Myocardial infarction (MI) results in dysfunction and irreversible loss of cardiomyocytes and is among the most serious health threats today. Bone marrow mesenchymal stem cells (BMSCs), with their capacity for multidirectional differentiation, low immunogenicity, and high portability, can serve as ideal seed cells in cardiovascular disease therapy. In this review, we examine recent literature concerning the application of BMSCs for the treatment of MI and consider the following aspects: activity of transplanted cells, migration and homing of BMSCs, immunomodulatory and anti-inflammatory effects of BMSCs, anti-fibrotic activity of BMSCs, the role of BMSCs in angiogenesis, and differentiation of BMSCs into cardiomyocyte-like cells and endothelial cells. Each aspect is complementary to the others and together they promote the repair of cardiomyocytes by BMSCs after MI. Although transplantation of BMSCs has enabled new options for MI treatment, the critical issue we must now address is the reduced viability of transplanted BMSCs due to inadequate blood supply, poor nourishment of cells, and generation of free radicals. More clinical trials are needed to prove the therapeutic potential of BMSCs in MI. Cardiovascular disease is a major problem harmful to human health worldwide due to its high incidence. In the event of acute myocardial infarction (MI) or other heart diseases, the number of surviving cardiocytes declines. With the formation of fibrous cicatricial tissue and remodeling of ventricular tissue after MI, the contraction ability of the myocardium declines. Eventually, the decline in cardiac function may induce the reoccurrence of heart failure as a further threat to life. Although thrombolysis, coronary implantation of stents, and coronary artery bypass grafting have been used to treat MI clinically, these methods cannot reverse the damage to infarcted myocardium or improve heart function fundamentally. Finding a method to improve cardiac function through regeneration of damaged and nonfunctioning myocardium has therefore become a new direction for research. In recent decades, scientists have exerted great effort and energy into the use of stem cells to repair damaged myocardium and restore cardiac function. Currently, transplantation of exogenous stem cells into infarcted myocardium is regarded as a promising route for treating MI. Bone marrow mesenchymal stem cells (BMSCs) have emerged as the primary research focus among all of the various types of stem cells examined. A recent study has shown that pharmacological activation of the exchange protein directly activated by the cAMP (Epac)/Rap1 signaling pathway improved cardiac function through better survival, adhesion, and differentiation of transplanted BMSCs in rat . The appMI is a disease that seriously threatens people’s health. Degeneration of cardiac tissues, a major cause of mortality in the western world, is likely to become a greater problem in the forthcoming decades. Cardiac damage is associated with dysfunction and irreversible loss of cardiomyocytes . At presMesenchymal stem cells (MSCs), originating from mesoderm adult stem cells, retain the ability to amplify and self-renew in vitro and differentiate into cartilage, fat, bone, and nerve cells under certain conditions. MSCs are in great demand because of their low immunogenicity and immunomodulatory capacity, effectively reducing or avoiding immune rejection. MSCs can be derived from a variety of tissues including bone marrow, fat, muscle, and synovial membrane. Among all MSCs examined, BMSCs are the most popular in application because of their obvious advantages. In addition to their relatively easy acquisition from an extensively rich resource, BMSCs are free from ethical issues because they can be transplanted autologously. Furthermore, the relatively simple cultivation and separation, rapid proliferation, and high genetic stability of BMSCs allow for their easy amplification in vitro. Finally, their capacity for multidirectional differentiation, low immunogenicity, and high portability make BMSCs ideal seed cells for therapy of cardiovascular diseases. Because of the activity of chemotactic protein stromal cell derived factor 1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4), BMSCs have the ability for automatic homing on the infarction area after transplantation –9, signiAfter MI, the ischemic anoxic environment seriously affects the survival of transplanted cells. In-depth research into BMSC transplantation in the treatment of MI has led to the realization that the effect of single-cell transplantation is limited. Therefore, researchers have tried to improve the harsh environment after infarction and enhance the capacity of transplanted cells to resist ischemic anoxia. Numerous studies discussed in the following have reported that hypoxic preconditions, various drug combinations, and joint cytokine and gene transfection treatments can improve the anti-oxidative stress capacity of transplanted BMSCs and increase their survival rate.As a novel strategy for preconditioning BMSCs, treatment with hypoxia-inducible factor (HIF)-1α and the prolyl hydroxylase inhibitor dimethyloxalylglycine has been shown to greatly improve the cell survival rate in vivo and in vitro, and to reduce the area of MI to enhance the effect of cell therapy . Some re2 for 24 h and found that the migration and homing of hypoxia-treated cells to the site of myocardial injury was enhanced significantly, which may be connected to Kv2.1 channel and focal adhesion kinase activation in vitro. Cheng et al. [In addition to cell viability, migration and homing of BMSCs is another crucial factor that influences their therapeutic effect. BMSCs demonstrate a migratory tendency to infarcted myocardial tissues after transplantation through the intravenous route, which can obviously delay deterioration in cardiac function caused by LV remodeling. However, because of the need to reach the infarction area by blood circulation, this method requires an excessive quantity of injected cells, which may cause venous embolism in a rat model . Therefog et al.  demonstrMSCs possess the features of weak immunogenicity and antigen-presenting ability as a consequence of low expression of major histocompatibility complex (MHC) class II molecules and Fas ligand and no expression of MHC class I molecules, which enables MSCs to inhibit T-cell proliferation , resultiAs a type of MSC, BMSCs can also suppress the inflammatory response after MI. A study demonstrated that exosomes were the active ingredient of paracrine secretion by BMSCs, which stimulated neovascularization, restrained the inflammatory response, and improved cardiac function after ischemic injury in vitro and in vivo . Hsu et After the occurrence of MI, many cardiocytes die and are replaced by fibroblasts in the infarcted area. Heart failure is triggered by LV remodeling and arrhythmia, which is a major cause of cardiovascular death. Stem cells can inhibit the activation of fibroblasts, reduce the deposition of collagen and other extracellular matrix, thereby reducing LV remodeling, and improve cardiac function after MI mainly by regulating matrix metalloproteinases and inhibitors of matrix metalloproteinases. HGF, a well-known anti-fibrosis factor, was demonstrated to be a major contributor to the anti-fibrosis function of MSCs in vitro . AnotherAngiogenesis, an important process in the treatment of MI, refers to development of great vessels and capillaries. Abundant paracrine factors such as VEGF and SDF-1 are released by MSCs transplanted into the surrounding infarcted area, can regulate angiogenesis, and inhibit signaling pathways to promote the formation of novel vasoganglion.An increasing volume of literature has reported that miRNAs participate in the regulation of vascular cell differentiation, proliferation, migration, and other biological processes. Some miRNAs possess the ability to promote angiogenesis, such as miR-126, miR-132, and others. The excessive expression of miR-126 facilitated angiogenesis around the infarcted area by regulating the AKT/ERK signaling pathway in a rat model . AnotherPOS/NKX2.5POS BMSCs isolated from Sprague–Dawley rat femurs into cardiomyocytes [MSCs present a zonal distribution in myocardial tissue after transplantation similar to the distribution of cardiocytes. The increase in cardiac-specific marker proteins such as troponin preliminarily confirms the differentiation of BMSCs into cardiocytes. The activation of Notch1 signaling contributed to multilineage differentiation of c-Kitmyocytes . Retrogrmyocytes . A combimyocytes . In addimyocytes .BMSCs can be differentiated not only into cardiomyocyte-like cells but also into endothelial cells, which contribute to the regeneration of the vasculature after MI. For example, it has been demonstrated that atherogenic cytokines regulate VEGF-A-induced differentiation of BMSCs into endothelial cells in vitro .Although transplantation of BMSCs has brought a new option for MI treatment, there are still significant problems to be solved. Because of the lack of a specific marker on the surface of BMSCs, exclusive identification can only be made based on cell shape. Unfortunately, the cellular viability of transplanted BMSCs has not been high because of the lack of blood supply, poor nourishment of transplanted cells, and the generation of free radicals . SpontanBMSCs can serve as ideal seed cells in cardiovascular disease therapy because of their capacity for multidirectional differentiation, easy acquisition, rapid proliferation, low immunogenicity, and high portability. Furthermore, transplanted BMSCs can reduce apoptosis, migrate to infarcted myocardial tissues, inhibit fibrosis and inflammation, promote neovascularization, and differentiate into cardiomyocyte-like cells which contribute to the repair of cardiomyocytes. Despite these advantages of BMSCs in the treatment of MI, the most important problem we must now address is the reduced viability of transplanted BMSCs due to inadequate blood supply, poor nourishment of cells, and generation of free radicals. In clinical trials, the feasibility and safety of BMSC therapy have been tested, but the optimal dose and route of administration of BMSCs should be investigated in the treatment of MI.


Agriculture is a major contributor to greenhouse gas emissions, an important part of which is associated to deforestation and indirect land use change. Appropriate and coherent food policies can play an important role in aligning health, economic and environmental goals. From the point of view of policy analysis, however, this requires multi-sectoral, interdisciplinary approaches which can be highly complex. Important methodological advances in the area are not exempted from limitations and criticism.We argue that there is scope for further developments in integrated quantitative and qualitative policy analysis combining existing methods, including mathematical modelling and stakeholder analysis. We outline methodological trends in the field, briefly characterise integrated mixed methods policy analysis and identify contributions, challenges and opportunities for future research. In particular, this type of approach can help address issues of uncertainty and context-specific validity, incorporate multiple perspectives and help advance meaningful interdisciplinary collaboration in the field. Substantial challenges remain, however, such as the integration of key issues related to non-communicable disease, or the incorporation of a broader range of qualitative approaches that can address important cultural and ethical dimensions of food. Recent definitions of food sustainability have highlighted the existence of multiple inter-related dimensions including environmental, health, socioeconomic and cultural aspects . RelatedIn particular, certain topics such as the “food versus fuel” debate or the debate around the allocation of resources for animal feed versus plant-based food for direct human consumption have drawn attention to the importance of such interactions across sectors within the broader food system . The mosOn the one hand, the need to incorporate this complexity has led to significant methodological developments. These include the design and application of integrated conceptual frameworks , as wellConcerns have been raised, however, about the limitations of these increasingly complex models. In particular, researchers have pointed out the excessive uncertainty in the results as well as the lack of comparability in terms of both results, assumptions and methodologies . In addiOn the other hand, approaches based on stakeholder analysis have frequently been applied to the fields of natural resource management, alongside land use planning and social forestry , 11 and,Stakeholder analysis is inherently context-specific although not necessarily bound by specific geographical or sectoral constraints. Moreover, the theoretical frameworks underlying these research methods, unlike most quantitative analysis in this field, tend to highlight the socially constructed nature of reality and focus explicitly on perspective and the existence of potentially conflicting objectives. Although this type of approach has its own set of limitations , it has What we mean by “integrated mixed-methods policy analysis for sustainable food systems” is a combination of quantitative economic and biophysical modelling and stakeholder analysis  which aims to include different dimensions of sustainability across several sectors and their interactions, adopting a system perspective and a policy focus rather than addressing a specific site or technology. Similar methodological approaches have been recommended and applied in areas related to sustainable food systems over the last decade. In particular, variants of this type of approach have been recommended in fields such as sustainable nutrition at the household level , sustainThe main contribution of this kind of approach is probably the explicit acknowledgement of different perspectives and possibly conflicting interests alongside the analysis of intersectoral impacts and linkages, increasing transparency and diversity in policy processes. Although this methodology can also itself be captured and manipulated by specific interests, it has frequently been applied to empower fringe, marginal or vulnerable stakeholders, and methods have been developed for this purpose, such as radical transactiveness . In the Despite the many opportunities offered by integrated mixed methods policy analysis, there remain significant challenges for its application to the field of sustainable food systems. Firstly, further work is needed in order to incorporate complex health and nutrition impacts. In particular, there is a need for further integration of emerging issues of non-communicable disease, where changing food environments and food processing mediate between health outcomes and environmental or socioeconomic impacts. Furthermore, the cultural and ethical aspects of diets are also frequently neglected in food policy analysis, despite being increasingly recognised as an integral dimension of sustainability. The adequate assessment of cultural and ethical implications of food policy might require broadening the range of qualitative methodologies within multi-sectoral policy analysis, including anthropological approaches at the household, industry and food environment levels . To conc


Koelliker renamed the ganglion withthe eponymous designation Meynert'sches Basalganglion, a name which endures to the present day, anddescribed its topographical spread in relation to neighboring structures.Meynert and Koelliker also described aspects of cell composition of the ganglion(or nucleus) with a better account of the latter. Both, together with Reil andGratiolet, were the outstanding personalities of the 19th century whoperformed the pioneering studies on basal formations of the forebrain. Afterthese works, a considerable body of research appeared in the 20thcentury, with a focus on Meynert's basal nucleus and related structures. Thedevelopment of further knowledge about these structures revealed their greatimportance in the activity of the brain, as evidenced in both normal andpathological states.Meynert described the "loop of the peduncular foot"  The highlightsof this chronicle will be reviewed and commented in the following paragraphs.As for almost all knowledge in neuroscience, a long period elapses, sometimes acentury or more, in the transition from anatomical research to the resultingcorollary application. This is the case for the basal structures of the forebrain,and the included cholinergic nuclei, which involved some of the most outstandingpersonalities of the 193Theodor Hermann Meynert (1833-1892) was an outstanding anatomist, neuropathologist,and psychiatrist. He described numerous nervous structures, some for the first time,and also developed theories regarding correlations between neuroanatomical andmental processes.4. It is opportune to write a few words about these tworesearchers, considering their pioneering descriptions, importance, and Meynert'squotes , and describes bundles in the uppermesencephalon, underneath the basal ganglia, that constitute a kind of belting, andemphasizes one which he names Schlinge des Hirnschenkelfusses (loopof the peduncular foot), with a course transverse and approximately parallel to theoptic tract . He relates it to the deepeststratum of the Substantia innominata of Reil, or the Ansapeduncularis of Gratiolet (p 734). The description is illustrated  (Substantia innominata of Reil may be divided into 4layers: (i) the loop of the lenticular nucleus(Linsenkernschlinge),...(Schl); (ii) the Ganglion derHirnschenkelschlinge (L),...; (iii) the inferior peduncle of the optic thalamus (St), and (iv) theanterior temporal part of the stratum zonale (Z)..."8Meynert published his findings, initially in a chapter of Stricker's book, and laterin his own. In Stricker's book (1872 - volume 2 - Chapter XXXI - pp694-808), p 728) , and in nd stratum of Reil's Substantiainnnominata, or Gratiolet's Ansepédonculaire...". There is also a short description of thecellular component of the ganglion (p 732): "The cells of this ganglion reach theexternal capsule,...a small number of bundles, isolated or together with otherscontacting 50 µm long, 15 µm wide fusiform cells..."4.The description of item (ii) above further details the ganglion: "... a flat extendedganglion , that lays below the cerebral peduncular loop, a mass whichrepresents the 29, he reiterates his former findings and gives someadditional details on anatomical aspects and extent of the ganglion: "...a densetransversely placed particular layer of ganglion cells, parallel to the fiberradiation, which extends laterally until the external capsule...it constitutes aflat well bounded special ganglionic formation, which equals in extension the sizeof the anterior perforated space"..."this formation shows its cells parallel to thecourse of the peduncular loop (Ansa peduncularis), being traversed by its bundles,and represents the Ganglion ansae peduncularis (ganglion of the peduncular loop)".He illustrates the anatomical location of the peduncular loop on a finely dissectedbrain . However, there is no depiction or indication of aganglionic formation , despite a well cut section of the region. Hedid not offer further details or elaboration on the anatomic structure of theregion, nor on the cellular structure of this ganglion or its connections, addingvery little to his initial description.Twelve years later, in his own book (1884 - pp 87-88)th edition of hisbook published in 1896 (pp 456-458),10, describes in detail the extension, variation in size andposition of the ganglion in relation to neighboring structures, as follows: "...TheSubstantia innominata (Reil) Forel is theanterior prolongation of the Zona incerta, where, appearing as aspecial formation, beside the already mentioned loop of the lenticular nucleus andthe inferior thalamic peduncle, lays the ganglion of the peduncular loop  (Ganglion der Hirnschenkelschlinge [Nap][Nucleus ansapeduncularis]) ...". This designation hasremained as an eponym of this formation to the present day. He follows with adetailed description of the cell clusters of the basal ganglion, analyzing numeroussections, three of them illustrated , and the changes insize as it spreads out among the bounding structures, the posterior end of themammillary bodies, underneath the lenticular nucleus and the radiation of theanterior commissure, above the anterior perforated space and the optic tract, medialto the grey matter of the 3rd ventricle wall and to the septal area, theexternal capsule as the lateral limit, and the anterior limit represented by theregion of the floor of the inter-hemispheric fissure, where it graduallyterminates.Albert von Koelliker (born Rudolf Albert Koelliker) (1817-1905), a Swiss biologist,embryologist, histologist and physiologist, in the 6ularis]) , asnameGanglion basale I cannot report much. Its cells are20-30 µm large, multipolar, appearing as two rows, one unstained, and theother strongly pigmented, nearly as those of the Locus coeruleus.Around the cells everywhere are found well developed delicately woven fibers, thoughin the Weigert's preparations I examined there was not any hint about the course ofthe axons of these cells".Regarding the histology of the ganglion, he describes: "About the finer organizationof the human 10Reviewing the literature, Koelliker affirms that Meynert's ganglion of the peduncularloop, his "basal ganglion", as far as he knows, was mentioned only by Forel,Brissaud, and Honegger. However, no relevant information was added to the knowledgeon this subject.3.After some time, the initially "unnamed medullary substance" was intenselyscrutinized, and numerous studies appeared focusing on the histological segmentationof this richly populated region in several divisions and nuclei, adding otherrelated ones, such as those of the diagonal band and of the septum. The developmentof specific histological techniques, allowed the identification of cells accordingto their neurotransmitters, and among them the detection of cholinergic neurons inthe late 1970s and early 1980s. A new nomenclature was also proposed to identify theseveral neuronal clusters of the nbM and associated nuclei, and these were alsoidentified as the major source of long projection neurons for cholinergicinnervations11. Thesestudies were paralleled by pathological demonstration of neuronal loss in the nbM inbrains of patients with Alzheimer, and later in other neurodegenerative diseases.During this same period, functional studies about the relationship betweencholinergic deficiency and memory loss were also carried out, which culminated inthe proposal of a "cholinergic hypothesis", and later in the development of specifictherapeutic strategies12.After Meynert's and Koelliker's contributions, the latter responsible for the eponym, the region was apparently disregarded for a longperiod. Although additional details of the surroundings of the region were describedin the years that followed, several authors made no mention of it at all, possiblydue to its unknown relevanceth century was the time when four personalities, engaged in thestudy of forebrain basal structures, stood out, namely– Reil, Gratiolet, Meynert andKoelliker.The 19Schlinge des Hirnschenkelfusses (the loop ofthe peduncular foot), and its ganglion (Ganglion derHirnschenkelschlinge) as one of the layers of Reil's Substantiainnominata, or Gratiolet's Ansa peduncularis.Apparently he drew on Reil's poorly defined topography of the area and Gratiolet'slimited report of the region to build up his findings by adding a few structuraldetails and a reduced account on the cellular composition of the ganglion,describing as well as systematizing the components found in this transitional regionbetween the upper mesencephalon and basal formations of the forebrain.Meynert described the Ansa peduncularis or theSchlinge des Hirnschenkelfusses with the designationMeynert'sches Basalganglion , aneponym that endures until the present day, and described the extension, variation insize and position of the basal ganglion in relation to neighboring structures. Mostnotable in his observation is the revelation of the wide extent of the ganglion andits cell clusters, which spreads out in the basal region of the forebrain.Koelliker renamed the ganglion of the Both Meynert and Koelliker described the cell composition of the ganglion or nucleus.However, it is possible to note some differences, with a better account by thelatter (remembering he was one of the finest histologists of his time), regardingnot only the location and extent of the nucleus, but also its cellular component,concerning the size and the shape of the neurons that each found. It is possiblethat the authors described cells from different regions, or possibly, from differentclusters."nucleus basalis" or "basalnucleus". However, the picture given was somewhat incomplete.Nevertheless, this was a seed thrown in a productive field, which in the20th century would reveal an extraordinary development. A large bodyof studies appeared, increasing the understanding of the basal nucleus and relatedformations, benefited by advances in histological techniques and equipment andallied to pharmacological investigation, which revealed the great importance ofthese structures in the activity of the brain, as evidenced in both normal andpathological states.The result of these studies was the establishment of the general topography of theregion and the description of the extent and some characteristics of the cells foundthere, mainly of the so-called


Unrelated spore-forming bacteria share unique characteristics stemming from the presence of highly resistant endospores, leading to similar challenges in health and disease. These characteristics are related to the presence of these highly transmissible spores, which are commonly spread within the environment and are implicated in host-to-host transmission. In humans, spore-forming bacteria contribute to a variety of pathological processes that share similar characteristics, including persistence, chronicity, relapses and the maintenance of the resistome. We first outline the necessity of characterizing the totality of the spore-forming bacteria as the sporobiota based on their unique common characteristics. We further propose that the collection of all genes of spore-forming bacteria be known as the sporobiome. Such differentiation is critical for exploring the cross-talk between the sporobiota and other members of the gut microbiota, and will allow for a better understanding of the implications of the sporobiota and sporobiome in a variety of pathologies and the spread of antibiotic resistance. The unique characteristics of spore-forming bacteria are conditioned by the presence of endospores that are practically impermeable due to various traits, including the components of the core, cortex, coat and membranes .The resistance of these spores results in their long-term survival under unfavorable conditions and various types of environmental exposure, such as high and low temperatures, UV, radiation, nutrient and water deprivation, antimicrobial agents, and the host immune system . Such reThe effectiveness of microbiota research is influenced by the source from which it isolated , as well as the components of the microbiota. Thus, to elucidate the bacterial components of microbiota, bacterial microbiomes are studied; viral or fungal components are investigated as part of virome or mycobiome research, while the determination of the collection of all antibiotic resistance genes requires the study of the resistome –8. Such We first outline the necessity of describing spore-forming bacteria as a separate entity within the global ecosystem. Then, we summarize the major unique characteristics of spore-formers, especially those related to human health—particularly to the gut—and discuss opportunities for future research.We identified traits that allow the identification of endospore-forming bacteria as an independent functional group within global microbiota Table .Table 1UWe suggest that the collection of all spore-forming bacteria be referred to as the sporobiota. To extend the functional analysis of the sporobiota, it can be can be classified based on different levels of representation, from the global sporobiota to the clinical (disease-associated) sporobiota of specific organisms or organ systems such as gut sporobiota Fig. .Fig. 1CoSimilarly, we propose that the collective genomes of all genes of spore-forming bacteria related to a specific ecological niche be referred to as the sporobiome, which can be divided into different subgroups in accordance with the sporobiota’s identification.Taking into consideration the unique characteristics of spore-forming bacteria analyzed in the present study, we suggest that the differentiation (identification) of spore-formers as sporobiota and the collection of all their genes into a sporobiome can shed new light on their particular interplay with other members of the microbiota.Notably, the study of the sporobiota and the sporobiome as independent components of the microbiota and the microbiome will facilitate the identification of their individual impacts on human health including gut health. Furthermore, these studies may aid in the elucidation of the specific roles of the sporobiota and the sporobiome in horizontal gene transfer between ecological niches and their contribution to the spread of antibiotic resistance.An emerging factor in characterizing the sporobiota and sporobiome independently is that due to advances in technology, we now understand that the true role of endospore-forming bacteria is poorly studied because the investigation of their biodiversity remains challenging , 9, 10.The traditional approaches for determining the diversity of spore-forming bacteria in environments and hosts are challenging due to technical and biological difficulties. One of the challenges involved is that endospores are resilient to many traditional methods of DNA isolation and are therefore potentially undetectable . AnotherGenomic-based workflows using combined genetic, culture and metagenomics methods are implemented for targeting endospore-forming bacteria and allow the identification of novel families, genera and species in the environment and human microbiome , 16, 17 Some of these bacteria recently identified in the human microbiome have never previously been identified in humans or are representatives of previously unknown species, including species contributing to diseases . In agreWe further summarize the major unique characteristics of spore-formers, especially those related to human health.Clostridiaceae family and they are the causative agents of a variety of diseases, including tetanus, gas gangrene, and botulism [Clostridium difficile causes a variety of intestinal diseases, from mild diarrhea to severe life-threatening inflammation of the colon [Lachnospiraceae are abundant in the digestive tracts of mammals and have been linked to obesity, whereas colonization by members of the Erysipelotrichaceae is associated with gut disorders such as inflammatory bowel diseases and colorectal cancer [In addition to recently isolated spore-forming bacteria, there are several endospore-forming species associated with the human gut microbiome. The most prominent anaerobic bacterial spore-formers in the healthcare environment are members of the botulism . Clostrihe colon . Membersl cancer , 23.Bacillaceae family are well-known representatives of aerobic endospore-forming bacteria isolated from the human gut. While Bacillus anthracis was the first member of this group to be associated with human pathology, Bacillus cereus is currently recognized as being associated with human diseases such as endocarditis, diarrhea, and irritable bowel syndrome, in addition to being a pathogen associated with traumatic wounds and burns [Aerobic endospore-forming bacteria are also implicated in human health. The members of the nd burns .Paenibacillus spp. bacteria were not known to cause human disease until recent reports implicated P. alvei, P. thiaminolyticus, and P. sputi, Paenibacillus sp. VT-400 in bloodstream, respiratory and urinary tract infections [fections , 25, 26.Persistence within the host is an important characteristic of spore-formers and is a common characteristic of disease processes caused by these bacteria , 28.A major challenge contributing to persistence is that spores are metabolically dormant and show reduced susceptibility to biocides, thus playing an important role in disease chronicity .Notably, most infections are attributed to the biofilm mode of growth, which is associated with reduced susceptibility to antibiotics, and microbial communities formed by spore-forming bacteria are particularly resistant to antimicrobial therapy .Clostridium spp., a few days after antibiotic withdrawal, animals exhibited recurrent infection with the same isolate  [Clostridium spp. is known to be as high as 35% [Clostridiales species [Bacillales are characterized by relapses, with restoration of bacterial growth after successful antibiotic treatment followed by the clinical improvement [The same characteristics contribute to the high relapse rate of infections caused by spore-forming bacteria; after the death of vegetative cells, spores allow bacterial regrowth . Thus, rrelapse) . In clinh as 35% . Based o species . SimilarAnother challenge associated with members of the sporobiota is that spore-associated elements, such as nucleic acids of the core or core proteins, trigger host immune responses with detrimental effects . Taken tThe robustness of spores is attributed to their resistance to various physio-chemical treatments, including most disinfectants, in addition to their strong binding properties. As such, spores are the primary agents of the rapid dispersal-conditioned global spreading of endospore-formers , 37.Spore-forming bacteria exhibit unique survival strategies that facilitate their dispersal to and subsequent colonization of new locations; thus, they play a unique role in gene flow and horizontal gene transfer –40.Bacilli and Clostridia [Spore-forming bacteria are globally distributed, including in extreme environments. Existing metagenomics methods indicate that in the outer environment, endospore-formers are relatively rare, with an abundance of more than 1% being observed only for ostridia . Howeverostridia , 4.The transmission potential of members of the sporobiota and sporobiome plays an important role in human health and diseases. First, spores are specialized for host-to-host transmission. This property has important implications for the inheritance of the microbiota and its colonization of the infant gastrointestinal tract , 41. SpoEnvironmental spore-forming bacteria that produce spores (including those found in soil) are constantly introduced into the human microbiota, as they more aero-tolerant than non-spore-formers . Such baIn the aggregate, the transmission of spore-forming bacteria has implications for the spread of antimicrobial resistance and the transfer of resistance genes from the environmental resistome into human commensals and pathogens. Bacterial spores contain a complete copy of the genome and represent a pool of virulence and antibiotic resistance genes that may be implicated in the horizontal transfer of resistance genes to other bacterial species , 46.We have previously identified many antibiotic resistance genes in a number of novel species of spore-forming bacteria isolated from the human gut , 11, 16.Recent studies have also shown that environmental spore-forming bacteria exhibit an extremely high diversity of antibiotic resistance genes.Taking into consideration high transfer rates and apparent overlap between different ecological niches of the members of sporobiota including overlap between environmental and clinical species, this represents a particular challenge for the spread of antibiotic resistance , 48, 49.In this article, we propose the new terms sporobiota and sporobiome, highlighting that this distinction is not solely an academic issue. Based on specific, common characteristics of endospore-formers compared with other representatives of the microbiota, such a differentiation has important implications, predominantly for human health and diseases. These characteristics are related to the presence of highly transmissible spores, which are commonly spread within the environment and are implicated in host-to-host transmission. Such similar characteristics of the pathological process include a chronic and recurrent course, the specific immune response to the spores, and the spreading and maintenance of the resistome.We first outlined how such a distinction will reveal the particularities of the interaction of the sporobiota with other ecosystem components of the environmental and human microbiota, which will facilitate the identification of new disease treatments and ways to overcome the spreading of antimicrobial resistance.The high transmission dynamics and geographic distribution of spore-formers are well documented. However, the study of sporobiota biodiversity will require improvements in molecular tools. Existing genetic methods, such as high-throughput sequencing, have insufficient analytical accuracy for the elucidation of biodiversity and do not allow the evaluation of the true abundance of spore-formers in the environment or hosts. Further research is likely to be concentrated on the improvement of computing power, the development of specific isolation workflows combining traditional culture approaches with genetic strategies and the creation of specific databases. Using developed workflows, we have only just begun to understand the high level of diversity that has been revealed and to just scratch the surface of the sporobiota and sporobiome. Much more work remains.


Numerous data show a reciprocal interaction between REM sleep and thermoregulation. During REM sleep, the function of thermoregulation appears to be impaired; from the other hand, the tonic activation of thermogenesis, such as during cold exposure, suppresses REM sleep occurrence. Recently, both the central neural network controlling REM sleep and the central neural network controlling thermoregulation have been progressively unraveled. Thermoregulation was shown to be controlled by a central “core” circuit, responsible for the maintenance of body temperature, modulated by a set of accessory areas. REM sleep was suggested to be controlled by a group of hypothalamic neurons overlooking at the REM sleep generating circuits within the brainstem. The two networks overlap in a few areas, and in this review, we will suggest that in such overlap may reside the explanation of the reciprocal interaction between REM sleep and thermoregulation. Considering the peculiar modulation of thermoregulation by REM sleep the result of their coincidental evolution, REM sleep may therefore be seen as a period of transient heterothermy. The primary function of rapid-eye movement sleep (REMS) is still unknown, but the finding that the daily amount of REMS is “homeostatically” regulated , by postural adjustments that optimize thermal exchanges   and the dorsal deep mesencephalic reticular nuclei (dDPMe)   and the ventrolateral preoptic nucleus (VLPO) play a role in REMS regulation  for heat retention, necessary for cold defense  and dorsolateral- (dl) PBN neurons, respectively. From here, elPBN glutamatergic neurons convey the cold thermal signal to the GABAergic Median preoptic (MnPO) neurons (Tan et al., The thermoregulatory network sends its branches to several brain areas that control metabolic, cardiovascular, osmolar and respiratory functions and, conversely, receives feedback from these areas, thus modulating thermoregulatory responses (Morrison et al., Two relevant populations of neurons that modulate thermoregulation are located within the LH: orexin neurons and MCH neurons. Orexin neurons send direct projections to the rRPa (Oldfield et al., PAG neurons receive projections from the main thermoregulatory hypothalamic nuclei (Rizvi et al., The tight reciprocal link between REMS and thermoregulation suggests the existence of mechanisms underlying this interaction at the level of the brain areas shared by the two regulatory networks. In fact, it is noteworthy that the sleep network and the thermoregulation network overlap in some brain areas Figure . This ovAnother overlap between the two networks occurs at the POA level, in particular, the MnPO. The MnPO is a very important integrative site for homeostatic function, since it receives inputs from different sensory pathways and contains osmoresponsive, thermoresponsive, and sleep-related neurons, which, to some extent, reciprocally interact (McKinley et al., A further possible site of overlap between REMS regulation and thermoregulation is the VlPAG. On one hand, a consistent number of either REMS-off or REMS-on neurons have been found in VlPAG (Sapin et al., A way to consider changes in the activity of MnPO in REMS deprivation and recovery (Gvilia et al., The clamping of Thy, during REMS, by a diathermic warming of the thermally irresponsive POA, doubled episode duration even at a Ta well below the lower limit of TNZ (Parmeggiani et al., Thus, taken together, these results suggest that REMS may be considered as a transient heterothermic state fulfilling, within the far-reaching protection of a rest period, specific needs of endotherms brain activity, rather than energy saving. This view appears in line with the hypothesis of a coevolution of REMS and thermoregulation (Lee Kavanau, On these bases, the interplay between REMS and thermoregulation may be linked to the simultaneous evolution of the two functions, and the sharing of regulatory areas may be the results of some evolutionary constraint in terms of developmental physiology. Thus, the study of the interaction between REMS and thermoregulation may open new perspectives on how the two functions developed and shed light on the yet unknown purpose of REMS.This manuscript is the result of the common effert of MC, ML, DT, GZ, and RA. All the authors contributed to the development of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The Deepwater Horizon (DWH) oil spill in the Gulf of Mexico in 2010 resulted in serious damage to local marine and coastal environments. In addition to the physical removal and chemical dispersion of spilled oil, biodegradation by indigenous microorganisms was regarded as the most effective way for cleaning up residual oil. Different microbiological methods were applied to investigate the changes and responses of bacterial communities after the DWH oil spills. By summarizing and analyzing these microbiological methods, giving recommendations and proposing some methods that have not been used, this review aims to provide constructive guidelines for microbiological studies after environmental disasters, especially those involving organic pollutants. The DWH oil rig exploded in the Gulf of Mexico in April 2010. The spill lasted for approximately 84 d, which was recorded the largest oil spill in United States to date  or natural processes   and culture-independent methods . Additionally, we propose some prevalent methods  that exhibit great potential for the future studies.Alcanivorax, Alteromonas, Cycloclasticus, Halomonas, Marinobacter, and Pseudoalteromonas) with hydrocarbon-degrading abilities were isolated from surface slicks and deep oil plumes , which were the dominant microorganism in the oil plume.Traditional methods, such as isolation and purification of bacterial strains from various environments are essential as exemplified in microbiological studies of the DWH spill. The isolation of microbes in pure culture can provide valuable information on the functions, metabolic pathways, and physiological characteristics of bacteria that respond to an oil spill. During the DWH spill, different bacterial strains  are always neglected or difficult to setup in the ex situ experiments, which limit the isolation of oil-degrading bacteria  or in situ in the deep-sea environment. The development of novel cultivating technologies to isolate previously uncultured bacteria could permit a more comprehensive understanding of unexplored bacterial communities, including their metabolic pathways, and functions.Despite the successful isolation of some oil-degrading bacteria, most of the indigenous bacterial strains could not be isolated by conventional culture-based methods. This might be attributed to the fact that artificial culture conditions are different from the in situ hybridization (FISH), and real-time quantitative polymerase chain reaction (RT-PCR) are useful techniques in investigating the composition and potential functions of indigenous bacterial communities in a specific environment.The majority (>99%) of bacterioplankton in marine environments remains largely recalcitrant to cultivation. Applications of molecular biological methods such as 16S rRNA clone library, terminal restriction fragment length polymorphism (T-RFLP), denaturing gradient gel electrophoresis (DGGE), temperature gradient gel electrophoresis (TGGE), fluorescence Oceanospirillales in the γ-Proteobacteria class as dominant in deep-sea plumes. Oceanospirillales were not detected in most of the plume samples in June, while Cycloclasticus and Colwellia were dominant (more than 95% of the sequences). This indicates that the DWH Oceanospirillales bloomed initially, followed by Colwellia and Cycloclasticus  phylogenies and for the investigation of microbial diversity  and temperature gradient gel electrophoresis (TGGE) are two commonly used gene fingerprinting techniques that separate different DNA/RNA in the same sample via chemical or temperature gradients. Muyzer et al.  first inAfter the DWH oil spills, DGGE provided some of the first information on naturally occurring microbial communities in the sediment from shorelines along the northern coast of the Gulf of Mexico Lisle, . Some acFlavobacteria, which is a secondary consumer of methane, oil, or cellular decay products  for the FISH assay, McKay et al. . The FISH method has been widely used to investigate composition of bacterial communities in recent years. It can provide fluorescent images indicating the existence and relative abundance of target genes combing with special fluorescent probes. 16S rRNA genes or functional genes can be detected by this approach without PCR amplification , composition , and abundance (Clone Library and RT-qPCR) of microbes. Nevertheless, the information generated by these approaches is finite, and the unit cost (the cost per sequence) is relatively expensive. For instance, only dozens of DGGE bands or clones could be identified by combining the techniques of DGGE and clone libraries which could only generate limited information and hardly reflected on the real composition of bacterial communities. Furthermore, the unit cost for a single sequence can be much higher by Sanger sequencing than NGS. With the development of new approaches, such as DNA/RNA microarrays, NGS, and SIP, ecological microbiology research is faced with new opportunities. These currently prevalent techniques can generate massive data sets for detailed investigation on the composition and diversity of bacterial communities in different habitats or following particular events. Some new techniques that provide impressive information have been used in investigating the succession and function of the microbial communities after the DWH oil spill.DNA microarrays are collections of microscopic DNA spots, representing single target genes, that are attached to a chemical matrix and arrayed on a solid surface. By DNA-DNA or DNA-RNA hybridization, DNA microarrays can provide qualitative or quantitative measurements of microbial diversity and functional gene expression , dramatically increased during the oil infiltration of sediments. In contrast, bacterial phyla of Verrucomicrobia, Cyanobacteria, and Planctomycete showed obvious decreases due to their relatively low tolerance to oil pollution. GeoChip microarray-based analysis was used to identify 16,383 unique functional genes. The results indicated that a relative abundance of functional genes involved in hydrocarbon degradation  were significantly increased between June and July in the inlet sediments . They also found that the bacterial composition of the floc samples  was different from those in the sediment samples .The DWH oil spill occurred in 2010, when the use of high-throughput sequencing was on the rise. The new techniques of microbial ecology were comprehensively applied after the event to reveal the impacts of the oil spill on bacterial communities and the responses of different bacterial phyla  could extend our understanding of the successional changes of the dominant microbial players  and databases (DB) have been produced for bioinformatic analysis, including Greengenes  ide Lasken, ; (3) rev Lasken, ; (4) pre Lasken, .In the first microbial study after the oil spill, Mason et al.  applied 13C, 15N, and 18O). The labeled molecular markers can then be analyzed by 16S rRNA gene sequencing (clone library or NGS), metagenomic analysis, metatranscriptomic analysis, and mass spectrometer (MS) analysis. These methods can be used to generate data to reveal the bacterial community and activity. SIP analysis is a powerful tool for linking microbial species and metabolism , Gutierrez et al.  that are labeled with a stable isotopic element , provide qualitative impressions about the functional bacteria conducting biodegradation. Prevalent microbiological molecular techniques  have also generated a great amount data on bacterial composition and predicted potential pathways for hydrocarbon degradation. For future investigation, we recommend an informed application of prevalent NGS-based genomic technologies and microbial network reconstruction in conjunction with conventional culture-dependent approaches. Especially, integrated application of different approaches could afford a more comprehensive view of indigenous bacterial communities and their potential functions in polluted sites.SZ, ZH, and HW provided substantial contributions to the conception and design of the work. SZ and HW drafted the work. SZ, ZH and HW agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In this review article, we discuss various functions of the vagus nerve which make it an attractive target in treating psychiatric and gastrointestinal disorders. There is preliminary evidence that vagus nerve stimulation is a promising add-on treatment for treatment-refractory depression, posttraumatic stress disorder, and inflammatory bowel disease. Treatments that target the vagus nerve increase the vagal tone and inhibit cytokine production. Both are important mechanism of resiliency. The stimulation of vagal afferent fibers in the gut influences monoaminergic brain systems in the brain stem that play crucial roles in major psychiatric conditions, such as mood and anxiety disorders. In line, there is preliminary evidence for gut bacteria to have beneficial effect on mood and anxiety, partly by affecting the activity of the vagus nerve. Since, the vagal tone is correlated with capacity to regulate stress responses and can be influenced by breathing, its increase through meditation and yoga likely contribute to resilience and the mitigation of mood and anxiety symptoms.The vagus nerve represents the main component of the parasympathetic nervous system, which oversees a vast array of crucial bodily functions, including control of mood, immune response, digestion, and heart rate. It establishes one of the connections between the brain and the gastrointestinal tract and sends information about the state of the inner organs to the brain  The vagus nerve is the main contributor of the parasympathetic nervous system. Other three parasympathetic cranial nerves are the nervus oculomotorius, the nervus facialis, and the nervus glossopharyngeus.The most important function of the vagus nerve is afferent, bringing information of the inner organs, such as gut, liver, heart, and lungs to the brain. This suggests that the inner organs are major sources of sensory information to the brain. The gut as the largest surface toward the outer world and might, therefore, be a particularly important sensory organ.Historically, the vagus has been studied as an efferent nerve and as an antagonist of the sympathetic nervous system. Most organs receive parasympathetic efferents through the vagus nerve and sympathetic efferents through the splanchnic nerves. Together with the sympathetic nervous systems, the parasympathetic nervous system is responsible for the regulation of vegetative functions by acting in opposition to each other . The parThe ENS arises from neural crest cells of the primarily vagal origin and consists of a nerve plexus embedded in the intestinal wall, extending across the whole gastrointestinal tract from the esophagus to the anus. It is estimated that the human ENS contains about 100–500 million neurons. This is the largest accumulation of nerve cells in the human body –25. SincThe connection between the CNS and the ENS, also referred to as the brain–gut axis enables the bidirectional connection between the brain and the gastrointestinal tract. It is responsible for monitoring the physiological homeostasis and connecting the emotional and cognitive areas of the brain with peripheral intestinal functions, such as immune activation, intestinal permeability, enteric reflex, and enteroendocrine signaling . This brBoth neural (vagus) and hormonal (HPA axis) lines of communication combine to allow brain to influence the activities of intestinal functional effector cells, such as immune cells, epithelial cells, enteric neurons, smooth muscle cells, interstitial cells of Cajal, and enterochromaffin cells . These cIn case of food intake, vagal afferents innervating the gastrointestinal tract provide a rapid and discrete account of digestible food as well as circulating and stored fuels, while vagal efferents together with the hormonal mechanisms codetermine the rate of nutrient absorption, storage, and mobilization . Histolovia a CCK-dependent mechanism. Exogenous administration of CCK appears to inhibit endogenous CCK secretion  requires the surgical implantation of a small pulse generator subcutaneously in the left thoracic region. Electrodes are attached to the left cervical vagus nerve and are connected to the pulse generator by a lead, which is tunneled under the skin. The generator delivers intermittent electrical impulses through the vagus nerve to the brain . It is pus nerve . A pilotus nerve . Five yeus nerve . Since tvia the NTS, the vagus nerve has structural connections with several mood regulating limbic and cortical brain areas   and the Further, beneficial effects of VNS might be exerted through a monoamine-independent way. Thus, VNS treatments might result in dynamic changes of monoamine metabolites in the hippocampus  and seveSerotonin is also an important neurotransmitter in the gut that can stimulate peristalsis and induce nausea and vomiting by activating the vagus nerve. In addition, it is essential for the regulation of vital functions, such as appetite and sleep, and contributes to feelings of well-being. To 95%, it is produced by enterochromaffin cells, a type of neuroendocrine cell which reside alongside the epithelium lining the lumen of the digestive tract . SerotonMajor depressive disorder ranks among the leading mental health causes of the global burden of disease . With a The overdrive of the HPA axis is most consistently seen in subjects with more severe  depression, when the cortisol feedback inhibitory mechanisms are impaired, contributing to cytokine oversecretion . It has A European multicenter study demonstrated a positive effect of VNS on depressive symptoms, in patients with treatment-resistant depression . The appPatients with depression have elevated plasma and cerebrospinal fluid concentrations of proinflammatory cytokines. The benefit of VNS in depression might be due to the inhibitory action on the production of proinflammatory cytokines  and markLactobacillus-species have received tremendous attention due to their use as probiotics and their health-promoting properties (Lactobacillus rhamnosus (strain JB-1) caused a reduction in stress-induced corticosterone levels and in anxiety-like and depression-like behavior (L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and LC. In addition, L. rhamnosus (JB-1) reduced GABA(Aα2) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(Aα2) in the hippocampus (L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. This is not surprising, since alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression  . Some yoIyengar yoga has been shown to decreased depressive symptoms in subjects with depression . IyengarPosttraumatic stress disorder is an anxiety disorder that can develop after trauma and is characterized by experiencing intrusive memories, flashbacks, hypervigilance, nightmares, social avoidance, and social dysfunctions . It has via the myelinated vagal fibers varies with respiration. Thus, the vagal influence on the heart can be evaluated by quantifying the amplitude of rhythmic fluctuations in heart rate—respiratory sinus arrhythmia (RSA). A recent study has demonstrated a reduced resting RSA in veterans with PTSD  induced a more proactive behavioral response to a psychosocial stressor  in the treatment of PTSD –178. DurInflammatory bowel disease comprises mainly two disorders: ulcerative colitis (UC) and Crohn’s disease (CD) . The halInflammatory bowel disease affects about 1.5 million persons in the USA and 2.2 million in Europe , and aboVagus nerve stimulation attenuates the systemic inflammatory response to endotoxin  and inteVagus nerve stimulation should be of interest in other inflammatory diseases, such as rheumatoid arthritis, another TNF-α-mediated disease. In patients with rheumatoid arthritis, a study that demonstrated an improvement of symptoms in the early and late stages of the disease through 1–4 min of VNS daily . This stLactobacillus plantarum 299V prevented the onset of disease and reduced established colitis , this pathway might be involved in perceiving or manifesting various somatic and cognitive symptoms that characterize stress-related disorders.Psychotropic drugs, such as serotonin reuptake inhibitors, have effects on both the brain and the gastrointestinal tract and consequently should be understood as modulators of the brain–gut axis.Research investigating the interaction between nutritive factors, somatic factors, such as heart rate, psychological and pharmacological treatments, and vagal activity has the potential to lead to integrative treatment options that incorporate VNS, nutritional approaches, drugs, and psychological interventions, such as mindfulness-based approaches, which can be tailored to the needs of the individual patient.SB, AK and GR reviewed literature and wrote this paper. GH outlined structure of this paper, reviewed literature, and wrote this paper.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 reviewer JD and handling editor declared their shared affiliation.


Injuries of the sciatic nerve are common causes of pain and limitation in thelower limbs. Due to its particular anatomy and its long course, the sciaticnerve is often involved in diseases of the pelvis or leg. In recent years,magnetic resonance neurography has become established as an important tool forthe study of peripheral nerves and can be widely applied to the study of thesciatic nerve. Therefore, detailed knowledge of its anatomy and of the mostprevalent diseases affecting it is essential to maximizing the accuracy ofdiagnostic imaging. Ideally, MRN involves the use of 3.0 Tmagnets and the protocol includes the following: graded fluid signal-sensitivesequences with fat suppression; a TE > 66 ms; thin slices; and acquisition in thebest anatomical planes for study of the nerve or plexus. The use of a TE > 66 msserves to avoid the magic angle phenomenon, which is related to anisotropy of theperipheral nerve and can simulate signal abnormality. These sequences providegreater spatial and contrast resolution for neural study. MRN reveals peripheralnerve abnormalities by identifying changes in signal intensity, notably onT2-weighted images, together with changes in the cross-sectional area and course ofthe nerve, as well as disorganization or absence of the typical fascicular pattern.Another focus of MRN-based peripheral nerve studies is the denervation of muscles,an abnormality that can manifest as a pattern of edema or, in chronic cases,hypotrophy of the muscles innervated by the sciatic nerveClinically, lesions or diseases of the sciatic nerve manifest as pain of varyingintensity in the lower lumbar region, with irradiation to the gluteal region and tothe posterior region of the ipsilateral lower limb. Those manifestations can beaccompanied by changes in sensitivity or motor deficits.-7. Recent studies have demonstrated that thistechnique can also be used in the study of peripheral nerves, although we found no studies withan emphasis on the specific evaluation of sciatic nerve abnormalities in humans.Recent experimental studies involving animal models of crush injury and sciaticnerve traction injury showed that DTI tractography, using routine clinical 1.5 T MRIscanners, is a promising tool in the assessment of sciatic lesions,10. In those studies, DTI was able to differentiate betweennerves with nerve damage and control group nerves. In addition, the values and timecurves of fractional anisotropy and the eigenvalue lambda (perpendicular) correlatedwell with the histological findings of Wallerian degeneration and with functionalrecovery.Another MRI technique that can be used for the study of neural pathways istractography, which involves diffusion-weighted acquisition-typically diffusiontensor imaging (DTI)-and is classically used in studies of the central nervoussystemThe aim of this essay is to illustrate the imaging aspects of neuropathies and theanatomy of the proximal segment of the sciatic nerve by MRN. Among the causes ofneuropathies, we illustrate those that are neoplastic, compressive, traumatic,hereditary, iatrogenic, or idiopathic in nature.,4, as depicted in The lumbosacral plexus is composed of ventral rami of the L4-S3 nerve roots, whichjoin to form the tibial  nerve, the common  peroneal nerve, and theposterior cutaneous nerve of the thigh. The sciatic nerve consists of the tibial andcommon peroneal components, which are encased in a common sheath and exit the pelvisthrough the sciatic notch-13.Benign or malignant neoplasms can arise from nerve fibers or from the cuff of thesciatic nerve sheath , and5. On MRN, a typical finding is an expansile lesion involving the sciatic nerve. Here,we illustrate examples of primary sciatic nerve neoplasms as well as secondaryinvolvement of the sciatic nerve in cases of neoplasms in the region of the pelvisand proximal thigh.. Inimaging studies, the finding typical of Charcot-Marie-Tooth disease is diffuse nervehypertrophy. Clinically, patients with Charcot-Marie-Tooth disease present muscularweakness, pain, and a variety of deformities related to muscular atrophy.Chief among the hereditary causes of sciatic neuropathies is Charcot-Marie-Toothdisease, which is a spectrum of diseases related to alterations currently describedin more than 30 genes,17.As previously noted, the proximal segment of the sciatic nerve has an intimaterelationship with the piriformis muscle. Variations include the sciatic nervecoursing anterior to, posterior to, or within the ventral portion of the piriformismuscle. When it is related to an abnormality in the piriformis muscle, neuropathy ofthe proximal segment of the sciatic nerve can be called piriformis syndrome,although there is controversy in the literature about the existence of this causalrelationshipIn compressive sciatic neuropathy, MRN findings include changes in the path,thickness, or signal of the sciatic nerve, with or without abnormalities of thepiriformis muscle anatomy. We illustrate two examples of piriformis musclealteration with neuropathy of the proximal portion of the sciatic nerve  and 10.. In such cases, imaging findings include, other than thechanges typical of neuropathy, alterations to the surrounding soft tissues, such asmuscle bruising. The clinical correlation, if available, reveals a history oftrauma, thus confirming the diagnosis.Because of its particular anatomy and long course, the sciatic nerve can be affectedby direct trauma or pelvic ring fracture, which are common in automobile accidents.Dislocations of the coxofemoral joint, which occur in cases of high-energy trauma,are also common causes of sciatic neuropathyWe illustrate a case of neuropathy caused by direct trauma resulting from a fall fromstanding height .. The development of neural changes related to radiotherapy tendsto occur at 5-30 months after treatment, its incidence peaking between months 10 and20. In radiation-induced neuropathy, the imaging findings are nonspecific andinclude changes in the thickness and signal intensity of the affected nerve. Theclinical correlation with a history of radiotherapy is fundamental to suggestingthis diagnosis. Clinically, radiation-induced neuropathy is initially characterizedby sensory manifestations, mainly pain and paresthesia, in some cases evolving tomuscle weakness-21.One of the main iatrogenic causes of sciatic nerve neuropathy is radiotherapy forpelvic neoplasms, including prostate, gynecological, and colorectal cancer,resulting in radiation-induced neuropathy, as depicted in Figure 12, can also be demonstrated (Neuroma  is a comnstrated . Like raThe sciatic nerve is often affected in diseases of the pelvis or lower limbs, as wellas by lesions that originate within the nerve itself. Its course is long, whichpredisposes it to various types of compression. MRN is an important tool for theevaluation of peripheral nerve diseases and should be widely used for the study ofthe sciatic nerve whenever possible. Detailed knowledge of its anatomy and of theimaging aspects of the main diseases affecting it is fundamental to optimizingimaging studies of the sciatic nerve.


Bony hyperostosis is commonly associated with meningioma growth and is considered one of the characteristic signs on imaging; however, recurrence of meningiomas in the sphenoorbital area, including associated hyperostosis, is typically precluded by gross total resection of the lesion. This 63-year-old man presented with progressive double vision and proptosis in the right eye. He underwent frontotemporal craniotomy and partial removal after magnetic resonance imaging demonstrated a right sphenoorbital meningioma extending to the orbit and middle fossa. He had transient improvement of his symptoms postoperatively but experienced a progressive recurrence of symptoms and new onset of right facial hypoesthesia in the distribution of V1 and V2. We performed a right frontotemporal craniotomy with removal of the nodular part, as well as extensive drilling. Although the postoperative computed tomography scan revealed a gross total resection, the five-year follow-up scan demonstrated a recurrent hyperostosis in the region of the lesser and greater sphenoid wings, the middle cranial fossa floor with inferior extension toward the infratemporal fossa, and the sphenoid sinus wall. After another redo surgery, the patient continues to be monitored with yearly imaging. The extent of surgical resection is one of the most important predictors of meningioma recurrence postoperatively, and cases of recurrence after gross total resection are rare. The sphenoorbital area is the most common location for meningiomas in the skull base; these lesions represent 20% of all meningiomas and 4% of all orbital tumors -2. SphenA 63-year-old man presented to an outside institution with a history of progressive double vision and proptosis in the right eye over a three-month period. On examination, he had an afferent pupillary defect in the right eye, 7 mm of exophthalmos, and an inferior visual field defect in the right eye. Magnetic resonance imaging (MRI) of the brain revealed right sphenoorbital meningioma extending to the orbit and middle fossa for which he underwent a right frontotemporal craniotomy and partial removal. The pathological diagnosis was WHO Grade I meningioma. The patient had transient improvement of his symptoms postoperatively but experienced a progressive recurrence of his symptoms and a new onset of right facial hypoesthesia at the distribution of V1 and V2. Computed tomography (CT) and MRI scans of the brain showed recurrence of his meningioma with extensive hyperostosis of the lesser sphenoid wing, the lateral and posterior wall of the orbit, and the middle fossa (Figure We performed a redo right frontotemporal craniotomy with removal of the nodular part, as well as extensive drilling of the lesser sphenoid wing, sphenoid ridge, lateral orbital wall, and clinoid, and decompression of the optic nerve, superior orbital fissure, foramen rotundum, and cavernous sinus lateral wall. A postoperative CT scan showed a gross total removal of the lesion Figure , and theAfter five years of continued yearly imaging follow-up, the patient’s CT scan revealed a recurrent hyperostosis in the region of the lesser and greater sphenoid wings, middle cranial fossa floor with inferior extension toward the infratemporal fossa, and sphenoid sinus wall Figure . The patThe recurrence in our case is purely bony hyperostosis without a soft tissue component on imaging and, so far, has not required surgical removal because the patient is asymptomatic. Depending on the extent of the tumor on imaging and patient presentation, in our practice, the goals of surgery for sphenoorbital meningioma include the removal of the tumor mass, decompressing the optic nerve, superior orbital fissure, and the orbital contents. These goals are achieved by removing the adjacent dura with a safe margin when possible, drilling the orbital roof and lateral wall, completing an anterior clinoidectomy, decompressing the optic nerve and superior orbital fissure, and removing any intraorbital tumor extension along with the periorbita. The bony removal in these cases typically extends as far medially as the posterior ethmoid sinus and lateral wall of the cavernous sinus and as far laterally as the foramen rotundum and maxillary division of the trigeminal nerve. When the sinus wall is violated, a muscle plug with fibrin glue is used to prevent a cerebrospinal fluid leak. In our experience, removal of all tumor, including soft tissue and hyperostotic bone, provides the longest recurrence-free survival and symptomatic relief for patients.To our knowledge, this is the first report of a recurrent hyperostosis after a gross total resection of sphenoorbital meningioma with complete removal and drilling of the involved orbital bone, sphenoid bone, and middle cranial fossa floor. Sphenoorbital meningiomas can be primarily intraosseous without nodular growth intra- or extradurally . HyperosThe extent of surgical resection of sphenoorbital meningioma is a very important determinant of postoperative recurrence. Recurrence rates in recent studies have typically been between 5 and 10%. In one series of 25 patients with sphenoorbital meningioma, 70% of patients underwent complete surgical resection, and the five-year recurrence rate was 8% . A higheComplete removal of hyperostosing sphenoorbital meningioma is often limited by the complexity of skull base approaches, the proximity of the cranial nerves, poor accessibility, dural attachments, and an involvement of structures in the extracranial compartment, especially the nasal sinuses. However, whenever possible, gross total removal of these tumors, including the dura and surrounding bone, should be one of the goals of the surgery, especially in young and healthy patients to prevent recurrence.


Although the heterogeneous nature of psychosis is well established in the literature, genetics, neurophysiology, and neuroimaging have not yet succeeded in an unequivocal classification of the diverse clinical presentations. For the time being, the field relies mostly on a symptom-based, descriptive diagnostic system. The purpose of the current study was to use seven previously identified positive symptom domains to identify possible subgroups of first-episode psychosis (FEP), using cluster analysis. In addition, we tested whether possible subgroups differed across a number of sociodemographic and clinical variables.We analyzed data from a large FEP sample (n=247) to identify possible clinical subgroups of psychosis based on positive symptoms; specifically, delusion and hallucination domains resulting from previous factor analyses of Scale for the Assessment of Positive Symptoms (SAPS) items in this sample. A rigorous methodology was applied to perform cluster analysis and identify FEP subgroups. Kruskal-Wallis tests with pairwise post-hoc comparisons were used to check the differences in each positive symptom domain between the subgroups. Bivariate analyses comparing subgroups on a number of sociodemographic and clinical characteristics were performed.Five FEP subgroups were identified based on the severity of seven domains of delusions and hallucinations. Three of them  shared a similar psychopathological profile, with typical psychotic symptoms differing in severity. Another subgroup was characterized by high severity on typical and atypical symptoms , and the other by high severity in somatic delusions (Somatic Delusions Subgroup). The five subgroups did not significantly differ in terms of gender, age at onset, family history, mode of onset of psychosis, premorbid functioning, and alcohol and non-cannabis drug use disorders, though some potential signals were identified, . Significantly different prevalence rates of cannabis use disorder were found across the five subgroups.In our analysis, five possible FEP subgroups were identified based on the severity of seven domains of delusions and hallucinations: three of them shared a similar psychopathological profile differing in severity, and two were characterized by different atypical symptoms. Despite several acknowledged limitations, our results highlight the potential to identify clinical phenotypic subgroups of FEP, which may be helpful in future research aimed at filling the gaps between clinical, neuropathological, and genetic explanations of psychosis etiology. Such an approach may also lead to better targeted preventive interventions and more individualized and effective treatments.


A brief introduction considering Darwin's work, the evolutionary synthesis, and thescientific biological field around the 1970s and subsequently, with the molecularrevolution, was followed by selected examples of recent investigations dealing withthe selection-drift controversy. The studies surveyed included the comparison betweenessential genes in humans and mice, selection in Africa and Europe, and the possiblereasons why females in humans remain healthy and productive after menopause, incontrast with what happens in the great apes. At the end, selected examples ofinvestigations performed in Latin America, related to the action of selection formuscle performance, acetylation of xenobiotics, high altitude and tropical forestadaptations were considered. Despite dissenting views, the influence of positiveselection in a considerable portion of the human genome cannot presently bedismissed. Everything started with the flash of genius of Charles Darwin (1807-1882), whichoccurred in 1842, followed by a careful review of the available information up to1859, when he published his seminal work, "The Origin of Species" . In thisHe hesitated in extending this principle to the human species, and only in 1871, 12years later, he published "The Descent of Man"  in whichWhat are these conclusions, and the added comments? He maintained that the whole bodyof evidence undeniably indicated that we had derived from an animal ancestor. Inrelation to objections of the church to this view, he asserted that faith in God hadbeen considered the most completed distinction between humans and animals, but itwould be impossible to maintain that this faith is innate or instinctive in humans;and that if it was considered non-religious to explain the human origin from adistinct species by natural selection, then the same would apply for the explanationof the birth of individuals through the laws of normal reproduction.Darwin made a clear distinction between natural and sexual selection. According tohim, sexual selection depends of the success of some individuals in relation toothers of the same sex regarding the species reproduction, while natural selectiondepends on the success of both sexes, at all ages, in relation to this process. Moregenerally, he added that he would rather prefer to be considered a descendant of anon-human primate than to persons who torture the enemies, consider women as slaves,have no shamefacedness, and are tormented by an enormous amount of superstitions.One of the weaknesses of Darwin's theory, which he himself recognized, was theignorance at the time of the laws that determined the biological inheritance inliving organisms. But the fundamentals of these laws were clearly delineated in 1866,seven years after the publication of "The Origin of Species", by Gregor Mendel(1822-1884). Mendel's work, however, was not recognized by his peers, and only 34years later (1900) it was rediscovered and duly appreciated.th century, between 1930 and 1950, through the Synthetic Theoryof Evolution. Elsewhere, in Chapter 1 of The fusion between Darwin's and Mendel's works occurred in two very fertile decadesof the 20th and 21st centuries by a series of empirical dataand mathematical models.In 1870, Alfred Russel Wallace (1823-1913) who developed independently of Darwin theconcept of the key role of natural selection in biological evolution, questioned itsrole in relation to our species. How could the conventional natural selection selectthe exceptional capacities developed by the human mind? The answer would be providedin the 20At the end of the sixties th century morphological traits wereinvestigated using qualitative, obtained by visual inspection, or quantitativemethods, through the use of anthropometric measurements. During the 20thcentury immunological and biochemical techniques were employed to study variation atthe protein level, but towards the end of this century and the present one it becamepossible to study the genetic material directly through, among others, the use of thepolymerase chain reaction (PCR) technique and by increasing sophisticated sequencingmachines. Parallel developments in bioinformatics and the implementation of theInternet made possible increased interaction between research teams, with theformation of consortia for the study of specific problems at the world level; and theestablishment of data banks, with the possibility of analysis of a huge amount ofdata. The opportunity was open, therefore, to investigate problems that were defyingsolution, such as the selection-drift controversy.Methods for studying population variability had progressed at a fast rate, especiallyin the last years. In the 19In what follows I will present some selected examples of work performed by differentgroups of researchers, giving emphasis, at the end, of studies performed by ourresearch team. Before that, however, I would call attention to a recent review I madeof the selection or drift debate in Chapter 2 of The review ended by listing selected examples of studies that could be classified asfollows: (a) six emphasizing the role of mutation, demography, and drift for theexplanation of human genomic variability; (b) five that considered the role ofnegative selection on this variability; and (c) fifteen emphasizing the role ofpositive selection in the human genome. The conclusion was that the influence ofpositive selection in a considerable fraction of our genome cannot be dismissed. Butdissent views continue to be presented. A highly selected list would include Escherichia coli and in the yeast Saccharomycescerevisae. They therefore can be used as sources of comparison with dataon humans. The most dramatic effect that can occur in the phenotypic expression of a gene isloss of essentiality. Genome-wide gene-deletion in the experiments with informationabout the fitness of each deletion strain had been performed in the bacteriumAn alternative approach that would make human comparisons with microorganismsfeasible was followed by The African Genome Variation Project comprises a network of collaborative researchteams from Africa, Europe and USA, and a recent publication describing its findingsis summarized in The modern sequencing techniques, coupled with enhanced methods of ancient DNAcapture and study, are opening perspectives undreamed even a few years ago. The workby Senescence can be defined as the age-related deterioration of organismal function andfitness. Must all organisms age? The answer seems to be yes, since the overwhelmingmajority of metazoans show clear aging signs, and even unicellular organisms presentthis phenomenon through asymmetrical cell division .The classical explanation for the existence of aging is antagonistic pleiotropy. Anyfavorable mutation acting early in life would be positively selected even if itincreases the risk of death or infirmity later in life.As far as humans are concerned, women's fertility ends at about the same age thatfertility ends in other females of the great apes; but while our closest livingrelative became decrepit and die soon, female humans can remain healthy andproductive well past menopause. Why? The answer may be cooperative breeding – thegrandmother, older siblings, and other members of the extended family can helpmothers to raise their children in a healthy way.On the other hand, increased maternal age at reproduction is often associated withdecreased offspring performance in numerous species of plants and animals, includinghumans. So far, so good, but what if elders who contribute to cooperative breeding show adeterioration of their cognitive capacities? High quality muscular constitution is of course of prime importance in humans. Thistype of ability may have been especially significant during the time when our specieshad hunter-gathering as a way of subsistence. Both high speed (needed to flee frompredators) and endurance running (providing persistence hunting and easier access tocarcasses) would be important in the early days of our evolutionary history.ACTN3) gene islocated in the long arm of chromosome 11, codifying a binding protein related to fasttwitching the muscle fibers. Its lack leads to a slower, but more efficient aerobicpathway. A C >T transition at the ACTN3 557 residue converts arginine to apremature stop codon; this change is polymorphic (rs 1815739), and surveys conductedat different regions of the world have led to the data summarized in The human alpha-actinin skeletal muscle isoform 3 . The corresponding alleles are located onchromosome 8p22, in a gene with two exons, only one of which presents variation. NAT2is an enzyme responsible for catalyzing the N- or O-acetylation of aromatic andheterocyclic amines and hydrazines present in a wide range of xenobiotics and othersubstances, including medicines and food. In particular, it was found that the enzymeis responsible for the genetic metabolic response to isoniazid (an antituberculosisdrug) and many other commonly prescribed drugs, such as sulfamethoxazole, used in thetreatment of Acquired Immune Deficiency Syndrome (AIDS).NAT2 polymorphisms lead to distinguishable haplotypes, associated with high orreduced enzymatic activities, which were correlated with fast  orslow (derived) acetylator/metabolizer phenotypes. The slow condition can lead tocollateral effects of disease treatment, as was well demonstrated for isoniazid.Based on a worldwide analysis of this polymorphism, *4) and the remaining three with the derived, slow condition,are responsible for 90% to 100% of the genetic constitution of the Latin American andSiberian subjects studied. As a comparison, note the much larger variability observedin Africa (these four haplotypes are responsible for only 64% of their genomes).Eskimo and Native American hunter-gatherers do not differ markedly in relation tothese haplotypes, but the same is not true in relation to the three sets of otherNative Americans or the two Mestizo population samples studied. No significantdifferences were found between hunter-gatherers and agriculturalists, but the numberof hunter-gatherer individuals tested was not large (166+76=242). The markedinterpopulation variability found among hunter-gatherers , notfound in the agriculturalist set, could also have contributed to the lack ofsignificance between hunter-gatherers/agriculturalists. The interpopulationvariability difference observed, however, is compatible with that expected accordingto the genetic models outlined above.The results obtained are summarized in There is a voluminous literature related to human high altitude adaptation. Aclassical interdisciplinary investigation was performed by Paul T. Baker andassociates in the 1960s .More reThe systems studied, related to the Tumor Protein 53 (TP53) pathway, have beenextensively investigated in relation to disease associations, but much less studiedfor its population variability and related evolutionary significance. Our researchwas concentrated in five single nucleotide polymorphisms of genes from this pathway:(a) TP53 gene and associated p53 protein, which act by activating or repressing alarge number of target genes related to metabolism and apoptosis, rs 1042522; (b) E3ubiquitin-protein ligase, MDM2, which mediates the activity of TP53; rs 2279744; (c)Protein MDM4, a negative regulator of p53, rs 1563828; (d)Ubiquitin-specific-processing protease 7, USP7, which deubiquitylates p53, protectingit from proteasome degradation, rs 1529916); and (e) Leukemia Inhibitory Factor, LIF,a cytokine expressed in various cell types, favoring blastocyst implantation, rs929271.USP7-G, LIF-T, and MDM2-T aswell as their interactions, showed significant evidence that they were selected inrelation to the harsh environmental variables related to high altitudes in the Andes,and probably connected to the well-known reproductive adaptation of Andean women tothese conditions. A secondary effect could be related to the reported lower cancerincidences observed in Andean high altitude groups.While variation in the TP53 polymorphism itself furnished non-significant results,Tropical forests, characterized by high temperatures and rainfall, dense vegetation,as well as an enormous pathogen diversity, are, undoutedly, a very harsh environmentfor humans; and it is unclear whether we would ever have subsisted there withoutdepending on external sources, such as agriculture or exchange with neighboringpopulations. They provide, therefore, an ideal model for the investigaton of naturalselection, and an attempt in this direction was made by The investigation included not less than 660,918 SNPs, tested using Illumina chips,studied in Mandenka and Yoruba (grouped as West Africa), African Biaka and Mbutipygmies , Suruí, Karitiana, Pima and Zapotec Native American populations. Theywere compared in different sets, according to whether they inhabited or not  in Africa or the Americas  tropical forests.After a series of sophisticated analyses, seven regions (clusters), located in fivedifferent chromosomes, were detected as showing clear indications of positiveselection related to tropical forest adaptations. The main genes related to them arelisted in This review included investigations performed outside and inside Latin America involvinggenes that are essential for survival in humans and mice, traits of medical importancein Africa, ancient and modern DNA studies in Europe, human aging, muscle performance,acetylation of xenobiotics, and high altitude and tropical forest adaptations. As can beinferred by the wide variety of subjects considered, it is now impossible to deny theimportance of natural selection in shaping a considerable portion of the human genome.But there is much work still to be done. Especially important would be methodologicaladvances for the analysis of different types of selection regimes, such as selection onstanding genetic variation and the dynamics of polygenic systems.


Supercomputing facilities are becoming increasingly available for simulating electrical activity in large-scale neuronal networks. On today's most advanced supercomputers, networks with up to a billion of neurons can be readily simulated. However, building biologically realistic, full-scale brain models requires more than just a huge number of neurons. In addition to network size, the detailed local and global anatomy of neuronal connections is of crucial importance. Moreover, anatomical connectivity is not fixed, but can rewire throughout life , new methods are described for measuring and data-basing microscopic and macroscopic connectivity. In the second theme , novel models are introduced that incorporate morphological plasticity and rewiring of anatomical connections. In the third theme , simulations of large-scale neuronal networks are presented with an emphasis on anatomical detail and plasticity mechanisms. Together, the papers in this research topic contribute to extending high-performance computing in neuroscience to encompass anatomical detail and plasticity.Axer et al. demonstrate how to bridge microscopic visualizations of fibers obtained by 3D-PLI  provides such a reference space for rodent brain data. The aim of the study by Schubert et al. was to extend the WHS rat brain atlas with information about cytoarchitecture, receptor expression and spatial orientation of fiber tracts, derived from autoradiography and PLI images. To incorporate these distinct classes of information into the WHS, the authors improved currently available registration algorithms to align sections and to correct for deformations. The extended WHS rat brain atlas now enables combined studies on receptor and cell distributions as well as fiber densities in the same anatomical structures at microscopic scales. Furthermore, the methods developed facilitate future integration of data of other modalities.Capturing different aspects of brain organization, such as connectivity and molecular composition, necessitates the use of different neuroimaging techniques. To subsequently integrate the multiscale and multimodal data into a complete 3D brain model requires an accurate definition of the spatial positions of structural entities. Defined by MRI, the Waxholm Space (WHS) .Fauth and Tetzlaff review experimental and modeling studies that address the formation and deletion of synapses  and how this is regulated by electrical activity. Whereas adapting existing synapses in a Hebbian manner predominantly serves memory consolidation, the de novo formation of synapses and deletion of existing synapses can, together with other synaptic mechanisms, grant stability to a network facing continuously changing inputs. The authors point out that these different plasticity mechanisms may be involved in different neural functions and, remarkably, may respond very differently to changes in neuronal activity.Bezelos et al. introduce a simulation tool for systematically varying the morphology of any type of neuron, which will help investigate the role of neuronal morphology and morphological changes in large-scale neuronal networks.Changes in the anatomical layout of connections  are crucially dependent on morphological changes in individual neurons. A lack of understanding of how structural changes affect network function is partly due to the absence of tools for studying the impact of neuronal morphology on neuronal function. Therefore, Diaz-Pier et al. go beyond the level of single neurons and describe an approach based on a recent model of homeostatic structural plasticity , the simulation could be carried out in real-world time. This approach opens up new opportunities for studying long-term plasticity in neural networks, e.g., in the context of memory consolidation.Knight et al. demonstrate that large-scale models that incorporate complex and demanding plasticity mechanisms (in this case, based on the Bayesian Confidence Propagation Neural Network paradigm; Lansner and Holst, Zhou et al. rely in their work on the established neuro-simulator NEURON (Hines and Carnevale, Kozloski positions his modeling and simulation work at brain-scale, comprising the neocortex, basal ganglia and thalamus. The proposed model is based on the principle of information-based exchange and does not cover anatomical details. Nevertheless, it is grounded in neuroanatomical observations and accounts for various forms of plasticity. Modeling at this rather abstract level enables long-term simulations at brain-scale and extensive parameter variations. In this specific study, variations in dynamic set points and modulations were investigated, leading to a theory about the emergence of neurodegenerative diseases.Biologically realistic large-scale brain models require, besides a huge number of neurons, the right layout of local and global connections. Moreover, they need to capture the plasticity mechanisms operative in the adult brain. These mechanisms include, in addition to changes in the strength of synapses, structural modifications in anatomical connections. With the articles in this research topic, we hope that the reader will become aware of the methods and models by which large-scale brain networks running on supercomputing facilities may be extended to include anatomical detail and the full plastic potential of the brain.MB, WS, and AvO wrote the Editorial.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.