Adventitial cystic disease (ACD) of the radial artery is a rare condition, with few cases described in the literature. We report the case of a 62-year-old white male with a history of diabetes, hypertension, and chronic kidney disease with indications for renal replacement therapy who was found to have a cystic lesion of the radial artery while undergoing surgical creation of an arteriovenous fistula. The surgical technique adopted was resection of the cystic segment and preservation of the radial artery. Fistula creation was completed successfully. Early diagnosis and appropriate treatment of ACD are effective, and can prevent complications and recurrence.  Adventitial cystic disease (ACD) is a rare, non-atherosclerotic arteriopathy, predominantly involving vessels of the lower extremity, of which the popliteal artery is most commonly affected.  It is more common in men, with a 5:1 male-to-female ratio. Since ACD was first described in 1947, our understanding of this disease has largely been based on individual case reports and literature reviews. The overall prevalence of this arteriopathy remains unknown; an estimated 500 cases have been reported.  ACD is characterized by a buildup of mucinous or gelatinous matter in the adventitial layer of the vessel wall. Its etiology remains controversial. Trauma, associated systemic processes, or development of mucin-secreting cells within the adventitia have all been proposed as hypotheses; more recently, evidence has arisen in support of the synovial theory. ,, Patients with ACD of the radial artery may present with a pulsatile mass, though symptoms of luminal narrowing or occlusion may emerge due to compression of the involved artery. Pain, weakness, paresthesias, and even ischemia of the hand have been reported.  Several different treatment options have been described, such as resection of the compromised cystic segment, percutaneous cyst aspiration, resection and reconstruction of the affected artery segment, and endovascular treatment.  Written informed consent was obtained from the patient for publication of this case report and the accompanying images.  A 62-year-old white male with a history of diabetes, hypertension, and chronic kidney disease with indications for renal replacement therapy presented for surgical creation of an arteriovenous fistula for hemodialysis. After assessment by the Vascular Surgery team, a radiocephalic arteriovenous fistula in the left upper extremity was deemed most appropriate.  During surgical creation of the fistula in the left wrist, dissection of the radial artery revealed a large cystic formation enmeshed in the vessel, with no clear borders between the cyst and artery   , but wi Gross pathological examination of the surgical specimen revealed a viscous substance within the cystic mass. Histopathological analysis confirmed the presence of a cystic lesion of the arterial wall   . The pa The first case of ACD was reported in 1947, involving the external iliac artery. ,,,- The etiology of ACD is highly controversial and remains open to debate. Proposed theories include: (A) Repetitive trauma leading to cystic degeneration. This theory is contested because most patients with the condition have no history of trauma;  Torres-Blanco et al. reported a case of radial artery ACD in which a pedicle was found passing through the superficial palmar branch of the radial artery and connecting to the wrist joint, thus providing additional evidence in favor of the synovial hypothesis. , As ACD is considered a rare disease entity, there are no guidelines for its management. Several options have been proposed, including nonsurgical management, cyst aspiration (percutaneous or open), angioplasty, or surgical treatment. Surgical options include incision and decompression, isolated cyst resection, venous or synthetic patch repair, or venous or synthetic graft reconstruction.  Motaganahalli et al. retrospectively analyzed 10 years of information from a standardized database covering 14 facilities, in the largest-ever published series of ACD cases. Of the 47 patients assessed, only three (6.38%) had ACD of the radial artery. The authors concluded that, among the currently available treatment options, cyst resection and graft reconstruction is associated with the highest likelihood of symptom resolution and a low rate of reintervention due to cyst recurrence.  In the case described herein, ACD of the radial artery was diagnosed during surgical creation of an AV fistula for hemodialysis. As the artery had to be preserved for the fistula, the decision was made to simply resect the cystic segment, thus allowing completion of the surgical procedure originally planned.  Adventitial cystic disease of the radial artery is quite an unusual entity. Detection of a pulsatile mass in the anatomical course of this artery should raise clinical suspicion of ACD. Although its etiology remains controversial, early diagnosis and appropriate treatment of ACD are effective, and can prevent complications and recurrence.


Compared with two-dimensional cultures, the three-dimensional structure of organoids provides a more realistic environment and structural organization of in vivo organs. Similarly, organoids are better suited to reproduce signaling pathway dynamics in vitro, due to a more realistic physiological environment. As such, organoids are a valuable tool to explore the dynamics of organogenesis and offer routes to personalized preclinical trials of cancer progression, invasion, and drug response. Complementary to experiments, mathematical and computational models are valuable instruments in the description of spatiotemporal dynamics of organoids. Simulations of mathematical models allow the study of multiscale dynamics of organoids, at both the intracellular and intercellular levels. Mathematical models also enable us to understand the underlying mechanisms responsible for phenotypic variation and the response to external stimulation in a cost- and time-effective manner. Many recent studies have developed laboratory protocols to grow organoids resembling different organs such as the intestine, brain, liver, pancreas, and mammary glands. However, the development of mathematical models specific to organoids remains comparatively underdeveloped. Here, we review the mathematical and computational approaches proposed so far to describe and predict organoid dynamics, reporting the simulation frameworks used and the models’ strengths and limitations.Organoids are engineered three-dimensional tissue cultures derived from stem cells and capable of self-renewal and self-organization into a variety of progenitors and differentiated cell types. An organoid resembles the cellular structure of an organ and retains some of its functionality, while still being amenable to  Diverse culture systems have been developed to reproduce models of a gastrulating embryo . These bin vivo counterparts.All the mathematical models described above have contributed to a deeper quantitative understanding of intrinsic mechanisms that take place during the development and maintenance of organoids. These findings can be also translated into a better comprehension of the events that occur in their Nonetheless, there are limitations that need to be considered. The majority of intestinal and optic-cup organoid models discussed in this review are agent-based models. These formalisms simulate the properties and behavior of individual cells (agents) and the interactions among agents and the environment and can aid in the understanding of cell–cell interactions, cell–media interactions, and macro-level effects such as growth size and structure. One advantage of these types of models is that they allow the agents to make decisions according to a set of rules and provide realistic heterogeneous patterns, which can be valuable in the study of organoid phenotypes. However, they require significant computation power as compared with aggregate or equation-based models; for instance, the model generated by On the other hand, models developed to date for cerebral organoids and gastruloids are aggregate equation-based models , without focusing on individual-cell properties. These models are designed to analyze homogenous populations and tend to be easier to develop, fit, and implement, and faster to simulate. However, these formalisms are not easily able to account for spatially complex dynamics or heterogeneity. There are important experimental aspects of organoid cultures that determine the accuracy and required complexity of the corresponding computational models. For instance, self-organizing systems develop their own endogenous interactions according to the signals received between the elements that constitute the system. This results in heterogeneity in viability, size, and shape of organoids. It is important to understand the rules that govern the self-organization and self-assembly of the cells to improve the accuracy of mathematical models. The agent-based models described here take into account general organoid characteristics as diameter, cell turnover, spatial cell distribution, and growth curves to obtain the necessary parameter values for their simulations. Nonetheless, reliable fits of agent-based organoid models require more detailed information than equation-based models. For example, details of the biomechanics of different cell types can address the suggestion made by some intestinal organoid models about the link between cell biomechanics and growth phenotypes. Furthermore, as mentioned in It is worth mentioning that there is another important classification of organoids called tumor organoids. Tumor organoids are cancer-cell-derived organoids that provide a potentially useful tool in the understanding of tumor morphology and gene mutations and in the research of targeted tumor treatment responses. There are many experimental studies capable of biologically modeling the main features of primary tumors in 3D . The curAlthough there are relatively few mathematical and computational models of organoid systems, it is essential to mention that many other models have been generated for similar or more general systems, which could be modified to represent organoid models. For example, Okuda et al. created 3D computational models that recapitulate general properties of cellular tissue before developing a model focused on the formation of optic-cup organoids. One such model explored the effect of apoptosis in morphogenesis . More reIn conclusion, mathematical and computational models are valuable to understand and explore the intrinsic mechanisms of organoids. Nonetheless, the production of these models is not an easy task and requires the participation of multidisciplinary teams. An all-round model for every organoid type does not currently exist and will be difficult to generate due to all the different cell fates, signaling pathways, and specific self-organization and self-assembly characteristics. It would be worthwhile to explore properties shared across organoid systems, integrate them into a general platform, and contribute to the creation of mathematical and computational models for other organoids, such as the liver, pancreas, and lungs, not considered so far.SM-O, LM, and MH conceived and designed the study; SM-O performed the literature review and wrote the first draft of the manuscript. All authors contributed to manuscript editing and revision and read 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.This work was funded through the UK Medical Research Council (grant MR/N021444/1 to LM) and the Mexico Consejo Nacional de Ciencia y Tecnología (CONACYT) PhD scholarship provided to SM-O.


Scanning microscopy techniques have emerged as powerful scientific tools for analysing materials of architectural or archaeological interest, since the commercialization of the first scanning electron microscopy instrumentation in the early 60s. This study is aimed at reviewing and highlighting the significance of several scanning microscopy techniques employed in the protection of built heritage. The diffusion of scanning electron microscopy with energy-dispersive X-ray spectroscopy analysis (SEM-EDX) is proven to be the widest among the available scanning microscopy techniques, while transmission electron microscopy (TEM) applications are steadily present in the field of built heritage protection. The building material characterization, the weathering mechanism investigation, and the development of compatible and performing conservation materials are some major research areas where the application of the aforementioned techniques is discussed. The range of techniques, along with aspects of instrumentation and sample preparation are, also, considered. A vast variety of building materials has been used for constructive or artistic purposes since prehistory: natural stones, earth materials, bricks, lime, and gypsum mortars prevail in the history of architecture . From thNowadays, the concept of cultural heritage preservation includes cement or modern concrete constructions, as well. In parallel, the tendency for sustainable and alternative architecture has turned the interest to the use of traditional building materials in modern constructions. The adverse environmental impact, escalated by the climatic change and anthropogenic activities, dictates the need to increase the scientific knowledge on the behaviour of both traditional-historic and contemporary building materials, in order to provide solutions. Conventional and new intervention materials and methods need to be evaluated and monitored in terms of effectiveness, reversibility (whenever applied), and compatibility. Within the above framework, the use of natural and chemical analytical methods in the field of architecture and artworks conservation, as well as in humanities, has been established as essential for unveiling the evolution of materials and techniques used by mankind throughout geographical regions and different time periods. Historic structures and their comprising materials are subjected to constant research in order to understand their behaviour and properties. This approach has, also, emerged as a necessary prerequisite in order to plan appropriate restoration and conservation strategies for the rehabilitation of historic and modern constructions.Regarding the characterization of historic materials, the analytical methodology that needs to be adopted depends on the questions that are to be answered and on the amount of sample available. The approach is differentiated per case; for example, a sample that derives from an archaeological site sets chronological and provenance issues as the primary to be addressed, while when it comes to the restoration of a historic structure, the knowledge of the authentic building materials is the base for designing compatible conservation interventions and their durability assessment.In addition, the knowledge of the technological development of building materials such as limes, concretes, mortars, metals, tiles, and glasses is of high anthropologic and historical interest, since it sheds light to the development of civilization and commerce throughout centuries, while pigments, binders, or additives identified in mortars or paintings allow the in-depth investigation of the utilized traditional and local techniques, contributing to the record of their progress.While many characterization techniques have been practised in the field of building materials, new techniques and methodologies are constantly emerging. Chemical analyses like atomic absorption spectroscopy/atomic emission spectroscopy (AAS/AES), X-ray fluorescence (XRF), inductively coupled plasma optical emission spectrometry (ICP-OES), gas chromatography (GC), mass spectrometry (MS), laser-induced breakdown spectroscopy (LIBS), high-performance liquid chromatography (HPLC), laser-induced fluorescence (LIF), particle-induced X-ray emission (PIXE), and particle-induced gamma-ray emission (PIGE) are used. However, they present significant limitations, as they are not able to detect the exact composition and structure of materials, they require a great amount of sample or complicated preparation routes, and they are time-consuming.Fourier transform infrared (FTIR) and Raman spectroscopic techniques offer the chemical characterization of small size samples, while X-ray diffraction (XRD) analysis provides the mineralogical composition of materials under examination, but all of them lack the ability to offer morphological information.Each one of the abovementioned analytical techniques may be employed in order to address special issues of cultural heritage like the identification of pigments and binding media , 5, in aIn the field of building materials characterization and especially in the field of architectural heritage, knowing at microscopic level the composition, texture, and structure of building materials has been a revolution. The classical approach in microscopy involves the use of optical and petrographic microscopy. These techniques are relatively simple and versatile tools for the textural examination and the petrographical/mineralogical composition of a range of building materials, such us stones, limes, mortars, tiles, bricks, glasses, metals, and wood. Confocal optical microscopy has, also, emerged as an in-depth morphometric tool and offers the possibility for the 3D reconstruction of the sample surface .The use of scanning microscopy techniques in the examination of historic building materials has evolved as a well-established analytical tool soon after the commercialization of the first scanning electron microscopy instrument (SEM) in the early 60s . SEM couthe lack of need for preliminary preparation and thus the nondestructive treatment of valuable specimensthe nanoscale resolution offered by modern SEM and thus the precision levelthe variation of the examined region  by adjusting the magnificationthe qualitative and quantitative analysis offered by coupling SEM with EDX microanalysisThe main advantages of the SEM-EDX analysis areTransmission electron microscopy (TEM) has, also, been introduced in the field of cultural heritage materials; the information in this case is, as well, both morphological and chemical (when combined with EDX), and the magnification level here is even to subnanometre scale. However, the small size of the analyzed area (only a few square micrometres) does not permit a broad sample examination, while sample homogeneity is required for a full-potential TEM analysis.Furthermore, another scanning microscopy technique, recently developed, is the atomic force microscopy (AFM). It was commercially introduced in 1989 and is a nanoscale technique aiming at measuring the topography of a nonconductive sample, providing 2D and 3D images. There is some work published using this technique in the field of cultural heritage, e.g., . Howeverhttps://www.elsevier.com/solutions/scopus) and Google Scholar (https://scholar.google.com). Hereby, the results obtained are presented and discussed.As already discussed, scanning and transmission electron microscope techniques have been widely applied in the characterization and in the evaluation of the performance of new and traditional methods for the preservation of monuments. In an effort to numerically evaluate how really diffused SEM and TEM techniques are in the field of architectural heritage, a bibliographic research was conducted in two of the most common search databases: Scopus , 425 commercial publications, 350 book series, Medline (full coverage), 375 million quality web pages through Scirus 17, and 24.8 million patent registrations. As stated in the guidelines, Google Scholar allows you to search through many disciplines and sources: documents approved for publication, theses, books, abstracts and articles of academic publishers, professional orders, databases of studies not yet published, universities, and other academic organizations. However, Google Scholar does not allow a selection of materials, so you only get information about the number of publications related to a given topic.The comparison among these two search engines can give some really interesting conclusions in particular on how different results can be obtained starting from the same key words. The key words used in the search were “scanning electron microscopy” AND “cultural heritage” or “transmission electron microscopy” AND “cultural heritage.” The period of time considered was between 2005 and 2018. Using the key words “scanning electron microscope” AND “cultural heritage,” the research on Scopus results in 200 documents, 20 of which as open access. The majority of these are articles in journal (82.5%), papers related to conferences (13.5%), and in minor number reviews (4%). All the documents are spread in a total number of 110 journals, including journal proceedings. Among these, the Journal of Cultural Heritage is the one with the higher number of papers on SEM applications (10 papers), followed by the Journal of the Total Environment (9 papers), Applied Physics A Materials Science and Processing (8 papers), Surface and Interface Analysis (7), and Applied Surface Science (6). The most cited paper (71 citations) focused on the deterioration due to fungal and bacterial growth of marble treated with a synthetic resin . The reshttp://www.harzing.com/pop.htm) which calculates, using Google Scholar data, citation indexes for individuals, magazines, and institutions. Applying again the key words “scanning electron microscopy” AND “cultural heritage,” PoP selects 780 publications between 2005 and 2018. The most cited paper (466 citations) is an archaeological study of 2010 published in Nature concerning the use of stone tool manufacture  lattice plane of the anatase. The SEM image of the same nanocomposite  and zosteric sodium salt (SZ), were tested and encapsulated in silica nanoparticles. Figures The comparison of the SEM and TEM images of the NC with the nanocapsules loaded with the synthesised biocides was needed to verify that the process did not promote any variations in terms of shape, but in size only. Based on the TEM-associated size distribution (shown in ), the siThe images highlight, in particular, how both samples, compared to the starting nanosilica containers, appear agglomerated probably due to the presence of organic residual. The application of SEM and TEM analytical techniques is in this case fundamental not only for the validation of the encapsulation process but also for understanding the nanocontainers' interaction with the products. In the case of biocides, the presence of the products within the containers is a crucial aspect in order to assure a controlled release of nontoxic and environmentally friendly biocides.TEM measurements have also proved extremely useful in the examination of the interface and possible reaction rims between the binder part and the aggregates of historical mortars, thus revealing their production technology and explaining their excellent properties.Pozzolanic mortars can be found in several archaeological sites and monuments, as early on as 1500 BC . In the Byzantine and Ottoman period, many monuments were constructed with the use of lime mortars with crushed brick, where the crushed brick plays the role of an artificial pozzolan. These monuments have shown excellent behaviour throughout the ages and despite negative environmental factors.Specifically, in The same gel, with a foil-like morphology, was also noticed in historical traditional brick mortars found on various monuments in the island of Rhodes , furtherThe most widely used scanning microscopy techniques in the field of the protection of built cultural heritage are scanning electron microscopy and the transmission electron microscopy.SEM-EDX applications are widespread and commonly found in the field of built heritage, and therefore, SEM-EDX can be considered a routine technique, rather than a research technique, for (a) building material characterization, (b) patina identification, (c) environmental impact assessment on building materials regarding pollution, salt crystallisation, and biodeterioration, and (d) assessment of conservation materials and treatments, such as cleaning, consolidation, and protection. The morphological, microstructural, and chemical information that can be collected and recorded by a SEM-EDX application, in combination with the little to no need of sample preparation, has established the key role of this technique in the field of built cultural heritage, where sampling is rather limited, and therefore techniques which allow approaches of diverse data are significantly valuable.TEM applications, on the other hand, are not so commonly found in the field of built heritage, mainly due to the heterogeneity that building materials present, a fact that leads to reduced applicability of this technique, without ignoring the demanding procedures of sample preparation, especially when considering that sample preparation has a great impact on the quality of TEM results. However, TEM becomes an indispensable tool in cases such as (a) the detection and examination of nanostructures in historical building materials, disclosure of their production technology and interpretation of their properties, and (b) the development evaluation of cutting-edge nanomaterials, specially designed for the conservation of built heritage.Technological advances will further evolve the capabilities and the applicability not only of the two aforementioned techniques but also of other scanning microscopy techniques, in material science, contributing to the application of improved methodological approaches for the sustainable protection of built cultural heritage.


The adult subventricular zone (SVZ) of the mammalian brain contains neural progenitor cells (NPCs) that continuously produce neuroblasts throughout life. These neuroblasts migrate towards the olfactory bulb where they differentiate into local interneurons. The neurogenic niche of the SVZ includes, in addition to NPCs and neuroblasts, astrocytes, ependymal cells, blood vessels and the molecules released by these cell types. In the last few years, microglial cells have also been included as a key component of the SVZ neurogenic niche. Microglia in the SVZ display unique phenotypic features, and are more densely populated and activated than in non-neurogenic regions. In this article we will review literature reporting microglia-NPC interactions in the SVZ and the role of this bilateral communication in microglial function and in NPC biology. This interaction can take place through the release of soluble factors, extracellular vesicles or gap junctional communication. In addition, as NPCs are used for cell replacement therapies, they can establish therapeutically relevant crosstalks with host microglia which will also be summarized throughout the article. They comprise a population of about 5%–20% of glial cells, from which they differ, among other properties, in their embryonic origin. While macroglial cells derive from the ectoderm, microglia derive from myeloid progenitors in the yolk sac that invade the CNS during development  and the dentate gyrus of the hippocampus, display special features with respect to microglial cells of non-neurogenic niches. First, microglia are more densely populated in these two neurogenic regions  and contains neural stem cells which are known as type B cells , Cx45 and Cx26  is the most common and malignant tumor of the CNS. The cellular origin of these tumors remains unknown. While earlier data proposed that GBM originate from normal glial cells, recent research has shown that they may arise from neural stem cells located in the SVZ (reviewed in Capdevila et al., Microglia/macrophage are able to infiltrate in the tumor mass in response to chemoattractive cytokines released by the tumor, such as colony-stimulating factor (Imai and Kohsaka, Indeed, infiltrated microglia/macrophages enhance GBM cells’ invasion by degrading the extracellular matrix (Markovic et al., Recent reports have shown that one of the mechanisms by which the tumor cells manipulate microglia to instruct a tumor-supportive phenotype is through the release of extracellular vesicles containing specific miRNAs, mRNAs and encoded proteins (de Vrij et al., NPCs proliferate and differentiate depending on the composition of the cellular and molecular niche in which they are immersed. Microglia, as cellular components of the SVZ niche, can be a source of molecules that modulate the cell cycle and fate of adjacent NPCs. Microglial activation status in turn depends on factors released by NPCs and by other cell components of the niche, and varies with age and with pathology. NPCs and microglia establish a bilateral dialog in the SVZ, through paracrine-, gap junctional- and extracellular vesicles-mediated communication. This crosstalk seems to be essential for maintaining a precise control of neurogenesis in healthy and in pathological conditions. Interactions taking place between grafted NPCs and microglia from the host also play a role in shaping the host microenvironment to reduce tissue damage and/or enhance endogenous repair mechanisms. Glioma-initiating cells of GBMs, which resemble NPCs of the SVZ, and surrounding microglia, also establish a complex dialog by which microglia infiltrate into the tumor and support its growth. The analysis of possible differences in the bilateral communication between NPCs-microglia in the SVZ, that instructs microglia towards an adequate tuning of the neurogenic process, and GBM-microglia, that instructs microglia towards a tumor-supportive phenotype, could provide important cues on the mechanisms of control of stem cell proliferation and survival.EM, RT and AP designed the structure of the review, wrote the manuscript and edited the figures.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer, HA and the handling Editor declared their shared affiliation at the time of the review.


Sepsis remains a major therapeutic challenge and is associated with a high rate of morbidity and mortality. It is a dynamic condition in which multiple parameters change over time, rendering it difficult to overcome the various injurious responses, which worsen the prognosis in these patients. The prognosis of sepsis is associated with a disbalance of compensatory responses to infectious triggers, part of which can be deleterious. Marked inter- and intra-patient variability characterizes the mechanisms that underlie sepsis progression and determine the response to therapy. In this paper, we review some of the data on the use of chronopharmacological approaches for the treatment of patients with sepsis and discuss the role of the autonomic nervous system in the mechanisms associated with immune response and chronotherapy in these patients. We describe the implementation of an individualized platform that is based on the personalized autonomic nervous system, immune, and chronobiology-derived parameters for generating a patient-tailored therapeutic regimen. The notion of overcoming the deleterious compensatory response in a highly dynamic system in sepsis is presented to ensure an improved response to current therapies. Sepsis is a life-threatening condition caused by a dysregulated host response to infections and is a leading cause of mortality worldwide . It is aIn this article, we review some data on the use of chronopharmacological approaches for the treatment of patients with sepsis and describe the establishment of a personalized quantified signature and chronobiology-based platform as a mean of improving the response to therapies in patients with sepsis.The prognosis of sepsis is determined by a balance between the pro- and anti-inflammatory responses. During sepsis, infectious insults lead to the activation of the innate immune system, and alteration of macrophages, lymphocytes, platelets, and complement system function. These are associated with the release of pro-inflammatory mediators, which assist in the elimination of pathogens. Further, induction of tissue regeneration may also mediate tissue damage. Local tissue injury and inflammatory responses are associated with a “spill-over” phenomenon of chemotactic mediators and pro-inflammatory cytokines that recruit monocytes, lymphocytes, and polymorphonuclear leukocytes (PMNs). These cells secrete activating vasoactive mediators, stimulate platelets and the coagulation cascade, and further increase the vascular permeability. This process leads to systemic pro-inflammatory response syndrome (SIRS). In turn, SIRS leads to a vicious cycle wherein an increase in the vascular permeability augments tissue injury . HoweverThe clinical elements suggestive of CARS include cutaneous anergy, leukopenia, and susceptibility to infections . CARS isThe balance between the opposing systemic pro- and anti-inflammatory responses (SIRS and CARS) is vital for determining the prognosis in sepsis. The two opposing processes occur simultaneously . A predoHumans have developed an endogenous timing system that optimally synchronizes the physiological processes and behavior with the environmental stimulus . The cenChronobiology or the regulation of the biological systems by the circadian rhythm is required for the proper functioning of cells and tissues . ChronobAltered circadian rhythm or chronodisruption is associated with alterations of the immune response, immunosenescence, impairment of energy metabolism, and reduction of the pineal and extra-pineal melatonin production . DiverseThe inflammatory response to various triggers also follows a circadian pattern. Cytokines and hormones secretion manifest significant diurnal variations in the plasma concentration . A day-nDisrupted circadian rhythm has been described in sepsis affecting the response to triggers including infections . CircadiReciprocal relationships between the circadian genes and the immune system have been shown. Disruption of the circadian clock genes induces pro-inflammatory mediators, which further alters the clock. Lipopolysaccharide (LPS) increases serum TNFα levels and reduces Per1 and Per2 gene expression . The corThe risk of sepsis was suggested to follow a diurnal variation . Mice deThe confinement of sepsis patients in intensive care units (ICU) imposes environmental constancy throughout the day and night leading to further chronodisruption. It is associated with sleep impairment with a pro-inflammatory trajectory . The daiImmune tolerance or “sepsis-induced immunosuppression” is typical for sepsis survivors and is characterized by a hypo-responsiveness of the immune system. This condition renders the host vulnerable to a persisting infection or the occurrence of secondary opportunistic infections leading to an increased mortality rate . Prior sMelatonin follows a stable circadian rhythm and regulates the sleep-wake cycle by interacting with the neuroendocrine and immune systems. Sepsis and drugs disrupt the circadian secretion of melatonin compromising the immune response. Impaired circadian melatonin secretion in sepsis patients led to abnormalities in the urinary level of 6-sulfatoxymelatonin (6-SMT), the major melatonin metabolite . The excVariability is inherent to all biological systems from the cellular to the whole organ levels and is a part of the function of the normal tissues ,b,c,d,e.Heart rate variability indices are divided generally to time domain, frequency domain, and non-linear measurements . Time-doHeart rate variability measures, mean RR, SDNN, HF, LF, and LF/HF are reduced among night shift workers . HealthyThe ANS may also be associated with the regulation of the immune system, and HRV has been shown as a marker of inflammation . The ANSThe utility of HRV has been also proposed in malignant diseases. A systemic meta-analysis concluded that there is a role of HRV in predicting the survival of patients with cancer . HRV corSystemic inflammation induces alterations in the sympathetic-vagal balance in the ANS. The rhythmic recruitment of leukocytes in the tissues is regulated by signals received from the sympathetic nervous system delivered by adrenergic nerves . LeukocyThe dysfunction of the ANS has been described in sepsis . Both alChanges in HRV maybe associated with impending septic shock and increased mortality in sepsis patients . A systeHowever, reduced HRV is associated with end-organ responsiveness of cardiac pacemaker cells or with their functional dynamics, rather than altered activity of the ANS. The reduction in HRV sepsis might reflect modulation of inflammatory mediators on cardiac pacemaker cells, rather than alteration of the ANS signaling itself . EndotoxSepsis is a highly dynamic system in which multiple factors determining the course of the disease and response to therapy are involved. Marked inter- and intra-patient changes occur in sepsis, as well as in the compensatory response to the infectious and other triggers in patients. These make it difficult to design a “one bullet for all” therapeutic regimen.The association of sepsis prognosis with immune response, chronobiology, ANS, and HRV, respiratory rate, systolic blood pressure, and temperature, indicates that these parameters should be considered in the individualization of sepsis therapy. This association underlies the platform for improving the response to therapy in sepsis in a personalized manner. Dysregulation of the inflammatory response contributes to the mechanism of sepsis. Inflammation may lead to recovery and homeostasis. However, in cases where the compensatory response is inadequate, a persistent inflammatory state remains and is associated with a bad prognosis . ComputaThe establishment of a new platform for improving the prognosis of sepsis patients is based on comprising the following three steps into a distinct dosing regimen. In the first step, chronotherapy-based regimens are implemented into the treatment regimen. HRV, which reflects the ANS tone, can serve as a chronobiological marker for directing therapy during sepsis. These are performed based on regular therapeutic regimens that are associated with chronobiology in a non-personalized way. The use of alternate dosing regimens was suggested to improve the therapeutic effects of chronic medications overcoming the loss of response, which is common in patients with chronic diseases .In the second step, signatures of variability, such as HRV and immune-derived signatures which are linked to the pathogenesis of the disease and response to therapy are implemented in the treatment algorithm. These are suggested to overcome the adaptation of the body system, manifested by a deleterious compensatory response and loss of the effects of drugs. Implementing randomness in the dosing and timing of therapeutic maneuvers including mechanical ventilation parameters and medications are introduced in a non-individualized way. Preliminary attempts in this direction can be seen, for example, in the application of HRV for prediction of mechanical ventilation weaning results  and realIn the final step, individualization of chronotherapy and variability measures are being implemented in the treatment algorithm in a continuous dynamic way, which works in a closed loop and responds to individual alterations recorded from each patient. Personalized chronotherapy and variability-based signatures can be quantified and implemented into the treatment algorithm. A multi-dimensional sepsis management personalized model incorporates HRV alongside immune signatures, laboratory parameters, imaging findings, and clinical parameters.The implementation of the proposed platform faces some challenges. First, additional researches on the mechanisms of ANS role in sepsis and on HRV alteration during sepsis are needed to firmly establish the theoretical basis of the proposed platform. Second, on the practical level, continuous HRV measurement in hospital setting might be challenging and requires interfaces with current hospital monitoring systems. However, novel wearable monitoring devices being developed provide accessible monitoring of HRV among other measures. This can enable the integration of other continuous measures effected by the ANS, such as respiratory rate and systolic blood pressure in the suggested personalized approach.In summary, improving the therapy of patients with sepsis is a major unmet need. Being a highly dynamic condition in which multiple parameters continuously change over time, it is difficult to overcome the compensatory responses that are sometimes deleterious and contribute to the worsening of the prognosis. Moreover, the marked inter- and intra-patient variability, which characterizes both the pathogenic mechanisms and the response to therapy, necessitates the use of a model that could individualize the therapeutic regimens. Ongoing studies will determine the ability to implement individualized platforms based on biological variability parameters, ANS-based sensors, immunity, and chronobiology-derived signatures for generating a patient-tailored therapeutic regimen for improving the response to current drugs and therapeutic maneuvers.Both authors wrote the manuscript.YI is the founder of Oberon Sciences and is a consultant of Teva, ENZO, Protalix, Betalin Therapeutics, Immuron, SciM, Natural Shield, Oberon Sciences, Tiziana Pharma, Plantylight, and Exalenz Bioscience. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Parkinson's Disease (PD) is a common neurodegenerative disorder manifesting as reduced facilitation of voluntary movements. Extensive research over recent decades has expanded our insights into the pathogenesis of the disease, where PD is indicated to result from multifactorial etiological factors involving environmental contributions in genetically predisposed individuals. There has been considerable interest in the association between neurological manifestations in PD and in inherited metabolic disorders (IMDs), which are genetic disorders characterized by a deficient activity in the pathways of intermediary metabolism leading to multiple-system manifestations. In addition to the parallel in various clinical features, there is increasing evidence for the notion that genetic mutations underlying IMDs may increase the risk of PD development. This review highlights the recent advances in parkinsonism in patients with IMDs, with the primary objective to improve the understanding of the overlapping pathogenic pathways and clinical presentations in both disorders. We discuss the genetic convergence and disruptions in biochemical mechanisms which may point to clues surrounding pathogenesis-targeted treatment and other promising therapeutic strategies in the future. Parkinson's disease (PD) is one of the most common neurodegenerative disorders, with a substantial, worldwide growth in prevalence in recent years. It is a debilitating disorder, manifesting as reduced facilitation of voluntary movements attributed to a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the formation of intracellular inclusions containing aggregates of alpha-synuclein (a-syn) . Over thInherited metabolic disorders (IMDs) are a complex and diverse group of genetic disorders characterized by the disruption of cellular biochemical functions and deficient activity in the pathways of intermediary metabolism. Consequential toxic substance accumulation or end-product deficiency leads to a multi-systemic clinical picture from liver dysfunction and cardiomyopathy to progression to encephalopathy, coma, or death if left untreated . The preGaucher Disease (GD), a prevalent inherited lysosomal storage disease (LSD), is caused by deficient glucocerebrosidase (GCase) activity due to mutations in the coding gene (GBA). The resulting accumulation of glucosylceramide (GlcCer) in lysosomes of reticuloendothelial cells leads to complex systemic manifestations involving the liver, spleen, bone marrow, and to progressive neurodegenerative diseases . The thrEvidence linking GBA mutations to the clinical characteristics of PD, including disease phenotype, progression, and prognosis, has been extensively documented. At the point of diagnosis, the clinical presentation of GD patients with PD can be almost identical to that of idiopathic PD . The mosClinical reports of an association between GD and parkinsonism instigated further investigation into the mechanistic and genetic overlap between the two syndromes. The fundamental finding that a GBA1 gene mutation is a significant risk factor for PD development is of significant interest , 80, 81.The overexpression of the poorly functional GBA1, leading to reduced GCase levels and subsequent accumulation of its lipid substrate GlcCer, is found to be linked with increased a-syn accumulation and subsequent neuronal cell death. The accumulation of GlcCer contributes to the destabilization of a-syn tetramers and increase the susceptibility of human dopaminergic neurons to the cytotoxic exposure to pathologic a-syn fibrils –41. It wConversely, reduced levels of GCase were also associated with increased a-syn in idiopathic PD patients without GBA mutations, indicating that a-syn can independently inhibit GCase enzyme activity , 91–93. An alternate theory is the association between heterozygote GBA mutations and dysregulations in the protein degradation systems, which have been implicated as a common mechanism underlying neurodegenerative diseases. PARK2 gene mutations encoding parkin, the E3 ubiquitin ligase, has been identified as a significant cause for an autosomal recessive form of PD . Parkin Niemann-Pick Disease (NPD), a neurovisceral LSD, presents with a broad clinical spectrum ranging from a rapidly fatal disorder in neonates to a chronic neurodegenerative disease later in life. The two distinct metabolic abnormalities include, firstly, a deficiency in the enzyme sphingomyelinase (ASM) resulting from mutations in the SMPD1 gene accounting for types A and B NPD. Growing evidence suggests they represent opposite ends of the clinical spectrum with regard to the disease severity and neurologic involvement. The second category accounting for NPD type C (NP-C) involves a dysfunction in cholesterol transport due to NPC1 and NPC2 gene mutations , 97. NP-Presentations of parkinsonian symptoms have been reported in several cases of patients with mutated NPC1, encoding a lysosomal cholesterol transporter that regulates vesicular trafficking. Parkinsonian symptoms are less frequent manifestations compared to the more prevalent deep brain signs such as cerebellar ataxia and supranuclear opthalmoplegia in NP-C . PresentIn vivo evidence of increased vulnerability of midbrain dopaminergic neurons and exacerbation of PD symptoms to hypercholesterolemia  found that several of the identified PD risk genes play an integral role in lysosomal biology and autophagy . ConversWilson's Disease (WD), an inborn error of copper (Cu) metabolism, is caused by a mutation in the copper-transporting gene ATP7B. This autosomal recessive disease is characterized by excessive copper deposition, primarily within hepatocytes and in the CNS . MovemenParkinsonian symptoms of WD includes rigidity, bradykinesia, shuffling gait, hypophonic speech, hypomimia, and micrographia. The tremor observed may be resting, intentional, postural, or action-induced, though the most common form of tremor in WD is an irregular, jerky, dystonic tremor –25. DysaThe indicated underlying pathomechanism of parkinsonian manifestations amongst heterozygotes for WD describes the process of prolonged free Cu and iron accumulation leading to oxidative damage in the basal ganglia. This stems from the frequent observation of Parkinson symptoms among WD patients as well as the reduced level of ceruloplasmin and Cu dyshomeostasis reported in PD patients . Cu dyshCeruloplasmin deficiency leads to the binding between a-syn and excess free Cu, which acts as a ferrireductase and increases the availability of iron. The increase in iron deposition, occurring as a result may be involved in the underlying pathophysiology of PD onset and development , 51. TheFurther research is necessary to explore the role of copper, ceruloplasmin, and iron dyshomeostasis in PD and the possibility of an underlying heterozygote WD in some PD cases, in which help in an early diagnosis and in establishing promising therapeutic strategies.Hemochromatosis is an autosomal recessive disorder which leads to abnormal iron deposition in multiple organs, including the brain, leading to the development of neurodegenerative diseases. Rare reports of parkinsonian syndrome in hereditary hemochromatosis describes characteristic symptoms of resting tremor, bradykinesia, rigidity, and an asymmetric onset. Mixed resting and action tremor were also reported in one patient case –29.Iron is essential in the maintenance of normal neurological function through its role in oxidative metabolism and the synthesis of neurotransmitters and myelin . As prevFurthermore, recent data has demonstrated the neuroprotective role of iron chelators against dopamine neuronal degeneration and suggests its therapeutic potential for PD treatment , 127. AlPhenylketouria (PKU), a prevalent inherited defect in amino acid metabolism, is characterized by an underlying deficiency in phenylalanine hydroxylase, the hepatic enzyme that catalyzes the hydroxylation of phenylalanine (Phe) to tyrosine (Tyr) . The resIt has been suggested that signs of parkinsonism may be secondary to the depletion of dopamine activity in the brain, a result of the reduction of brain Tyr, a dopamine precursor, as a biochemical consequence of PKU , 57, 58.Maple Syrup Urine Disease (MSUD), a disorder of branched-chain amino acid metabolism, manifests as toxic encephalopathy in early life. Treated adults commonly present with movement disorders, predominantly paroxysmal dystonia or ataxia. Patients with parkinsonism in MSUD present with bradykinesia on finger tapping with no resting tremor. These neurological symptoms were speculated to be secondary to the early cerebral damage and chronic reduction in levels of neurotransmitters .in vitro findings have indicated that accumulating metabolites caused the suppression of brain energy metabolism through the blockade of the respiratory chain, contributing to neurological impairment in patients  in MSUD . Free rapatients . The deppatients .Methylmalonic acidemia is an autosomal recessive disorder of branched chain amino acid metabolism, caused by deficient activity of methylmalonyl-coenzyme A mutase. While primarily recognized as a pediatric condition, significant multi-systemic morbidity may be present in patients who reach adulthood . Among oMitochondrial diseases are a heterogeneous group of disorders with multi-systemic involvement, from musculoskeletal to cardiac to gastrointestinal presentations. The spectrum of mitochondrial pathologies has been reported to result from mutations in the mitochondrial DNA which led to impaired oxidative phosphorylation and dysfunction of the mitochondrial respiratory chain . GrowingThe role of mitochondrial dysfunction in the pathomechanism of PD was initially observed through the findings of induced parkinsonism following the administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP), an inhibitor of the mitochondrial respiratory chain (MRC) complex I , 140. ThGenetic evidence has further supported the common pathway between PD and the maintenance of mitochondrial function in dopaminergic neurons . A GWAS In addition to the oxidative stress and genetic polymorphism which has long been a focus in PD research, recent studies suggest that the disruption in the breakdown of MIRO  may contribute to the impaired process in the cleranace of damaged mitochondria. This reduced degradation of MIRO and the delay in the dysfunctional mitochondrial clearance appears to be a common characteristic of familial and sporadic PD .The clinical convergence between PD and IMDs has instigated further research into the overlapping genetic and biochemical dysregulations between the two conditions. The discovery of shared pathways of an unbalanced homeostasis continues to expand our understanding of the clinical implications of oxidative stress and aberrant protein accumulation on the process of neurodegeneration. Despite the substantial progress that has been made, much work remains to determine the validity and strength of the proposed link between IMDs and PD. Further genetic and biochemical studies may provide insights into risk factors that synergistically favor the development of parkinsonism in particular subsets of IMDs patients. The better understanding of how these factors interact and contribute to the development of parkinsonism may point to clues surrounding pathogenesis-targeted treatment. This includes the possibility of a prognostic marker to establish prompt diagnoses, leading to the availability of genetic counseling and promising therapeutic strategies which may alleviate the onset and progression of this disorder.NL Project administration, Supervision, Visualization, Writing review, and editing. PI Supervision, Writing review, and editing. MH and KP writing review and editing.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.


Nowadays, the significant increase in the prevalence of obesity worldwide is directly associated with an increased risk of developing noncommunicable diseases such as diabetes, cardiovascular disease, dyslipidemias, inflammatory disease, cancer, and even neurodegenerative diseases. In this regard, obesity and chronic diseases are not only limited to developing countries, nor to the adult population. On the contrary, the greatest increase in the incidence of obesity in the last 20 years has been observed in developing countries and young population.Important risk factors involved in obesity development comprehend (i) high-energy intake; (ii) excessive fat consumption ; (iii) excessive intake of simple carbohydrates ; (iv) insufficient intake of vegetables and fruits , legumes (dietary fiber), and fish and seafood (sources of polyunsaturated fatty acid); and (v) unhealthy lifestyle . These factors directly favor oxidative stress, which is a relevant metabolic disturbance related to the development of other pathologies.In this sense, diet chemical composition and food preparation play a relevant and direct role in regulating several of the metabolic and molecular pathways involved in the prevention and treatment of obesity and its related comorbidities. For this reason, it is necessary to identify and understand molecular pathways involved in these events in order to develop nutritional strategies that contribute to the prevention and treatment of oxidative stress linked with the obesity.In this special issue, the impact of specific diet and nutritional interventions destined to prevent or attenuate obesity-related oxidative stress injuries is presented. By reading the different articles, readers will be able to identify relevant aspects underlying molecular changes generated by oxidative stress as a consequence of obesity in different study models. The risk of developing metabolic syndrome and cardiovascular alterations in humans, as well as dietary interventions using foods or bioactive compounds (polyphenols or other micronutrients) to treat these alterations, is addressed in this issue. It should be noted that some of the studies published here suggest the protective effect of bioactive compounds and exercise on oxidative stress and other alterations generated by obesity. Thus, in this special issue, results about reproduction, oxidative stress, aging, obesity, and related noncommunicable diseases and their interaction with nutrients and diet are reported.Rodrigo ValenzuelaUndurti N. DasLuis A. VidelaCarolina G. Llorente


While stress responses have been studied at both organismal and cellular levels, less attention has been given to the effect of stress on the germ line. Effective germ line adaptations to stress are essential to the propagation of a species. Recent studies suggest that germ cells share some cellular responses to stress with somatic cells, including the assembly of RNP granules, but may also have unique requirements. One fundamental difference between oocytes and sperm, as well as most somatic cells, is the long lifespan of oocytes. Since women are born with all of their eggs, oocytes must maintain their cellular quality over decades prior to fertilization. This prolonged meiotic arrest is one type of stress that eventually contributes to decreased fertility in older women. Germ cell responses to nutritional stress and heat stress have also been well-characterized using model systems. Here we review our current understanding of how germ cells respond to stress, with an emphasis on the dynamic assembly of RNP granules that may be adaptive. We compare and contrast stress responses of male gametes with those of female gametes, and discuss how the dynamic cellular remodeling of the germ line can impact the regulation of gene expression. We also discuss the implications of recent  Stress granules . They cagranules . A recengranules . Stress granules . P-bodiegranules . P-bodiegranules ; howevergranules .Drosophila, to years in Xenopus, to decades in humans  and the UPR . Adverse species .In terms of RNP remodeling in the mammalian germ line, during mouse oocyte growth P bodies seem to disappear at the same time that subcortical aggregates (SCAs) assemble . The SCAin vivo functions of RNP granules during stress. In particular, the germ line has unique requirements for regulating gene expression, and its adaptive stress responses may differ from those in somatic cells. At a basic level, we still do not know what the visible phase separation of RNP granules means at a molecular level. Many hypotheses exist as to whether stress-induced RNP granules assemble to: maintain the protein or RNA components within them, prime cells for rapid protein synthesis and recovery after stress ceases, reduce the concentration of RNA binding proteins in the bulk cytoplasm surrounding the granules, or whether the granules are just a consequence of more global remodeling occurring throughout the cell (in vitro studies have identified many types of interactions that promote phase separation outside of cells: protein-protein, RNA-RNA binding protein, roles of intrinsically disordered regions of proteins, RNA-RNA, and electrostatic interactions between RNA and protein. Triggers of phase separation in vitro also include the concentration of proteins and RNA, phosphorylation state, and salt concentration (in vivo are more complex than those in vitro, the relative contributions of these various triggers are not yet clear. Complementary in vivo studies have also revealed regulators of RNP granule assembly. Chaperone proteins have now been implicated in regulating RNP granule assembly in both somatic cells and in the germ line (Drosophila studies showing germ granule assembly is regulated by recruitment of single transcript RNPs to homotypic clusters (C. elegans (in vitro reconstitution assays, improved single molecule FISH methods, and increased attention on the impact of RNP remodeling on gene expression. Combinations of in vitro and in vivo approaches will likely be important to illuminate the function of stress-induced RNP granules in the germ line.The past few decades have been exciting in terms of identifying and characterizing a variety of RNP granules induced by stress. RNP granules have received additional attention as broadly conserved examples of phase separation. The preponderance of studies utilize yeast and mammalian cell culture for their ease; however, these studies are limited in the insights they can provide regarding the the cell . Creativntration . Becauseerm line . The rolclusters . Autopha elegans ; therefoJS wrote the manuscript and prepared the figure.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Decades of technological developments have populated the field of brain-machine interfaces and neuroprosthetics with several replacement strategies, neural modulation treatments, and rehabilitation techniques to improve the quality of life for patients affected by sensory and motor disabilities. This field is now quickly expanding thanks to advances in neural interfaces, machine learning techniques, and robotics. Despite many clinical successes, and multiple innovations in animal models, brain-machine interfaces remain mainly confined to sophisticated laboratory environments indicating a necessary step forward in the used technology. Interestingly, Elon Musk and Neuralink have recently presented a new brain-machine interface platform with thousands of channels, fast implantation, and advanced signal processing. Here, how their work takes part in the context of the restoration of sensory-motor functions through neuroprostheses is commented. Significant research in biology, medicine and engineering has sought to obtain effective solutions to improve quality of life of human subjects affected by sensory-motor disorders. Neuroprosthetics are implantable devices designed to replace or improve the function of a disabled part of the nervous system . This teUp till now, patients who used brain-machine interfaces have had a quite poor perception of the instantaneous behavior, position, or motion of the robotic device, which has prevented them from operating in fully closed-loop and natural control. The restoration of sensory feedback and voluntary control, along with the development and successful integration of these sensor modalities, is a mandatory step towards the realization of future bidirectional neuroprostheses .The challenges described above can be addressed by creating a brain-machine interface that utilizes the processing power of the human brain to control the robotic device. Directly connecting to the human nervous system means closing the gap between user intent and the expected behavior of the apparatus. Furthermore, generating a shorter loop between user intent and device behavior or motion (by eliminating part of the low-level sensor-based control) will allow for easier control, a reduced learning investment, and a reduced cognitive burden of operating the device.Neural interfaces play a pivotal role in the efficacy of a neuroprosthetic. Due to their ability to read out electrical activity from the nervous system, it is possible to decode signals into cognitive, sensory, or motor information through the use of computational methods. This information can then be used to control a prosthetic device, robot, or computer. It also induces better understanding of brain behavior through the recording of neural activity, providing information about sensory areas responsible for hearing or sight (sensory prosthetics), or helping to regulate malfunctioning motor functions (motor prosthetics). On the other hand, pacemaker or bladder control neuroprosthetics also use similar physical principles, targeting the autonomic nervous system and helping patients with paraplegia due to spinal cord damage .In a recent article, Elon Musk and his company Neuralink presented a new platform to target the brain for neuroprosthetic applications . They usIn this field, many devices and smart materials have been presented as effective solutions to interfacing with nervous tissues, enabling an intimate connection between the brain and machines in animals and even in humans . UnderstIn the near future, neurotechnologies will continue to grow. More accurate and advanced computer simulations  will allow researchers to test and validate these technologies even quicker. Implantable neurotechnologies will literally become part of us. Direct bidirectional communication between the brain and external devices, the transformation that this connection brings about, and the blurring of the boundaries between humans and machines, are issues that raise several ethical, social, and cultural concerns. Personal identity, physical integrity, and the human dignity  of peopl


While skeletal evolution has been extensively studied, the evolution of limb muscles and brachial plexus has received less attention. In this review, we focus on the tempo and mode of evolution of forelimb muscles in the vertebrate history, and on the developmental mechanisms that have affected the evolution of their morphology. Tetrapod limb muscles develop from diffuse migrating cells derived from dermomyotomes, and the limb-innervating nerves lose their segmental patterns to form the brachial plexus distally. Despite such seemingly disorganized developmental processes, limb muscle homology has been highly conserved in tetrapod evolution, with the apparent exception of the mammalian diaphragm. The limb mesenchyme of lateral plate mesoderm likely plays a pivotal role in the subdivision of the myogenic cell population into individual muscles through the formation of interstitial muscle connective tissues. Interactions with tendons and motoneuron axons are involved in the early and late phases of limb muscle morphogenesis, respectively. The mechanism underlying the recurrent generation of limb muscle homology likely resides in these developmental processes, which should be studied from an evolutionary perspective in the future. The fossil record reveals that the evolutionary rate of vertebrate morphology has been variable, and morphological deviations and alterations have taken place unevenly through history –5. SporaIn the vertebrate body, skeletal muscles are connected to specific sites of connective tissues, such as bones, and these connections are generally unchanged after their initial formation. Thus, evolutionary changes in muscle connections, which can also be observed in fossil bones, correspond to changes in morphogenetic process, unlike other morphological characters that may change during growth. Skeletal muscles thus exhibit clear advantages for the integration of paleontology and evolutionary developmental biology. This paper aims to summarize the current understanding of the evolution and development of skeletal muscles in the hopes of providing a basis for future studies. In particular, from the perspective of the role of developmental constraints in evolution , we focuIn comparative anatomy, the homology of forelimb muscles among extant tetrapod species is identifiable based on gross anatomy, such as the connections between these muscles and bones or innervations, and the same set of names has been applied to different tetrapod classes –16, althThe evolution from fin muscles to limb muscles occurred deep in time Fig. , arrow aPelvic fins evolved in placoderms and crown-group gnathostomes , and froDuring the evolutionary transition from pectoral fin to forelimb, the ulna became as large as the radius, and the articular facets of the elbow and wrist joints turned, enabling the support of the body on a substrate –48, althAs for muscles, it is likely that the major morphological and topographical transitions took place concomitantly with the skeletal evolution, giving rise to the elbow and wrist joints of the forelimb. Indeed, the cross-section shape of the humerus and some muscle attachment sites on its surface in a basal limb-bearing tetrapod , 50 are Despite the conservation of limb muscle homology, the development of limb muscles is variable in timing and in the environment surrounding the progenitor cells. In amniotes, limb muscles develop almost in parallel with other skeletal muscles during embryonic development, and become functional before birth, whereas in many species of extant amphibians, the limbs and their muscles develop during larval stages –53. SuchExtant amphibians consist of only a fraction of several anamniote tetrapod lineages, and the phylogenetic position(s) of extant amphibians remains a matter of controversy. In one hypothesis, extant amphibians are all included in a single clade, the Lissamphibia, which evolved from the Temnospondyli, whereas the Amniota evolved from another clade, from which the extinct Seymouriamorpha and Lepospondyli also branched off , 70–72 . An alteEusthenopteron  and sternalis muscle as variations of the pectoralis muscle [Dromaius novaehollandiae), suggesting relaxed stability of the developmental mechanism in the vestigial limb [The developmental process explained above allows modest intraspecific variability in morphology of forelimb muscles. Since forelimb muscles are present as paired structures, intraspecific variations showing fluctuating asymmetry , 286 ares muscle –295. In ial limb . Future As mentioned above, after their evolutionary origin, forelimb muscles have evolved without drastic modification. However, recent studies of evolutionary changes in forelimb position along the body axis have found that the mammalian diaphragm likely evolved from a shoulder muscle, through a partial duplication of the forelimb MMP population , 297. InTbx5 and Hgf, unlike the hypobranchial muscles [Some classical papers of comparative anatomy , 299 hav muscles , 153. In muscles –302. As  muscles , it is pAs a candidate exception to forelimb muscle homology, the diaphragm offers an exclusive opportunity for understanding when and how a drastic modification was possible in the evolutionary history after the establishment of an evolutionary novelty, or a new developmental constraint.At the pectoral fin-to-forelimb transition, the number of muscles increased, while the number of spinal nerves innervating these muscles decreased. The brachial plexus is an evolutionary novelty of tetrapods. Within the tetrapod lineage, limb muscle homology has been largely conserved.Forelimb muscles develop from diffuse migrating somitic cells, or MMPs. The limb muscle homology is generated mainly through subdivision of myoblast masses (muscle splitting). The LPM-derived limb mesenchyme likely provides the information for the proper distribution of MMPs, and subsequently the MCTs differentiated from the LPM-derived limb mesenchyme subdivide each myoblast mass into individual muscles. Development of blood vessels plays some role in the latter process.The reciprocal interaction with tendon progenitors is necessary for the morphogenesis of individual muscles, but the tendon and muscle progenitors begin their differentiation independently of each other.Although the topography of the brachial plexus and the relationship between the nerves and their innervating forelimb muscles are evolutionarily conserved, the developmental mechanism recurrently generating them remains largely unclear, and should be the subject of future analyses.In addition to further studies on the developmental mechanism recurrently generating the forelimb muscle homology, particularly focusing on MCTs and tendons, studies on intraspecific variability of the forelimb muscle morphology and research on the diaphragm as a putative derived forelimb muscle will lead to our better understanding of the role of developmental constraints in evolution.


Flavivirus, cause high viremia and occasionally fatal clinical disease in humans. Given the genetic austerity of the virus, they depend on cellular factors and organelles to complete its replication. One of the cellular components required for flavivirus infection is cholesterol. Cholesterol is an abundant lipid in biomembranes of eukaryotes cells and is necessary to maintain the cellular homeostasis. Recently, it has been reported, that cholesterol is fundamental during flavivirus infection in both mammal and insect vector models. During infection with DENV, ZIKV, YFV, and WNV the modulation of levels of host-cholesterol facilitates viral entry, replicative complexes formation, assembly, egress, and control of the interferon type I response. This modulation involves changes in cholesterol uptake with the concomitant regulation of cholesterol receptors as well as changes in cholesterol synthesis related to important modifications in cellular metabolism pathways. In view of the flavivirus dependence of cholesterol and the lack of an effective anti-flaviviral treatment, this cellular lipid has been proposed as a therapeutic target to treat infection using FDA-approved cholesterol-lowering drugs. This review aims to address the dependence of cholesterol by flaviviruses as well as the basis for anti flaviviral therapy using drugs which target is cholesterol synthesis or uptake.In recent years the emergence and resurgence of arboviruses have generated a global health alert. Among arboviruses, Dengue (DENV), Zika (ZIKV), Yellow Fever (YFV), and West Nile (WNV) virus, belong to the genus  Viral infections transmitted by mosquitoes, such as those caused by the flaviviruses dengue (DENV), yellow fever virus (YFV), West Nile virus (WNV), and Zika virus (ZIKV) represent important health challenges. In the last years, the emergence or reemergence of different arboviruses have generated a global health alert. In this sense, DENV continues to increase in tropical and subtropical regions of the world, whereas outbreaks of YFV in humans have been reported in Angola and some countries in South America. Moreover, the emergence of ZIKV, which is strongly associated with microcephaly in newborns, Guillain-Barre syndrome in adults and the ability to be transmitted sexually and through trans placental route, as well as the neurotropic behavior of WNV; making these viruses a latent threat to global health Barrett, . AlthougOn the other hand, there is a close correlation between cholesterol levels and type 1 IFN response. High levels of cholesterol induce a poor IFN response  infected with DENV , the presence of cholesterol in DENV virions was more crucial for infection , and a homolog of cholesterol transporter NPC2, and the downregulation of the LDLr  is secreted , which are found in the cholesterol-rich microdomains, lipid rafts , also induces a strong inhibition in WNV, ZIKV, and DENV infection (Soto-Acosta et al., On the other hand, there is an indirect way to induce inactivation of the HMGCR enzyme, using metformin, a drug commonly prescribed to treat patients with type 2 diabetes (Crofford, Another compound related with the inhibition of cholesterol metabolism is that related with the blockage of enzyme 7-dehydrocholesterol-Δ7-reductase that performs the final conversion step of 7-dehydrocholesterol to cholesterol, by AY-9944 (Mackenzie et al., Further analysis in animal models and clinical trials is essential to determine whether the use of drugs such as other statins, metformin or other AMPK activators in single-dose or in combination as a treatment against flavivirus infections is feasible.Since the increase in cholesterol levels during flavivirus infection is the consequence of an increase in cholesterol synthesis and an increase in cholesterol uptake through the LDL receptors (Soto-Acosta et al., in vitro and in vivo models induce a reduction of infection with DENV and ZIKV among others. Additionally, the close interaction between cholesterol synthesis and IFN response pathway indicate that the reduction in cholesterol levels could also increase IFN response inhibiting viral infection. Thus, cholesterol can be considered an excellent target to inhibit flavivirus infection. The use of FDA-approved cholesterol-lowering drugs alone or in combination can be tested in new clinical trials.Viral infections transmitted by mosquitoes, such as those caused by the flaviviruses DENV, YFV, WNV, and ZIKV represent essential health challenges. The presence of the four DENV serotypes in many parts of the world, the propagation of the mosquito vector and the climate conditions for mosquito proliferation increase the risk to contract severe dengue. On the other hand, the association between ZIKV infection with microcephaly in neonates and with Guillain-Barré syndrome in adults, in addition to its ability to be transmitted through sexual and transplacental routes, made it a threat to global health. Finally, although YFV was confined mainly to monkeys, outbreaks in humans in Angola and Brazil have generated an alarm. Although in Brazil part of the population is immunized and new vaccination programs are in progress, in the rest of America and the world, most of the human population is not immunized. These facts highlight the importance of the study of flaviviruses and the development of new control strategies. It is well-known that every step of the viral life cycle, from entry to viral release requires close interaction with cellular proteins. Therefore, viruses hijack cellular proteins, components and processes to be replicated in the host cell. One of these components is the cellular cholesterol, required for the formation of RC, present in the ER. The reduction in the cholesterol levels with FDA-approved drugs that inhibit cholesterol synthesis or uptake JO-R, JR-R, and RdA preparing manuscript, writing, correction, and figures design. JR-R and JO-R performed infection and performed microscopy assays.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.


Alcohol availability, measured in terms of geographic density of alcohol-sales outlets, is linked to specific patterns of alcohol-related motor vehicle crashes in communities. To curb alcohol-related problems such as violence, traffic crashes, and drinking and driving, community advocates often focus on reducing alcohol availability through modifications of zoning laws and licensing requirements. In developing interventions and policy activities to reduce alcohol availability, community policymakers should assess the effects of outlet density using an adequate community “biogeography” of the interrelationships among drinkers, their drinking environments, the locations of alcohol outlets, and the locations of alcohol problems. Communities also should consider that the economic development of downtown areas, which is often accompanied by the rapid growth of alcohol outlets, is likely to affect the incidence and prevalence of alcohol-related problems in surrounding areas. Alcohol-related violence, traffic crashes and injury, and drinking and driving are all issues of concern to communities. To curb alcohol-related problems such as these, community advocates frequently focus on reducing alcohol availability, a policy area typically under local control . Restrictions on alcohol availability may in turn, however, encounter resistance from economic development and other local community interests. The challenge to communities is to balance these clashing interests, whereas the challenge to researchers is to provide scientific evidence to inform these important policy decisions.This article presents recent research findings on the relationship between the availability of alcohol within local communities and the incidence and prevalence of alcohol-associated problems, most notably violence and drinking and driving. In the studies mentioned, the geographical areas investigated range from collections of small cities , 1995 anMost recent studies conclude that a relationship exists among alcohol availability, alcohol use, and alcohol-related problems . One recIn a study of the connections between alcohol sales and the prevalence of drinking and driving in Perth, Australia, This research has established that the availability of alcohol is linked to specific patterns of alcohol-related motor vehicle crashes in community settings. To better clarify the link between the number of alcoholic beverage outlets and the incidence of alcohol-related crashes in four California communities, The researchers selected traffic-crash measures that represented specific alcohol-related events  . EnvironTo ensure accurate comparison, each community was partitioned into a number of relatively small geographic units whose sizes generally reflected local population densities . The ranges of various measures in the study across these geographic units differed from one unit to another, sometimes dramatically. For example, the proportion of people who abstained from using alcohol ranged from 3 to 61 percent, unemployment rates varied from 0 to 12 percent, and outlet densities varied from 0 to 4 outlets per kilometer of roadway. , the city council had begun considering easing alcohol regulations to promote downtown growth, a move supported by the local chamber of commerce, which ultimately opposed all new CUP ordinances.The third community was working within the context of a comparatively primitive regulatory environment. For example, until midway into the intervention period (1995), alcohol licenses were reviewed in the State capitol, effectively blocking local representation at licensing hearings. When the State Alcoholic Beverage Control agreed to conduct licensing hearings in the local community, the regulatory change allowed local citizens to intervene more effectively in the licensing process. Around the same time, the city council began to allow local police to testify in alcohol licensing hearings. The police provided official information concerning problem outlets to help lobby for their closing.Although the three communities’ approaches to reducing alcohol-related problems diverged, each community began the process in the same way: by developing a coalition and gathering scientific support for the intervention activities. These three brief case studies show that local communities can apply the scientific evidence supporting the existence of a relationship between alcohol availability and alcohol problems. As a prime example, in all three communities, advocates for constraints on alcohol availability used evidence from studies such as those cited in this article to suggest that increasing the required minimum distance between outlets would be the best first step toward reducing availability and decreasing alcohol-related problems. Thus, by proposing planning and zoning changes, the advocates implemented the scientific observation that geographic outlet density has the greatest impact on alcohol-related problems in the community.From the perspective of those interested in reducing alcohol problems in their communities, the physical availability of alcohol makes an attractive policy target. Unlike alcoholic beverage taxes, the location of alcohol outlets is subject to local regulation and can be closely monitored by community groups. In addition, and again unlike alcoholic beverage taxes, alterations in the physical availability of alcohol can have immediate effects on patterns of alcohol use within communities and can reduce access substantially in locations where high-risk behavior is likely . Another appeal of regulating alcohol availability is that regulations affect access to all beverages sold by an outlet (regardless of price) to all segments of the population (regardless of income). In contrast, alcohol taxation takes place in an environment where beverage prices differ by orders of magnitude and the effects of a tax may be diluted by the range of beverage prices and other factors. To support community activities in reducing the availability of alcohol, much further research must be performed. As noted in this article, the evidence for a direct link between availability, alcohol use, and specific alcohol-related problems at the community level has been scant, consisting of only a handful of studies. In addition, theoretical models of the geographic relationships between availability and alcohol-related problems are still in their infancy  and increased access to alcohol may be key to determining the geographic distribution of types of drinking problems. In the case of drinking and driving, the location of alcohol use —not the location of the drinker’s home—may be directly related to motor vehicle crash sites . As anotMany communities are confronted with serious problems regarding alcohol availability and associated alcohol-related problems. Moreover, drinking and driving and the crashes that result are not limited to those areas of the community with the greatest concentration of alcohol outlets; the effects spread across adjacent community areas that may have comparatively low alcohol-outlet densities. Therefore, communities need to assess the impact of increased outlet density in broader geographic terms. In addition, communities must consider that the economic development of downtown areas, often accompanied by the rapid growth of alcohol outlets, is likely to be accompanied by rapid growth of alcohol problems in surrounding areas.In communities grappling with alcohol-related problems, activists will continue to pose the following central questions: “How do we prevent or reduce alcohol-related problems in the community?” and “Are reductions in availability sufficient to reduce these alcohol problems, or are changes in enforcement and preventive education also necessary?” The advancement of theoretical models of the geography of alcohol problems and the application of methods to mapping these problems will help answer these questions and make possible more targeted preventive interventions.