A 40-year-old Caucasian man presented with sudden onset of left-sided hemiparesis associated with dysphonia, dysphagia, and right-sided weakness on shoulder elevation and head rotation. The clinical examination revealed deviation of the tongue to the right, absence of right-sided gag reflex, right-sided palatal and vocal cord paresis, and weakness of the right trapezius and sternocleidomastoid muscles; all were in addition to left-sided brachiocephalic-accentuated hemiparesis. The diagnostic examination revealed dissection of the right carotid artery with occlusion of the middle cerebral artery and infarction in the lenticular-striatal artery territory. Mechanical thrombectomy with stent angioplasty of the right internal carotid artery was performed. The paresis of the left side of the body completely regressed within a week after symptom onset, but the dysphonia, weakness of the right trapezius and sternocleidomastoid muscles, and especially dysphagia persisted and regressed slowly but gradually. The patient required percutaneous gastric tube feeding for the next 12 weeks, possibly because of involvement of subcortical white matter tracts. The constellation of symptoms and clinical findings were consistent with Collet-Sicard syndrome, an extremely rare disorder caused by direct compression of the caudal cranial nerves at the base of the skull. Collet-Sicard syndrome is a very rare clinical condition characterized by combined paralysis of cranial nerves IX through XII , 2. The A 40-year-old left-handed Caucasian man was admitted with sudden onset of moderate left hemiparesis, hoarseness, dysphagia, and weakness on lifting the right shoulder and turning the head to the left. There was no evidence of Horner syndrome. The medical history was unremarkable. He was not taking any regular medications. He reported no major or minor head or neck trauma and no recent infection.The clinical examination revealed left-sided hemiparesis, most pronounced in the arm and face, right-sided tongue weakness, right-sided palatal and vocal cord paresis, right-sided palatal hyposensitivity, and paresis of the right trapezius and sternocleidomastoid muscles. Aphasia was not present. The computed tomography of the brain 3 h after symptom onset was unremarkable . Additiovia a percutaneous gastric tube. Twelve weeks after the onset of symptoms, the swallowing function was restored and the percutaneous feeding tube was removed. Limited tongue mobility and mild hoarseness with nasal speech were still present.Fiberoptic examination of swallowing function was performed on admission. Penetration and aspiration of liquids and all foods were noted. Within 7 days of symptom onset, the left-sided hemiparesis regressed, leaving only mild deficits in the fine motor function of the hand. The dysphagia, dysphonia, hyposensitivity of the palate, and moderate weakness of the right trapezius and sternocleidomastoid muscles persisted but gradually regressed. Ten weeks after the onset of symptoms, the patient was still fed Lesions of the cranial nerves occur in up to 12% of extracranial dissections of the internal carotid artery . Collet-The prognosis of lower cranial nerve impairment in Collet-Sicard syndrome is generally considered good to excellent  but depeAdditional neurophysiologic studies such as electromyographic examination of the muscles innervated by the inferior cranial nerves  or functional MRI were not performed in our case but could have provided additional information about the nature and severity of the peripheral nerve fiber damage and the brain lesion.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.DN and FS drafted the manuscript. RL, PA, VS, KS, and CW added clinical data and revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Molecular Exercise Physiology and Omics approaches represent an important step toward synthesis and integration, the original essence of Physiology. Despite the significant progress they have introduced in Exercise Physiology (EP), some of their theoretical and methodological assumptions are still limiting the understanding of the complexity of sport-related phenomena. Based on general principles of biological evolution and supported by complex network science, this paper aims to contrast theoretical and methodological aspects of molecular and network-based approaches to EP. After explaining the main EP challenges and why sport-related phenomena cannot be understood if reduced to the molecular level, the paper proposes some methodological research advances related to the type of studied variables and measures, the data acquisition techniques, the type of data analysis and the assumed relations among physiological levels. Inspired by Network Physiology, Network Physiology of Exercise provides a new paradigm and formalism to quantify cross-communication among diverse systems across levels and time scales to improve our understanding of exercise-related phenomena and opens new horizons for exercise testing in health and disease. The explanation of macroscopic sport-related phenomena cannot be reduced to molecular levels. Physiological states are products of nested dynamics of vertical (among levels) and horizontal (among components of the same level) nonlinear interactions. Network Physiology of Exercise provides data analysis techniques to investigate how systems coordinate and synchronize in an integrative way. The field of Exercise Physiology (EP) studies how the body adapts to acute and chronic exercise stimuli and has an enormous impact on both basic physiology and sports science. Interventions related to training and testing, physical fitness and conditioning, and sports medicine in general are based on empirical and theoretical evidence derived from EP research. Despite the fundamental discoveries, vast progress, and achievements in EP for over a century, the reductionist framework that has traditionally dominated research in the field has imposed limitations to the exploration and understanding of the regulatory mechanisms underlying complex physiological responses to exercise. The investigation of exercise-induced fatigue is a clear example of such limitations. Focusing the attention on molecular processes with few exceptions , 2, the Recent Molecular Exercise Physiology and Omics investigations have extended their scope beyond the study of single tissues or molecular targets to overcome such limitations. Omics focuses on analyzing large pools of biological molecules of certain kinds, such as proteins, metabolites, genes, etc., in a cell, organ, or organism. With technological and computational advances, such approaches seek to map molecular/omics networks of systemic adaptations to exercise in a holistic, unbiased, and integrated manner . Their mThere is a tremendous potential for network approaches to better understand the complexity and interconnectedness of molecular processes through genomic and proteomic interactions to (a) assess and quantify biological adaptations to exercise and (b) fill critical gaps in the current understanding of the underlying molecular mechanisms of exercise. However, complex network approaches based on graphs theory are limited to the static representation of genomic and proteomic associations , 13. MolThe challenge of coping with the complexity of sport-related phenomena, emerging from coupling and network interactions among physiological systems and subsystems across spatiotemporal scales, cannot be solved only by focusing on a collective characterization and quantification of pools of biological molecules. Cross-disciplinary collaboration and advancements in both technology and data analytics methods can also be insufficient if reductionist theoretical and methodological research assumptions of EP are kept.Find general principles of physiological processes to explain every new context or exercise condition adequately,Use general explanatory concepts and principles valid in biology/physiology and other dimensions  and levels of matter organization ,Focus on the physiological processes' dynamics  instead of associations between static measures,Investigate multilevel vertical  and horizontal interactions among physiological systems to explore multilayer network-based mechanisms underlying the emergence of exercise-related phenomena rather than reducing them to static measures performed at the molecular level.This opinion paper outlines the main challenges in EP and the future directions of research to improve our understanding of the complex mechanisms underlying exercise-related phenomena:The reader can find the rationale for these challenges and the directions for future research of EP based in network science in a previous publication . Within Life is a property emerging from the interaction of cell components and cannot be explained either by any single component or by their simple aggregation because in biology, “more is different” , and relNew properties that cannot be directly deduced from those of the level below emerge at each physiological level . Then, macroscopically defined sport-related phenomena  cannot be inferred from simple extrapolation of the properties of elementary molecular components. For instance, one cannot explain exercise-induced fatigue through metabolic substrates or end products . In otheUnderstanding the biological behavior at each level requires specific research that is as fundamental in its nature as any other. Paraphrasing Anderson , the abiHence, future research in EP has to address several fundamental questions like (a) how hierarchical integration among physiological systems is produced across levels, that is, how to re-compose the previously decomposed (through reductionism) physiological mechanisms, (b) how the entire ensembles capture key emergent properties, and (c) how to provide an integrated and synthetic explanation of sport-related phenomena . PhysiolThe nature of this organizational hierarchy of physiological processes has not been a research subject in sports science, and its description is usually simply anatomic. It is worth noting that Fig. Although correlated, the operating timescale of each physiological level is different. For instance, cellular metabolic adaptations occur faster  than adaptations at the organ level  and organismic level . Although it is often assumed that molecular and cellular changes are the most relevant in physiology, social and psychological constraints, changing more slowly in time, have a more permanent effect . For insInstead of focusing on a microscopic molecular level, Bizzarri et al.  propose The Dynamic Systems Theory (DST) conceptual framework  , 38–42 cThe progressive integration of the DST framework within Molecular and Cell Biology, Genomics and all Omics approaches , 44–48 aComplex systems science, born with integrative scientific purposes, and searching common principles among substance organization levels, provides concepts able to re-compose the decomposed through reductionism, and physiological mechanisms and integrate the fragmented information . RecogniIn CAS, the adaptation properties are based on biological intelligence, defined as the capacity to evade or escape states of reduced functional solutions . Many biIn EP, the emergence of adaptation properties has been described as a tendency to prevent states of reduced fitness, that is, states of reduced functional diversity potential , 51. ThiThese exercise effects can mainly compensate for the tendency of aging and disease to reduce the diversity potential of individual physiological systems and the entire organism , 61. TheThe function of biological intelligence is to allow physiological systems and organisms to escape states with reduced diversity potential, such as aging, fatigue, injuries or other unexpected perturbations. This is done by creating new synergies among systems, which may include new dimensions, not only those related to exercise modalities . ExercisBiological intelligence is linked to properties of CAS, which are commonly not considered in the theoretical framework of Molecular Exercise Physiology research as:Spontaneous formation of synergies: flexible patterns of coordination arising from local or global interactions between parts [en parts , which fen parts , 66. Whien parts , 68. In en parts , 69) or en parts , 70. Proen parts . This meSelf-organized dynamics may play a crucial role in phenotypic traits. Molenaar  discussePleiotropy: The same components and processes may be assembled to produce multiple functions. For instance, the skeletal muscle, with genuine/primordial contractile functions, may also exert immunological and endocrine functions [unctions , 75.Degeneracy: Different components produce the same function, and different synergies may be activated to attain the same task goal [ask goal , 77. Forask goal .Nonlinear dynamics: The interactions among parts are such that non-proportional effects to perturbations may arise [ay arise , 79. Foray arise .Readers can contrast further theoretical research postulates of the current EP paradigm from the framework of Networks Science , 81, 82.Molecular Exercise Physiology and Omics approaches focus on data collection to catalogue exercise-regulated pathways , 7, 11. Network Physiology of Exercise emerged as a new area of research inspired by the multi-disciplinary field of Network Physiology , 83, 84 Identifying and quantifying functional forms of coupling, studying network interactions among diverse physiological systems and processes, and finding the mechanisms of causality and network control are significant challenges due to the complex dynamics of organ systems , 86–89. In contrast to traditional complex network theory, where edges/links are constant and represent static graphs of association, novel approaches in Network Physiology take into consideration (i) the complex dynamics of individual systems (network nodes), (ii) dynamical aspects of network links representing organ communications in real time, (iii) the evolution of organ interactions with time, and (iv) the emergence of collective network behavior in response to changes in physiologic states and conditions.Table The methodological steps followed by Molecular Exercise Physiology and Omics approaches are similar to those followed by EP. For instance, in correlational studies: (a) measuring N physiological variables on K number of subjects, (b) calculating the group-pooled Pearson correlations matrices, and (c) performing some form of data reduction technique. This group-pooled data analysis ignores the critical caveat that results obtained at the group level cannot be unconditionally interpreted as relations or effects that exist at the individual level .In contrast, genuine network analysis research follows the following steps: (a) analysis of a set of time series at the individual level and formulation of individual networks, (b) check for general features of networks among individuals, and (c) determine the degree of generalization of certain network features at a population level. It also detects and discusses individual-specific characteristics.Instead of using only molecular data to establish bottom-up statistical timeless inferences from micro to macroscopic phenomena , Network Physiology of Exercise proposes the study of the time-variability properties of mesoscopic or macroscopic behavioral variables extracted at action level . The stAnother crucial methodological difference refers to the analysis of the acquired physiological data. Most of the research on Molecular Exercise Physiology and Omics approaches infer intra-individual phenomena from the study of inter-individual variations obtained through group-pooled data. This approach has some fundamental methodological issues that should be discussed in detail. The main aim of EP research, performed at any level of analysis, is to find the regulatory mechanisms that occur at the intra-individual  level as an effect of exercise. The intra-organismic processes, not the population, are the explanatory target. It is important to note here that intra-individual variability and co-variability unfold in time and must be measured through time series analytical tools.While the problem of sample to population generalization has been much discussed, investigated, and used in inferential statistics, much less attention has been focused on the justification of sample or population to individual generalization. A tacit assumption has been that the results obtained at the sample and generalized to the population level are representative of the changes of a ‘typical’ [i.e., average) individual , 102. InPooling-over group subjects is the predominant research practice in EP, particularly in exercise and health-related research. Even the state-of-the-art software packages for time series analysis  are baseIn recent years, research in EP has made significant strides toward Molecular Exercise Physiology and the implementation of novel Omics technologies to investigate exercise-related phenomena. While molecular and Omics approaches to EP have led to substantial new insights, exploring the effects of exercise at the macroscopic organism level cannot be reduced to the molecular levels only. Group-pooled data analysis, characteristic of EP research, can produce statistical population artifacts of cause–effect relations that may not exist at the individual level. Thus, such group-pooled results cannot be directly generalized to the macroscopic organism level without knowing the causal processes and network interactions at the intra-individual mesoscopic scales.In addition to focusing on microlevel molecular and Omics processes, recent developments in Network Physiology have utilized novel empirical and modeling approaches based on adaptive networks of dynamical systems to open new horizons. These involve exploration of coupling forms and network dynamics of physiologic interactions and investigation of the mechanisms of integration at the meso- and macroscopic levels, where the emergence of order is of physiological relevance for exercise-related phenomena.Such dynamic network approaches to EP at the meso- and macroscopic levels are essential to (i) uncover laws of cross-communication and causality among systems, (ii) establish principles of adaptation and hierarchical integration, and (iii) build a new mechanistic picture of the control processes underlying the emergence of exercise-related physiological states and functions, and (iv) facilitate the classification and prediction of behaviors at the organism level in response to exercise, based on dynamic maps of network interactions among physiological and organ systems.The future challenges of EP to go beyond molecular and Omics approaches are the following: (i) focus on general principles of physiological processes to understand adequately every new exercise context, (ii) use general concepts and principles derived from DST and networks of dynamical systems, valid for all levels of substance organization, to conceptualize, investigate and explain exercise-related phenomena, (iii) focus on nonlinear dynamic interactions instead of static associations, and (iv) provide multilayer network-based phenomenological explanations of exercise-related phenomena as products of nested dynamics of nonlinear interactions within vertical (among levels) and horizontal (among components at the same level) integration.Network Physiology of Exercise, a new branch of Network Physiology, has emerged to explain physiological states and functions as products of such nested network dynamics. Novel data analysis techniques have been developed and successfully utilized to investigate how physiological processes and systems coordinate and synchronize as a network. Such approaches can lead to a new class of evaluation tools to assess the effects of exercise. Specifically, building the theoretical formalism for Network Physiology of Exercise will facilitate the development of network-based biomarkers, able to track how physiological states evolve under exercise settings and improve our knowledge about the mechanisms underlying diverse exercise-related phenomena.


Throughout the animal kingdom, olfaction underlies the ability to perceive chemicals in the environment as a fundamental adaptation with a plethora of functions. Unique among senses, olfaction is characterized by the integration of adult born neurons at the level of both the peripheral and central nervous systems. In fact, over the course of life, Neural Stem Cells (NSCs) reside within the peripheral Olfactory Epithelium (OE) and the brain’s subventricular zone that generate Olfactory Sensory Neurons (OSNs) and interneurons of the Olfactory Bulb (OB), respectively. Despite this unique hallmark, the role(s) of adult neurogenesis in olfactory function remains elusive. Notably, while the molecular signature and lineage of both peripheral and central NSC are being described with increasing detail and resolution, conflicting evidence about the role of adult born neurons in olfactory sensitivity, discrimination and memory remains. With a currently increasing prevalence in olfactory dysfunctions due to aging populations and infections such as COVID-19, these limited and partly controversial reports highlight the need of a better understanding and more systematic study of this fascinating sensory system. Specifically, here we will address three fundamental questions: What is the role of peripheral adult neurogenesis in sustaining olfactory sensitivity? How can newborn neurons in the brain promote olfactory discrimination and/or memory? And what can we learn from fundamental studies on the biology of olfaction that can be used in the clinical treatment of olfactory dysfunctions? As part of the nervous system, our senses are highly plastic. They adapt to our experiences and the world that surrounds us ultimately influencing how we experience it. Accordingly, sensory loss often evokes remodeling and adaptation of our other senses improving or reallocating their function . Among tIn vertebrates, odor detection begins when odorants reach the Olfactory Epithelium (OE), part of the peripheral nervous system. Here, Olfactory Sensory Neurons (OSNs) express G-coupled Olfactory Receptors (ORs) encoded by more than 1,000 genes in rodents and nearly 400 in humans making them the largest gene family in our genomes . To dateUpon activation, OSNs initiate action potentials encoding and transmitting information to the brain’s Olfactory Bulb (OB), the first olfactory station of the central nervous system. Here, projections of OSNs form synapses with mitral and tufted cells within spherical structures, nearly 2,000 in mouse and 6,000 in human, known as glomeruli . NotablyIn addition to the topographic organization of glomeruli, another level of control is imposed by local and centrifugal inhibitory circuits in which OB interneurons are key players . The mosIn summary, fundamental features characterizing the olfactory system, namely sensitivity, discrimination, and memory can overall be assigned to the three regions of the OE, OB, and OC, respectively. In turn, this raises the question: Can adult neurogenesis modulate any of these three fundamental abilities?Specifically, both the OE and the OB are characterized by the integration of newborn neurons throughout life. Within the OE, Neural Stem Cells (NSCs) were first described over four decades ago  but onlyWhile NSCs within both the OE and OB have long been considered important to maintain structural plasticity underlying homeostasis and regeneration, several fundamental questions arise with regard to additional roles of adult neurogenesis in odor sensitivity, discrimination, and/or memory. Here, we will address central questions pertaining to the role of newborn neurons in olfaction, namely: (i) Can peripheral adult neurogenesis in the OE promote odor sensitivity? (ii) Are newborn neurons in the OB promoting discrimination, memory, or both? And (iii) how can studies in model organisms help us define novel treatments for olfactory dysfunction in a clinical setting?The OE is the most active neurogenic niche and the only one characterized in a peripheral sensory system . Due to Olfactory sensitivity is defined by the lowest concentration of an odorant that can be detected. Since most ORs are promiscuous and bind different odorants with different affinity, it is intuitive to conclude that OE sensitivity may ultimately depend on the number of OSNs expressing a given OR, the relative proportion of OSNs expressing it as well as the expression level of a given OR in a particular set of OSNs. Notably, adult neurogenesis inherently provides the means to constantly renew the number of OSNs and the OR expression pattern of the whole OE, hence, dynamically remodeling its sensitivity. However, to date this seemingly logical inference was not experimentally validated and the molecular mechanisms underlying it not investigated.Here, we envision different models by which adult neurogenesis may drive the remodeling of olfactory sensitivity under olfactory experiences such as increased stimulation of the OE or, conversely, odorant deprivation or desensitization. In addition to a change in the expression levels of a given OR within mature OSNs, it is important to consider that olfactory experience may influence the choice of OR expression itself within immature, newborn neurons . This, iWhile this effect of olfactory experience in regulating the specification and survival of newborn neurons would seem intuitive, to our knowledge no report characterized it thus far. In addition, an even more intriguing possibility is that olfactory experience may itself regulate the activity of the NSCs themselves. Increased levels of adult neurogenesis would, in turn, provide increased numbers of OSNs whose OR expression may be additionally regulated either through stimuli-dependent maturation, as described above, or stochastically, to adapt sensitivity to novel stimuli . Such liUnlike the OE, the cellular composition and physiology of the central station of the OB are well characterized. Yet, the role of adult neurogenesis in the OB has remained elusive. In the last years, first studies have suggested a role of newborn neurons in supporting olfactory memory. Partly contradicting each other, these studies suggested effects of adult neurogenesis on short-term  or long-Experimental evidences were provided in support of the above-mentioned hypothesis. Inhibiting adult neurogenesis resulted in impaired discrimination  while, cSpecifically, excluding the first model discussed (a), For obvious reasons, adult human neurogenesis in the central nervous system is poorly characterized and long debated both at the level of the hippocampus  and the Ongoing clinical practice provides a remarkable example of how olfactory experience may trigger a recovery in olfactory functions. Pioneered by the Hummel group , olfactoFirst, olfactory training was found to be more effective in younger patients  and, secHere, we discussed how adult olfactory neurogenesis not only sustains the structural and cellular homeostasis of the olfactory system but also how it may actively promote its functionality based on environmental stimuli at both the peripheral and central levels. In parallel, we formulated several questions pertaining to the mechanisms underlying such effects and proposed hypotheses to explain how neurogenesis may be critical in understanding the fundamental biology of the sense of smell, and improving the clinical treatment of olfactory dysfunction . While eThe original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.VA and FC conceived and wrote the manuscript. TH revised the manuscript. All authors approved the submitted version.


Scoliosis is a three-dimensional deformity of the spine and trunk , and desHigh-quality studies have expressed doubts about the possibility of bracing to change the natural history in mild scoliosis patients ,6. Some Evidence is also growing regarding exercises, with former Cochrane Review results  reportinWhile we wait for a deeper understanding of the aetiology that would allow us a more specific treatment, based on current evidence, there are novel challenges that clinicians and researchers must face. After focusing on effectiveness for decades, research concerning bracing should now focus on protocols and biomechanical effectiveness. The high dosages (hours per day of brace wearing) are a documented key factor for success . HoweverEvidence for PSSEs is quite promising , with noPoor-quality research remains crucial in limiting the possibility of increasing our knowledge and implementing the best available treatments. Several years ago, we described some of the most frequent issues related to this, including selection bias, inappropriate outcome measures and follow-ups, the misinterpretation of findings and missing evaluations of skeletal maturity . These pIn conclusion, in recent decades, knowledge on idiopathic scoliosis and its treatment has grown thanks to broader interest in and better quality of research. The creation of the Scientific Society on Scoliosis Orthopaedic and Rehabilitation Treatment (SOSORT) strongly supported the increased number of published papers. Nevertheless, some areas are still under investigation, and poor-quality articles are still being published. We need to focus on these areas and provide the best possible evidence for the sake of our patients. The present Special Issue is an example of interest in bridging this gap between current knowledge and the needs of clinicians.


Post-translational modifications (PTMs) exponentially increase the complexity of the human proteome and ensure that the right form of each protein is expressed in specific cells across our bodies at specific time points. Addition of functional groups or proteins, as well as proteolytic cleavage, regulate protein structure, activity, localization, immunogenicity and interaction with other proteins. Intracellular signal transduction heavily relies on a cascade of PTMs that ensure rapid message relay, mobilization of key enzymes and activation of appropriate cellular responses. However, also proteins with extracellular function are subjected to PTMs, including proteolysis, ROS-induced oxidative changes, carbamoylation and citrullination, which often occur at sites of inflammation. PTMs of extracellular immune mediators and antigens exert profound influences on all aspects of immunity.In this Research Topic, we collated original articles and reviews illustrating current research and opinions pertaining to immunoregulatory roles of PTMs in extracellular signalling and highlighting the increasing interest in studying these PTMs in the context of host defense, immunopathology, and cancer immunotherapy.Frezza et al. demonstrate here that IL-1α and IL-36 cytokines are processed and activated by a variety of proteases derived from common allergens of plant, insect, fungal and bacterial origin, further cementing the idea that IL-1 family cytokines have evolved to recognize and signal the presence of exogenous proteases of various origin.Proteolytic processing is an efficient method to regulate the biological activity of target proteins. Proteases can efficiently inactivate and degrade substrate proteins or, on the contrary, unlock their bioactivity by removing inhibitory domains. For example, proteolytic maturation of IL-1 family members by extracellular proteases, derived from infiltrating immune cells at sites of inflammation, is considered as a safeguard mechanism ensuring that the full biological potential of these cytokines is only unleashed when required , thus facilitating the production of anti-citrullinated protein antibodies. Interestingly, a variety of proteins involved in the pathogenesis of RA are citrullinated. For example, Grillet et al. detected citrullinated forms of matrix metalloproteinase 9 in the synovial fluid of RA patients, although a causative link between PTMs of matrix degrading enzymes and RA pathogenesis remains to be established. In addition to RA, citrullination and carbamoylation are actively studied in the context of tumour biology. Amongst others, these PTMs have been shown to regulate cell death, differentiation, epithelial-to-mesenchymal transition and metastasis citrullinated peptides.Protein citrullination and homocitrullination, also known as carbamoylation, occur on the basic amino acids arginine and lysine respectively and lead to the loss of positive charge, which consequently affects electrostatic properties and conformation of the modified protein. This PTM has attracted a lot of attention since autoantibodies to (homo)citrullinated peptides were identified as the most specific biomarkers for rheumatoid arthritis (RA). It has been originally proposed that particular RA-associated variants of the major histocompatibility complex (MHC) class II molecule HLA-DRB1 contain a common sequence motif, the so-called shared epitope, that favors binding of citrullinated peptides and thus promotes presentation of citrullinated antigens to auto-reactive T cells . Howevertastasis  and the In conclusion, we believe that this Research Topic provides a representative snapshot of current questions pertaining to immunoregulatory effects of extracellular PTMs. The contributions included in this Topic highlight interesting new developments, and provide directions for future research in areas ranging from host defense in barrier tissues, to pathogenesis of autoimmune and chronic inflammatory diseases, and to tumour immunobiology, thus emphasizing the broad influence of extracellular PTMs on immune responses in general.IA wrote the first draft of the manuscript. All authors contributed to the manuscript, read, and approved the submitted version.IA holds a fundamental mandate of the Foundation against Cancer (code 365C06721) and is supported by a Grant from the Fund for Scientific Research Flanders (FWO) (code 3G086521), as well as by an Early Career Research Grant from the National Psoriasis Foundation (grant No. 849077). LF’s work is supported by the National Psoriasis Foundation and by a FOREUM research grant. GP’s work is supported by the Swiss National Science Foundation (grant 310030-188470), the Rheumasearch Foundation, and by a generous donor advised by Carigest SA. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The blood–brain barrier (BBB), built by brain endothelial cells (BECs), is impermeable to biologics. Liposomes and other nanoparticles are good candidates for the delivery of biologics across the BECs, as they can encapsulate numerous molecules of interest in an omnipotent manner. The liposomes need attachment of a targeting molecule, as BECs unfortunately are virtually incapable of uptake of non-targeted liposomes from the circulation. Experiments of independent research groups have qualified antibodies targeting the transferrin receptor as superior for targeted delivery of nanoparticles to BECs. Functionalization of nanoparticles via conjugation with anti-transferrin receptor antibodies leads to nanoparticle uptake by endothelial cells of both brain capillaries and post-capillary venules. Reducing the density of transferrin receptor-targeted antibodies conjugated to liposomes limits uptake in BECs. Opposing the transport of nanoparticles conjugated to high-affine anti-transferrin receptor antibodies, lowering the affinity of the targeting antibodies or implementing monovalent antibodies increase uptake by BECs and allows for further transport across the BBB. The novel demonstration of transport of targeted liposomes in post-capillary venules from blood to the brain is interesting and clearly warrants further mechanistic pursuit. The recent evidence for passing targeted nanoparticles through the BBB shows great promise for future drug delivery of biologics to the brain. The brain harbors a vascular barrier system consisting of the blood–brain barrier (BBB) and the blood–cerebrospinal fluid (CSF) barrier. Together, they limit the passage from the bloodstream into the brain parenchyma of virtually any drug unless highly lipophilic or smaller than approximately 70 Daltons ,2,3,4. THowever, the presence of the brain barrier system is inconvenient from a pharmacological perspective as many of the existing and forthcoming drug candidates, e.g., polypeptides, or genetic material-based pharmaceutics like siRNA or cDNA, are unable to pass the brain barriers . This isThe discovery of the selective expression of targetable proteins by brain endothelial cells (BECs) has changed the scene and provides new optimism, as several biologics conjugated to targeting antibodies are now amendable for uptake and transport across the BECs ,5,6. TheHere, we review the most successful attempts made to enable targeted uptake and transport of nanoparticles across the BBB. As most studies target the transferrin receptor, our delineation of the existing literature mainly addresses this receptor. We describe how specific proteins expressed by BECs enhance the binding and uptake of antibodies from the circulation. Next, we cover how targeted nanoparticles can undergo specific binding and uptake, when conjugated with antibodies weakened in affinity or avidity. We also discuss the therapeutic use of targeted nanoparticles in conditions with brain pathology.The BBB proper consists of endothelial cells connected by tight junctions. The blood–CSF barrier is formed by choroid plexus epithelial cells also connected by tight junctions, but opposed to the BBB; the capillaries of the blood–CSF barrier are leaky, meaning that solutes of the plasma diffuse into the extracellular space of the choroid plexus where the epithelial cells selectively transport molecules to the CSF ,3,14. FrThe BBB prevents large molecules and particles in blood plasma from entering the brain . This inThe first indicator of specific uptake and transport of a plasma protein came from observations showing that the brain has a high binding capacity for transferrin, the transporter of the essential metal iron . Later, Among the large proteins present in blood plasma, transferrin stands out because of its potential for binding to the transferrin receptor of the BECs ,24. The Counteracting the notion of receptor-mediated endocytosis and retro-endocytosis of transferrin at the BBB, other studies suggested that the iron-containing transferrin may be transferred across the BECs ,29. A caThe expression of transferrin receptor by BECs varies throughout development, with transferrin transport into the brain being higher in the developing brain than at later ages ,31,32. IReturning to the attempts to enable transport through the choroid plexus, it should not be overlooked that there is strong morphological and physiological evidence for vesicular transport by transcytosis through this epithelium. Ultrastructurally, tracer studies using peroxidases demonstrate that the choroid plexus epithelium can take up large molecules like horseradish peroxidase (HRP) with transfer from the basolateral to the luminal side eventually leading to release into the ventricles ,34,35. TThe functional capacity of the brain endothelium to bind and internalize antibodies targeted to the transferrin receptor  spawned The injection of antibodies targeted to the transferrin receptor dramatically increases the brain uptake as compared to non-targeted antibodies ,36,37. NWhile the development of antibodies entering the brain was generated using antibodies targeting the transferrin receptor and the insulin receptor, it should not be overlooked that targeting other proteins of the brain endothelium has been pursued. The large amino acid transporter (CD98hc), glucose transporter 1 (GLUT1), and basigin (CD147) are particularly rich in their selective expression by the BECs compared to capillaries in the periphery, e.g., lung and liver, and are alternatives for targeting the brain endothelium ,38,48,49The plethora of in vivo studies on nanoparticle transport typically omit to characterize the pharmacokinetics that leads to transport through the BBB. They rather focus on pharmacodynamics or therapeutic effects after the particles have undergone transport into the brain., Often the evidence for the latter is scarce and is extrapolated from pharmacological studies, where improvement in behavioral tasks of experimental animals treated with nanoparticles is used as evidence for BBB transport. Many studies determine fluorescent nanoparticles using whole-brain imaging, which prevents the distinction of nanoparticles in BECs versus neurons or glia. Other studies determine changes in protein or gene expression by neurons and glia in dissected brain preparations without taking the expression levels in BECs into consideration, e.g., by analyses of brain capillaries isolated and separated from the remaining brain tissue . In spite of the limited number of studies dealing with the uptake and transport kinetics by BEC, a common observation is that the uptake of nanoparticles, e.g., liposomes, gold nanoparticles, or quantum dots, from the circulation is significantly enhanced when conjugated to the transferrin receptor targeted antibodies ,53,54,55The uptake of RI7217-conjugated liposomes at the BBB is significantly higher compared to stealth liposomes conjugated with non-immune IgG . In cont3 antibodies/μm2) led to the highest binding and uptake [The number of antibodies present on the surface of antibody-functionalized gold nanoparticles and cargo-loaded stealth liposomes influenced the targeting to BECs in vivo. Hence, the highest density out of a selection of different densities , or rabies virus glycoprotein (RVG) ,66,67. ADespite being available for experimental use for more than three decades, the transferrin receptor is by far still considered the most relevant target for nanoparticle drug delivery. It is only a few other candidates, such as CD98, GLUT1, basigin (CD147), and the insulin receptor that were being taken into consideration as an alternative, but other than the insulin receptor, these receptors remain unexploited for their targetability to BECs with regard to nanoparticles . Anti-transferrin receptor-targeted monoclonal antibodies weakened in affinity for the receptor readily undergo transport across the BBB in a dose-dependent manner, becoming detectable in neurons . BispeciAntibodies with low affinity for the transferrin receptor seem to follow a cellular route identical to that of high-affine antibodies, as prior exposure to high-affine antibodies leads to reduced transport of low-affine antibodies across the BBB both in vivo and in vitro . The twoThe paucity of studies examining intracellular trafficking of nanoparticles in BECs in vivo limits the available information about their transport mechanisms. Some lessons may be learned from comparison of endogenous transferrin and unconjugated, targeted anti-transferrin receptor antibodies. Although this difference obviously should be taken into account, the low-affinity antibodies and low-affinity antibodies conjugated to PEGylated liposomes share great similarities in transport through the BBB with unconjugated low-affinity and low-affinity anti-transferrin receptor antibodies ,54.Endogenous transferrin enters the BECs after the interaction with the transferrin receptor on the luminal surface, facilitating subsequent formation of clathrin-coated pits, and eventually, formation of endosomes ,16,24. TWhereas the docking and endosomal formation relate to the affinity of the transferrin receptor, it can be argued that the intracellular trafficking of the endosomes follow routes that occur independently of the luminal receptor internalization ,16,51. BA morphological approach to detect transferrin at the ultrastructural level in rats subjected to the brain in situ perfusion failed to detect HRP-conjugated iron-transferrin near the abluminal side, which, in turn, was outnumbered by the presence of HRP-transferrin in multiple vesicular-like structures near the luminal side of the BECs . HoweverThe binding to high-affine anti-transferrin receptor antibodies also leads to the formation of endocytotic vesicles that mainly localize near the luminal membrane ,16. The It goes beyond doubt that the optimal transport of targeted nanoparticles at the BBB depends on the binding of anti-transferrin receptor antibodies to the endothelial surface . The traThe use of 2-photon microscopy (2PM) for in vivo studies has revolutionized the concept of how the brain works and has recently entered the field of the BBB research . 2 PM viOne study showed the contribution of endothelium at capillaries , which iThe study of Kucharz et al.  clearly The use of targeting approaches to promote enhanced drug delivery to the brain in pathology is only coming of age. Targeting approaches in conditions with cerebral pathology can roughly be separated into attempts to treat the brain in acute and chronic conditions. In acute conditions, e.g., ischemic stroke and traumatic brain injury, liposomes are advantageous among nanoparticles because they can be formulated to contain degradable lipids with enzymes like matrix metalloproteinases and phospholipases known to be increased in expression and released from the brain in acute pathology ,77,78,79Recent efforts aim to utilize a dual targeting approach using antibodies targeting the transferrin receptor and intercellular adhesion molecule-1 (ICAM1), both conjugated to liposomes. This resulted in higher binding compared to liposomes targeted to only transferrin receptor or ICAM1 antibodies alone . This apIn chronic brain disorders, like Alzheimer’s disease and Parkinson’s disease, the brain does not increase the expression of liposome-degradable enzymes like metalloproteinases and phospholipases to the same extent as seen in acute neuropathology, and therefore, the strategy of substrate degradable liposomes may not apply. Instead, it may be advantageous that the BEC expression of the transferrin receptor remains unchanged in Alzheimer’s disease , which fBECs are practically incapable of uptake of native liposomes from the blood, which requires the addition of targeted molecules. Experience gained from different targeting approaches justifies the choice of antibodies targeting the transferrin receptor for targeted delivery of nanoparticles to BECs. Liposomes functionalized by conjugated anti-transferrin receptor antibodies are taken up by endothelial cells at both brain capillaries and post-capillary venules. Modulating the number of transferrin receptor-targeted antibodies shows that limiting the number of targeting antibodies conjugated to liposomes reduces uptake in BECs. In comparison, lowering the affinity of the targeting antibodies or implementing bispecific antibodies with low avidity increases transport by BECs into the brain parenchyma. With increasing evidence of successful preclinical trials and advances in biochemical and analytical approaches, the transferrin receptor-targeted nanoparticles have great promise for future use in drug delivery as they evidently pass the BBB.


For reducing the switching frequency between the radio frequency (RF) chain and transmit antennas, a class of new sparse space shift keying modulation (SSSK) schemes are presented. This new class is proposed to simplify hardware implementation, through carefully designing the spatial constellation mapping pattern. Specifically, different from traditional space shift keying modulation (SSK), the proposed SSSK scheme utilizes more time slots to construct a joint design of time and spatial domain SSK modulation, while maintaining the special structure of single RF chain. Since part of the multi-dimension constellations of SSSK concentrate the energy in less time slots, the RF-switching frequency is effectively reduced due to the sparsity introduced in the time domain. Furthermore, through theoretical analysis, we obtain the closed-form expression of the bit error probability for the SSSK scheme, and demonstrate that slight performance gain can be achieved compared to traditional SSK with reduced implementation cost. Moreover, we integrate transmit antenna selection (TAS) to achieve considerable performance gain. Finally, simulation results confirm the effectiveness of the proposed SSSK scheme compared to its traditional counterpart. The concept of spatial modulation (SM) , charactMeanwhile, with the idea of the fifth generation (5G) becoming reality, the upcoming sixth generation (6G)  has focuAlthough the basic idea of SSK focuses on the most efficient implementation of modulation for MIMO, a new challenge lies in that the unaffordable RF-switching frequency becomes a bottleneck for information transmission, which remains an unsolved problem as increasing the implementation cost. To alleviate this issue, a class of offset SSK and SM schemes were developed in ,22 for rAgainst the above background, the major contribution of this paper lies in that, a class of sparse SSK schemes are proposed, characterized by carefully designing and optimizing the constellation in both the spatial and time domain. Meanwhile, with regard to effectively reducing the switching frequency between the RF chain and multiple antennas, part of the multi-dimension constellations of SSSK concentrate the energy of multiple time slots and hence the RF chain does not switch in this duration, while strictly maintaining the single-RF structure of original SSK. Furthermore, a closed-form expression of the union bound on bit error probability for the proposed scheme is also derived by theoretical analysis, in order to demonstrate its slightly improved bit-error rate (BER) performance over original SSK. Finally, in order to further enhance the performance by increasing the transmit diversity, the concept of transmit antenna selection (TAS) is integrated. Specifically, different TAS criteria are firstly compared in terms of transmission performance and computational complexity, then a class of low-complexity TAS algorithms are designed to strike a balanced tradeoff between performance and complexity.The remainder of this paper is organized as follows. The conventional SSK is reviewed and then the sparse SSK is presented in Notation 1.We use K represents the sequence length. For the conventional SSK scheme, the groups of Let us consider a generic MIMO system with Then the modulation vector is transmitted over an In general, the structure of original SSK offers a special low-cost implementation at the cost of increasing the switching frequency between the RF chain and transmit antennas. Therefore, a new challenge occurs as the overhead of RF-switching frequency. On the one hand, the RF-switching frequency becomes a new bottleneck to enhance the transmission rate. On the other hand, the increase of the RF-switching frequency also introduces extra cost for hardware implementation.Similarly, we consider an  is given by the well-known union bound  as:(1)PbAveraging (21) over the channel matrix The MGF of most fading distributions can be obtained by standard Laplacian transformation or numerical integration and common fading distributions such as Rayleigh MGF is expressed asThus, the unconditional PEP can be calculated under Rayleigh fading asWhen considering the reduction of the number of RF chains, spatial resources could also be utilized to improve the BER performance rather than spectral efficiency, and an abundance of methods have been proposed, among which transmit antenna selection could achieve considerable performance gain in conventional MIMO systems. Specifically, due to the lack of diversity, TAS is usually suggested to adapt SM and SSK in order to enhance the error performance via extra spatial diversity. Focusing on different aspects of the channel matrix, multiple TAS algorithms have been suggested as the norm-based capacity optimized antenna selection (COAS) and the Euclidean distance(ED)-based Euclidean distance optimized antenna selection (EDAS) ,27.The aforementioned two algorithms evaluate the channel matrix with totally different criteria, resulting in different tradeoff between complexity and performance. In this treatise, COAS, EDAS and a compromised TAS algorithm are conceived for SSSK systems, while the complexity will be further quantified.q columns in the channel matrix The COAS uses the simultaneous SNR to evaluate the quality of the selected antenna set. Due to the feature of additive white Gaussian noise, COAS focuses on the Frobenius norm of the selected Compared to COAS, the EDAS algorithm adopts a different criterion with much increased complexity to select the antennas. In EDAS, the Euclidean distance between transmit vectors which are distorted by the partial channel matrix Algorithm 1 Compromised TAS algorithm.Input: ⌀, Initial ⌀Output: Selected antenna index set 1:Get Equation  with par2:3:q;Get Equation  with par4:return In order to balance the performance and complexity for adapting the SSSK scheme, a compromised method of antenna selection, taking both performance and computational complexity into account, is conceived to combine the above-mentioned two criteria. Specifically, a primary selection could be performed with low-complexity norm-based algorithms as COAS, to alleviate the computational complexity, and a complicated, near optimal antenna selection could be performed afterwards to acquire better BER performance. Algorithm 1 could be depicted as follows.The parameters The computational complexity is measured by the real number float operations per second (flops), including complex addition and multiplication. For given complex matrices ctively, .L, while q columns of channel matrix are selected. For convenience, define Assume an SSSK system with i and j, i and j, and the overall complexity is With regard to EDAS, the problem becomes different from that in conventional MIMO systems for the sparsity of SSSK transmit vectors. For any For the compromised algorithm, the TAS process could be divided into two steps, as the primary COAS and EDAS, and the computational complexity is strongly correlated with the temporarily selected antenna number N be the number of combined time slots for SSSK modulation. Moreover, the theoretical curve is given in each figure. As shown in the figures, the upper bound derived becomes very tight upon increasing the SNR values for both SSSK and SSK which is helpful for verifying the correctness of the simulation results. The details for both will be given as follows.In this section, the comparison of RF-switching frequency and a range of numerical BER performance simulation results of the sparse SSK and conventional SSK are presented and compared with different numbers of transmit antennas and receive antennas. In all the simulation results, unless otherwise specified, the Rayleigh fading channel is considered while perfect channel state information is assumed. When channel estimation is not ideal ,30, the Firstly, to demonstrate the advantages of SSSK in detail, a comparison of the RF-switching frequency between SSK and SSSK is shown in Subsequently, we present the BER performance curves of the SSSK and SSK modulation with N decreases under the same antenna configuration. Secondly, when N increases, the advantage of SSSK is gradually reduced. Moreover, we give the results in the case of The above-mentioned antenna selection schemes are validated in SSSK systems, and SSSK without TAS is also simulated as a reference. The total transmit power is set to be unit per time slot. Assume perfect channel state information is available at the receiver and the result of TAS is conveyed to the transmitter through the feedback channel.The complexity of the aforementioned TAS algorithms is also illustrated in In general, through the above-mentioned simulation works, we demonstrate the following issues for the developed SSSK scheme. Firstly, SSSK has the unique advantage of reduced RF-switching frequency without the CSI at the transmitter, while offering slightly improved BER performance compared to its traditional counterpart as SSK. Secondly, the TAS is proved to be effective at combining SSSK for reaping its spatial diversity advantage offered. Lastly, the proposed low-complexity TAS-SSSK is capable of striking a balanced trade-off between performance and complexity.In this paper, we introduce a class of sparse SSK modulation techniques toward low-cost implementation of MIMO in terms of reduced RF-switching frequency, characterized by the construction of a joint index modulation in the space and time domains. Furthermore, a theoretical upper bound is achieved through theoretical analysis, to further quantify the performance advantage compared to traditional SSK. In addition, for further improvement of the BER performance through spatial diversity enhancement, the transmit antenna selection is considered while several detailed algorithms are compared. We finally conclude that the developed low-complexity TAS algorithm can strike a balanced trade-off between BER performance and computational complexity.


While keeping their original purpose of training medical students, pathology museums hold great biological value, offering unique specimens for scientific research through modern radiological, pathological and biomolecular techniques. Moreover, the artefacts, models and drawings displayed in these museums are a precious cultural and artistic heritage. Preservation of the anatomical samples and maintenance of the facilities are neither easy nor inexpensive and call for patronage. The development of a European Pathology Museum Network would undoubtedly facilitate study, access and divulgation of antique pathology collections. Data from a survey conducted by the European Society of Pathology (ESP) History of Pathology Working Group have allowed creation of a comprehensive, multifaceted portrait of European university museums, reflecting their history, diversity, geography, institutional status, stakeholders, projects, professionals, audiences, policies and best practices. Since its foundation in 2010, on the initiative of Professor Jan G. van den Tweel (1942–2020), the European Society of Pathology (ESP) History of Pathology Working Group has grown steadily, thanks to the commitment of all its members of different ages and from different scientific fields. The main goal of the Working Group is to spread the values of historical discoveries, messages and material, which the ESP acknowledges can inspire new generations of undergraduate and postgraduate students.Anatomy and pathology museums are no exception to the gradual loss of interest in scientific museology, and, without forgetting their conservative priorities, it is mandatory to keep in step with the times if they are to maintain their original didactic role . During European Pathology Museum Network would promote the study, access and divulgation of historical collections. The ESP History of Pathology Working Group has endeavoured to produce a comprehensive picture of the many facets  of European pathology museums.Preservation of specimens and facilities is neither easy nor costless and calls for patronage. The development of a Twenty-seven members of the ESP History of Pathology Working Group, from 14 countries, participated in the study Fig. . The onlThe vast majority of respondents are affiliated to academic institutions with the exception of one independent collection centre. Approximately 30% of pathology museums do not have dedicated employees. If they do, staff consists of one or two persons in 50% of cases and three or more in 23%.For hundreds of years, educational and training programmes developed in pathology museums have been milestones along the path to becoming a physician. It was during the sixteenth and seventeenth centuries that specific spaces, housing anatomical and pathological specimens were instituted with the aim of teaching medical students . Patholo“He who attempts to teach anatomy without a museum”, stated the Scottish anatomist Frederick Knox 1794–1873), “strictly deserves the name of impostor” , “strict. The relWith the use of the microscope for scientific purposes in the first decades of the nineteenth century, histopathology emerged as a new medical field and became the prerogative of pathologists . PatholoMuseum collections encompass wet/dry specimens and artificial models in various proportions, with the former being more frequent Fig. . The majAnatomical and pathological specimens are usually preserved in formalin-based solution in fully labelled glass jars. Before adequate fixation techniques were available, the difficulties in conserving pathological material prompted the decision to set up duplicates in order to instruct young doctors without resorting to corpse dissection. Among the various materials by which models are made, wax takes pride of place. Wax models portraying normal and pathological anatomy are often hidden gems in scientific museums. The development of pathology as a scientific discipline was an important prerequisite to the art of moulaging , 10. DurClinical histories and autopsy records are invaluable resources for scientific investigation into museum collections. Contextualisation of the medical knowledge of the time, enriched with fragments from the personal stories of patients, unveils the cultural value of these specimens. A detailed catalogue helps achieve the educational purpose of a collection, providing evidence of which organ systems and diseases are on display . WithoutPublic access is allowed in 48% of pathology museums. In approximately one third of these cases, stored collections are part of normal displays, with the remainder preferring to design museum experience as pre-booked visits (47%) and advertised events (13%), or having a specific workspace for the purpose (7%). The majority of institutions (54%) do not register the number of visitors. “Word of mouth” (53%) is the main means of communication regarding contents of the collections, while written/e-mail/telephone enquiries are the rule in 30%. A few museums rely on Internet resources (4%), and 13% hold a hard copy catalogue. Collections are listed online only in 12% of cases.Multimedia and information technology has dominated medical education over recent years. Virtual microscopy courses and technically elaborated learning tools are in easy reach of pathologists and their students. Digitisation presents a great opportunity for scientific museums, providing access to materials via the web, minimizing damage to original items, increasing interest in these institutions and ensuring maximum public access to their collections , 12. IndApproximately 60% of institutions plan to implement collection information online, and a higher proportion of responders (86%) aim to increase use of collections. In particular, strategies to improve the use of collections include establishing a collection centre (38%), allowing open storage (29%), scheduling regular tours (15%) and organising more displays (18%). Unfortunately, the general feeling is that innovation is hampered by limited financial resources (25%), staff shortages (25%) and lack of space (18%).Due to difficulty in sourcing new samples to museum exhibits, there has been no increase in many collections, whose integrity is threatened by the inherent fragility of anatomical preparations , 14. CurAntique anatomical collections allow the study of disease aetiology and pathomorphosis in relation to the profound changes in socio-economic conditions of resident populations over the centuries. Most preparations date back to the pre-industrial or pre-antibiotic era, and it is now common knowledge that genome-environment interactions play a crucial role in human carcinogenesis. Molecular investigations on ancient tumours can help shed light on the history of cancer and the relationships between genetic alterations, lifestyle and environmental risk factors . PatholoManagement, custody and display of human remains entail a vast amount of responsibility regarding several ethical and legal issues. Historical museum exhibitions may reflect the attitude of Western Countries prior to the recognition of human rights and respect for other cultures . Far froPathology museums hold materials unique in displaying anatomy and disease in three dimensions. They generally encompass different types of collections, each integral to the other in outlining a cognitive path. This body of evidence, re-interpreted on the basis of current medical practice and implemented by radiological, histological and biomolecular data, allows a more accurate diagnostic definition of antique anatomical preparations and the assessment of new museological strategies.Promotion of these institutions relies on standardised approaches of conservation and cataloguing, but introduction of multimedia and interactive systems is equally essential. Permanent digital archives of anatomical collections should be created, thereby facilitating research and cooperation networking. Cultural heritage is the legacy that we attain from the past, experience in the present, and convey to future generations.


Morphological study is a common approach in the field of anterior disc displacement (ADD) pathology; however, analysis based on three-dimensional reconstructive imaging has not been investigated. This study investigated the association between ADD and the status of the mandibular condyle and articular fossa.Thirty-four patients were divided into three groups: normal articular disc position (NADP), anterior disc displacement with reduction (ADDwR), and anterior disc displacement without reduction (ADDwoR). Multiple grouped comparisons of three different disc statuses were performed by Kruskal–Wallis H test and variance analysis respectively. Receiver-operating characteristic curve was plotted to assess the diagnostic efficacy of the morphological parameters. Multivariate logistic regression analysis was used to investigate the interfering factors of ADD.P < 0.05). Both CV and superior joint space (SJS) presented a good diagnostic accuracy for NADP-ADDwoR , and ADDwR-ADDwoR . CSA presented a good diagnostic accuracy for ADDwR-ADDwoR (AUC = 0.813). A multivariate logistic ordinal regression model showed that the CV , SJS , and medial joint space (MJS)  had a significantly impact on the groups.The condylar volume (CV) and condylar superficial area (CSA) in the NADP, ADDwR, and ADDwoR groups exhibited obvious changes (CV, CSA, SJS, and MJS were significantly associated with the different disc status, and the condyle in ADD exhibited 3-dimensionally altered dimensions. They could be considered as promising biometric markers to assess the ADD.The online version contains supplementary material available at 10.1186/s12903-022-02438-1. Temporomandibular joint disorders (TMD) comprise several oral and maxillofacial diseases and frequently occur in young and middle-aged individuals. TMD affects up to 15% of adults, with a peak incidence at 20–40 years of age –5.The temporomandibular joint (TMJ) comprises soft tissue  and the osseous structure; because of its complex anatomy and biomechanics, it is susceptible to pathological changes . The artThe purpose of this imaging study was to quantitatively evaluate changes in the morphology and inclination of the mandibular condyle among different position of the articular disc, as well as analyzing the influential factors of changes in disc status, to achieve more insights into the natural course of ADD of the TMJ. The hypothesis proposed herein refers to that the alterations of mandibular condyle may dictate the risk level for disc displacement.To address the research purpose, the investigators designed and implemented a cross-sectional retrospective study. The study population was composed of all patients presenting for evaluation and management of TMJ ADD recruiting from the Temporomandibular Joint Specialist Clinic, The First Affiliated Hospital of Xinjiang Medical University, China, between March 2018 and May 2021. The study protocol was approved by the Ethics Committee of the Stomatological School of Xinjiang Medical University, The First Affiliated Hospital of Xinjiang Medical University  and followed the principles outlined in the Declaration of Helsinki. Informed consent was provided by all families. All data generated or analyzed during this study are included in this published article.Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD)  = 0.011; 92 were r, SJS (ORAs a crucial aspect of biomechanical research, morphological analyses have been widely used in clinical research because their intuitive understanding of the structural characteristics and simple method of obtaining data. The morphological study of TMJ has important application value in the field of TMD pathology ; howeverBefore performing the biometric process, we examined and distinguished the resting-state functional MR images of the temporomandibular disc position to create precise subgroups. Our study showed that both the CV and CSA dimensions diminished from NADP to ADD without reduction, which explained that the abnormal position of the temporomandibular disc was in line with the degenerative alteration of the condyle. Insufficient CV can lead to anomalies of the relative position between the condyle and articular disc, which will lead to TMJ ADD and is consistent with the clinical symptoms of TMJ internal derangement. Additionally, the condylar alteration could cause ADD and other degenerative TMJ diseases , 35, 36,The available scientific literature regarding measuring the glenoid fossa is nonexistent. However, we were able to accurately determine the fossa-related parameters. In contrast to the CV and CSA, the FV and FSA were lower in the ADD with reduction group than in the NADP group but higher in the ADD without reduction group. We considered that fossa attrition occurred with ADD with reduction because of the anomalous dynamic relationship among the condyle, disc, and fossa; however, the fossa might experience progressively compensatory growth during the transition from ADD with reduction to ADD without reduction. Although this was not statistically significant, this “irregularity” was still embodied by the objective values. The CV% and CSA% both increased gradually during the transformation from NADP to ADD with reduction to ADD without reduction, which explained how the displaced disc pushed the condyle to the articular fossa. Furthermore, during the early stage of the lesion, the temporomandibular disc is not completely deformed, and its location is in front of the condyloid process, pushing on the condyloid process with more force. The more obvious the pushing effect, the greater the proportion of condyle in the fossa. Correspondently, temporomandibular disc displacement involves the limited ability to open the mouth with ADD with reduction and with ADD without reduction in clinical practice.The variations of all linear dimensions aligned closely with the TMJ ADD status. With progression from NADP to ADD with reduction to ADD without reduction, the displaced articular disc continuously pushes the condyloid process to the glenoid fossa, so the SJS is reduced incrementally. Furthermore, with the biofunction of the lateral pterygoid muscle, it is capable of pulling the articular disc inward and forward; therefore, the MJS with ADD with reduction was smaller than that with NADP. However, when the disc was irreversibly distorted, it could rotate medially, resulting in an increased MJS with ADD without reduction, which could be discovered by MRI. Because the mouth-opening status changes with progression from NADP to ADD with reduction to ADD without reduction, the disc should be placed in front of the condyle, resulting in limited mouth-opening ability, so the AJS is widened and the PJS is narrowed; nevertheless, when the limitation disappears during the later stage, the disc should be located in the neck of the condyle to create changes in the AJS and PJS.The ROC analysis demonstrated that the CV and SJS could detect the morphological changes of the condyloid process during the progression from ADD with reduction and ADD without reduction and distinguish ADD from NADP. Additionally, the CSA can precisely assess the condyle size occurring with ADD with reduction, thereby distinguishing ADD with reduction from ADD without reduction. Therefore, the CV, CSA and SJS could be considered effective and persuasive biometric markers when evaluating the osseous structure of the TMJ in patients with ADD without reduction. Most importantly, a mathematical model was generated for the first time for TMJ ADD prediction. The CV, SJS, and MJS had a significantly positive influence on the groups. Further calibration curves and nomograms could be applied to assess the agreement of the nomogram-predicted probability with the actual observed probability during future multicenter studies including a larger sample size.Because our sample size was small, our findings should be verified by studies involving larger sample sizes and other morphological parameters. Furthermore, another limitation of the present investigation include the restricted population in the 3 groups, lack of sex and age matching, the potential association between these parameters of ADD and different age and sex distributions should be clarified. In addition, the sample size of men was smaller than that of women, reflecting the lower prevalence of TMJ ADD in men . LongituDuring this study, for the first time, we analyzed the effects of TMJ ADD on the biometric dimensions of the osseous structure by applying 3D stereoscopic models reconstructed based on the combination of MRI and CBCT. The CV, CSA, SJS, and MJS may be associated with the different disc displacement types, and the condyle in TMJ ADD exhibited altered dimensions. Therefore, they could be considered promising biometric markers for assessing the ADD status. This nomogram prediction model will help enable early diagnosis of TMJ ADD.Additional file 1: Table S1. Conditions that may mimic temporomandibular disc displacement without reduction.


Frequent outbreaks of cyanobacterial blooms have become one of the most challenging water ecosystem issues and a critical concern in environmental protection. To overcome the poor stability of traditional detection algorithms, this paper proposes a method for detecting cyanobacterial blooms based on a deep-learning algorithm. An improved vegetation-index method based on a multispectral image taken by an Unmanned Aerial Vehicle (UAV) was adopted to extract inconspicuous spectral features of cyanobacterial blooms. To enhance the recognition accuracy of cyanobacterial blooms in complex scenes with noise such as reflections and shadows, an improved transformer model based on a feature-enhancement module and pixel-correction fusion was employed. The algorithm proposed in this paper was implemented in several rivers in China, achieving a detection accuracy of cyanobacterial blooms of more than 85%. The estimate of the proportion of the algae bloom contamination area and the severity of pollution were basically accurate. This paper can lay a foundation for ecological and environmental departments for the effective prevention and control of cyanobacterial blooms. Water is the source of life and an important resource for the survival and development of human beings. However, with increasing human activities and climatic changes, water resources have experienced unprecedented threats, including nutrient enrichment, and inorganic and organic pollution . Water eCurrently, routine methods for analyzing cyanobacterial blooms have been widely applied through field sampling and laboratory analysis . HoweverHowever, the above applications of vegetation index are all performed with the help of satellite image data, which require a long acquisition period and are inadequate in monitoring low-concentration algal bloom areas in real time. Small UAV remote-sensing technology, which has the advantages of low cost, low risk, high timeliness, and high resolution, is widely used in various scenarios and has become a research hotspot in recent years ,21,22. IIn addition, due to the influence of reflections, shadows, and floating objects on the river surface, the detection thresholds of cyanobacterial blooms in different channels are not consistent. Obviously, only using a vegetation index to quantify cyanobacterial blooms is not effective enough, and a more robust algorithm is needed to assist in the detection of cyanobacterial blooms. Deep learning is a powerful and adaptive learning method that can classify or predict non-linear data accurately under complex conditions, which makes it a promising tool in performing image-level semantic segmentation of cyanobacterial blooms. Here, semantic segmentation is necessary and advantageous because of the irregular shape of cyanobacterial blooms. Jonathan et al.  from theIt is worth noting that few previous studies have paid attention to the phenomenon in which the boundary classifications of cyanobacterial blooms and other objects often give incorrect results. Among the many deep-learning algorithms, the transformer model has a strong model generalization ability. It has a flexible structure and makes essentially no assumptions about the structural errors in the input data, and can be pre-trained to handle large amounts of unlabeled data. More importantly, the attention mechanism will make the semantic association between adjacent pixels better . TherefoIn this paper, a multispectral detection model for cyanobacterial blooms based on a transformer network is proposed. The spectral features of the multispectral data of cyanobacterial blooms captured by UAV were extracted using an improved vegetation-index method. To classify the feature boundary, feature-enhancement and region-correction modules were added to the original transformer model. The proposed method not only improved the accuracy of detection of cyanobacterial blooms, but also allowed for assessment of the extent of cyanobacterial-bloom pollution and its proportion out of the total size. The results of this study can provide a reference for the control of cyanobacterial blooms in the fields of ecology and the environment.Data were collected using Phantom 4 multispectral version of the UAV made by DJI. The UAV carries a high-resolution multispectral lens and has six camera sensors, including one color sensor for visible imaging and five monochrome sensors for multispectral imaging in the blue band (B1), green band (B2), red band (B3), red edge-band (B4) and near-infrared band (B5). Healthy and flourishing plants were more reflective in these bands; thus, they can be used to detect cyanobacterial blooms.The experimental data in this paper were collected from August to October 2021 in several areas of China with severe cyanobacterial blooms, covering many rivers and lakes in Kunming, Yunnan Province; Suzhou, Jiangsu Province; and Huzhou, Zhejiang Province. The data also covered a wide range of weather conditions and external-disturbance scenarios. The dataset included 5400 images and 10 videos, as shown in In this paper, a cyanobacterial-bloom detection algorithm based on deep learning is proposed. The major steps involved image pre-processing, multi-spectral feature extraction and detection model construction, as shown in Due to the influence of various environmental factors, multi-dimensional random noise, which interfered with the feature extraction of cyanobacterial blooms, existed in the obtained multi-spectral image data. Aimed at noises of different sizes and shapes in the images, adaptive median filtering was used to improve signal-to-noise ratio. Then, aimed at the small area of bright light spots in the image, a light mask was used to reduce the influence of bright light on the extraction of effective information.As multispectral images involve multi-band spectral data, traditional vegetation indices are difficult to apply to feature extraction for all types of data. Therefore, deep-learning methods are introduced to extract data features based on pre-designed rules.In view of the multispectral images collected in this paper, a vegetation-index method based on the fusion of improved band features and details was proposed. In order to better explore the differences in the reflectance of different features, multispectral images with rich information in the dataset were selected to count the image element values of cyanobacterial blooms, clean water bodies, floating vegetation, surface litter, boats and other materials in each waveband. Since the pixel values of cyanobacterial blooms and other interfering objects basically did not overlap in B1, B3 and B5, the multispectral feature-extraction method was verified based on the reflectivity of these three bands. NDVI is calculated based on the reflectance of B3 and B5 and is often used to detect vegetation growth and vegetation cover. The formula is shown in Equation (1):As cyanobacterial blooms vary in size and shape and are mostly irregularly distributed, it is easy to miss some important image details during feature learning and misclassify pixel points at the junction of different objects or in some boundary areas. Therefore, on the basis of the improved vegetation index, this paper proposed an improved transformer model based on feature enhancement and region correction, achieving the following two improvements to robustly detect cyanobacterial blooms.(1)Feature-Enhancement ModuleIn the data processing stage, the improved vegetation index was used to calculate the Boundary classification can mainly be achieved in two ways: one is to directly transfer the feature mapping of the shallow network in the model to the corresponding deep network, which is continuously transferred and superimposed; the other is to pool and convolve a certain network layer in the network structure for calculation. Both of the above methods are able to retain small amounts of spatial information, but the former greatly increases the computational load of the model, while the latter cannot guarantee the balance of the shallow-feature and deep-feature information to a certain extent. Aimed at these shortcomings, this paper designed a new feature-enhanced network architecture unit.The design structure of the feature-enhancement module is shown in For a given multispectral feature image matrix, this feature-enhancement module performed several convolution calculations for different purposes to obtain rich, shallow and deep image features, respectively. The feature information was balanced to obtain multi-scale feature mapping, which not only helped to avoid feature loss caused by increased layers in the traditional deep-learning model, but also improved the convergence rate of training and obtained more comprehensive and rich multispectral image information.(2)Region Correction ModulePixel similarity is scored based on the similarity of information content between images, and the number of scores is used to determine the similarity of image information content, which is also used for image semantic segmentation. Ahn et al.  proposedGiven a multispectral image, the corresponding Vector Class Activation Map (CAM) was calculated. The calculation method of the target class CAM is as in Equation (3) :(3)Mc refers to the ratio of the number of pixels whose categories are correctly predicted by the algorithm to the total number of pixels, which can be understood as the percentage of correctly classified pixels. It is the most common and intuitive evaluation index in image segmentation [TP, FP, FN and TN represent true positive, false positive, false negative and true negative cases, respectively. However, PA cannot determine whether the predicted cyanobacterial blooms are correctly located and may misclassify pixel points, not serving as a good indicator of the results in the case of unbalanced samples. Therefore, PA alone does not provide an accurate measure of algorithm performance. Intersection over Union (IoU) refers to the ratio of the intersection and union of the model’s prediction result and the true value for a certain category. It is a standard performance measure for object category segmentation problems [Pixel Accuracy :In the detection of cyanobacterial blooms, the diversity of the river and lake environment—as evidenced by distracting factors such as birds, boats, reflections and shadows on the surface of the water body—can, to some extent, affect the detection accuracy of the algorithm; this makes the detection of cyanobacterial blooms very difficult. For different scenes, we compared the feature extraction effects before and after the improved vegetation-index method, and input the different features extracted into the same transformer model to analyze and compare the model output results.sqrt as the input of the transformer model. There is still a small amount of misclassification at the riverbank boundary, but the model has enhanced the learning of the spectral features of cyanobacterial blooms. It can be seen intuitively that compared with NDVI, NDVIsqrt identifies cyanobacterial blooms at low concentrations or in the early stages of growth. Provably, NDVIsqrt can improve detection accuracy by extracting cyanobacterial spectral features that are weaker and more difficult to identify.sqrt was able to extract more accurate spectral features, coupled with the stronger learning ability of the attention mechanism. High-precision detection of cyanobacterial blooms can still be achieved, even under strong light conditions.sqrt was able to practice efficient retrieval, even when covered.sqrt was proven to extract features, so it was applied in subsequent deep-learning models.A comparison of the detection performance of several feature-extraction methods for cyanobacterial blooms in different test scenarios is shown in sqrt has great application value in practical scenarios.Among the more typical river channels tested, we studied the Daqing River and the Haigeng Park river channel; these are more complex river scenarios, with interference from boats, birds and litter on the river surface, in addition to strong light and reflections. A comparison of the detection performance of several feature-extraction methods for cyanobacterial blooms in different typical river channels is shown in To further verify the effectiveness of the improved transformer model, we used the improved vegetation index for feature extraction and compared the detection results of the improved transformer model with those of FCN and SegNet.Both PA and IoU were still used here to quantitatively evaluate the detection performance of several image-segmentation algorithms. The comparison of the detection performance of cyanobacterial blooms in different test scenarios is shown in According to the quantitative assessment method of algal blooms in the Technical Specification for Remote Sensing and Ground Monitoring and Evaluation of Algal Blooms promulgated by the Ministry of Ecology and Environment of China in 2020 , this paIn this paper, we used DJI SmartMap software to stitch together the Daqing River, Xujiang River, Jinji Lake and Baoxiang River to estimate the proportion, and judged the pollution level of cyanobacterial blooms. Taking the Daqing River as an example for demonstration, As can be seen from The conventional method of field sampling combined with laboratory analysis has insufficient capabilities for detecting cyanobacterial blooms in large-scale river channels. Owing to the influence of cloud cover, effective data for lakes and rivers from remote-sensing satellites are limited, and it is impossible to accurately monitor cyanobacterial blooms in small rivers in real time. However, low-altitude imaging remote-sensing technology can flexibly acquire multi-scene data according to demand. This technology does not require atmospheric correction of image data, but it will certainly magnify spatial interference such as shadows, lighting, and floating objects from sky light and the water’s surface, so certain preprocessing work is required. Low-altitude remote-sensing technology also makes it possible to monitor daily changes in cyanobacterial blooms, which can provide more real-time information for early warnings and salvage treatments of cyanobacterial blooms.sqrt has an accuracy of more than 85%, which is 5% higher than the 79.60% of the reference [The spectral characteristics of water bodies are determined by the absorption and scattering properties of optical radiation. The chlorophyll content in water increases rapidly, resulting in changes in its spectral characteristics when cyanobacterial blooms occur. The absorption peaks and reflection peaks of different wavelength bands of reflection spectral characteristics are different, so the vegetation-index method aims to judge the cyanobacterial blooms and distinguish other objects by calculating the reflectivity matrix of specific bands. Some research groups have reported improved vegetation indices and applied them to different river scenarios ,17,18,19eference . CompareDeep learning is a powerfully adaptive method with many achievements in image classification. It is necessary to introduce semantic segmentation for cyanobacterial-bloom detection, because cyanobacterial blooms are mostly granular, appearing as flocculent suspended matter, and the distribution shape is irregular. The detection accuracy of reference  is 93.68As shown in This work introduced a multispectral detection model for cyanobacterial blooms based on deep learning. Images were preprocessed with adaptive median filtering and light masks. The traditional vegetation-index method was improved to extract the multispectral features of cyanobacterial blooms, and then the transformer neural network was used for the first time to perform pixel-level semantic recognition of cyanobacterial blooms. Finally, the algorithm was applied to multiple rivers to accurately evaluate their pollution area and pollution levels. This method not only greatly reduced the sampling time, but also improved the accuracy and efficiency of the cyanobacterial-bloom detection algorithm, providing the possibility for online monitoring of cyanobacterial blooms. The research results of this paper contribute to the fields of water-quality anomaly detection, remote-sensing technology and deep learning. On the one hand, the improved vegetation index showed a better feature extraction effect than other indices in the dataset of this paper, and may expand the applicability of vegetation indices in the field of low-level multispectral cyanobacterial-bloom monitoring. On the other hand, the transformer neural network was first applied in the detection of cyanobacterial blooms, and showed good results when modifying the corresponding network structure. The work of this paper has certain enlightenment significance for the application of the transformer model in the multispectral detection of cyanobacterial blooms, and provids strong support for the application of neural networks in the field of environmental monitoring.For future work, research on preprocessing methods can be introduced to eliminate insignificant environmental interference before feature extraction. In addition, higher sampling frequency may reveal the trends of cyanobacterial blooms, and a corresponding early-warning model, with the help of time series analysis, is recommended to develop a method of predicting future growth trends of cyanobacterial blooms; this is significant for early warnings and the rapid treatment of cyanobacterial blooms.