Pulmonary Complications of HIV summarizes current practices for diagnosing and treating common HIV-related pulmonary complications. It is a well-written, educational work that will interest anyone managing the care of HIV-infected persons. The content and amount of information packed into this easy-to-read textbook is impressive. Each chapter is well organized and well referenced, and important concepts and definitions are laid out clearly.Since HIV/AIDS was first described, clinicians have found that the lung is the site most frequently affected and that pulmonary complications are a major cause of illness and death for HIV-infected persons. However, over the years, the discovery and use of antiretroviral therapy has increased life expectancy for HIV-infected persons, and the spectrum of infectious and noninfectious pulmonary complications has changed. For example, the incidence of opportunistic pneumonias has declined dramatically, whereas the incidence of bacterial pneumonia has not decreased proportionately. Furthermore, noninfectious complications, such as chronic obstructive pulmonary disease and lung cancer, are increasing. It is critical for anyone managing the care of HIV-infected persons to be aware of these lung complications and understand their diagnoses, possible treatments, and prevention. Pulmonary Complications of HIV does an excellent job discussing these aspects.The authors are well-respected researchers and clinicians from throughout the world who work in the fields of pulmonary medicine and HIV-related lung diseases. The literature on HIV-related pulmonary complications is still lacking in certain areas, which most likely led to some chapters  to be shorter and less comprehensive than others. Of the book’s 19 chapters, the first 2 discuss the global epidemiology of HIV and current antiretroviral therapy guidelines, which will be useful for clinicians who might not regularly manage the care of HIV-infected patients. The third chapter discusses pulmonary immunity, a complicated topic but one the authors explain simply by emphasizing essential concepts. The next several chapters highlight various diseases and strategies for preventing them in the field, including vaccine guidelines. In addition, the authors cover a number of other key aspects to HIV care, such as pregnancy, pediatrics, and infectious and noninfectious complications, completing a thorough review of the literature. Although infectious disease specialists and others who care for HIV-infected patients might consider the first few chapters too simplistic, the latter chapters on pulmonary complications will be relevant and instructive. Pulmonologists will find that the first few chapters discuss aspects of HIV care to which they are not readily exposed and the latter chapters provide information on the epidemiology, clinical manifestations, diagnosis, and management of common complications seen in HIV-infected persons.Pulmonary Complications of HIV does an exceptional job summarizing the major pulmonary manifestations of HIV/AIDS and discussing the progress in overall HIV treatment. Because the book itself is fairly short (265 pages), it appears to be more of a simple paperback rather than a reference textbook. Regardless, it is worthy of a spot on your bookshelf. As a clinician, educator, and researcher in the field of HIV-related lung disease, I found the book to be informative, easy to read, and a quick and simple reference to have on hand. It would be valuable to any medical trainee or clinician who manages the care of HIV-infected patients.


Endocrine dysfunction is a common effect of traumatic brain injury (TBI). In addition to affecting the regulation of important body functions, the disruption of endocrine physiology can significantly impair mental functions, such as attention, memory, executive function, and mood. This mini-review focuses on alterations in mental functioning that are associated with neuroendocrine disturbances in adults who suffered TBI. It summarizes the contribution of hormones to the regulation of mental functions, the consequences of TBI on mental health and neuroendocrine homeostasis, and the effects of hormone substitution on mental dysfunction caused by TBI. The available empirical evidence suggests that comprehensive assessment of mental functions should be standard in TBI subjects presenting with hormone deficiency and that hormone replacement therapy should be accompanied by pre- and post-assessments. TBI represents one of the leading causes of cognitive, emotional, and motor disability in both, industrialized and non-industrialized countries; falls, road, occupational and recreational accidents, and violence are the most frequent causes of TBI .Functional impairments after brain injury are usually explained in terms of morphological and pathophysiological alterations of cortical and subcortical brain structures. This view is consistent with the fact that injury to local and distributed components of brain networks, and their interplay, can alter cognition, affect, and behavior . While fThis mini-review focuses on alterations in mental functioning  that are associated with neuroendocrine disturbances in adults who have suffered traumatic brain injury (TBI); it also considers the role of hormones in brain plasticity. Specifically, the article will address the following issues: (a) hormonal contributions to the regulation of certain mental functions; (b) the consequences of TBI on mental health and neuroendocrine homeostasis; and (c) the effects of hormone replacement on mental dysfunction caused by TBI. Our review of the available empirical evidence suggests that improvements in the identification and management of hormone deficiencies in TBI subjects requires the inclusion of comprehensive, standardized neuropsychological assessment; this will help better understand and explain functional impairments in TBI.Abundant evidence in humans and animals points to the important role of the endocrine system in brain development and the regulation of cognitive, emotional, affective, motivational, and social behaviors; endocrine hormones also regulate behaviors that are essential for individual and species survival . Space restrictions allow us to illustrate this by just a few examples that represent the different classes of endocrine secretions.A large array of peptides of cerebral origin , best known for their role in the regulation of the peripheral endocrine tissues, exert direct  or indirect effects on cognition and mood . The pit-peptidergic hormones produced in the periphery also exert strong effects on brain functions. These hormones  pass across the blood-brain barrier because of their relative lipophilicity or through binding to specific transporters . All of them can elicit long-lasting effects in the brain by binding to receptors that are ligand-activated transcription factors. Receptors for each of these classes of hormone are present in diverse brain regions and, are especially abundant in corticolimbic structures as well as the hypothalamus. Although primarily implicated in thermogenic processes, thyroid hormones  are crucial for the maturation of neural cells and are essential for learning and memory and overall cognitive performance )It becomes clear from the experimental and clinical data available, that hormones play an important role in maintaining optimal brain functioning in the adult. Subjects with endocrine dysfunction may exhibit mental disorders, spanning the cognitive, affective and/or behavioral domains. Notably, subjects with endocrine alterations show more global, unspecific cognitive dysfunction, with mental slowing and impaired executive regulatory process being dominant features; these can be alleviated by GH replacement. This observation fits with the idea of a final common pathway disorder, which is based on the premise that any type of dysfunction of the complex network underlying executive, regulatory components of cognition and mood may produce a similar pattern of disorders ,56. Whilvs. primary neuroendocrine dysfunction) remains a challenge. The evidence briefly reviewed here underscores the need for the identification and timely appropriate clinical management of hormone deficiencies, as well as for a comprehensive neuropsychological and psychopathological assessment in subjects with TBI. Likewise, the need for endocrine profiling and replacement in subjects with hypopituitarism deserves further attention, including the definition of criteria regarding indication of hormone replacement and evaluation of treatment efficacy . The laacy (see ,59; cf.Given the multifactorial nature of TBI, it is imperative that an interdisciplinary approach is developed to improve clinical outcomes ,60. Howe


This network can improve pertussis prevention and control and be a model for surveillance programs. Bordetella pertussis isolates. Data collected through EPS have been instrumental in understanding the rapidly evolving epidemiology and molecular epidemiology of pertussis and have contributed essential information regarding pertussis vaccines. EPS also serves as a platform for conducting critical and timely evaluations of pertussis prevention and control strategies, including targeting of vaccinations and antimicrobial prophylaxis.Despite high coverage with pertussis-containing vaccines, pertussis remains endemic to the United States. There have been increases in reported cases in recent years, punctuated by striking epidemics and shifting epidemiology, both of which raise questions about current policies regarding its prevention and control. Limited data on pertussis reported through the National Notifiable Disease Surveillance System have proved insufficient to answer these questions. To address shortcomings of national pertussis data, the Emerging Infections Program at the US Centers for Disease Control and Prevention launched Enhanced Pertussis Surveillance (EPS), which is characterized by systematic case ascertainment, augmented data collection, and collection of  Haemophilus influenzae type b infection, and diphtheria. Pertussis remains endemic to the United States, and the number of reported cases has been increasing steadily since the late 1980s, with notable epidemic peaks in recent years (Pertussis (whooping cough) has proven to be a frustratingly persistent public health problem. Although annual numbers of reported cases decreased >99% in the United States after introduction of whole-cell pertussis vaccines in the 1940s, this highly contagious respiratory illness has refused to go the way of other vaccine-preventable diseases of childhood, such as polio, nt years . In 2012,Bordetella pertussis at the molecular level, such as loss of pertactin, a key aP vaccine antigen  from 57 public health jurisdictions  ? Has the spectrum of clinical illness changed, and does it differ by factors such as age and vaccination status? In the setting of waning aP-induced immunity, should additional doses of the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) be recommended, and if so, for which populations? Is B. pertussis incidence and existing pertussis surveillance infrastructure. The principal objectives of EPS are to determine overall and age-specific incidence and epidemiologic characteristics of pertussis, to characterize the molecular epidemiology of circulating B. pertussis strains, to monitor the effects of pertussis vaccines, and to provide a platform for conducting special studies, including critical and timely evaluations of pertussis prevention and control strategies. As a secondary objective, the system collects data to describe the epidemiology and molecular characteristics of other Bordetella species, including B. holmseii, B. parapertussis, and B. bronchiseptica.In 2011, Enhanced Pertussis Surveillance (EPS) was undertaken by 6 states within the Emerging Infections Program (EIP), a collaborative network between CDC and state and local health departments, academic institutions and laboratories that serves as a national resource for surveillance, prevention, and control of emerging infectious diseases  pertussis case definition, and all modifications made to the case definition at the national level are adopted by EPS  at no cost to catchment-area health care providers or to patients without access to health care to ensure testing whenever The standardized EPS case report form mirrors the NNDSS form, but collects several supplemental demographic, clinical, and epidemiologic variables. The EPS case report form is revised annually, maintaining the flexibility to address key public health questions in a timely manner.Local investigators and surveillance personnel work to interview each case-patient or parent proxy and the case-patient’s diagnosing health care provider and complete follow-up interviews when necessary. Multiple procedures are used to obtain accurate vaccination histories, including routine review of state immunization information systems and school immunization records, and occasionally contacting additional health care providers of a case-patient.B. pertussis. Approaches range from promoting centralized testing at a state public health laboratory, to identification of sentinel site providers for specimen collection, to recovering isolates from PCR-positive specimens. Once collected, B. pertussis isolates are sent to CDC, where they undergo susceptibility testing to erythromycin and azithromycin and a full panel of molecular characterization, including pulsed-field gel electrophoresis, multilocus variable number tandem repeat analysis, and multilocus sequence typing. More recently, laboratory testing has evolved to include phenotypic and genotypic assays for detection of pertactin-deficient isolates, as well as whole-genome sequencing of B. pertussis.This feature is an arduous task, given the increasing reliance on non–culture-based methods for diagnosis of infection with Key advancements have been made in molecular characterization of clinical isolates. In response to these advancements, EPS is positioned to monitor characteristics of a larger population of circulating strains and to follow the molecular epidemiology of pertussis.B. pertussis among select population groups.As of 2014, EPS is conducted in the 5-county Denver metropolitan area of Colorado; 8 counties in metropolitan Atlanta, Georgia (added at the beginning of 2014); the 15-county Rochester and Albany areas of New York; the 3-county Portland area of Oregon; and statewide in Connecticut, Minnesota, and New Mexico. Although EPS is conducted in ≈5% of the US population, the demographic composition of the EPS catchment area is similar to the whole United States in terms of racial, ethnic, and age distributions, which enables characterization of the epidemiology of Since its inception, data collected through the EPS system have maintained a higher level of completeness than surveillance data reported through NNDSS. A comparison of data collected from both systems during 2011–2012 found significantly more complete data from EPS on race  and ethnicity  . High-quOverall and age-specific incidence rates have tracked 1.5–3.3 times as high among EPS sites as national NNDSS rates . State-sMore than 20 EPS-specific data elements have been added to the case report form, many of which are intended to inform policy or help monitor the impact of new vaccine recommendations. As we await potential licensure of the expanded use of >1 dose of Tdap, and the Advisory Committee on Immunization Practices (ACIP) considers additional doses for special populations, EPS is tracking the burden of pertussis among health care personnel, a target group for which few data are available on the burden of pertussis. To protect young infants at highest risk for severe illness and death from pertussis, the ACIP recommended Tdap vaccination of pregnant women in October 2011 and expanded the recommendation in 2012 to include a dose during every pregnancy . Little is known about the course of illness and complications of pertussis among pregnant women, a group for which pertussis vaccination is currently recommended as a means of protecting young infants. EPS has also been documenting the source of infant infection and has identified a shift from mothers to siblings as the most commonly identified source of disease transmission to infants , EPS gathered data that helped guide revisions to the national CSTE pertussis case definition for infants <1 year of age, which included removing the required 14-day cough for PCR-confirmed or epidemiologically linked cases , prompting the question, why are older children and adults being hospitalized for pertussis? EPS investigators conduct expanded reviews of medical records of all hospitalized EPS case-patients. Data gathered enable characterization of the severity of infections in hospitalized patients across age groups, determination of reasons for hospital admission, documentation of underlying health conditions associated with severe illness, assessment of current practices in treatment, and outcomes of severe pertussis infection.–,Although data suggested that maternal antibody transfer resulting from Tdap vaccination during pregnancy would probably confer protection and modify the severity of pertussis among infants, at the time the ACIP recommendation was made for women to receive a dose of Tdap during pregnancy, there was no direct evidence demonstrating effectiveness of the strategy in preventing infant disease  developed by CDC and the Food and Drug Administration. In addition, the EIP sites are assessing the clinical utility of the tests as they relate to stage of pertussis illness, age of patient, antimicrobial drug use, and vaccination status. Data from the evaluation will ensure that validated, standardized laboratory assays are available to help improve the diagnosis and reporting of pertussis, which will ultimately facilitate prevention and control efforts.Current evidence indicates that the resurgence of pertussis in the United States is real and not simply an artifact of improved surveillance. Furthermore, current vaccination strategies are not expected to reduce further the growing burden of disease in the United States. Because pertussis remains a notable public health challenge, EPS is well-positioned to monitor the changing epidemiology of this disease and provide timely, reliable surveillance data to help answer key questions. The flexibility and expertise of the EIP network can be relied on to tackle challenging public health issues and to make direct recommendations to advance the prevention and control of pertussis in the United States and can serve as a model for collaborators abroad hoping to implement standardized surveillance for pertussis in the international setting.


The human microbiome is overly exposed to antibiotics, due, not only to their medical use, but also to their utilization in farm animals and crops. Microbiome composition can be rapidly altered by exposure to antibiotics, with potential immediate effects on health, for instance through the selection of resistant opportunistic pathogens that can cause acute disease. Microbiome alterations induced by antibiotics can also indirectly affect health in the long-term. The mutualistic microbes in the human body interact with many physiological processes, and participate in the regulation of immune and metabolic homeostasis. Therefore, antibiotic exposure can alter many basic physiological equilibria, promoting long-term disease. In addition, excessive antibiotic use fosters bacterial resistance, and the overly exposed human microbiome has become a significant reservoir of resistance genes, contributing to the increasing difficulty in controlling bacterial infections. Here, the complex relationships between antibiotics and the human microbiome are reviewed, with focus on the intestinal microbiota, addressing (1) the effects of antibiotic use on the composition and function of the gut microbiota, (2) the impact of antibiotic-induced microbiota alterations on immunity, metabolism, and health, and (3) the role of the gut microbiota as a reservoir of antibiotic resistances. Bifidobacterium and marked increases of Proteobacteria. Moreover, the microbiota of those infants who were not treated, but whose mothers received antibiotics prior to delivery, showed the same alterations seen in the microbiota of the treated infants  due to nosocomial pathogens are a frequent occurrence. These are often associated with organisms such as  colitis . A mouseifficile .Enterococcus has been shown to precede bloodstream infection by this pathogen, and experimental work in mice has established that antibiotic treatment sets the stage for the intestinal outgrowth of this bacterium  and an increase of some Gram-negative bacteria (Porfiromonadaceae) often responsible for inflammatory processes , a devastating inflammatory disease for newborns. A low abundance of EC onset , 2013. MEC onset  and infaEC onset , presentEC onset . This dirocesses . In the rocesses . Althougrocesses .Increasingly, the gut microbiota is being established as an important factor in the regulation of host metabolism, in particular as it relates to energy homeostasis and adiposity. Several metabolic disorders have been linked with gut microbiota dysbiosis. In particular, obesity has been associated with phylum-level changes in the gut microbiota, reduced bacterial diversity, and altered representation of bacterial genes and metabolic pathways, differences that endow the obesity-associated microbiota with an increased capacity to harvest energy from the diet , 2009. TOn the other hand, antibiotics have also recently been implicated in increasing the risk for type 1, insulin-dependent diabetes, an autoimmune disease whose incidence has been steadily going up in industrialized countries in the last decades. In an epidemiological study involving a large UK population, the repeated use of penicillin, cephalosporins, macrolides, or quinolones was associated with increase in diabetic risk . In a moBesides their direct ecological effects on the composition of the gut microbiota, antibiotics affect the manner in which this community interacts with the host and regulates basic physiological processes. Regarding the immune system’s capacity to fight infections, antibiotics indirectly alter the effectiveness of both innate and adaptive immune responses. As microbiota composition changes, not only non-resistant organisms capable of outcompeting potential pathogens are lost, but the altered community will present a substantially different repertoire of microbial-associated molecular patterns (MAMPS) to the receptors located in immune and epithelial cells. This will result in an altered stimulation of receptors such as NOD1 and the Toll-like receptors (TLRs), which can cascade down through a variety of immune processes, including lymphoid tissue development, T cell differentiation, neutrophil priming, production of antibacterials, and cytokine release . A serieOn the other hand, the cellular and molecular mechanisms by which gut microbiota alterations impact immunotolerance have long been debated . The balin vitro cell cultures have revealed different specific bacteria and bacterial products that are capable of Treg cell induction  involve an increase of bacteria containing lipopolysacharides (LPS) in the cell wall, resulting in higher serum levels of this pro-inflammatory molecule, and experiments mimicking the HFD state through continuous subcutaneous infusion of LPS result in the induction of some aspects of metabolic syndrome . A deficAnother main route through which microbiota dysbioses will induce their effects on immunity and metabolism is likely to be the alteration of short-chain fatty acids (SCFA) production. Intestinal microbes consume non-digestible carbohydrates to produce SCFAs, particularly acetate, propionate, and butyrate, which are used locally by colonocytes or transported across the gut epithelium into the bloodstream. SCFAs are major players in the maintenance of gut physiology and integrity, promote immune and metabolic homeostasis and have important anti-inflammatory and antitumorigenic effects . In partThe dysbioses brought about by antibiotics bear the added disadvantage of enriching the microbiota in resistant organisms. The human gut microbiota has been established as a significant reservoir of antibiotic resistances . The scaAlarmingly, not only the microbiota of adults constitutes a resistance reservoir, but children and infants also harbor a variety of ARGs . Recent In the case of infants, resistances may be vertically inherited, as maternal gut microbes can be transmitted to the offspring , with seBacteroides, as well as between Bacteroides and Gram-positive bacteria, has been documented (E. coli (Importantly, the human gut, given its enormous density of bacterial cells and species richness, is likely to be especially prone to horizontal gene exchange and to contribute to the spread and reassortment of ARGs among bacterial taxa. Transfer of ARGs between gut microbiota isolates of the genus cumented . Identic(E. coli  as well (E. coli . Experim(E. coli . Further(E. coli . Of most(E. coli . TherefoFigure 1. In light of this knowledge, and given that bacterial infections remain a major public health concern, strategies are needed to minimize the negative consequences of antibiotics when their administration is required. Use of probiotic bacteria aimed at impeding dysbiosis or at reestablishing the gut microbiota after antibiotic treatment is a promising approach. On the other hand, strategies could also be aimed at reestablishing the interactions altered by antibiotic treatment through the targeted use of bacterial molecules that bind specific innate immune receptors (It is clear that the excessively widespread use of antibiotics has created many threats. These include the increasing resistance of bacterial pathogens to antibiotics, which has become a global challenge for infection control. But the effects of excessive antibiotic exposure can be seen, not only in pathogenic bacteria, but also in the symbiotic microbiotas of the human body . As a reeceptors . Much fuAn equally important line of research should aim at understanding the patterns of dispersion and expansion of antibiotic resistant strains in the human gut microbiome, as well as the routes of gene exchange that may distribute resistances across different gut taxa. Virome and mobilome analyses should enable us to establish the associations of ARGs with specific genetic elements, providing clues to the paths through which they can be disseminated within and across gut microbial communities. Understanding the flow of resistances within the gut microbiome will contribute an important piece to the puzzle of antibiotic resistance epidemiology, which needs to integrate information from human and environmental microbiomes to the analysis of resistance spread in pathogenic isolates.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease of unknown aetiology, leading to progressive damage of bone and cartilage with functional impairment and disability. Whilst the synovial membrane represents the epicentre of the immune-inflammatory process, there is growing evidence indicating the potential involvement of additional anatomical compartments, such as the lung, bone marrow, and secondary lymphoid tissues. Draining lymph nodes represent the elective site for tissue immune-surveillance, for the generation of adaptive immune responses and a candidate compartment for the maintenance of peripheral tolerance. Despite the precise role of the juxta- and extra-articular lymph node stations in the pathogenesis of RA remaining poorly defined, several lines of research exploiting new technological approaches are now focusing on their assessment as a potential new source of pathobiologic information, biomarkers, and complementary therapeutic targets. In this review we present an updated overview of the main concepts driving lymph node research in RA, highlighting the most relevant findings, current hypothesis, and translational perspectives. In chronic inflammatory and autoimmune diseases, the cross-talk and reciprocal modulation between peripheral and lymphoid tissues represent an integral part in the development, maintenance and progression of undesired immune responses. Studies using the nonobese diabetic (NOD) mouse model of autoimmune diabetes have shown that islet-cell antigens are presented to autoreactive T cells within the pancreatic draining lymph nodes (LNs) , and earRheumatoid arthritis (RA) is a complex autoimmune disorder that primarily targets the synovium of diarthrodial joints. Cell-cell and cytokine networks established within the inflamed RA synovium sustain disease chronicity, amplify autoimmune responses and ultimately elicit cartilage and bone destruction –11. SynoCollectively, compared to organ-specific autoimmune conditions, in which the autoimmune reaction targets a particular organ via a humoral and/or cellular response against specific autoantigens since the very early phases of the disease, the pathogenic processes of RA thus appear to originate and progress in a variety of anatomical districts. Such complexity, together with the lack of knowledge of the target autoantigen(s), makes the analysis of local and systemic lymphoid tissue reactions particularly challenging in RA. Experimental animal models of arthritis and the introduction of imaging techniques capable of evaluating LN responses in humans have only recently opened a window onto the possible participation of the lymphoid compartment to RA. In this review, we present an updated summary of the main findings related to LN involvement and potential pathobiologic role in course of chronic arthritis. To provide a contextualized framework of the anatomical concepts, functional processes and imaging findings that have been the object of analysis in pathological settings, the review is introduced by a brief summary of the general structural features of the homeostatic LN and of the main structural changes induced by immunological challenges under controlled experimental conditions.LN are encapsulated oval-shaped fibrovascular organs, strategically distributed through the body of mammals, that represent the elective site for lymph filtration, antigen surveillance, antigen-presenting cell (APC)-lymphocyte interactions, effector/memory cell generation and antibody secretion. These functions are favored by the dynamic structure of the LN, capable of integrating cell trafficking from the bloodstream, drainage of cells and soluble factors from peripheral tissues through the afferent lymphatic system and effector cell/molecule output from the efferent lymph.The anatomical and functional nodal unit is the lymphoid lobule, a polarized structure that can be schematically subdivided into three main areas with specific and complementary roles: (1) an apex, consisting of the B cell rich superficial cortex, where B lymphocytes can interact with resident follicular dendritic cells (FDCs) and undergo affinity maturation within germinal centres (GCs), (2) a deep paracortex, characterized by paracortical cords where T lymphocytes can interact and establish cognate interactions with antigen-loaded dendritic cells and (3) a base, or nodal medulla, consisting of medullary cords, where plasma cell precursors derived from the GC response migrate and mature into antibody-secreting plasma cells .Functional communication between the above described areas and the periphery is guaranteed by lymph-filled sinuses, interconnected structures surrounding lymphoid lobules: the subcapsular sinus associated with the afferent lymphatics at the LN apex , the transverse sinuses, and the paracortical-medullary sinuses ending with the efferent lymphatic vessel at the hilum (the output route of cells returning to the systemic circulation) . The comUpon immune-inflammatory challenges, the homeostatic architecture and processes described in the previous section are subjected to modifications that lead to specific changes involving both the lymphocytic and the stromal component. These changes are collectively referred to as LN reactivity, a dynamic process involving induction and resolution phases, essentially aimed at the eradication of the triggers and return to homeostasis.β receptor (LTβR) signaling and the TNF ligand superfamily member 14 (TNFSF14/LIGHT) [One of the most traceable pieces of evidence of reactivity is LN hypertrophy, the clinical sign and macroscopic outcome of a series of biological modifications, partly dependent on lymphotoxin 4/LIGHT) , inducin4/LIGHT) , 34, and4/LIGHT) . Collect4/LIGHT) .Whilst changes in cellular input to the node are in part mediated by changes in HEV molecular activation , LN reac in vivo [In parallel with the described modifications of the blood vascular system, the reactive LN can also undergo substantial changes in the local lymphatic apparatus and lymphatic drainage, processes that are now the object of growing attention in the field of chronic inflammatory diseases as potential check-points of peripheral pathology control see . For dec in vivo , 45, 46,Indubitably, full understanding of LN responses following experimental immunization represents an essential step to provide a rationale biologic platform for the development of LN research in humans. However, to what extent does experimental manipulation fully recapitulate the dynamics of LN challenge in chronic inflammatory settings remains the object of intense investigation. In particular, for what concerns RA, there are at least three issues that need to be taken into account: (1) the chronicity of the peripheral inflammatory process, which may last for months , leading to potential exhaustion of LN response mechanisms acting in course of acute inflammation, (2) the lack of knowledge regarding the nature and anatomic distribution of the primary triggers of the dysregulated immunological response, whose activation may be ubiquitous or tissue-specific, transient or intermittent, unresponsive to conventional treatments or subjected to therapeutic interference, and (3) the unique pathologic features of the inflammatory process that can lead to massive hypertrophy of the target tissues with potential unbalance in draining LN response capacity during the progression of the disease. Due to the intrinsic difficulties and ethical limitations in assessing the functional and dynamic properties of the LN compartment in course of human disease, animal models of chronic (autoimmune) arthritis represent therefore a fundamental tool to advance mechanistic knowledge in the field.The main aspects of RA pathology that could be supported by the activity or by a defective function of peripheral nodes can be summarized into three, nonmutually exclusive, points: (1) the local generation of autoimmune responses, (2) the maintenance of peripheral tolerance, and (3) the regulation of the peripheral inflammatory status through drainage of cells and fluids .Compelling evidence supporting the possible contribution of the LN in the generation and perpetuation of arthritogenic autoimmunity has been provided by Mandik-Nayak et al. . The aut bona fide adaptive immune response-independent model of arthritis, starting in the ankles, with subsequent heterogeneous involvement of the knees, preceded by dynamic changes in popliteal LN volume, blood flow, and lymphatic sinuses' size [In keeping with this concept, the dynamics and regulators of the joint-draining LN functional unit in course of arthritis have been the object of intense investigation in recent years, with increasing attention also on nonimmunological aspects. Several studies in this direction have been performed in the TNF-transgenic system, aes' size –50. Despes' size , initiales' size . Throughes' size , 53.The observed heterogeneity of popliteal LN draining capacity, and its recognized pathophysiologic relevance during the spontaneous course of the disease in TNF transgenic mice, has led to further studies aimed at characterizing the cellular regulatory mechanisms of these processes. In this context, a relevant observation has been the identification of the potential antibody-independent role of nodal B cells  on the mTo what extent (i) is the process of B-cell driven LN “collapse” a generalized feature of LN reactivity to immune-inflammatory challenge (see previous section) or is a specific response to chronic inflammation and (ii) whether these dynamics can be applied to human disease and treatment, still remain to be defined.Clinically, LN involvement in patients with RA is well established, and lymphadenopathy is consistently recognized among the possible extra-articular manifestations of the disease . Since iγ-globulins, reported the presence of RF in GC-localized cells and plasma cells in one out of ten GCs from a seropositive RA patient with active disease. These studies were confirmed 30 years later by Imai et al. [Histologically, lymphadenopathy associated with RA usually demonstrates reactive follicular hyperplasia and polyclonal plasma cell infiltration in the interfollicular area –63 as wei et al. , who demA critical question that remains unsolved is whether the LN compartment represents a primary site for the generation of initial autoimmune responses leading to RA. Incidentally, the occurrence of LN reactive hyperplasia before the onset of joint symptoms was already documented in historical studies performed in healthy subjects with unexplained lymphadenopathy . More reAs summarized in In this context, a challenging issue still remains the full understanding of the temporal dynamics and anatomic distribution of (draining) LN involvement across the different phases of the disease, an objective that would require reliable and noninvasive methods of LN evaluation for serial and systemic analyses. Imaging studies performed in the oncology field have shown that power doppler ultrasonography (PD-US) allows sensitive assessment of the nodal structure and macrovessel architecture , which tThe data presented in the previous sections of this review support the role of the LN as a potential relevant component of arthritis pathology, opening the attracting perspective of extending our research focus to this anatomic compartment as a complementary tool for the implementation of current prognostic biomarkers, the definition of preventive strategies, as well as the development of novel therapeutic approaches . The sam ex vivo has been proved in the inflamed synovium of patients with established disease [In this regard, one of the most critical issues  is represented by the actual contribution of the LN to the induction, maintenance, and perpetuation of the autoimmune response, with specific reference to the activation of ACPA-positive B lymphocytes, an RA-specific autoimmune trait related to a more severe course of the disease and contributing to the upstream phases of osteoclastogenesis , 79. Des disease , 81, cir disease , and the disease . This su disease , 82, 83. disease , 28, 84  disease , both caDespite the assessment of these issues in humans still faceing considerable technical challenges, it certainly represents a critical target for our full comprehension of the disease and, hopefully, the conception of future therapeutic reprogramming strategies. In this perspective, it is important to emphasize that the LN not only acts as a site of construction of adaptive immune responses, but also represents a constitutive site of maintenance of peripheral tolerance. Data supporting this concept derive from different studies in mice and humans demonstrating the functional localization in nodal cells of the transcription factors autoimmune regulator (AIRE) and deformed epidermal autoregulatory factor-1 (DEAF-1), molecules that physiologically mediate autoreactive T cell deletion through the ectopic expression of a broad spectrum of peripheral tissue-restricted antigens (PTA) –89. How Beside the importance of understanding LN immunological behaviour, the same compartment may also be seen as a potential new source of biomarkers. Despite the introduction of biological agents and the optimization of clinical management  have considerably improved the outcomes and quality of life of patients with RA, the disease still presents a high degree of variability in terms of therapeutic response and radiographic progression. Validated tools able to fully predict this variability, likely determined by the intrinsic genetic and pathobiologic heterogeneity of the disease, are still missing, with consequent limitations in our possibility to define standard algorithms in critical stages of the disease, such as the selection of the appropriate approach in patients with early RA, the selection of the appropriate biological agent in patients nonresponding to conventional disease modifying antirheumatic drugs, and the identification of patients achieving pharmacologically induced clinical remission that can taper or suspend treatment with maintenance of health. Though the synovial tissue certainly represents the elective site for the definition of reliable indices embedded in the pathologic process –14, it iOur conception of RA as a disease with exclusive synovial extrinsication has greatly expanded over the past decades, with increasing awareness of the potential involvement of several articular and extra-articular districts along the time-line of RA development. Being the nerve centre for the generation of immune responses and the regulation of inflammatory processes, the lymphoid compartment comes to primary attention within the complex pathogenetic scenario of RA. Better understanding of the systemic and local LN responses might help clarifying the many uncertainties that still characterize the immunopathological features and clinical behaviour of chronic arthritis.


Neurodevelopment is a complex, dynamic process that involves a precisely orchestrated sequence of genetic, environmental, biochemical, and physical events. Developmental biology and genetics have shaped our understanding of the molecular and cellular mechanisms during neurodevelopment. Recent studies suggest that physical forces play a central role in translating these cellular mechanisms into the complex surface morphology of the human brain. However, the precise impact of neuronal differentiation, migration, and connection on the physical forces during cortical folding remains unknown. Here we review the cellular mechanisms of neurodevelopment with a view toward surface morphogenesis, pattern selection, and evolution of shape. We revisit cortical folding as the instability problem of constrained differential growth in a multi-layered system. To identify the contributing factors of differential growth, we map out the timeline of neurodevelopment in humans and highlight the cellular events associated with extreme radial and tangential expansion. We demonstrate how computational modeling of differential growth can bridge the scales–from phenomena on the cellular level toward form and function on the organ level–to make quantitative, personalized predictions. Physics-based models can quantify cortical stresses, identify critical folding conditions, rationalize pattern selection, and predict gyral wavelengths and gyrification indices. We illustrate that physical forces can explain cortical malformations as emergent properties of developmental disorders. Combining biology and physics holds promise to advance our understanding of human brain development and enable early diagnostics of cortical malformations with the ultimate goal to improve treatment of neurodevelopmental disorders including epilepsy, autism spectrum disorders, and schizophrenia. We highlight how physical forces act as regulators in translating these cellular mechanisms into the gyrogenesis of the human brain. We demonstrate how computational modeling of differential growth can predict the classical pathologies of lissencephaly and polymicrogyria, and how the underlying model could be expanded toward other neurodevelopmental disorders including microcephaly and megalencephaly. We conclude with a critical discussion of the role of physics and biology in human brain development and identify future challenges and new frontiers.Neurogenesis involves a precisely orchestrated sequence of cellular events. It begins with the formation of the neocortex at the rostral end of the neural tube, near the outer surface of the embryonic cerebral vesicle (Sidman and Rakic, Intracranial pressure is now recognized as an important regulator of normal brain development Desmond, . In the Between weeks 4 and 5, early development is characterized by interkinetic nuclear migration, an oscillation process during which neuroepithelial cells divide symmetrically at the margin of the ventricle and undergo four phases (Bystron et al., Weeks 4–5 also mark the time period when the first primitive layer of meningeal cells becomes visible (O'Rahilly and Müller, Around gestational week 5, the progenitor cells in the ventricular zone, the radial glial cells, begin to switch from symmetric to asymmetric cell division (Iacopetti et al., As Figure The ventricular and subventricular zones form an active proliferate zone, the site of origin of pyramidal neurons. Pyramidal neurons eventually migrate outward along the radial glial cells to form the characteristic six-layered cortical structure from inside to outside (Raybaud et al., Before the radial migration of pyramidal neurons begins, early-born cells of various type fill the space near the basal surface to form a dynamic, transient structure, the preplate (Bystron et al., Around week 7, radially migrating neurons from the ventricular and subventricular zones initiate the development of the cortical plate. In its early stages, the cortical plate is divided into two layers, a thin superficial marginal zone and an underlying subplate. The marginal zone contains cells that have mostly migrated tangentially; those cells arrest the migration of radially migrating pyramidal neurons to guarantee the inside-out formation of the cortex (Rakic and Zecevic, Cortical neurons accumulate above the subplate in an inside-out sequence: The earliest-born neurons are destined to become the innermost layer 6, the last-born neurons will become the outer layer 2. Early projection pyramidal neurons of the inner cortical layers originate from apical radial glial cells in the ventricular zone, whereas later neurons in the superficial layers progressively originate from secondary progenitor cells in the subventricular zone (Lui et al., The cell-sparse compartment between the proliferative ventricular and subventricular zones and the cortical plate is known as the intermediate zone. It consists of radially and tangentially migrating cells, former preplate cells, and long-range axons (Bystron et al., Between weeks 9 and 12, the human subplate thickens considerably and its cell density decreases (Carney et al., Between weeks 13 and 15, the ventricular zone becomes progressively thinner as a large percentage of its cells moves outward (Sidman and Rakic, The period after week 22 is the most significant time for areal, laminar, and cytological differentiation of the cortical plate. Gyral formation begins around week 24 at the parieto-occipital and central sulci (Takahashi et al., By week 28, layer 1 has fully developed. It contains a few neurons and is largely filled with arborizations of apical dendrites and intrinsic tangential axons. The cells that had initially arrested the migration of pyramidal neurons during neuronal migration have now disappeared (Raybaud et al., Taken together, numerous interacting modes of cell migration shape the developing neocortex. A proper radial and tangential development of the mammalian brain requires different types of progenitor cells, depending on species and stage of development. As a common paradigm, radial glial cells tend to expand the cortex tangentially, whereas intermediate progenitor cells tend to fill the cortical layers radially. In addition to the radial gradient of development, there is a pronounced tangential gradient from primary, via secondary, to highly associative cortices. This tangential gradient results in a similar developmental gradient of connectivity and gyrification, and, after term, in a similar gradient of cortical myelination.Figure The most prominent connective structure in the human brain is the corpus callosum, a wide, flat bundle of more than 200 million contralateral axons, which connect the left and right cerebral hemispheres (Luders et al., In the cortex, the formation of connections follows the radial gradient of the inside-out proliferation: First, the early-born deep layer 6 neurons extent branches to the basal gray matter; around week 17, layer 5 neurons form connections with the internal capsule, the brainstem, and the spinal cord; between weeks 22 and 27, layer 4 neurons receive thalamo-cortical connections; last, from week 28 to 32, layer 3 and 2 neurons form intrahemispheric, cortico-cortical association fibers and interhemispheric, commissural connections (Raybaud et al., Not only neurons, but also other cellular components such as astrocytes, oligodendrocytes, microglial cells, and capillaries play a crucial role in the proper formation of neuronal connectivity Barres, . ActuallAstrocytes are a sub-type of glial cells in the central nervous system. They play a major role in synaptic transmission and information processing, they guide the migration of developing axons and neurons, and have extensive contacts with blood vessels (Powell and Geller, Morphologically, we can distinguish two types of astrocytes as illustrated in Figure Oligodendrocytes are a type of neuroglial cells. They provide structural support and form a myelin sheath around the axon to enable rapid impulse propagation Freeman, . The firMyelination occurs early during oligodendrocytic differentiation within a narrow window of 12–18 h Barres, . It is rOligodendrocytes and their myelin sheaths are more susceptible to damage than any other cell type in our brain. After demyelination caused by disease, for instance in multiple sclerosis, axons can retrieve new myelin sheaths. During remyelination, inactive adult oligodendrocyte progenitor cells proliferate, switch from their quiescent state to a regenerative phenotype, and generate new oligodendrocytes (Franklin and Ffrench-Constant, In rodents, myelination begins already during neurogenesis. In humans, it mainly occurs after birth, when neuronal migration has ceased and primary and partially secondary folds have formed. Myelination in rodents only takes a few weeks, compared to decades in the humans (Yakovlev and Lecours, Microglial cells contribute to neuronal proliferation and differentiation, clear debris, and remodel synapses Harry, . Unlike The vasculature of the brain ensures its supply with oxygen and nutrients. The cerebral vesicles begin to form around week 5. During week 6–7, blood channels develop to form a dense capillary bed within the ventricular zone. Since the development of the vascular system closely correlates with cell proliferation and connectivity, it follows the radial gradient from inside to outside and the tangential gradient from primary to secondary and highly associative cortices (Norman and O'Kusky, Synaptogenesis, the formation of synapses between the individual neurons, begins before week 27, but occurs mainly after birth, concurrent with the growth of dendrites and axons and with the myelination of axons in the subcortical white matter (Huttenlocher and Dabholkar, Postnatally, from infancy to adulthood, our brain increases in size by a factor five (Craik and Bialystok, While the early developmental processes are relatively well-characterized on the cellular level, later development of the entire brain with its distinct folded surface morphology remains less well-understood (Ronan et al., Around week 23, the first primary sulci begin to form. Primary gyrification follows the same tangential gradient as proliferation and connectivity, from primary via secondary to high-association cortices. Through term, secondary sulci extend concentrically around the primary sulci. After term, tertiary sulci develop together with short association fibers. Gyrification typically begins slightly earlier in the right hemisphere than in the left (Raybaud et al., The expansion of the cortex is an important regulator of brain folding. Several cellular processes correlate with gyral development: cell division in the subventricular zone is most abundant in highly folded regions (Lukaszewicz et al., In relation to the timelines of cell division and migration in Section 2 and connectivity in Section 3, gyrification occurs simultaneously with the late migration of superficial neurons and with the formation of neural connectivity as the number of astrocytes, oligodendrocytes, and microglial cells increases.A physics-based approach, which has recently gained increased attention, attributes cortical folding to differential growth between the cortex and the subjacent intermediate zone that later transforms into white matter tissue (Richman et al., The significance of the connectivity-driven tangential expansion of the superficial layers is supported by the fact that by week 18, when the cortex is still smooth, only radial but no tangential intracortical connections have formed (Noctor et al., Although cortical folding does not occur before neuronal migration has ceased and all cortical layers have been established, cellular processes during neurogenesis play a major role in pattern selection (Raybaud et al., Physics-based models predict that the gyral wavelength increases with increasing cortical thickness Allen, , which i3 predicts the emergence of 22, 48, 76, and 92 major folds. If both total volume and cortical thickness were to increase proportionally, brains morphology would scale isometrically and similar folding patterns would emerge (Zilles et al., Figure In vivo, magnetic resonance elastography suggests that mature gray and white matter are rather indistinguishable with shear stiffnesses on the order of 3 kPa in ferrets (Feng et al., Physics-based models predict that the gyral wavelength increases with the third root of the stiffness contrast between cortex and subcortex (Bayly et al., The microstructure of brain tissue–and with it the mechanical properties–change drastically during early brain development: While gray matter remodels from a radial to a tangential organization and intercellular cross-linking increases significantly during the third trimester, the degree of cross-linking in white matter remains low until term (Raybaud et al., The realistic prediction of cortical folding with the help of physics-based models requires the clarification of the mechanical properties of gray and white matter tissue–not only in the mature, but more importantly in the developing brain. Ultimately, this could unravel an important point of criticism against the hypothesis of differential growth, the fact that instabilities would manifest themselves in the form of creases rather than folds if gray matter was softer than white matter at the onset of the instability (Hutchinson, Malformations–as a result of interrupted cortical development–are common causes of mental disorders including developmental delay and epilepsy (Barkovich et al., Lissencephaly literally means smooth brain and is associated with abnormal neuronal migration (Barkovich et al., The cortex of the lissencephalic human brain is significantly thickened–10 to 20 mm compared to 2–4 mm in normal brains–and typically consists of only four layers: an outer marginal layer 1, a superficial cellular layer 2 with numerous large and disorganized pyramidal neurons, a variable cell sparse layer 3, and a thick deep cellular layer 4 composed of medium and small neurons (Golden and Harding, Figure Polymicrogyria is a developmental malformation of the human brain characterized by an excessive number of small folds. It evolves from abnormal development or loss of neurons in the deep cortical layers after completion of neuronal migration Friede, . TypicalFigure Microcephaly is a rare developmental disorder associated with an abnormally small brain. In microcephalic brains, an altered cleavage plane during progenitor cell division reduces vertical, symmetric cell division and promotes horizontal, asymmetric cell division. This reduces the overall number of progenitor cells and neurons and decreases the cortical volume. In mild cases, the decrease in the total number of neurons is not accompanied by a commensurate loss of cortical folding (Bond et al., Megalencephaly is a rare developmental disorder associated with an abnormally large brain. In megalencephalic brains, during early brain development, shortened cell cycles and increased cell cycle reentry increase the number of progenitor cells and neurons (Sun and Hevner, Neurodevelopment involves a highly orchestrated sequence of events, which is tightly regulated by the complex interplay of various cell types both in space and time. The objective of this review was to summarize the timeline of human brain development and to correlate events on the cellular level to pattern selection and surface morphogenesis on the organ level. To bridge these biological scales, we have adopted a popular physical model for brain folding: the mechanism of differential growth.Neurodevelopment begins with cell division and cell migration, which ultimately result in the formation of the characteristic six-layered cortex. Throughout this process, intermediate progenitor cells tend to fill the cortical layers radially, while radial glial cells tend to expand the cortex tangentially. From a mechanical point of view, unconstrained radial growth causes a thickening of the cortex, whereas constrained tangential expansion generates compressive stress, which may eventually induce cortical folding. When neuronal migration is mostly completed, cortical neurons begin to form connections with other neurons. Neuronal connectivity involves the growth of neuronal dendrites and axons, the generation and expansion of astrocytes, oligodendrocytes and microglial cells, the formation of synapses, and the development of the vasculature system. These phenomena collectively result in an excessive tangential expansion of the outer cortex, an increase in cortical stress, and a folding of the cortical layer. Postnatally, synaptogenesis, synaptic pruning, and myelination mediate further cortical and subcortical growth, alter the cortical stress state, and reshape the cerebral cortex. Disruption of any of these events can result in severe cortical malformations, which are associated with neurological disorders including developmental delay and epilepsy. Although gyrification occurs in synchrony with neuronal connectivity–after all neurons have reached their final position in the developing cortex–early neuronal migration has a significant influence on cortical folding. Neuronal migration sets the stage for the folding process; disturbed initial conditions trigger disrupted neuronal connectivity and cortical malformations.Lissencephaly, for instance, originates from disrupted early migration, although its classical hallmark–the absence of folds–does not make an appearance until the neuronal connectivity initiates folding. The absence of folding in the lissencephalic brain can be explained by a fairly simple physics-based model for growth-induced mechanical instabilities: the compressive forces induced by neuronal connectivity are distributed over an extensively thickened cortex; the resulting tangential stress within the cortex, the force divided by the thickness, is therefore significantly smaller than in healthy brains and fails to initiate folding. Even if the connectivity process itself is entirely normal, the smooth cortex precludes the formation of short association fibers and normal functioning of the brain. Polymicrogyria, in contrast, is a true organization disorder. At the end of neural migration, the cortex exhibits regular initial conditions, but the connectivity process itself is disturbed. Increased cell death and damage of deeper cortical layers result in a cortex with small superficial folds. Although the origin of this pathology is entirely different from lissencephaly, the same physics-based model can explain its malformations: a locally thinned cortex and reduced tangential expansion in the deeper layers reduce the critical wavelength, and induce an increased number of small folds.Advances in the physical modeling and computational simulation of living systems can give insights into the underlying mechanisms of cortical folding that complement our current knowledge of neurodevelopment. They allow us to bridge cellular phenomena and whole organ form and function. Naturally, computational models of brain development have to simplify the complex biological problem. The challenge is to capture the critical processes without oversimplifying the biological system. In this review, we have shown that a fairly simple physical model can predict how the mammalian cortex evolves under physiological and pathological conditions. This model explains cortical malformations as emergent properties of cellular disruptions, either during early cellular division and migration or during later cellular organization and connectivity.Neurodevelopment is a complex, dynamic process that involves several contributing genetic, environmental, biochemical, and physical factors; it is unlikely to be deciphered by a single discipline alone. Researchers of various fields are beginning to come together to elucidate normal and abnormal brain development through close multidisciplinary collaborations. A traditional biological approach, for example, can identify cells and genes that regulate malformations of cortical development; yet, it fails to substantiate the classical hallmark of the disease, the malformed cortex. A physical approach cannot explain the genetic origin of cortical malformations; yet, it can explain growth-induced instabilities, quantify cortical stress, identify the critical stress necessary to induce folding, rationalize emergent folding patterns, and predict gyral wavelengths and gyrification indices. If calibrated and validated appropriately, physics-based models allow us to bridge the scales–from phenomena on the cellular level toward form and function on the organ level–and make quantitative predictions. Recent advances in neuroimaging would allow us to create high precision, personalized models for cortical folding. Combining biology and physics can help us advance our understanding of human neurodevelopment, identify early markers of cortical malformations, and, ultimately, improve treatment of developmental disorders including epilepsy, autism spectrum disorders, and schizophrenia.SB has performed the simulations, designed all figures, and written the manuscript. PS has discussed the outline and overseen the writing process. EK has implemented the initial computational method, discussed the outline, and mentored the writing process.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.


To study emotional aging is to study a very multi-faceted concept. In particular, the study of emotion and aging covers a wide range of topics. Taking a closer look, domains of functioning can be differentiated such as pertaining to the experiential nature of emotion or its regulation, as well as social-cognitive processes associated with the perception of emotion in others or emotion-related attention and memory retrieval. Importantly, evidence over the last two decades suggests that not all of these functional domains are negatively affected by the aging process. Rather late-life development in emotion-related functional domains is characterized by multi-directionality, in that aging seems to be associated with deterioration in abilities related to emotion perception and increased difficulty remembering (particularly negative compared to positive) emotional information, while emotional experience and emotion-regulatory capacities appear to remain relatively preserved or even improve with age.Also, the study of emotion and aging covers a wide range of theoretical orientations, paradigms, and methods to adequately capture the complexity of the phenomenon. In particular, emotional aging researchers use self-report, experience sampling, cognitive-behavioral observation, eye tracking, electro- and psychophysiological as well as different functional brain imaging techniques among their assessment tools to ensure recording from the multiple channels emotions can be expressed in, and to shed light on the phenomenon of interest from different angles.Emotion and Aging: Evidence from Brain and Behavior, 13 groups of researchers contributed with their expertise, and the included papers reflect the theoretical, methodological, and statistical diversity of this research field. In the following, we briefly introduce each paper contribution. For a more thorough discussion of the articles' theoretical innovation, methodological approach, and scientific advancement contextualized in the broader literature on emotional aging as well as for a constructive reflection about topics untouched in this research topic and future directions the field could take, see Ebner and Fischer . Moreover, to overcome methodological heterogeneity between studies that complicates direct comparison across studies, future research that applies multiple methods to the same sample is warranted. We look forward to seeing this Frontiers research topic inspire exciting new research on emotion and aging in a multi-faceted and integrated manner.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.


Symmetric lipomatosis is definitively characterized by symmetric, tumorous lipomatous proliferation of adipose tissue that often develops in the head and neck, shoulders, and upper trunk. However, in the oral region, symmetric lipomatosis of the tongue (SLT) is an extremely rare condition related to generalized lipidosis that is often caused by chronic alcoholism. It is characterized by multiple symmetric lipomatous nodules and diffuse bilateral swelling located within the tongue. We report an extremely rare case of SLT arising in an 80-year-old man with a long history of alcoholic liver cirrhosis. He exhibited multiple soft nodular protrusions on the bilateral margin of the tongue presenting as macroglossia for years. Although MR imaging showed multiple fatty masses on both sides of the tongue, there was no elevated tumor mass on the bilateral margin. The patient underwent bilateral partial glossectomy under general anesthesia. Histopathologically, the resected tumor exhibited diffuse infiltration with mature adipose tissue lacking a fibrous capsule. Due to the lipidosis and the unusual presentation of multiple lesions, the lesion was ultimately diagnosed as SLT. At present, after surgery, the patient wears a full-denture and is in excellent condition, with no sign of recurrence, improved QOL, and recovery of masticatory, articulatory, and speech intelligibility functions.  Benign symmetric lipomatosis (BSL) was first reported by Brodie in 1846  in 1944,2). Extraoral findings showed facial symmetry and a good complexion. There were no significant findings in the cervical lymph nodes. Preoperative laboratory examination revealed high levels of TG (202 mg/dL), but TC and HDL and LDL-cholesterol were normal.The patient was an 80-year-old man who was referred to our division for the chief complaints of macroglossia and articulatory disorder. Oral findings showed painless tumors on the bilateral margins of the tongue and dysarthria/dysphasia . His medMultilocular tumors were found on the bilateral margins of the tongue, which formed macroglossia, and xanthic, elastic soft tumors were evident in the shallow submucosa. The surfaces of the tumors were smooth, and in particular, the left tongue margin was significantly elevated.While there were no abnormalities in perception/taste, dysarthria was observed. MR images showed T2 hyperintensity and well-defined borders in the bilateral margins of the tongue and ill-defined trabecular structures like muscle bundles in the deep part of the tongue, which suggested that it might be symmetric lipomatosis . The patThe resected specimens showed a relatively well-defined border in the mucosa but the encapsulation was not clear in the deep portion .The tumor consisted of proliferation of mature adipocytes, and there were no signs of encapsulation in the muscle layer or atypia, such as mitotic figures Figures . Based oAt the present time, there has been no sign of postoperative dysfunction or complication, and the dysarthria and dysphasia have improved significantly. The patient's clinical course remains excellent .Lipoma is the most common nonepithelial benign soft tissue neoplasm and monostotic solitary lesion and can occur in any part of the body. Meanwhile lipomatosis is one of multiple systemic tumors that are characterized by diffuse proliferation of adipose tissue in normal tissues. Lipomatosis is differentiated from lipoma by specific characteristics, such as ill-defined borders and nonencapsulation. However, while lipomatosis is relatively rare in the oral region, it can sometimes develop bilaterally on the tongue.Lipomatosis in the tongue is classified by gross appearance into two types, nodular type and diffuse type . The nodWith respect to the association between SLT and alcoholic liver injury, fatty deposits in the body might occur due to increased blood acetyl CoA levels, which is the primary source of fatty acid derivatives during the metabolism of alcohol to acetate by alcohol dehydrogenase and acetaldehyde dehydrogenase in the liver , 10.The most common causes are alcohol dyslipidemia and liver damage, as in the present case, followed by HT, viral hepatitis, and stroke. The local factors include fatty degeneration with aging of the superficial lingual muscle, hyperplasia of the fat layer of the lingual septum, adipose tissue formation during granulation formation caused by occlusion error, and stimulation and trauma caused by the teeth/occlusion. In our case, we considered that the systemic factor was alcohol dyslipidemia and that the local factors were fatty degeneration with aging of the superficial lingual muscle, which was proposed by Staudt et al. , and hypRecently, there have been some reports of treatment strategies, such as tumor resection and surgical debulking, with consideration also given to prevention of dysfunction . Recentl


Zoophycos is one of the most complex and enigmatic trace fossils recorded in marine strata from Cambrian to Quaternary worldwide, which is invaluable for the study of Phanerozoic development of organism–environment interactions. Here we address and demonstrate the macroevolution of Phanerozoic Zoophycos by assembling 448 points in constructing the Phanerozoic Zoophycos database based on 291 papers from 1821 to 2015 and 180 specimens from Cambrian to Palaeogene. The comprehensive dataset reveals, for the first time, five peaks and six depressions in Phanerozoic Zoophycos occurrence frequency. Secondly, the palaeogeographical distribution of Zoophycos is closely associated with the supercontinent Pangaea shifting, independent of the latitude. Our data also attest that the bathymetrical shift of Zoophycos from the littoral–neritic to bathyal environments is synchronized with the tiering shift from shallow to deep. By detailed comparison with body fossils, geochemical and palaeogeographical records, we conclude that the macroevolution of Phanerozoic Zoophycos is multi-affected by the global biodiversity expansion, benthic nutrient enhancement, and the biotic macroevolution of the Zoophycos-producers. The macroevolution of development evidenced by the morphological changes of Zoophycos and other trace fossils, may have great implications on the behavioural and physiological adaptation of ancient animals to the environments. Zoophycos is one of the most complex, enigmatic and widespread trace fossils in Phanerozoic marine environments1234Zoophycos was initially named as a plant genus by Massalongo6442115Zoophycos and related forms. Most researchers favour the term ‘Zoophycos Group’Zoophycos has been speculated to evolve from simple to complex in morphology and from shallow to deep marine in environmental distribution during the Phanerozoic1314Zoophycos reports only from Europe and America. Detailed studies of Phanerozoic major bio-environmental events in recent years16Zoophycos database based on a worldwide collection of literature and specimens . From the Cambrian to Devonian, Zoophycos were represented by simple circular/elliptical spreiten or tongue-like spreiten made of centrifugal (tending to move away from a center) U-shaped protrusive or J-shaped retrusive burrows with one whorl and evenly spaced primary lamellae  U-shaped protrusive burrows with two to five whorls, secondary lamellae regularly distributed between primary lamellae (such as Zoophycos morphotype C1)  . CretaceZoophycos took the shape of complex, irregular skirt-like spreiten in several whorls with many long marginal lobes and alternating primary and secondary lamellae  created by the lateral shift of the und 4 mm . From cuund 4 mm .Zoophycos shifted gradually from the shallow to deep tiers of marine substrates in the Phanerozoic  and mass extinctions in the Phanerozoic but also show variance in the timing and scale of certain changes.From the above evidences, the occurrence frequencies and palaeolatitudinal distribution of Phanerozoic Zoophycos radiation was maximized in the neritic seas of the Middle Devonian. The main reasons why Zoophycos occurrence frequencies had not significantly elevated in the Middle Ordovician could be the oligotrophic marine environments2687Sr/86Sr ratios and reduced shelf area at that time ; middle-sized, spiraling gently lobed circular/elliptical spreiten in three or five whorls with a few lobes in the Mesozoic ; to large, complex, spiraling, highly lobate spreiten in several whorls with numerous lobes in the Cenozoic  (Zoophycos rhodensis) may look like some branching forms of Mesozoic Zoophycos, which developed into a sub-circular, helical form with a central disk42Zoophycos caudagalli and Mesozoic–Cenozoic Zoophycos insignis both started with an initial U-tube or J-tube, and developed into sub-circular or lobate patterns. Feeding, gardening and farming in this proposed phylogenetic sequence are more a continuous track of improving efficiency rather than simple, discrete behavioral patterns. It culminated in forms of Zoophycos insignis that retained the initial U-tube or J-tube and inserted additional lobate whorls above the typical, sub-circular spreiten fields41Zoophycos rhodensis was the inclusion of several, slender, lobate spreiten extended from the apex and separated by shorter elongated lobesThe morphology of nsignis)  and 4c. Zoophycos is evident based on the above discussion of classic morphologies of Zoophycos in the Phanerozoic. The morphological changes of Zoophycos from simple to complex and from rough spreite structures to exquisite burrow systems reflect the strategic evolution (in considering the energy budget or efficiency) in feeding and living of Zoophycos-producers, which implies that animal behaviour can be well subjected to the basic laws of biological evolution, the same as have been practiced for anatomic feature, the biosphere, and ecosystem. This has already been suggested by the Jurassic–Cretaceous evolution of Zoophycos in FranceThe macroevolution of Zoophycos can be ascribed to 1) the evolution of genetic material and trace-making strategy, and 2) the behavioural and physiological adaptation to the environmental changes of the Zoophycos-producers. The most important bio-environmental impact on the Zoophycos-producers is the increased competition in the habitable neritic seas due to Phanerozoic biodiversity expansion, which forces the Zoophycos-producers to migrate from shallow-tier in the neritic sea to deep-tier in the deep sea, along with enhanced ability to tolerate dysaerobic conditions, as exemplified by increasingly low oxygen content in slope to abyssal environments. Since the Mesozoic, especially since the Middle Jurassic, deep-sea bottom nutrient conditions were greatly improved by increased particulate organic carbon and dissolved organic carbon derived from surface plankton blooms3135Zoophycos-producers. Therefore, environments select, eliminate, and transform organisms, and organisms also select (r- and K- selections), adapt and change environments, manifesting the coevolution of organisms and environments in the Phanerozoic.The morphological macroevolution of Zoophycos is usually considered to be produced by worm-like animals, of which several candidates have been proposed: sipunculida11112324Zoophycos through the past 500 Myrs does not seem be punctuated by any recognized major mass extinction events but reveals substantial bathymetric shift . We only select specimens or records that follow the principal morphological constructs we recommended in the text, which allow safe assignment to Zoophycos. Zoophycos have different morphologies on bedding surface, in cross-section and three dimensions, so we use different descriptive terms for the three perspectives.Some reports of Zoophycos points are mostly Stage-scaled, which are excerpted from the ‘geological setting’ sections in corresponding papers or related regional geological documents. For example, the paper reporting Zoophycos occurrence in the lower part of the Witteberg Formation in South Africa didn’t give the Stage for this Formation. By consulting related papers, a Givetian age was acquired.The geologic age of Zoophycos are largely divided into foreshore, nearshore, offshore, slope and abyssal according to the modern marine environmental zonation. The barrier island, lagoon or delta environments were subscribed into the above five marine zones according to water energy.Marine environments  in recorZoophycos in correlation with temperature, latitude, climate and other factors, palaeolatitudinal data of Zoophycos points were transformed from the modern longitudes and latitudes using the software PointTracker. The modern longitudes and latitudes were mainly extracted from the corresponding literature. If this is not available, we positioned the occurrence area in Google Earth to obtain the longitudes and latitudes.In order to check the distribution of Zoophycos database represents one occurrence, and we calculated the occurrences in each age and produced the Zoophycos occurrence frequency curve .


Tetrahymena and Paramecium. Using the monoclonal 414, specific to FG-containing nucleoporins, and anti-tubulin antibodies, we detected labeling at the distal part of basal bodies and as a spotted pattern around nuclei.The transition zone (TZ) of locomotory cilia participates in docking young basal bodies to the surface, stabilizes the basal body-membrane connection, forms a diffusion barrier and modulates the intraciliary transport. In vertebrate ciliated cells, nucleoporins and septins were suggested to be present in the TZ of locomotory and primary cilia. Here we present data suggesting the presence of nucleoporins, at both nuclear pores and ciliary TZ, in Tetrahymena, GFP-tagged septins  localized to mitochondrial/ER compartments but neither to basal bodies, cilia nor nuclei. Tetrahymena cells with knocked out septins display disrupted nuclear (Mac and Mic) membranes, abnormal mitochondria, but unaffected ciliary TZ. Similarly, in Paramecium, silencing of the SEP2 gene revealed affected nuclear membranes and mitochondria but normal TZ, and the mAb 414 and DAPI showed a normal labeling of the ciliary base, but patches of missing nuclear pores in the macronucleus.In previous studies on Our studies support the conclusion that some nucleoporins are present in both nuclear pores and ciliary TZ. In addition, the nuclear pore proteins seem to interact with septins, yet the lack of effect of septin silencing on the localization of the mAb 414 in the ciliary TZ suggests that nucleoporins may have different binding partners in nuclear pores and ciliary TZ.


The coagulation system constitutes an important facet of the unique vascular microenvironment in which primary and metastatic brain tumors evolve and progress. While brain tumor cells express tissue factor (TF) and other effectors of the coagulation system (coagulome), their propensity to induce local and peripheral thrombosis is highly diverse, most dramatic in the case of glioblastoma multiforme (GBM), and less obvious in pediatric tumors. While the immediate medical needs often frame the discussion on current clinical challenges, the coagulation pathway may contribute to brain tumor progression through subtle, context-dependent, and non-coagulant effects, such as induction of inflammation, angiogenesis, or by responding to iatrogenic insults (e.g. surgery). In this regard, the emerging molecular diversity of brain tumor suptypes (e.g. in glioma and medulloblastoma) highlights the link between oncogenic pathways and the tumor repertoire of coagulation system regulators (coagulome). This relationship may influence the mechanisms of spontaneous and therapeutically provoked tumor cell interactions with the coagulation system as a whole. Indeed, oncogenes  and tumor suppressors  may alter the expression, activity, and vesicular release of tissue factor (TF), and cause other changes. Conversely, the coagulant microenvironment may also influence the molecular evolution of brain tumor cells through selective and instructive cues. We suggest that effective targeting of the coagulation system in brain tumors should be explored through molecular stratification, stage-specific analysis, and more personalized approaches including thromboprophylaxis and adjuvant treatment aimed at improvement of patient survival. The vascular system plays a unique and consequential role in brain homeostasis, function, and pathology. Due to perfusion demands, high-energy metabolism, and endocrine signal exchange, blood supply to the brain parenchyma (neuropil) is programmed to be high, uninterrupted, and tightly controlled.4Intracranial dysfunction of hemostatic processes triggers profound local and systemic consequences, often with lethal outcomes including thrombosis, local vascular occlusion, hypoxic tissue damage, coagulation factor neurotoxicity, ischemic stroke, hemorrhage, and edema.Pathological disruption of the vascular continuity and barrier function in the brain leads to formation of abnormal contact points between coagulation proteases, cell surfaces, and extracellular matrix present in the neuropil. In this regard, TF acts as a high-affinity receptor/co-activator for the blood-borne coagulation factor VII/VIIa and thereby functions as the main trigger of the coagulation cascade. Formation of the TF/VIIa complex activates factor X (to Xa) and leads to the generation of thrombin (IIa), which catalyzes the formation of fibrin and activation of platelets, as well as triggers the amplification phase of the coagulation cascade. These mechanisms lead to the deposition of fibrin matrix, clots, platelets, growth factors, and enzymatic activities within the intravascular and perivascular microenvironment.7The coagulation system evolved for over 450 million years23The various facets of the coagulation system are persistently challenged during the development of human cancers.36How could coagulation system perturbations be triggered in cancer? Although the related events are likely context-specific, there are at least three major components of possible relevance to cancer coagulopathy that are worthy of more thorough consideration. First, vascular homeostasis is chronically challenged by the disruption of the tissue architecture associated with tumor growth, including vascular invasion and compression, persistent angiogenesis, chronic inflammation, extravasation of bone marrow-derived cells (BMDC), and metastatic entry of cancer cells into the vascular space. These events expose potentially procoagulant cells to coagulation factors in plasma. In addition, the breakdown of vascular barriers enables the uninhibited release of non-cellular material  from the tumor mass into the blood stream. Thus the chronically compromised integrity of the vessel wall, intermittent hemorrhage, increased vascular permeability, extravasation of plasma proteins, and activation of clotting factors through contact with coagulant surfaces of extravascular cells could collectively act as a “structural” trigger of the coagulation system in agreement with the known tenets of the Virchow triad .37Second, coagulation system perturbations may be triggered by the effects of anticancer therapy. For example, therapeutic interventions such as surgery, radiation, systemic administration of chemotherapeutic and antiangiogenic agents, placement of central venous lines, and protracted stasis due to bed rest may create procoagulant conditions.Third, a part of cancer biology may entail a procoagulant conversion of the tumor and stromal cell phenotype. Deregulation of cellular signaling pathways due to microenvironmental perturbations, hypoxia, exposure to inflammatory cytokines, and other factors may drive expression of coagulation-related genes and exaggerated procoagulant, anticoagulant, or fibrinolytic properties of tumor cells and their associated stroma. High cellular turnover rate, necrosis, and increased activation of cell death pathways may lead to the exposure of phospholipids and TF on the surface of dying cancer, inflammatory, endothelial, and stromal cells, leading to their increased procoagulant activity.47Procoagulant complications in cancer patients have long been considered to be “unspecific” side effects of the underlying malignancy, or undesirable aftermaths of the related care. Consequently, the development of thromboprophylaxis and treatment approaches has largely been guided by considerations predicated on the state of the hemostatic equilibrium, and the assessment of clinical symptoms and risks in various disease contexts.48However, the intrinsic risk of thrombosis varies greatly between different cancers, including their site of origin and stage of progression.43We have initially proposed that oncogenic transformation may have a role in triggering cancer coagulopathy.64Oncogenic mutations may also influence coagulation more directly.65The notion that cancer-specific transforming mutations may impact the coagulome of tumor cells and their ability to reprogram vascular micro-environment is consistent with the observed variation amongst human cancers in terms of the risk of the associated coagulopathy.Thus the vast majority of adult human cancers arise as a result of the accumulation of multiple genetic hits. As the “founder mutation” is compounded by additional mutational events, multiple cellular lineages with different genetic profiles emerge within a single lesion often colonizing different tumor microregions, or coexisting in dynamic mixtures composed of cells with different degrees of aggressiveness.Even within the same lesion, cancer cells that possess the same repertoire of genetic alterations are not phenotypically identical. Indeed, the disease-causing potential is thought to reside in a subset of cells harboring certain stem cell markers and referred to as tumor-initiating (stem) cells (TICs). These cells differ from their more differentiated but genetically related progeny with respect to gene expression profile, self-renewal, proliferative activity, and resistance to genotoxic insults.82As different TICs continue to acquire additional mutations their harboring cancers evolve to contain increasingly complex phylogenetic hierarchies of heterogeneous cellular clones.85In this context, it could be argued that cancer coagulopathy may not only differ between tumor typesThere are significant unmet needs regarding clinical management of both primary (PBT) and secondary (metastatic) brain tumors (SBTs).91TERT), amplification of chromosome 7 (EGFR gene), activating mutation of EGFR (EGFRvIII), and loss of chromosome 10 region (PTEN) amidst other changes.H3FA3, ATRX).93While the histological features of GBM are relatively consistent between different cases, genetic studies revealed the existence of several molecular pathways driving this disease as a function of age and repertoire of oncogenic mutations.In addition to this genetic diversity, the gene expression and methylation profiling of GBM through the efforts of the Cancer Genome Atlas (TCGA) Consortium resulted in the subdivision of these tumors into at least four molecular subtypes: proneural (PN), neural (NEU), classical (CL), and mesenchymal (MES) .75,93,94Similar efforts are ongoing in several other types of brain malignancies of which perhaps the most advanced is the molecular classification of primitive neuroectodermal tumors including medulloblastoma (MB), tumors occurring mainly in the cerebellum.These and other advances in the molecular pathology of brain tumors have rarely been considered in the context of the coagulome. While exuberant vascular features, hypoxia, and upregulation of VEGF in GBM have attracted considerable interest and led to experimental and clinical explorations of antiangiogenic therapy,Two classes of factors may influence the procoagulant potential associated with brain tumors, the nature of the brain milieu, and the intrinsic molecular characteristics of tumor cells themselves. Thus the brain microenvironment presents an a-priori heightened procoagulant activity due to the concentration of TF on the surface of astrocytes, but also due to other factors that still need to be identified.There is, however, mounting evidence that the profiles of coagulation effectors change with genetic progression of human brain tumors. It is important to note that while this may impact the intrinsic risk of clinically detectable thrombosis, changes in the cancer cell coagulome may also have other more subtle and context-dependent consequences. For example, the expression of either a procoagulant or fibrinolytic cellular phenotype may, at least in theory, alter the responses to surgical excision of the respective lesions, leading to changes in iatrogenic clotting or bleeding tendencies, respectively. Moreover, even in the absence of clinically detectable hemostatic perturbations, unopposed activation of the coagulation system due to intervention or disease progression may impact tumor cell growth/quiescence equilibrium,Progression of astrocytomas is linked to profound changes in coagulant properties of the respective tumors. For example, the risk of systemic thrombosis is high and continuous in GBM patients  and PAR activating peptides.Nonetheless, the causal relationship between oncogenic transformation and changes in the coagulome of glioma cells is well documented in preclinical studies. Thus the expression of the GBM-specific mutant of EGFR (EGFRvIII) in the U373 glioma cell line and in astrocytic cultured cells results in a dramatic upregulation of TF mRNA, protein, procoagulant activity, and proangiogenic signaling.67The relationship between oncogenic drivers and the coagulome are not restricted to cultured cells. Notably, interrogation of transcriptome data sets compiled through the TCGA-sponsored analysis of GBM tumor samples reveals that the aforementioned molecular subtypes of GBM exhibit vastly different profiles of coagulation-related gene expression.The coagulome is also altered by oncogenic pathways in brain tumors in which systemic thrombosis is not a common occurrence. For example, in cells derived from neuronal malignancies (such as MB or ETMR), the expression of activated MET, SHH, or certain microRNA species regulate the expression of TF, PAR-1, and other coagulation-related factors71The significance of studies on the role of the coagulation system in brain tumors is ultimately founded on their potential clinical utility. In this regard, coagulation-related events may contribute to outcomes through exacerbating thrombotic comorbidities,However, these approaches remain largely unexplored in spite of the increasing sophistication of anticoagulant and anti-platelet pharmacotherapy,Arguably, and due to the complexity of cancer coagulopathy, clinical explorations in this field have been conducted with an assumption of the fundamental similarity and hemostatic predominance of coagulation disorders in human cancers, and thus in the absence of molecular stratification, precision targeting, and biologically based personalization of the study design. Perhaps, one way to revisit these challenges and to formulate informative preclinical and clinical inquiries could be to bring forward two questions related to the aforementioned advances in cancer pathobiology: 1) Is there one or a spectrum of (molecular subtype-specific) coagulopathies in human brain tumors, and what are the implications of the latter possibility? 2) What are the disease subtype- and stage-related mechanisms, and what is the biological importance of coagulation system involvement in the progression of specific brain tumors? In other words, do specific coagulation effectors play a rate-limiting role throughout the disease, only at specific points in progression, or never in molecularly defined brain tumors? Is the role of the coagulation pathway the same or different at the time of tumor initiation, surgery, relapse, or progression?These questions remain unresolved. One possibly informative example of the stage-specific role of the coagulation system in the progression of brain tumors could be derived from studies on the regulation of tumor initiation and on the exit from the state known as tumor dormancy. Both of these events rely upon the ability of cancer cells to assume TIC characteristics, which could be influenced by the coagulant microenvironment directly, or through the role of inflammation, angiogenesis, and tissue repair processes.Recent experimental studies seem to suggest that this is at least a theoretical possibility. Indeed, the experimental expression of TF in a dormant glioma cell line was found to provoke recruitment of inflammatory cells and intense neovascularization followed by tumor formation after prolonged latency time.The coagulation system is a part of the regulatory network that integrates parenchymal cells with the vasculature and inflammatory responses. While blood clotting is the most studied manifestation of coagulation system activity, this is possibly a “tip” of the biological “iceberg” in the context of brain tumors, in which a unique coagulant milieu may play a pathogenetic role still to be fully characterized. We suggest that the repertoire of oncogenic drivers and the molecular diversity of primary and secondary brain tumors may result in a comparably diverse spectrum of coagulant perturbations with a unique potential for clinical consequences, worth exploring and possibly targeting. Indeed, it is the understanding of the possible diversity of brain tumor coagulopathies that represents an outstanding challenge.