very helpful to further fine-tune methods of modulating microglia in disease to mitigate disease progression and benefit recovery. Insight from CSF1R function, skeletal abnormalities are identified across vertebrate model systems. It is unclear whether this bone phenotype could contribute to the neuropathology, opening up intriguing opportunities for future research.It is clear that several important questions remain to be answered regarding how microglia, as well as peripheral macrophages, affect myelin development and the maintenance of white matter and brain health in both development and adult life. For example, defective osteoclasts and other macrophage populations can lead to skeletal abnormalities, as observed in some of the leukodystrophies described here. Skeletal abnormalities are present in several microglia-related leukodystrophies and are likely caused by abnormal osteoclast populations, which originate from similar hematopoietic progenitors as other macrophages and microglia . In the Integrating the application of novel methods on postmortem brain tissue of patients, including single-cell and high-throughput genomic, proteomic and metabolomic approaches with genetic model systems, in particular the zebrafish, will aid in unraveling how both microglia and other brain cell types modulate white matter integrity and overall brain health. Importantly, rare genetic brain disorders provide a unique window into human brain physiology and continue to provide clues to the inner workings of the brain and to potential avenues of therapeutic modulation that may be pursued for a broad range of neurological diseases.


Subtotal resection of the esophagus with resection of local lymph nodes is the oncological procedure of choice for advanced esophageal cancer. Reconstruction of the intestinal tract is predominantly performed with a gastric tube. Even in specialized centers, this surgical procedure is associated with a high complication but low mortality rate. Therefore, clinical research aims to develop peri- and intra-operative strategies to improve the patient related outcome.Transthoracic esophagectomy is currently the predominant curative treatment option for resectable esophageal adenocarcinoma. The majority of carcinomas present as locally advanced tumors requiring multimodal strategies with either neoadjuvant chemoradiotherapy or perioperative chemotherapy alone. Minimally invasive, including robotic, techniques are increasingly applied with a broad spectrum of technical variations existing for the oncological resection as well as gastric reconstruction. At the present, intrathoracic esophagogastrostomy is the preferred technique of reconstruction (Ivor Lewis esophagectomy). With standardized surgical procedures, a complete resection of the primary tumor can be achieved in almost 95% of patients. Even in expert centers, postoperative morbidity remains high, with an overall complication rate of 50–60%, whereas 30- and 90-day mortality are reported to be <2% and <6%, respectively. Due to the complexity of transthoracic esophagetomy and its associated morbidity, esophageal surgery is recommended to be performed in specialized centers with an appropriate caseload yet to be defined. In order to reduce postoperative morbidity, the selection of patients, preoperative rehabilitation and postoperative fast-track concepts are feasible strategies of perioperative management. Future directives aim to further centralize esophageal services, to individualize surgical treatment for high-risk patients and to implement intraoperative imaging modalities modifying the oncological extent of resection and facilitating surgical reconstruction. According to international and national guidelines, surgery is generally accepted as the mainstay of curative treatment for esophageal adenocarcinoma ,2,3. In As the surgical part of the multimodal concept, transthoracic esophagectomy with gastric reconstruction is currently considered to be the gold standard for esophageal adenocarcinoma ,12. WithWith respect to well-established prognostic factors of long-term outcome, the fundamental significance of oncological esophagectomy remains to achieve a complete resection of the primary tumor (R0 resection) and to perform an adequate lymphadenectomy (LAD), both in order to reduce the risk of locoregional or distant recurrent disease. In the majority of observational registry analyses, transthoracic esophagectomy yields a sufficiently high R0 resection rate usually exceeding 95% ,15. In cIrrespective of possible technical modifications, considerable postoperative morbidity and mortality have been reported for transthoracic esophagectomy, even in expert centers with a caseload above average ,15,17. IThis review aims to summarize the present evidence on surgical strategies currently applied for esophageal adenocarcinoma, but also to point towards unsolved questions associated with the surgical management of this tumor entity. Finally, a brief prospect will be given on possible future developments expected in this distinct field of surgical oncology.More than 80% of patients with esophageal adenocarcinoma receive some kind of neoadjuvant treatment prior to esophagectomy, and at the present it is not clear whether chemoradiotherapy and/or chemotherapy alone should be considered as a potential risk factor for postoperative morbidity. Several observational studies indicate that physical function deteriorates during multimodal treatment. In a prospective cohort study, the cardiopulmonary function was assessed using exercise testing in esophageal cancer patients before and after neoadjuvant chemotherapy and chemoradiotherapy . For botSarcopenia, defined as a state of severe muscle loss and function, has been clearly identified as risk factor of perioperative morbidity, and primarily reflects the reduced nutritional intake often associated with esophageal adenocarcinoma. In a recent meta-analysis including 29 studies with more than 3000 patients, sarcopenic patients had a higher incidence of pulmonary complications . HoweverIn a recent meta-analysis summarizing data from 39 eligible studies, various patient-related factors associated with major postoperative complication and mortality were identified . These iThe International ESODATA Study Group (IESG) database analyzed 8403 esophagectomies with an overall 30- and 90-day mortality rate of 2.0 and 4.2%, respectively [In summary, advanced age, the patient’s general condition, and the number of comorbidities remain the predominant predictors of a poor postoperative outcome and should be taken into account for the selection of patients undergoing oncological esophagectomy. The knowledge of validated risk factors and the appropriate selection process prior to esophagectomy is still the method of choice to achieve a low mortality rate. However, since a clear-cut score has not been established yet, the decision making in terms of esophagectomy is ultimately left to the surgeon’s personal experience and discussion with the patient at the preoperative evaluation.Prehabilitation summarizes the concept of conditioning single-organ dysfunctions in the preoperative period in order to facilitate postoperative rehabilitation and to improve surgical outcome. For esophageal cancer patients, predominant organ dysfunctions comprise an impaired pulmonary function, a poor nutritional status and a reduced physical fitness with a compromised cardiovascular reserve. Due to the potential of prehabilitation concepts to reduce postoperative morbidity, this emerging field has gained increasing scientific interest. However, current literature demonstrates a significant heterogeneity between studies, with a broad variety of preoperative interventions, timelines and outcome measures reported . So far,Fast-track protocols  intend to perioperatively maintain the physiological homoeostasis and thereby accelerate postoperative rehabilitation and reduce morbidity. Enhanced recovery after surgery (ERAS) protocols when compared to standard care pathways are gaining increasing interest in the perioperative management of esophageal cancer patients but have not reached the level of complete implementation, even amongst specialized centers yet.In a recently published meta-analysis, four randomized controlled and four nonrandomized, prospective trials with a total of 1133 patients (599 ERAS and 534 standard pathways) were eligible for further analysis . The oveFor esophageal adenocarcinoma, the esophageal resection can be performed via a transthoracic or a transhiatal approach, and is usually followed by a gastric-tube reconstruction ,40. A trThere is only one randomized controlled trial that compared outcomes of transthoracic (right thoracotomy) and transhiatal surgery in patients with an adenocarcinoma of the mid or distal esophagus ,48. ThisSince the results of the TIME trial were published in 2012, minimally invasive esophagectomy has enjoyed increasing interest worldwide . This trThe 2019 MIRO trial compared the open transthoracic procedure with a hybrid approach, in which the abdominal phase was performed laparoscopically and the thoracic phase open . The stuA third randomized controlled trial, the ROBOT trial, compared robot-assisted minimally invasive esophagectomy (RAMIE) with an open transthoracic procedure. The RAMIE approach consisted of a robot-assisted thoracoscopic phase and a laparoscopic abdominal phase . PulmonaThe superiority of either completely minimally invasive surgery, hybrid surgery or RAMIE over open surgery has been demonstrated in several observational clinical trials ,61,62. TWhen performing a transthoracic esophagectomy with gastric tube reconstruction, the anastomosis can be placed in the cervical (McKeown procedure) or intrathoracic compartment (Ivor Lewis procedure). Next to disease specifications, such as the exact location of the primary tumor and possible location of lymph node metastasis, surgeon preferences play a large role in the choice for a McKeown or Ivor Lewis procedure. From the ESODATA database, in which 24 high-volume centers from 14 countries register their esophagectomies, it emerges that over 60% of anastomoses are placed intrathoracically ,72. ReceInternational literature on the surgical treatment of esophageal cancer is abundant and mainly focusses on decreasing the considerable postoperative mortality and morbidity. However, postoperative morbidity rates have been reported to be as low as 17% and as high as 74% . Such heThe ECCG also maintains a database in which 24 high-volume centers from 14 countries register detailed esophagectomy information: the ESODATA database . Using EAdditionally, the identification of interhospital variation in clinical practice and outcomes of different hospitals within one country may pave the way towards nationwide quality improvement ,84,85,86The use of composite outcome measures should also be promoted in esophageal cancer surgery. Composite outcome measures combine multiple single outcome measures into one. This has several advantages, firstly, composite outcome measures are easier to interpret for clinicians and for patients. For example, textbook outcome  can be interpreted as a completely successful and uneventful operation . BesidesNext to measuring the clinical or oncological success (such as textbook outcome), health-related quality of life (HR-QoL) is an important outcome of esophageal cancer surgery. Since overall survival has improved in recent years, HR-QoL has gained increasing interest. HR-QoL can be measured using patient-reported outcome questionnaires. Currently, the most frequently used questionnaires are those from the European Organization for Research and Treatment of Cancer (EORTC) . The EOREsophageal cancer surgery severely impacts HR-QoL, but generally, HR-QoL restores to baseline levels after 1 year postoperatively . The occOver recent decades, evidence has been accumulating that higher case-volume results in improved short- and long-term patient outcomes after complex visceral surgery ,99,100. In this context, it has to be taken into consideration that the simple number of esophagectomies per year may not directly translate into better quality of care, and it has been shown that a positive volume-outcome effect of centralization even turns negative after reaching a certain annual caseload . TherefoPartial gastric devascularization prior to esophagectomy is a relatively new concept in esophageal surgery. The idea of ischemic conditioning (IC) is to optimize the gastric blood flow in preparation for later esophagectomy through preoperative selective occlusion of the left gastric ± short gastric arteries. Devascularization is accomplished by either surgical ligation or interventional embolization . The resTreatment of AL after esophagectomy has considerably progressed in recent years, and surgical revision has been largely replaced by interventional procedures. In addition to stent placement, endoluminal vacuum therapy (EVT) has become the treatment of choice in many specialized centers . In EVT,A novel concept is the application of EVT technology in a preemptive setting (pEVT) with the aim of preventing AL and reducing postoperative morbidity. The clinical efficacy and feasibility of pEVT in patients undergoing minimally invasive esophagectomy have recently shown excellent patient safety outcome parameters ,112. In Assessment of the viability of the tubulized stomach as an esophageal substitute typically relies on intraoperative subjective evaluation by the surgeon. A healthy gastric tube features rosy-colored tissues, a pulsating vascular arcade, and active bleeding from the staple line. However, depending on vascularization, vasoconstriction, fluid management, catecholamine dosage, and the actual hemodynamic situation, local ischemia is a frequent finding. Therefore, a range of innovative tools for intraoperative assessment of gastric tube viability has been developed over the last years: Laser Doppler flowmetry, near infrared spectroscopy, optical coherence tomography, and laser speckle contrast, infrared thermographic, fluorescence, and hyperspectral imaging. Some of these tools have become commercially available, and preliminary retro- and pro-spective cohort studies  and a reArtificial Intelligence (AI) in surgery is becoming increasingly popular in surgical literature, and well-recognized surgical units across the world have established their own working groups based on this topic. The Surgical Artificial Intelligence and Innovation Laboratory (SAIIL), consisting of upper gastrointestinal surgeons of Harvard Medical School and Engineers of MIT, has set the first standards to follow . At the When looking at AI and surgical therapy of esophageal adenocarcinoma specifically, it becomes clear that the literature is lacking in true surgical reports. Autonomous surgical robots are still far away from reality . EspeciaWith respect to the multimodal treatment of esophageal adenocarcinoma, the main tasks of transthoracic esophagectomy are (1) to achieve a complete resection of the primary tumor with a sufficient clearance of nodal metastasis, (2) to perform this complex surgical procedure without mortality and an acceptable low morbidity, and (3) to offer patients a reasonably high standard of HR-QoL postoperatively. Since the overall caseload remains limited even in specialized centers, an increasing effort is mandatory to develop national and international collaborations for the successful initiation of high-quality surgical trials. All future directives and associated clinical research projects need to address one of these three fields of esophageal cancer surgery to contribute to a general improvement in the patient-related outcome.


Atrial fibrillation is very common among the elderly and/or obese. While myocardial fibrosis is associated with atrial fibrillation, the exact mechanisms within atrial myocytes and surrounding non-myocytes are not fully understood. This review considers the potential roles of myocardial fibroblasts and myofibroblasts in fibrosis and modulating myocyte electrophysiology through electrotonic interactions. Coupling with (myo)fibroblasts in vitro and in silico prolonged myocyte action potential duration and caused resting depolarization; an optogenetic study has verified in vivo that fibroblasts depolarized when coupled myocytes produced action potentials. This review also introduces another non-myocyte which may modulate both myocardial (myo)fibroblasts and myocytes: epicardial adipose tissue. Epicardial adipocytes are in intimate contact with myocytes and (myo)fibroblasts and may infiltrate the myocardium. Adipocytes secrete numerous adipokines which modulate (myo)fibroblast and myocyte physiology. These adipokines are protective in healthy hearts, preventing inflammation and fibrosis. However, adipokines secreted from adipocytes may switch to pro-inflammatory and pro-fibrotic, associated with reactive oxygen species generation. Pro-fibrotic adipokines stimulate myofibroblast differentiation, causing pronounced fibrosis in the epicardial adipose tissue and the myocardium. Adipose tissue also influences myocyte electrophysiology, via the adipokines and/or through electrotonic interactions. Deeper understanding of the interactions between myocytes and non-myocytes is important to understand and manage atrial fibrillation. Atrial fibrillation is characterized by chaotic, ectopic electrical activity and uncoordinated contraction . It is sThe 2017 Heart Rhythm Society Consensus Statement defines nine types of atrial fibrillation, including episodic, paroxysmal and persistent forms ; the varIncreasing age , inflammThe association of atrial fibrillation with obesity opens a new avenue of investigation. Adipose tissue present on the epicardial surface is in direct contact with the myocytes and fibroblasts within the myocardium. Adipocytes, fibroblasts and myocytes are known to be in chemical communication. Epicardial adipose tissue also infiltrates the myocardium, influencing the architecture . Such faThis review will consider the role non-myocytes play in modulating the extracellular matrix and myocytes in the pathophysiology underpinning atrial fibrillation. Interactions among myocytes, (myo)fibroblasts and epicardial adipose tissue will be explored, studying how the physical, chemical and electrotonic interplay may lead to fibrosis and both trigger and perpetuate atrial fibrillation.Under healthy conditions, the myocardium is protected from developing re-entry loops which would give rise to fibrillation. However, with aging, the amount of fibrosis increases ,15. InflCardiac muscle exists as an electrical syncytium, in which the sequence of muscle activation optimizes efficient ejection while minimizing the risk of re-entry loop formation. The orderly sequence of action potentials across the myocardium is determined by the architecture of the myocardium and the biophysical properties of myocytes . The extWhile fibroblasts are the most populous cell type in the heart, the relative volume of fibroblasts is very small when compared to myocytes, particularly in the ventricles ,28. The Wound healing is associated with activation of fibroblasts to a ‘super-charged’ phenotype, myofibroblasts ,29,30. LFibrosis within the heart may occur in many forms , includiReactive fibrosis is primarily interstitial, surrounding myocytes in increasing amounts of perimysial collagen . EndomysIn addition to fibroblasts interacting with myocytes mechanically through the extracellular matrix and via chemical signaling, numerous studies have considered the effect of electrical coupling between these two populations. Both fibroblasts and myofibroblasts produce connexins and form gap junctions with neighboring cells within the myocardium. The current evidence supports homocellular, as well as heterocellular gap junctions forming within (myo)fibroblasts and myocytes ,40,41,42Unlike cardiac myocytes, cardiac (myo)fibroblasts are not excitable cells. They express a number of voltage- and ligand-gated, mechanosensitive, store-operated and transient receptor potential (Trp) channels mediating sodium, potassium, calcium and chloride currents, which modulate membrane potential and cell function fibroblasts has been predicted to act as current sinks ,25,26,45Heterocellular coupling between (myo)fibroblasts with myocytes has been demonstrated under culture conditions by dye coupling, loss of excitability in coupled myocytes when a large current was selectively activated in co-cultured myofibroblasts  and passDemonstrating coupling in vivo has been more difficult. In an elegant study using selective optogenetic expression of voltage-sensitive fluorescent dye in fibroblasts, myofibroblasts or myocytes, Quinn et al.  providedGiven that the atria have higher concentrations of fibrous tissue relative to the myocyte layers , electroIn the fibrotic myocardium, electrical spread across both excitable myocytes and non-excitable (myo)fibroblasts may represent a secondary mechanism to ensure that the endo- and perimysium do not undermine the electrical syncytium. In the healthy myocardium, this is not likely to be an issue, as the extracellular matrix is small relative to the myocyte volume. However, in atrial fibrillation, reactive and reparative fibrosis may impair myocyte-to-myocyte coupling and so, secondary coupling via (myo)fibroblasts may be of particular importance.Elegant studies by Miragoli, Gaudesius, Thomas and Rohr ,21 have These findings strongly suggest that under pathological conditions such as fibrosis and inflammation, electrotonic interactions between myocytes and (myo)fibroblasts may contribute to initiation and propagation of re-entry circuits, contributing to atrial fibrillation ,34. HoweObesity is a known risk factor for the development and progression of atrial fibrillation ,51. EpidEpicardial adipose tissue is found between the visceral layer of the serous pericardium and the epicardial surface of the heart, in intimate contact with the myocardium . It is dEpicardial adipose tissue varies across species as well. In small mammals such as rats A,B and mEpicardial adipose tissue is home to adipocytes, preadipocytes, fibroblasts and in healthy human hearts, a small population of macrophages ,65. It sIn addition to lying along the epicardial surface of the myocardium, epicardial adipose tissue is also found within the myocardium as fatty infiltrates. Even in cardiac samples from healthy human and other large mammals, fatty infiltrates of the myocardium appear common . In atriEpicardial adipose tissue is thought to play a number of important roles in the healthy heart. It provides a quick source of energy for the myocardium, as well as reducing the risk of lipotoxicity . EpicardThe thermogenic nature of epicardial adipose tissue is an intriguing aspect of its function. Adipose tissue is generally classified as brown or white, depending primarily on whether the adipocytes participate in thermogenesis. Brown adipose tissue is commonly found in infants and lost as the individual ages .Another phenotype has been described, ‘beige’ or ‘brite’ (‘brown-in-white’) adipose tissue, in which white adipocytes express ‘brown’ genes and characteristics, including uncoupled respiration and increased thermogenic potential ,73,74,75Aging and disease states appear associated with a phenotypic change from brown to white adipose tissue, which is linked to inflammation and lipid dysregulation ,74. For An intriguing question is whether the intimately associated epicardial adipocytes may form homocellular gap junctions within adipose tissue (both surface and the infiltrates) and heterocellular gap junctions with myocytes and/or fibroblasts within the adjacent myocardium. If so, then the epicardial adipose tissue may directly contribute to the creation of a heterogenous electrical environment in atria at risk of atrial fibrillation. Notably, gap junctions have been demonstrated in epicardial fat in hamsters ,81. MoreIn addition to being in direct contact with (myo)fibroblasts and myocytes within the myocardium, epicardial adipose tissue also participates in chemical communication. Adipokines within the epicardial adipose tissue secretome modulate leukocytes and fibroblasts within the adipose tissue as well as leukocytes, fibroblasts and myocytes in the associated myocardium. Numerous adipokines such as omentin, apelin and adiponectin are anti-fibrotic and anti-inflammatory, while others such as resistin, adipose fatty-acid-binding protein and visfatin are pro-inflammatory. Leptin may be protective or associated with pathological changes ; increased late sodium current and L-type calcium current; and reduced transient outward, delayed rectifier and inwardly rectifying potassium currents. Treatment with conditioned media from epicardial adipose tissue produced similar but less pronounced changes to the myocyte electrophysiology. Intriguingly, these authors noted that myocytes were rarely observed in direct contact with adipocytes in co-culture. This observation suggests that the enhanced effect of co-culture was not due to direct electrotonic interactions . Heart fOf relevance to this discussion are studies of adipocyte-derived stromal multipotent cell therapy in hearts damaged by myocardial infarction. Such stem cell therapy is promising in restoring myocardial function but holds a risk of evoking dysrhythmias through chemical or electrotonic interactions with myocytes. Using monolayers of cultured rat neonate ventricular myocytes, ten Sande et al.  tested tAtrial fibrillation is associated with fibrosis, changes in myocyte action potential duration, heterogeneity of conduction velocity, generation of triggered activity and re-entry loops. Pathological changes in epicardial adipose tissue and differentiation of fibroblasts to myofibroblasts are associated with fibrosis and are likely to play a role in the pathogenesis of atrial fibrillation associated with fibrosis.Numerous studies suggest that myocytes may interact chemically and electronically with non-myocytes. Key non-myocyte populations in the atria are (myo)fibroblasts and epicardial adipose tissue A. In silNumerous challenges arise when investigating the mechanistic unpinning of atrial fibrillation. One challenge is that atrial fibrillation may take many forms, which may reflect distinct underlying pathophysiologies. Studies of human patients suffering from atrial fibrillation generally include those experiencing paroxysmal or persistent atrial fibrillation. These participants are commonly grouped without distinction being made of which type of fibrillation the patients were experiencing. Furthermore, variability among human participants reduces the ability of studies to delineate clear mechanistic cause and effect, compared to non-human animal models.Another challenge lies in the choice of the correct non-human animal model for mechanistic studies. Small animal models may be useful when studying cardiac physiology. In particular, murine models are relatively low cost, readily available and have the potential for genetic manipulation through the production of transgenic mice ,107. RatGuinea pigs and rabbits have also been used and are considered to be a better representation of human atrial fibrillation. However, larger mammals such as goats, sheep and pigs in particular have hearts which more closely resemble the human heart anatomical structure, including more extensive epicardial adipose tissue . Hearts While atrial fibrillation in these larger species’ hearts have closer resemblances to human atrial fibrillation, there are limitations for their use such as cost, housing and ethical constraints . All of There are many questions yet to be answered. The exact phenotype of epicardial adipose tissue varies with location in the heart, age and disease. It appears to have a brown/beige/brite phenotype in health and switches to white adipose tissue with age and disease. The phenotype is relevant as brown/beige/brite adipose tissue express more gap junctions, when compared to white adipose tissue. It is not clear whether adipocytes are capable of forming functional gap junctions with adjacent (myo)fibroblasts and/or myocytes. If so, then electrotonic modulation of myocyte electrophysiology is likely, similar to that observed with (myo)fibroblasts and myocytes. If heterocellular coupling does exist with adipocytes fibroblasts could be studied in co-culture experiments similar to those of Gaudesius et al.  and MiraIt is also clear that in vitro systems cannot easily replicate the in vivo complexity of adipose tissue , fibrous tissue with attendant (myo)fibroblasts and myocytes. Optogenetic studies of atria as well as microelectrode studies of fresh intact atrial tissue may provide a way forward, in both human biopsies and non-human animal models of atrial fibrillation with comorbidities such as obesity.Another key direction for future studies is to determine what controls the switch in epicardial adipose tissue from cardioprotective (anti-inflammatory and anti-fibrotic) to pathological . This phenotypic switch is likely to vary with comorbidity . For example, it may occur more rapidly in patients with obesity and diabetes, compared to diabetes or obesity alone. The complex interplay between electrical, mechanical/architectural and chemical interactions between adipose tissue, myocytes and (myo)fibroblasts is likely to vary with such comorbidities, as well as showing regional  differences.Two avenues of research which will help delineate the complex interplay and changes associated with fibrosis, non-myocytes and myocytes in development and perpetuation of atrial fibrillation are genetic and epigenetic studies. The role that genetics play in atrial fibrillation is gaining momentum and candidate genes are being identified in which mutations and polymorphisms such as single nucleotide polymorphisms (SNPs), are associated with atrial fibrillation ,117.Most studies identifying candidate genes have been in patients experiencing lone atrial fibrillation with no underlying disease ,119. TheEpigenetics is another mechanism by which gene expression is controlled and subsequently can play a role in diseases . Of the Understanding these complex interactions may help understand the initiation and progression of atrial fibrillation. Adipose tissue and fibroblasts may represent important therapeutic targets in managing atrial fibrillation and preventing disease progression.


The kidneys carry out fundamental life-sustaining functions by removing waste substances, controlling salt and water balance, retaining substances vital to the body such as glucose and proteins, and maintaining blood pH balance . By perfBiomolecules entitled “Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease”, we have collected 11 papers that cover a variety of topics focusing on oxidative stress, mitochondrial dysfunction, and antioxidation enhancement implicated in kidney disease or kidney transplantation. To fend off the abovementioned insults, it is necessary to understand the underlying mechanisms of redox imbalance, oxidative stress, and mitochondrial abnormalities involved in kidney disease. In this Special Issue of +/NADH redox imbalance and their roles in diabetic kidney disease (DKD) [+/NADH redox imbalance leads to the disruption of mitochondrial homeostasis, and an increase in nephron oxidative damage that culminates as diabetic nephropathy reflected by deteriorating kidney functions. While mitochondrial oxidative stress is a central event in DKD, it is also hypothesized by Yan and Allen to be a unifying mechanism underlying cadmium-induced kidney toxicity [Among the 11 papers, seven are review articles, and four are original research articles. Yan reviewed the sources of NADse (DKD) . The gistoxicity  that maitoxicity . In the article “Glucose- and non-glucose-induced mitochondrial dysfunction in diabetic kidney disease” , Ito et Given that mitochondrial redox imbalance and oxidative stress are the central themes of kidney disease, it is natural to explore therapeutic approaches that can counteract kidney injury by mitigating oxidative stress and mitochondrial dysfunction. Indeed, several papers in this Special Issue have just explored such approaches. For example, the role of SGLT2 inhibitors as antioxidants in the kidney was reviewed by Liorens-Cebria et al. . AdditioIn summary, mitochondrial oxidative stress and redox imbalance drive renal mitochondrial abnormalities, which can be attributed to the over-production of mitochondrial reactive oxygen species. As summarized by Aranda-Rivera et al. and Ito et al. in their review articles published in this Special Issue ,12, nume