Here, we interpret malignant tissue transformation from the aging point of view, that is, as a result of insufficient cell adaptation to the needs of regeneration/repair and proliferation. A consequence of the aging (senescence) process is gradual loss of self-renewal potential. It limits lifespan and leads to death due to the decline of tissue/organ functions, failure of regulatory mechanisms, disruption of endogenous processes and increased susceptibility to exogenous factors. Recapitulation of the embryonic pathway of self-renewal/rejuvenation in adulthood is epigenetically determined. At the postembryonic stage, in the absence of immune privilege, this recapitulation is transformed into cancer (potency expansion of single structures composing the organism to the detriment of the whole organism or disintegrating growth). We suggest that the process of rebirth occurs in the same way as embryonic tissue growth. Thus, the idea to use the potential of the transformed cells to stop the aging process has been proposed. This article interprets malignant tissue transformation from the aging point of view, or in other words, as a result of insufficient cell adaptation to the needs of repair and proliferation. We suggest that the process of rebirth, or complete quantitative and qualitative restoration of tissues resulting in reversal of the aging process, occurs in the same way as embryonic tissue growth. The idea to use the potential of the transformed cells to stop the aging process is proposed. Someday perhaps it will turn out to be one of the ironies of nature that cancer, responsible for so many deaths, should be so indissolubly connected with life. Charles Oberling [Oberling According to previously formulated concepts ,3, the dOne of the main (noninfection-related) functions of the immune surveillance system is to maintain cellular (tissue) homeostasis (morphostasis) that is carried out through maintaining the growth processes in damaged tissues. In this process, the immune response to proliferating cells is carried out through the mechanism of active tolerance, when there is an immune response; however, it does not kill, but supports. The standard regenerative module during regeneration works within the program of relatively rigid-specific determination, and the level of tissue-specific differentiation is determined by the principle of submitting the interests of single units to the interests of the entire organism (IG). The active tolerance reaction ensures stability of this particular program. In the case of reontogenesis, that is, the recapitulation of morphogenetic modules of early ontogenesis (embryonic development program) with a specific tendency to autonomy, the same interactions ensure the stability of this particular inverse vector . In other words, the immune response ‘bluntly’ supports a growth program, which is launched when an absolutely critical or relative deficiency of tissue/functions occurs; regardless of whether the regenerative (within differentiation) or embryonic (with dedifferentiation and progressive autonomy) module works currently. The same takes place during pregnancy at the mother–fetus interface. However, during pregnancy, it happens at the interface of multinucleated, nondividing syncytium (syncytiotrophoblast), and the embryo is protected in the immunoprivileged zone. Due to this protection, the embryo gradually advances from totipotency to differentiation (the same IG).Therefore, DG is only epigenetically blocked differentiation, incomplete somatic embryogenesis or fragmented/unimplemented morphogenesis. The development of full immunological tolerance to the markers of the embryonic pathway  will allow avoidance of DG. Then, the embryonic pathway recapitulation, starting where and when aging/involution within the definitive structures has acquired an irreversible character, will be carried out as a closed cycle (rejuvenation circle) of dedifferentiation, redifferentiation, dedifferentiation, redifferentiation  appears logical and speculatively understandable. However, this is only true until the increasing shortage of tissues and functions and the aging senescence-associated secretory phenotype (SASP) signaling, through positive feedback, fail to eliminate these deficiencies through the recapitulation of morphogenetic modules of the early stages of ontogenesis (embryonic development), with its high self-renewal potential characteristic. It should be noted that the hypomethylation of growth-proliferative genes through demethylation caused by methyltransferase inhibition leads to the elimination of SASP through an increase of antisenescence TERT, bFGF, VEGF and ANG gene expression and a decrease of senescence-related ATM, p21 and p53 gene expression [The methylation landscape in cancer is heterogeneous. A large part of the genome is hypomethylated, while a small part of the genome is hypermethylated . The metpression , which fpression , which ipression . This isP21 are important transcriptional targets of p53. The activation of P21 results in cell cycle arrest, and in case of prolonged damage, it leads to cellular senescence. Activation of PUMA, BAX and BAK induces apoptosis. Their activation also leads to tissue degeneration and loss of function as well as depletion of stem cells and impaired renewal potential. All of these are hallmarks of the aging process [p53 hyperactivation demonstrated an increased resistance of mice to carcinogenesis, but premature aging and lifespan shortening [p53-induced apoptosis in gene-targeted mice did not lead to spontaneous tumor occurrence [Cyclin-dependent kinase inhibitor and a main regulator of the G1/S transition checkpoint  process . Studiesortening . Howevercurrence .Ras and Wnt5A in tumors is associated with signs of aging [Self-renewal capacity, such as the Wnt signaling pathway, is often deregulated in aged organisms. The accumulation of DNA damage and the activation of tumor-suppressor signaling pathways are other important factors underlying the reduced ability of the stem cells to regenerate and repair damaged tissues. There are two main tumor-suppressor signaling pathways, p53/p21 and p16INK4a/pRB, which result in cell growth arrest and, in the case of persistent stimuli, lead to senescence. Hypomorphic BubR1 mice show premature separation of sister chromatids, leading to progressive aneuploidy. They developed a characteristic progeroid phenotype with high p16INK4a expression in skeletal muscle and fat tissue. The suppression of p16INK4a in these mice resulted in increased longevity, a delay in their typically degenerative phenotype and a reduction of the accumulation of senescent cells. All these evidences support p16INK4a involvement in senescence and age-related pathologies . Staininof aging , but thiof aging ,25. Thisof aging . SimilarThus, cellular senescence, possibly due to the epigenetic suppression of growth-proliferative genes/signaling pathways and the activation of differentiation genes/cell cycle arrest/apoptosis, temporarily protects against cancer . However, SASP signaling and a certain critical level of tissue/function deficiency initiate the reverse process of rejuvenation through recapitulation of the embryonic pathway of development through the epigenetic derepression of the first and suppression of the second pathway . Furthermore, if we can manage to prevent cancer, that is, DG (potency expansion of single structures composing the organism to the detriment of the whole organism), the completion of rejuvenation leads to the disappearance of SASP signaling and returns cells to differentiation through negative feedback from the products of the growth genes. After some time, the SASP-aging signaling then accumulates again, and the process repeats. This closed circle of rejuvenation is the essence of the proposed new paradigm.in vitro and in vivo and form lymph node metastases. The authors concluded that cancer stem cells arise de novo from nonstem cancer cells after apoptosis turnaround, possibly through epigenetic modifications. The recovered cells have undergone epithelial–mesenchymal transitions in the primary tumors in situ and mesenchymal–epithelial transitions in the metastatic cells. Chemotherapy-induced senescence could change the stem cell properties of malignant cells, reprogramming nonstem bulk leukemia cells into self-renewing, leukemia-initiating stem cells [de novo from differentiated cells, and the hierarchical model of stem cell biology should thus include bidirectional interconversions between stem and nonstem cell states. These results showed that differentiated epithelial cells can return to a stem-like state in mammalian cells. According to the authors, if cancer cells can spontaneously dedifferentiate into CSCs, then targeting CSC populations is unlikely to be successful since the therapeutic eradication of existing CSC populations might be followed by their regeneration from non-CSCs within the tumor after the treatment.There are two major problems: the eradication of cancer and aging. For radical rejuvenation, gerontologists attempt to activate signaling pathways for rejuvenation/pluripotency. Quite often, such attempts result in the formation of tumors. This happens because the only way is to radically rejuvenate and this normally, without special intervention, leads to cancer. At the same time, oncologists are trying to suppress all these signaling pathways of rejuvenation, based on the idea that tumor cells are the enemies and that they should be eliminated by all available means. In short, this strategy can be called a killing strategy (both through direct action and creating conditions unfavorable for cell growth and proliferation). This flawed enemy-thinking paradigm is based on misreading the signs that are associated with cancer as the clinical phenomenon of DG itself. This currently applied killing strategy does not restore tissue and function deficiency but rather exacerbates it. That is why, after some clinical success, this strategy leads to a recurrence of cancer and the formation of cell clones that are resistant to therapy . These aem cells . In addiem cells . All of em cells . These fConsequently, what we have in the end as a result of the ‘enemy’-focused paradigm of oncology is neither rejuvenation nor salvation from cancer. This makes sense, since a train cannot move in opposite directions at the same time.As we noted earlier when presenting our unified model of aging and loss of regenerative potential , cancer Insufficiency of the effective self-renewal and failed adaptive and reparative capability of cells underlie the origin of malignant cell dedifferentiation. The suppression of regenerative cell proliferation is the primary event of initiation of dedifferentiated tissue growth. The transformation of normal cells into tumor cells is an adaptive response to a failure in self-restoration and repair capabilities. Due to the rebirth process, complete tissue renewal leading to the elimination of senescence occurs similarly to embryonic tissue development. We propose to use this potential of transformed cells to eliminate senescence. This will make it possible to direct the process of transformation toward an integrated growth path, to prevent the clinical phenomenon of malignancy and to use the potential of transformed cells to initialize the self-renewal program and program of unlimited life for the whole organism.The first postulate of the new paradigm: The embryonic rejuvenation and DG pathways are essentially the same, but at different stages of ontogenesis, this mechanism is carried out in opposite ways.PIWI acts as a so-called oncogene and is a marker of CSCs due to its restricted expression during embryonic development and aberrant expression in various types of cancer [PIWI in cancer is associated with certain already defined CSC-associated proteins and indicates the involvement of all these proteins in the process of tumor growth [Drosophila germline, and it resulted in repressing the activity of mobile genetic elements, also called transposable elements (TEs) or ‘jumping’ genes. This pathway is also active in various cell lines, which means that nonaging CSC cells acquire certain germline-specific characteristics. This indicates that soma-to-germline transformation occurs, with the activation of the Piwi–piRNA pathway and an unlimited proliferation capacity. In addition, certain planarians and cnidarians, such as the planarian flatworms and freshwater hydra, express components of the Piwi–piRNA pathway in the soma, leading to the unlimited self-renewal of soma. These organisms can be reproduced clonally, that is, the progeny can actually ‘be regenerated’ from the somatic cells of the parent body. Thus, besides the germline, the Piwi–piRNA pathway is also active in essentially all types of nonaging somatic cells in various organisms, including somatic stem cells of the sponges, jellyfish, planaria , sea slugs, fruit flies (where the germline function of Piwi proteins depends on somatic cells of the gonads), sea squirts and mammals. In humans, the Piwi–piRNA pathway is activated in both cancerous and hematopoietic stem cells. This pathway causes not only TEs silencing but also other various cellular processes, including epigenetic reprogramming, proliferation and self-renewal. It should be emphasized that the transposons responsible for the mutations of the functional DNA segments are effectively suppressed by the Piwi–piRNA mechanism in the nonaging germline and cancer cells. In contrast, aging somatic cells, in which the Piwi–piRNA pathway is inactive, are subject to a high level of transposition and mutations. It should be especially noted that the phylogenetically conservative mechanisms described above unite practically all living organisms, including humans.As shown in planarians , only thf cancer . Re-exprr growth . A positr growth . At the Thus, these and other data suggest that the pathways to rejuvenation and cancer are essentially the same. Rejuvenation features and cancer-associated signs are the same (with the exception of blocked redifferentiation), but they do not transform a normal cell into a cancerous one. Trying to kill cancer, we kill rejuvenation. Trying to radically solve the problem of rejuvenation without preventing the blocking of redifferentiation, we inevitably end up with cancer again.The basis of effective self-renewal is complete, both quantitative and qualitative replacement of aged and lost structures and functions by specific, full-fledged, functionally active structures. The efficiency of regeneration, which is based on definitive tissue-specific induction, weakens with age. Progression of cells toward a more differentiated state and a gradual increase in the level of tissue specialization lead to the narrowing of their adaptive potential spectrum (relative adaptive rigidity), the lowering of the rate of self-renewal, a further deepening in a state of differentiation, the appearance of nonself-reproducing units in self-replicating systems, a reduction of cell and tissue resistance to harmful environmental factors and substantial qualitative changes in the process of reparation (regeneration). As a result, replacement of dead structures with nonspecific, defective structures occurs. The metabolic provision of hyperfunctioning of the remaining structures becomes unsustainable, their functional insufficiency increases, the absolute tissue (organ) deficit reaches a critical level and endogenous intoxication processes are potentiated, making the body even more vulnerable to exogenous factors.It is impossible to achieve radical rejuvenation without the proper conditions that enable cancer cells to come back to tissue-specific commonality. This is because the increased deficiency of tissue/function and repair processes requires greater flexibility than can be provided within the definitive tissues characterized by firm determination and differentiation. Only embryonic induction, with its full reproduction of the forms and functions of the organs (tissues), will result in complete self-renewal. It becomes clear that the rejuvenation ability is nothing more than the ability for growth; therefore, rejuvenation must be carried out by the embryo-like type of tissue growth.Considering the above information and the fact that involution processes begin at different times in various organs, are not equally expressed in distinct structures of the same organ and develop at different rates and in different directions, we can answer the question regarding when and why this recapitulation of the embryonic pathway of development occurs. Therein lies the formulation of the second postulate of the new paradigm.The second postulate of the new paradigm: recapitulation (self-initiation) of the embryonic pathway occurs where and when the program of development of definitive structures cannot result in effective self-renewal. In other words, it starts as a rejuvenation program but is transformed into DG.Why does this happen? It is due to a blocked way back.The third postulate of the new paradigm: DG is simply epigenetic-blocked redifferentiation and unfinished somatic embryogenesis/rejuvenation and nothing more.YAP silencing is related to phosphorylation, inhibition of YAP entering the nucleus and decay in the cytoplasm, which inhibits cell division and induces premature cell senescence. It has also been shown that polyploid giant cancer cells are able to differentiate into all three germ layers. This indicates the preservation of the Hippo differentiation signal pathway, the activation/deactivation of which occurs epigenetically [It has recently been shown  that theetically .What blocks rejuvenation-like realization of the embryonic pathway and its conversion into DG?Embryos develop in immunoprivileged sites. Indeed, we believe this is the only fundamental difference that distinguishes the developing embryo, which advances from totipotency to specialization, and the differentiated cells that move in the opposite direction during recapitulation of the embryonic pathway. The data summarized earlier  indicateSo how can the immune response convert the rejuvenation process into DG?BRG1, which plays an important role in embryonic development (angiogenesis) [HOX genes; and PTPRG-AS1 –PTPRG (tumor suppressor). These epigenetic regulations have been found for synergistic interactions: LncRNA and pluripotency factors–SOX2-overlapping transcript (SOX2OT)-mediated expression via PCGF6 (PRC1 complex) of transcription factor SOX2, which is required for maintaining pluripotency. The regulation of the Wnt/β-catenin and PI3K/AKT/mTOR signaling pathways by LncRNA- and NuRD-mediated epigenetic activation of transcription factors/genes Nanog, Oct4, Sox2, Klf4, Esrrb, Sall4 and Myc, supporting pluripotency and the suppression of differentiation genes Foxl1 and Dusp4, was recently described in the literature [As we propose, development only in the immunoprivileged sites ensures the advancement from totipotency to differentiation. IG is carried out through epigenetic activation of genes/signaling differentiation pathways and epigenetic repression of growth-proliferative genes/signaling pathways of pluripotency. It is this fine self-tuning, that is, the stage-specific alternation of on/off of these two opposite signaling pathways through a complex network of positive and negative feedback loops, which results in methylation/demethylation of genes, ensuring the direction of the development vector. This tuning is carried out through the interaction of pluripotency -related factors (pathways), such as Oct4, Nanog, Sox2, Ronin, Rae28, Meis1, c-Myb, c-myc, Cbp, Gata-2, Mll and Bmi-1, which implement their functions through the blocking of two main pathways of differentiation , p16Ink4 and p19Arf, and factors/pathways of differentiation, such as p53, p21, p27, p15, which implement their function through p16Ink4 and p19Arf . A simigenesis) , and p53genesis)  as well genesis) . Anothergenesis) . It shouterature ,65. The terature . The rolterature . For exaMost likely, the dysregulation of these fine self-tuning networks is the cause of the conversion of rejuvenation into DG.p53 [These processes are complex and are not yet fully understood. For example, some authors argue that thymine DNA glycosylase  protectp53 . It is tThe fourth (and main) postulate of the new paradigm: The immune response (by type of active tolerance) to the markers of the embryonic developmental pathway causes an epigenetic blockage of the redifferentiation potential and the conversion of the rejuvenation pathway into the DG (cancer). Therefore, the induction of complete immunological tolerance to these markers  will make it possible to escape this conversion.To prevent the transformation of the rejuvenation path into the DG, it is necessary to create conditions that mimic the immunoprivileged conditions of fetal development through the induction of immunological tolerance to antigens associated with embryonic rejuvenation. An agent that can simultaneously turn on the rejuvenation process and can block DG (cancer) must have several features, in particular, tolerogenic properties, rejuvenation turn-on signal capabilities, the ability to start the process of removing by-products associated with the SASP from cells and the extracellular matrix and the ability to protect transformed cells from the host immune response.Without direct intervention in the genome/epigenomeThrough recapitulation of morphogenetic modules of early stages of ontogenesisThrough prevention of malignant conversion of this recapitulation and directing it into rejuvenation (completed somatic embryogenesis)We believe that only this method of aging elimination has real prospects for a future that is fraught with cancer, as we will be able to convert this risk into rejuvenation through the continuous cycling of cell dedifferentiation–differentiation processes, under the following conditions:At the cellular level, this will eliminate senescence, as the final stage of cells’ fate, making it only a transitional stage. At the level of the whole body, it will eliminate aging.This is real, since ‘crucial regeneration-driving genes are present in most animal genomes, implying the existence of an innate ability to regenerate lost tissues in most animals. Thus, a key aspect of diverse regenerative capacities is not the presence or absence of regeneration genes, but in the mechanisms controlling the activation of these genes after injury’ .The currently proposed approach is being rigorously tested in animal experiments.Further justification of the concept will be presented in part two of our publication with the subtitle, ‘Rejuvenation Circle.’IG – Integrating Growth, is defined here as the submission of potency of single cells composing an organism to the development program and functions of the whole organism.DG – Disintegrating Growth, is defined here as a priority of extension potency of single cells over the development program and functions of the whole organism.The embryonic rejuvenation and disintegrating growth (DG) pathways are essentially the same, but at different stages of ontogenesis, this mechanism is carried out in opposite ways.Recapitulation (self-initiation) of the embryonic pathway occurs where and when the program of development of definitive structures cannot result in effective self-renewal. In other words, it starts as a rejuvenation program but is transformed into DG.DG is simply epigenetic-blocked redifferentiation and unfinished somatic embryogenesis/rejuvenation and nothing more.The immune response (by type of active tolerance) to the markers of the embryonic developmental pathway causes an epigenetic blockage of the redifferentiation potential and the conversion of the rejuvenation pathway into the DG (cancer).


Some neoplasia—such as adrenal and thyroid glands tumors—have been associated with “tumor thrombi” both in humans and dogs. The detection and characterization of these venous tumor thrombi is important for both surgical planning and prognosis. In human medicine, contrast-enhanced ultrasonography (CEUS) is considered an accurate diagnostic technique for differentiating malignant from benign portal vein thrombosis in hepatocellular carcinomas. Data regarding the characteristics of tumor thrombi in dogs are currently lacking. Therefore, the aim of this study was to assess the feasibility of CEUS for the characterization of malignant venous thrombosis in dogs. On the basis of our results, CEUS appeared to be useful in the detection of malignant intravascular invasion; contrast uptake of the thrombus was present in all cases. In addition, CEUS may clearly detect newly formed vessels within the thrombus, and arterial-phase enhancement and washout in the venous phase were the main features in malignant thrombosis in our dogs. As CEUS is an easy to perform, noninvasive technique, its application in the detection of malignant thrombosis in dogs may be used to improve the diagnosis in oncological canine patients.Tumors of adrenal and thyroid glands have been associated with vascular invasions—so-called tumor thrombi, both in humans and dogs. The detection and characterization of venous thrombi is an important diagnostic step in patients with primary tumors for both surgical planning and prognosis. The aim of this study was to describe the use of contrast-enhanced ultrasonography (CEUS) for the characterization of tumor thrombi. Dogs with tumor thrombus who underwent bi-dimensional ultrasound (B-mode US) and CEUS were included. Seven dogs were enrolled in this retrospective case series. On B-mode US, all thrombi were visualized, and vascular distension and thrombus-tumor continuity were seen in three and two cases, respectively. On color Doppler examination, all thrombi were identified, seemed non-occlusive and only two presented vascularity. On CEUS, arterial-phase enhancement and washout in the venous phase were observed in all cases. Non-enhancing areas were identified in the tumor thrombi most likely representing non-vascularized tissue that could potentially be embolized in the lungs after fragmentation of the tumor thrombi. On the basis of these preliminary study, CEUS appeared to be useful for the characterization of malignant intravascular invasion. Tumor thrombi are defined as tumors extending into a vessel—typically a vein. It is crucial to distinguish tumor thrombi from non-malignant thrombi in the setting of neoplasia, as this often impacts staging and treatment approaches ,3,4,5,6.Ultrasound examination is fast and less invasive method to examine intra-abdominal structure, thyroid lobes and adjacent vessels, showing high sensitivity 100%) and specificity 96%) in detecting vascular invasion . In anot00% and s% in deteThe purpose of this study was to describe CEUS features of tumor thrombi in dogs, with particular attention to the risk of fragmentation and endothelial invasion and compare them with their conventional ultrasound (US) and CFD characteristics.Medical records of dogs admitted to the Veterinary Teaching Hospital of the University of Bologna from January 2012 through January 2016 were reviewed and dogs with primary masses and associated venous thrombi were selected. Dogs were included in the study if they had a complete US examination of the mass and associated thrombus, including B-mode US, CFD examination and CEUS. Only dogs with a cytological or histological diagnosis of the primary mass, associated venous thrombus or both were selected.The following information were recorded for each case: breed, sex, age, anamnesis, results of physical examination, laboratory tests and histological or cytological findings.Two-dimensional US, CFD and CEUS images were reviewed off-line. Bi-dimensional findings recorded were: Localization, shape, dimension, echostructure of the primary lesion, presence of intravascular thrombus showing anatomic continuity with the primary lesion and dilation of the invaded vessel. The evaluated CFD findings were: Presence of residual flow within the invaded vessel and presence of intralesional signal within the primary lesion and the thrombus. Finally, CEUS findings evaluated were: contrast uptake (present or absent), aspect of the contrast uptake (homogeneous/heterogeneous), margination of the thrombus (regular and well-defined/irregular and ill-defined), comparison between timing in contrast uptake by the thrombus and the invaded vessel and comparison between timing in contrast uptake by the thrombus and the primary lesion.Histological or cytological findings of the primary tumor or of the thrombus, when available, were recorded. Samples were collected by ultrasound-guided fine needle aspiration (FNA) and/or tissue core biopsy (TB) or at necropsy.Seven dogs met the inclusion criteria. The median age was 11 (7–13) years, and the median body weight was 27 (9–33) kg. Information regarding the signalment and clinical signs are summarized in ® diagnostic, Milano, Italy) through an indwelling cephalic venous catheter, followed by a rapid immediate bolus of 5 mL saline. The arrival of the contrast medium at the level of the target organ was then visualized using dedicated imaging software of the ultrasound machine that selectively displaces the signal deriving only from the contrast medium, allowing perfect definition of the perfusion pattern of the region of interest. Bi-dimensional US, CFD and CEUS findings are summarized in Bi-dimensional US and CFD examinations were performed using an ultrasound unit  equipped with different micro-convex, convex and linear array probes of different frequencies (2–9 MHz). For the CEUS examination, a linear array probe (3–9 MHz) was used. Contrast-enhanced US was performed by intravenously injecting 0.05 mL/kg (0.02 mL/lb) of a second generation US contrast medium  had surgical removal of the primary tumor and the thrombus. Histopathological diagnosis was consistent with solid-follicular thyroid carcinoma with neoplastic vascular invasion in the first case and with adrenocortical carcinoma associated with intravascular neoplastic thrombosis in the other one. Two dogs died few months after the US; necropsy showed a thyroid carcinoma with neoplastic invasion of the thyroid vein in one case (case 2) and a cortical adrenal gland carcinoma with neoplastic thrombotic caval invasion in the other (case 4). Necrotic areas within the tumor thrombus were detected at histology in one case (case 3) and endothelial invasion in another case (case 1).In 3 cases the neoplastic mass extending into the caval vein was associated with multiple hepatic lesions detected on US. In these cases, cytology of the liver nodules suggested adrenal medullary neuroendocrine tumor (cases 5 and 6) and retroperitoneal liposarcoma (case 7) as primary diagnoses. Surgery was recommended, but declined by the owners; accordingly, histopathology of the intravascular mass was not available for these last three cases, and the diagnosis of tumor thrombi in these cases was only presumptive.In this study, CEUS could identify all tumor thrombi, whereas B-mode US allowed their visualization but could not establish the continuity with the primary tumor in every case. In addition, CEUS could better describe the vascularity of the tumor thrombi compared to CFD.Conventional B-mode US is a fast and noninvasive tool to examine intra-abdominal structures, superficial neck structures, thyroid lobes and adjacent vessels. A recent study showed that conventional US is 100% sensitive and 96% specific in detecting vascular invasion of the caudal vena cava in dogs with adrenal gland tumors . HoweverConventional B-mode US detected venous thrombosis in all patients of our study. Bi-dimensional features of tumor thrombi have been previously reported in literature and they are characterized by continuity between the primary mass and the thrombus ,19 and dColor-Doppler examination of the thrombus may be helpful in detecting intralesional signal due to presence of newly formed tumoral vessels, suggesting a neoplastic origin of the thrombus. However, this technique is limited by the low sensitivity of Doppler in detecting small vessels, low velocity blood flow and microvascularization in general . In thisIn human medicine, CEUS showed higher sensitivity in detecting vascularized tumor thrombosis when compared to CFD examination ,15. In hIn dogs, some studies have been carried out in order to determine the utility of contrast-enhanced CT in the detection of vascular luminal invasion by adrenal gland masses ,24. TheyIn our case series, contrast uptake of the thrombus was considered the main feature of malignancy, and it was present in all cases. Contrast-enhanced US may also clearly detect new-formed vessels within the thrombus. Studies in humans, however, reported that CEUS may misdiagnose a benign thrombus when some of its portion are revascularized, mimicking a vascularized malignant neoplastic thrombosis .For this reason, other features were evaluated. Particularly, the timing of thrombus enhancement was always compared to the invaded vessel and in three cases to the primary neoplastic mass. Malignant thrombi showed a contrast uptake synchronous with the primary mass while the enhancement was always anticipated in the thrombus when compared to the invaded veins. This behavior is meant to be a consequence of newly formed arterial vessels inside the malignant thrombi  that typically receive the contrast before it reaches the systemic venous system .The aspect of the contrast uptake of the tumor thrombi was homogeneous in two dogs with thyroid tumors, while was heterogeneous, with several non-enhancing areas within the thrombus in the caval tumor thrombi. This aspect could reflect the presence of necrotic areas within the thrombus . The necrotic areas within a tumor thrombus could lead to its fragmentation and predispose to pulmonary thromboembolism. For this reason, the possibility of a thrombus to fragment should be taken in account when deciding the treatment, in case of surgery in deciding the timing for the surgery and to formulate a prognosis.Similarly, the possibility of CEUS to detect endothelial invasion could be extremely useful for surgical planning, as, for instance, a cavectomy is required in case of endothelial invasion from the neoplastic adrenal tissue. The irregular and ill-defined margination of the thrombus, with particular attention to the portions adjacent to the vessel walls, could reflect the endothelial invasion, as confirmed histologically in one of our cases.This study has some limitations mainly related to its retrospective nature. First of all, the limited number of cases associated with the absence of dogs affected by benign thrombi prevented the possibility to evaluate the accuracy of CEUS in distinguishing benign from malignant thrombi. The lack of histological confirmation of thrombus malignant origin in three cases and confirmation of necrotic areas within the thrombus or endothelial invasion in only two cases are others limitations of this study. Further studies, including cases of nonneoplastic thrombi, are needed in order to confirm the peculiarity of CEUS features of malignant thrombi.In conclusion, this is the first report describing the use of CEUS to characterize intravenous thrombosis in dogs with malignancies. On the basis of these preliminary experience, CEUS appeared to be easy to perform and useful for the detection of malignant intravascular invasion. In particular, the presence of an arterial-phase enhancement of the thrombus and a washout in the venous phase were consistently identified for the malignant thrombi characterized in this study.


It is of great importance for pipeline systems to be is efficient, cost-effective and safe during the transportation of the liquids and gases. However, underground pipelines often experience leaks due to corrosion, human destruction or theft, long-term Earth movement, natural disasters and so on. Leakage or explosion of the operating pipeline usually cause great economical loss, environmental pollution or even a threat to citizens, especially when these accidents occur in human-concentrated urban areas. Therefore, the surveying of the routed pipeline is of vital importance for the Pipeline Integrated Management (PIM). In this paper, a comprehensive review of the Micro-Inertial Measurement Unit (MIMU)-based intelligent Pipeline Inspection Gauge (PIG) multi-sensor fusion technologies for the transport of liquids and gases purposed for small-diameter pipeline (D < 30 cm) surveying is demonstrated. Firstly, four types of typical small-diameter intelligent PIGs and their corresponding pipeline-defects inspection technologies and defects-positioning technologies are investigated according to the various pipeline defects inspection and localization principles. Secondly, the multi-sensor fused pipeline surveying technologies are classified into two main categories, the non-inertial-based and the MIMU-based intelligent PIG surveying technology. Moreover, five schematic diagrams of the MIMU fused intelligent PIG fusion technology is also surveyed and analyzed with details. Thirdly, the potential research directions and challenges of the popular intelligent PIG surveying techniques by multi-sensor fusion system are further presented with details. Finally, the review is comprehensively concluded and demonstrated. At present, pipeline transportation systems are one of the safest, cost-effective and efficient transportation tools in comparison with conventional land-based, marine, air and railway transportation ,2,3. TheGenerally, there are usually three types of pipelines including the existing pipeline, the newly trenched pipeline and the trenchless pipeline. They are classified based on the pipeline surveying technologies underground, both in land and marine conditions . The advThere are a dozen types of PIGs used for different pipeline-related tasks ,23,24,25The inspection system of the intelligent PIG is made up of various inspection sensors according to the inspection principles of different inspection tasks for the pipeline ,30,31,32In this paper, to assist researchers and engineers to fully understand the development and applications of the intelligent PIGs, a comprehensive review of the Micro IMU (MIMU)-based intelligent PIG multi-sensor fusion technologies for small-diameter pipeline surveying is introduced. Specifically, the four types of intelligent PIGs and their corresponding pipeline defect detection methods that are typically used for the small-diameter pipeline surveying is introduced in Usually, there are four types of intelligent PIGs that are widely used for the PIM of the small-diameter pipeline, which are categorized by the regular smart PIG, the remoted PIG, the gyroscopic PIG and the SmartBall PIG according to their dynamic motion mechanisms for surveying various pipelines ,38,39,40In In In In The flow chart of different leakage inspection technologies is shown in To be more intuitive, The pipeline surveying technology by intelligent PIG is originally from the design and manufacture of the intelligent PIG, and it is usually classified by two main categories according to the key sensors installed in the intelligent PIG during the overall surveying process. This section reviews the non-inertial and the inertial-based intelligent PIG surveying technologies for the PIM during the online inspection.The regular smart PIG is a usually designed as a rectangular-shaped robot, which would fit tightly in the inner surface of cylindrical-shaped pipelines. At the beginning of the designing phase, only three symmetrical installed odometers are used as the travel distance measurement equipment of the regular smart PIG in the inspected pipeline, which is shown in In addition, the PIG transmitter and the PIG tracking and locating receiver, which are shown in Nevertheless, the 3D trajectory of the inspected pipeline is not accessible by using the non-inertial-based PIG surveying technology. The 3D trajectory of the inspected pipeline is of vital importance both for the PIM and for the digital and intelligent pipeline management especially when these pipelines are routed under the urban areas and geologically unstable areas ,60.To improve the surveying precision of the intelligent PIG and avoid the problems of the non-inertial-based PIG surveying technology, the inertial sensors are the best choice to remedy these problems . The ineCurrently, the typical tactical-grade FOG-based Inertial Measurement Units (IMUs) used for pipeline surveying in intelligent PIG are the North Grumman LN-200 FOG IMU a, the KVFor the intelligent PIG of small-diameter pipeline surveying, both the conventional mechanical gyroscope constructed PSINS and high-end FOG constructed SINS cannot be used directly because of their limitations in the measurement range and the dimensions of the small-diameter pipelines. Fortunately, with the rapid development of the MEMS sensor technology in recent years, the matured MEMS IMU could be installed inside the intelligent PIG and make possible pipeline surveying tasks, especially for the small-diameter pipeline ,72,73,74However, their surveying precision cannot meet the precision requirements when only adopting the conventional integration algorithms usually based on the SINS, odometers, aboveground markers (AGMs) and the related intelligent PIG surveying technology. This is mainly because the small dimensions of the small-diameter pipeline limit the power supply and travel distance for each launch and receiving of the intelligent PIG. However, the MEMS IMU needs the distance of two adjacent AGMs less than 100 m to ensure the surveying precision, while the tunnels, aboveground forests, high buildings, roads, and rivers usually make the AGMs difficult to implement within 100 m ,71. TherIn this section, five types of small-diameter intelligent PIG surveying technologies based on the multi-sensor fused algorithm are introduced. Except for the traditional error estimation algorithms when using the high-precision MIMU and different measurement updates, these methods also utilize the pipeline characteristics, such as Pipeline Junction (PJ), Pipeline Segment Length (PSL) and the PBA to improve the surveying precision of the small-diameter intelligent PIG.The first and often-used scheme of the intelligent PIG surveying technology is the SINS/Odo/AGM integration; its schematic diagram is shown in Generally, the Extended Kalman Filter (EKF) and the Rauch–Tung–Striebel Smoother (RTSS) are combined to implement the estimation of the SINS errors and the MIMU errors at the same time . The EKFHowever, this technical scheme is viable when the inspected pipeline length is within few hundreds of meters and only by using the MIMU. The characteristics of the inspected pipeline are not fully used to improve the surveying precision of the intelligent PIG. The surveying precision of the intelligent PIG usually cannot reach the precision requirements especially when the diameter of the pipeline is less than 30 cm, which is mainly because the precision performances of the MIMU cannot meet the requirements when compared with the commonly used FOG-based SINS.Pipeline Junctions (PJs), such as the valves, ring welds and the pipeline bending angles, are the key components that connect two adjacent Straight Pipeline Segments (SPS) or the Bent Pipeline Segments (BPS) ,79. PJs The second valuable scheme of the intelligent PIG surveying technology is the SINS/Odo/AGM/PJ integrated method. Its schematic diagram is shown in When the aboveground environments of the inspected pipeline are covered by tunnels, forests, high buildings, roads, rivers and so on, the coordinates of the AGMs cannot be obtained accurately within a few hundreds of meters because of the DGNSS signal is totally blocked or interrupted by the surrounding environment. Fortunately, the Pipeline Segment Length (PSL) information is possible to be archived since the first routing of the overall pipeline. The PSL information can be obtained from the routing files and utilized for continuous 3D coordinate updates at the SPS part of the inspected pipeline. As such, the PSL can provide alternative information for the continuous 3D coordinate updates in the SPS part, especially when the AGMs coordinates are not available.Based on the PSL information, the third scheme of the intelligent PIG surveying technology is the SINS/Odo/PJ/PSL integration structure. The corresponding schematic diagram is shown in PBA is another important property that could be adopted for the continuous azimuth and pitch angle updates at the PBA part and to improve the PBA detection precision and the overall surveying precision of the intelligent PIG. PBA information could be checked from the archived routing files of the inspected pipeline on one hand. On the other hand, the PBA could be calculated by combing the measurements of the symmetric installed odometers and the MIMU when the PIG travels through the PBA part ,54.The fourth scheme of the intelligent PIG surveying technology is the SINS/Odo/AGM/PJ/PBA integration, and its schematic diagram is shown in The fifth scheme of the intelligent PIG surveying technology is the SINS/Odo/PL/PSL/PBA integration; its schematic diagram is revealed in At present, the micro-inertial sensors are also sensitive to ambient temperature variation and dynamic shocks and vibrations from complex environments when compared with other high-precision, large-dimension and expensive FOG-based inertial sensors ,83. HoweMoreover, the redundant MIMU configuration is another way to improve the overall precision of the MIMU-based PIG surveying system, especially when the independent MIMU-based multi-sensor surveying system cannot satisfy the precision requirements ,88. ActuAll in all, the precision of the small-diameter intelligent PIG surveying system would also improve with the accuracy enhancement of the advanced inertial sensors technology.Except for the traditional EKF signal estimation and processing technology for improving the surveying precision of the intelligent PIG, the nonlinear signal filter and estimation algorithms such as the Unscented Kalman Filter (UKF), Particle Filter (PF), Cubature Kalman Filter (CKF) and their adaptive estimation algorithms are widely used in the navigation of vehicles, shipborne and aerospace fields ,90,91,92In addition, with the rapid development and application of the Artificial Intelligent (AI) technology, the AI-related intelligent technology is also a potential research direction for the optimal estimation of the multi-sensor-fused intelligent PIG surveying system ,97,98,99The multi-sensor fused technology of intelligent PIG surveying is one of the key technologies to implement the PIM for small-diameter operating pipelines . Specifi(1) Some of the inspected pipelines cannot obtain precise coordinate information of the AGMs before the pigging operation, which is used to coordinate corrections of the intelligent PIG surveying system. This is mainly because the aboveground environment of these pipelines is occupied by the infrastructures such as buildings, roads, lakes, forests and so on. The GNSS signal is blocked or interrupted by these objects, so the precise coordinate of the AGMs cannot be provided.(2) Some of the pipelines that can be surveyed by the intelligent PIG only have one entrance point and no exit point, so the intelligent PIG should be launched and received at the same entrance point. Meanwhile, the intelligent PIG surveying system only has the coordinate updates at the entrance point that would influence the overall intelligent PIG surveying precision.(3) The surveying precision of the small-diameter intelligent PIG should be higher, especially when their surroundings are covered by pipelines, buildings, roads, rivers and so on. This is mainly based on the need for convenient repair and will not destroy any adjacent infrastructures as well.(4) Modern digital and intelligent pipeline construction and routing technology requires PIG surveying technology to be fully digital and at least partially intelligent . Therefo(5) The integration of modern digital and intelligent pipeline technology, small-diameter pipeline inspection and surveying technologies, the Geographic Information System (GIS) ,107,108,Small-diameter pipelines account for approximately 1/3 of the total routed pipelines, which are used for different types of energies transportation. This paper introduced a comprehensive review of MIMU-based intelligent PIG multi-sensor fusion technologies for small-diameter pipeline surveying. The existing and most popular four kinds of intelligent PIGs and their corresponding pipeline defect inspection technologies for small-diameter pipeline surveying were reviewed. In addition, two types of intelligent PIG surveying technologies, non-inertial-based and inertial-based, were introduced. Then, five different schematic diagrams of the intelligent PIG surveying methods were demonstrated for different applications. Finally, the trends and challenges of small-diameter pipeline surveying technologies are also analyzed and revealed in this paper. Therefore, to implement the PIM and the safety operation of the routed small-diameter pipelines are of great importance to reduce the overall cost and negative social influence caused by the pipeline leakages or even explosions.As for the future work, we will further investigate low-cost multi-sensor fused small-diameter pipeline surveying technologies that focus on optimal estimation algorithms and new types of pipeline structures, as well as the redundant MIMU configuration-based multi-sensor fused intelligent PIG surveying system.


The development of climate change resilient crops is necessary if we are to meet the challenge of feeding the growing world’s population. We must be able to increase food production despite the projected decrease in arable land and unpredictable environmental conditions. This review summarizes the technological and conceptual advances that have the potential to transform plant breeding, help overcome the challenges of climate change, and initiate the next plant breeding revolution. Recent developments in genomics in combination with high-throughput and precision phenotyping facilitate the identification of genes controlling critical agronomic traits. The discovery of these genes can now be paired with genome editing techniques to rapidly develop climate change resilient crops, including plants with better biotic and abiotic stress tolerance and enhanced nutritional value. Utilizing the genetic potential of crop wild relatives (CWRs) enables the domestication of new species and the generation of synthetic polyploids. The high-quality crop plant genome assemblies and annotations provide new, exciting research targets, including long non-coding RNAs (lncRNAs) and cis-regulatory regions. Metagenomic studies give insights into plant-microbiome interactions and guide selection of optimal soils for plant cultivation. Together, all these advances will allow breeders to produce improved, resilient crops in relatively short timeframes meeting the demands of the growing population and changing climate. The species are subdivided into several groups, and not all are cross-compatible. In recent analyses, Oryza rufipogon, a wild species believed to be the immediate progenitor of O. sativa, showed higher sequence diversity and harbored sequence and genes completely missing from the population of cultivated rice  domestication. The domestication syndrome refers to a unique collection of phenotypic traits associated with the genetic change of an organism from a wild progenitor to a domesticated one. Most of the changes linked to the domestication syndrome, such as grain dispersal in wheat, barley, and rice; apical dominance in maize; fruit size in tomato; and grain quality in wheat, result from modification of a single or few genes  and Hordeum (barley genus) over 5 Mya  to identify a domestication-related gene controlling seed dormancy in soybean and then showed that orthologs of this gene in rice and tomato also display evidence of selection during domestication. Analysis of transgenic plants confirmed the conservation of function in soybean, rice, and Arabidopsis, highlighting the power of comparative genomics in new domestication target gene identification  observed significant differences in phenotypes (Polyploid plants possess three or more sets of homologous chromosomes stemming either from the duplication of a single genome (autopolyploidy) or hybridization followed by doubling of two diverged genomes  identified genomic regions associated with fertility, which harbored orthologs of A. thaliana genes involved in meiosis , a major crop accounting for 20% of world daily food consumption, is an allohexaploid plant originated via multiple hybridizations. The most accepted hypothesis of its origin is demonstrated in As an example, bread wheat  and surrounding plant roots in the soil (rhizosphere) have a significant impact on the host, including health and fitness, productivity, and responses to climate change . Plants rganisms . Some barganisms . At the rganisms .Soil microorganisms are in constant competition to accumulate around the root and access the plant secreted carbohydrates . Plants Puccinia triticina, one of the most common diseases of wheat globally, does not affect rice, maize, or any other crop. World-wide over-cultivation of a few crops  with low genetic diversity has led to the increased pathogen inoculum and accelerated pathogen evolution, promoting its spread globally  and conformation capture (Hi-C) revealed that the latter harbored ~3,000 assembly specific genes as well as over 500 previously unidentified transposable element (TE) families  or one of the classes of non-coding RNAs ncRNA; . Gene moproteins . Early ootations . Currentotations . Annotatotations .A. thaliana, >90% of genes have been annotated with putative functions and ~50% of genes have annotation supported by experimental evidence , capable of recruiting transcription factors and promoting gene expression. Changes in CREs are considered one of the key evolutionary mechanisms underlying, for example, emergence of novel morphological forms  and the bidopsis . SNPs cobidopsis . An SNP bidopsis . An insetication . In the d cotton . The rapd cotton . ImproveGeneration of the reference genomes and subsequent large-scale re-sequencing of hundreds to thousands of individuals per species revealed extensive genomic diversity, including large-scale presence/absence variation . As our In addition, the pangenome offers a natural replacement for the current paradigm of using a single reference genome, as the choice of the reference affects downstream genomic analyses, including GWAS and gene expression quantification . Using pAlmost all aspects of genomic analyses can now be supported by the development and implementation of machine learning algorithms. Machine learning algorithms find new patterns and “learn” the necessary predictive features from the data, rather than rely on pre-existing criteria. This property makes them suitable for analysis of complex, multilayer datasets, where expert knowledge is incomplete or inaccurate, and when the amount of data is too large to be handled manually . Severalde novo domestication feasible.Advances in molecular and genomic technologies resulted in isolation and characterization of many agronomically important genes, for example ones controlling seed shattering, dormancy, increasing seed number, and size . ImprovePlant phenotyping refers to the measurement of any morphological or physiological characteristics of plants. The phenotype can result from the action of individual genes, gene-by-gene, or gene-by-environment interactions. Many agronomically essential traits, such as yield and its components and drought/salt tolerance, are controlled by multiple genes with small effects and their interactions with the environment . For praHigh-throughput phenotyping platforms, which employ robotics and spectral-based imaging technologies, are rapid and reliable . The maide novo domestication and allow rapid improvement of orphan crop plants, targeting the current and future climate challenges. The success of genomics in crop improvement is also influenced by the type of trait under investigation. For example, traits strongly affected by the environment and the interaction between genotype and the environment are more challenging to study and modify.Recent advances in genome sequencing, assembly, and annotation allowed unprecedented access to crop plant genomic information. High-throughput phenotyping techniques have been significantly advanced through the introduction of hyperspectral cameras and specialized processing software. Integration of genomic and phenomic data provides an opportunity to identify new agronomically relevant genes and characterize their functions. This knowledge has direct practical implications and can be translated to crop plant improvement using genome editing. While genome editing is currently applied in major crops and model plants, the technique has the potential to accelerate Disease resistance and dwarfing genes were introduced into crops such as wheat and rice during the green revolution . BreederMP and AG contributed equally. 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.


Senescence is characterized by a permanent cell cycle arrest that is elicited in response to different stresses. In addition, senescent cells undergo multiple other phenotypic alterations, such as autophagy modulation, metabolic reprogramming, and the senescence-associated secretory phenotype (SASP). These senescence-related and inflammatory effects prevail within tumors and are strongly controlled by cancer properties, and inflammatory mediators further maintain and propagate the senescence process to adjacent cells. It is important to consider these detrimental effects that may drive tumorigenesis or cancer relapse. Importantly, cancer-associated adipocytes (CAAs) are one of the primary stromal cells in various tumor microenvironments and favor tumor progression by releasing various factors that can mediate local and systemic effects. However, it remains unclear whether CAAs possess senescent features. In this review, we discuss the complex relationship between senescence and CAAs and highlight important considerations for therapeutics. Adipocytes are one of the primary stromal cells present in multiple cancers, such as breast, ovarian and colorectal cancer . SpecifiCellular senescence was originally identified as stable growth arrest, and it is further thought to be a stress response that can be triggered by a variety of intrinsic and extrinsic types of damage, such as oncogenic activation, oxidative and genotoxic stress, mitochondrial dysfunction, irradiation, and chemotherapeutic agents . Many phAdipose tissue plays a central role in longevity and age-related disorders . The dysAutophagy is a mechanism for isolating and degrading various cytoplasmic structures, such as damaged organelles and invasive microorganisms, via lysosomes. Activated autophagy in the stroma promotes cancer progression. For example, high expression of Beclin-1, an inducer of autophagy, promotes the growth of fibroblasts in breast cancer . For humIn summary, studying autophagy in CAAs enables us to recognize the link between autophagy and senescence among these different compartments . In certin vitro and facilitate the vascularization of tumors in xenograft experiments by secreting VEGF (The SASP suggests that senescent cells communicate with neighboring cells to spread the stress response and influence their microenvironment. The SASP increases the expression of a range of chemokines (chemoattractants and macrophage inflammatory proteins), proinflammatory cytokines , growth factors , and matrix-remodeling enzymes . Interesing VEGF . Ultimating VEGF . In concSimilar to senescent fibroblasts within the tumor microenvironment, CAAs stimulate tumor growth, angiogenesis, invasion, and metastasis to facilitate the transformation process . The tumTumor-transformed adipocytes have been demonstrated to form via the expression of various tumor-derived inflammatory factors and contain multiple exosomes , 2019c. Cellular senescence, a typical characteristic of cancer, can be triggered by a variety of mechanisms in and around tumors and has deleterious effects on tumor initiation, growth, recurrence, and therapeutic efficacy. However, the senescent characteristics of adipocytes and the mechanisms by which they affect the phenotype of tumor cells remain incompletely understood. Indeed, autophagy, a central regulator in senescent cells, mediates the functions of CAAs. Therefore, further characterization of autophagy in CAAs and cancer is crucial for us to understand these mechanisms and develop targeted therapeutic approaches in the future. Additionally, it is important to again note the similarities between the SASP and the expression profile of CAAs. The overlap in expression profiles between these two tumor-promoting cell types suggests that the regulatory pathways that are further characterized in senescent cells will be directly applicable in CAAs. Given the potent tumor-promoting nature of the SASP, identifying the regulatory mechanisms that govern the expression of genes related to this phenotype will contribute to the development of stroma-targeting cancer therapies. This concept is consistent with our speculation that a subset of senescent CAAs is present and that OIS may be a major contributor to the generation of senescent adipocytes. The current challenge in the field is to discern which changes are critical for tumor progression and to determine how cell-autonomous mutations within incipient tumor cells influence stromal changes.QW and BL were responsible for collecting and collating documents. QW and BL were responsible for writing this review, while SiS was responsible for the revision and ShS was responsible for editing and submission. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Spinal cord injuries (SCIs) represent a variety of conditions related to the damage of the spinal cord with consequent musculoskeletal repercussions. The bone and muscle tissues share several catabolic pathways that lead to variable degrees of disability in SCI patients. In this review article, we provide a comprehensive characterization of the available treatment options targeting the skeleton and the bone in the setting of SCI. Among the pharmacological intervention, bisphosphonates, anti-sclerostin monoclonal antibodies, hydrogen sulfide, parathyroid hormone, and RANKL pathway inhibitors represent valuable options for treating bone alterations. Loss phenomena at the level of the muscle can be counteracted with testosterone, anabolic-androgenic steroids, and selective androgen receptor modulators. Exercise and physical therapy are valuable strategies to increase bone and muscle mass. Nutritional interventions could enhance SCI treatment, particularly in the setting of synergistic and multidisciplinary interventions, but there are no specific guidelines available to date. The development of multidisciplinary recommendations is required for a proper clinical management of SCI patients. Spinal cord injuries (SCIs) encompass a spectrum of conditions associated with modifications in the function of both central and peripheral nervous systems. Due to the crucial role of the spinal cord in linking the brain with the body, these alterations may lead to dramatic consequences in terms of motor, sensitive, and visceral controls .A complex variety of biological pathways arising in both bone and muscle tissues plays a clinically relevant role in SCIs. Hence, these patients experience important changes in the bones  that cause a significantly increased risk of fractures, even after minor traumas  , 3. ThesIn this scenario, understanding the biological interplay of the bone and muscle tissues is crucial for proper clinical management of SCIs. Here, we sought to provide a comprehensive portrait of the potentials and limitations of the various treatment options available (or proposed) to date for both osteoporosis and muscle atrophy occurring after SCIs.The use of single, combination, or sequential therapy protocols in the management of bone alterations in SCI is a matter of controversy. After the achievement of clinical benefits, the discontinuation of osteoanabolic treatments could result in a rapid loss of the newly gained bone –12. For Bisphosphonates are the most used class of drugs in the prevention and treatment of osteoporosis . SeveralMurine SCI models showed that anti-sclerostin antibodies could preserve the osteocyte morphology and structure, blocking the skeletal deterioration after either motor-incomplete  or motorHydrogen sulfide (H2S) is a colorless and poisonous gas acting as a gas transmitter to regulate different signaling pathways . It has Parathyroid hormone (PTH) is a well-known player in calcium metabolism. The subcutaneous intermittent administration of PTH has been used for two decades as a valid anabolic therapeutic agent for osteoporosis treatment , 24. A rThe receptor activator of nuclear factor-kB ligand (RANKL)/osteoprotegerin (OPG) system is one of the main regulators of bone remodeling . DenosumTo date, there is no robust evidence about local pharmacological agents that can be used to counteract the muscle loss after SCI. Most data currently available are derived from studies on healthy subjects or patients with chronic conditions of which some  share some pathophysiological pathways with SCI. In this setting, androgens have been extensively studied, either in animal models and in humans. Particularly, testosterone and anabolic-androgenic steroids (AAS) such as nandrolone, as well as the selective androgen receptor modulators (SARMs), have been proposed as pharmacological strategies to hinder the loss phenomena at the musculoskeletal level in different chronic illnesses, such as immunodeficiency, long term glucocorticoid treatment, and aging , 40. DatExercise is the first treatment to increase muscle mass and there is growing evidence that the basic mechanisms that regulate muscle hypertrophy can be used to counteract disuse atrophy . The mecA recent study performed on 42 male Wistar rats showed that stretching is helpful for the correction of contractures after SCI . In addiIn the early 1990s, functional electrical stimulation (FES) rowing exercise has been developed as an aerobic training program for SCI patients , 61. ThiIn the recent past, whole-body vibration (WBV) effects on bone architecture after SCI have been investigated with inconsistent results. In 2016, Dudley-Javoroski et al. showed that 12 months of vibration training did not preserve BMD or trabecular architecture in subjects affected by chronic SCI, showing bone tissue insensitivity to mechanical loading interventions . These rEpidural electrical stimulation (ESS) is a promising technique for improving motor recovery in chronic patients with SCI , 70. PreDespite a healthy diet is recommended in SCI individuals, there is a substantial lack of nutritional guidelines for these patients –73. In aThere is no unequivocal evidence about the superiority of a single therapeutic intervention to counteract the modifications in bone and muscle tissues after SCI. Given the complex and multifaceted nature of these conditions, it is conceivable that the best therapeutic strategy consists of the synergistic use of several different interventions in order to optimize the outcome at bone and muscle level in SCI patients.Considering the promising role of FES rowing exercise in promoting muscle contraction with combined mechanical loading of lower limb long bones in SCI patients, a therapeutic synergism with drugs acting at the bone level has been proposed . This coTeriparatide, a 34 amino acid peptide representing the N-terminal bioactive portion of human PTH, is the only anabolic agent approved to enhance bone mass and prevent fragility fractures , 84. A rDespite the progress that has been made in the field of regenerative spinal cord medicine, the majority of SCI patients continue to experience not only the direct neurological damage but also the clinically relevant secondary complications affecting the muscle and bone tissues. Due to the scarcity of available data, attention should be paid in making strong statements or recommendations for the management of these patients. However, it is anyway possible to translate some of the existing information into real-life clinical practice and to outline the future directions for primary research and clinical studies. The main bone and muscle therapeutic interventions in SCI animal models and human subjects are outlined in .Given that the bone and muscle tissues share not only their origin from the mesenchymal multipotent stem cell but also important signaling pathways, response to mechanical stimulation, and complications, it is reasonable to conceive that treatments should ideally target both tissues. From this perspective, physical exercise, nutrition, and electrical stimulation seem to be the most promising and rational way of treating both muscle atrophy and osteoporosis. In particular, the epidural electrical stimulation has the interesting potential of fostering both the neurological recovery and the increase of the muscle mass. Hormonal treatments represent another valuable option but their safety profile needs to be investigated in the long term.Another future therapeutic option might be the modulation of microRNAs (miRNAs) which are non-coding RNA molecules involved in transcriptional regulation that target pathways of human diseases. They might be considered not only a target to prevent bone and muscle modifications but also a potential powerful therapeutic intervention in improving the functional recovery after SCI. In this regard, it has been recently showed how miRNA-411 and miRNA-340-5p increase could reduce apoptosis, gliosis and glial scar formation, and all the inflammators in SCI rats , 87.SCIs encompass a wide variety of abnormal conditions that reverberate at the musculoskeletal level. Many secondary modifications show similarities and shared pathophysiological patterns to both muscle and bone tissues. The limited evidences in the literature summarized in this review suggests the need of an early start of any therapeutic intervention. However, clear evidence about the most effective treatment to counter bone and muscle modifications after SCI is missing.A deeper understanding of the bone and muscle interactions would improve the outcome of the patients affected by several conditions related to musculoskeletal changes, such as SCI, aging, space travels, and prolonged immobility. Additional insights in bone and muscle interactions will be germane for the development of multitargeted specific therapeutic and preventive strategies acting on both bone and muscle tissue. The development of multidisciplinary recommendations is required for the clinical management of these patients at an individualized level.MI and SC designed the study. MI, AS, SC, AB, FR, and LR reviewed the literature. MI, AS, NF, SC wrote the manuscript. All authors revised the paper and approved the final edition.The reviewer LP declared a shared affiliation, with no collaboration with one of the authors NF, to the handling editor at time of review. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In late December 2019, an outbreak due to a novel coronavirus, initially called 2019-nCoV, was reported in Wuhan, China ..14].The coronavirus spike protein is a surface protein that mediates host recognition and attachment. It consists of two functional subunits: the S1 subunit which contains a receptor-binding domain (RBD) responsible for host cell receptor recognizing and binding, and the S2 subunit which is involved in the fusion of the viral and host membranes . The spiTherefore, polymeric imprinted nanoparticles could be potentially used as drug-free therapeutics in the treatment of the SARS-CoV-2 infection. Plastic antibodies targeting vulnerable sites on viral surface proteins, indeed, could disable receptor interactions and protect an uninfected host that is exposed to the virus. In vivo applications demand MIPs in the form of nanoparticles and there are evidences that nanoMIPs are not toxic in cell culture or when tested with mice .Moreover, when loaded with antiviral agents, these nanoparticles could act as a powerful multimodal system combining their ability to block the virus spike protein with the targeted delivery of the loaded drug. In addition, the same nanoparticles can be further engineered to become an immunoprotective vaccine or an MIP-based sensor for diagnostic purpose.Based on these considerations, Molecular Imprinting represents a very promising technology for the preparation of polymeric materials with high selective recognition abilities for a target molecule. On the other hand, the imprinting of biomacromolecules, including peptides, proteins, whole viruses or parts of them, presents several challenges due to the size, solubility, fragile structure and stability of these templates. Moreover, virus and viral components availability is also a key issue. Last but not least, sensitivity and selectivity of these polymeric matrices require further improvement to be comparable to those of natural antibodies. The research work of Parisi et al. aims to overcome these limits to obtain MIP nanoparticles able to selectively recognize and bind the spike protein of the novel coronavirus and counteract the infection process.


The recent advancements in the knowledge of lysosomal biology and function have translated into an improved understanding of the pathophysiology of mucopolysaccharidoses (MPSs). The concept that MPS manifestations are direct consequences of lysosomal engorgement with undegraded glycosaminoglycans (GAGs) has been challenged by new information on the multiple biological roles of GAGs and by a new vision of the lysosome as a signaling hub involved in many critical cellular functions. MPS pathophysiology is now seen as the result of a complex cascade of secondary events that lead to dysfunction of several cellular processes and pathways, such as abnormal composition of membranes and its impact on vesicle fusion and trafficking; secondary storage of substrates; impairment of autophagy; impaired mitochondrial function and oxidative stress; dysregulation of signaling pathways. The characterization of this cascade of secondary cellular events is critical to better understand the pathophysiology of MPS clinical manifestations. In addition, some of these pathways may represent novel therapeutic targets and allow for the development of new therapies for these disorders. The knowledge on the pathophysiology of mucopolysaccharidoses (MPSs) has evolved over a long period of more than a century. The first MPSs were initially identified as distinct clinical entities ,2,3,4,5 The discovery of lysosomes and the characterization of their role in cell biology and human disease marked a decisive turn in the history of MPSs . Like foNowadays, with the changing vision of lysosomal biology, there is a renewed interest in the pathophysiology of LSDs, including MPSs. A large number of studies have challenged the traditional concept of lysosomes as exclusively degradative organelles, and LSDs are now viewed as disorders that simultaneously affect multiple cellular pathways and signaling cascades, each contributing to disease pathophysiology and to clinical manifestations.The MPSs are lysosomal storage diseases, due to deficiencies of enzymes involved in the breakdown of GAGs. GAGs are a heterogeneous family of highly sulfated, complex, linear polysaccharides that are composed of repeating disaccharide units and are present in every mammalian tissue . The degDifferent lines of research have changed our view of MPSs pathophysiology in recent years. Significant advances derived from studies on GAG functions in cell biology. GAGs have a variety of important biological roles. For a long time, they were thought to be exclusively constituents of extracellular matrix and membranes, and to be mainly involved in cell hydration and structural scaffolding. However, recent evidence indicates that GAGs also play a key role in cell signaling and modulate several biochemical processes that are fundamental for cell biology, including regulation of cell growth and proliferation, promotion of cell adhesion, anticoagulation, wound repair, and others . In partAdditional and critical information on the pathophysiology of MPS was gathered thanks to studies that clarified the role of lysosomes in cell biology. The degradative function committed to the turnover of cellular constituents was long considered the primary task of lysosomes. This function was seen as a “house-keeping” process that was constitutively active in cells. Recent studies have challenged these assumptions and have provided incontrovertible evidence that the lysosomal compartment is part of a complex pathway, the autophagic-lysosomal pathway (ALP), and that lysosomal biogenesis and the activation of this pathway are tuned in adaptation to environmental stimuli, through the phosphorylation status and subcellular localization of transcription factor EB (TFEB) ,12. ThesGiven GAGs role in cell biology and in signaling pathways, it is not surprising that mutations causing defects in the degradation of these molecules have highly debilitating consequences, with multisystemic involvement and variable association of somatic, neurological, hematologic, and ocular symptoms. In addition, according to the newest information on lysosomal biology and on their central role in many cellular functions, multiple and diverse events are now emerging as important players in the pathogenesis of MPSs. Specifically, these events include storage of secondary substrates unrelated to the defective enzyme; abnormal composition of membranes and aberrant fusion and intracellular trafficking of vesicles; impairment of autophagy; mitochondrial dysfunction and oxidative stress; dysregulation of signaling pathways and activation of inflammation; abnormalities of calcium homeostasis and signaling ,18,19,20In several LSDs, including MPSs, secondary storage of substrates that are not explained by the primary lysosomal defect has been consistently documented. The types of secondarily stored compounds are highly heterogeneous and include glycosphingolipids, phospholipids, and cholesterol ,25,26,27Secondary storage has been described both in patients affected by MPSs and in animal models from different species. A comprehensive analysis of brain cortex tissues from post-mortem autopsy samples in patients affected with MPS I, II, IIIA, IIIC, and IIID was performed by biochemical analytical procedures (high performance liquid chromatography) and by histochemical staining of fixed tissues. This analysis revealed both changes in GAG composition  and accumulation of secondary substrates including GM2 and GM3 gangliosides and lactosylceramide .Similar studies were also done in animal models. Morphological and histological studies in huntaway dogs, a canine model of MPS IIIA, showed variably stained storage granules within neurons, including some that stained for gangliosides. On ultrastructural analysis, these granules contained both dense granular materials interpreted as GAGs, and a variety of multilamellar bodies interpreted as ganglioside accumulation .In a feline model of MPS VI, abnormal lysosomal inclusions were pleiomorphic and resembled the zebra bodies and dense core inclusions typical of MPSs, while others appeared as membranous storage bodies characteristic of gangliosidoses. Pyramidal neurons showed positive staining for GM2 and GM3 gangliosides. In addition, positive filipin staining indicated storage of unesterified cholesterol . As gangSecondary storage is not only confined to lysosomes but may contribute to accumulation in other compartments of toxic storage materials, including aggregated-prone proteins, alpha-synuclein, and damaged mitochondria  associatThe mechanisms leading to secondary storage are not clear. In principle, secondary storage may derive from inhibition by primary substrates of other lysosomal enzymes, from modification of the lysosomal environment, such as pH changes, or from impairment of vesicle trafficking through the endosomal/lysosomal system and the autophagic pathway ,38,39. While in the past secondary storage was typically considered a nonspecific and insignificant pathological feature of MPSs, newer studies support a substantial role of secondary storage as a major determinant in the pathophysiology of these disorders. An important consequence of secondary storage is its effect intracellular vesicle trafficking. Specifically, some substrates, such as cholesterol and other lipids, have been thought to play a role in altering membrane composition and jamming the endolysosomal system ,38,39. FThe defective trafficking of vesicles has several deleterious consequences and has been thought to have a role in the development of neuropathology in MPSs. For example, in cultured adrenal chromaffin cells from in MPS type IIIA, evidence of impaired exocytosis was observed . It has In addition, recent data indicate that alpha-synuclein is a key chaperone assisting synaptic vesicle recycling and transmission at presynaptic terminals ,45 by suVPS33A gene, encoding a protein (VPS33A) that is involved in autophagy, resulted in an MPS-like disorder characterized by high levels of heparan sulfate in plasma and urine of patients, and in a phenotype sharing similarities with those of MPSs. An important and deleterious effect of lysosomal storage and of defective vesicle trafficking is the impairment of the ALP and a block or reduction of the autophagic flux. Autophagy is an evolutionary conserved catabolic process that allows lysosomal delivery of intracellular components destined to degradation and turn over. A functional ALP is critical for many cell functions and for cell survival; thus, an impairment of this process may have disastrous consequences. This pathway has been shown to be affected in several LSDs, including MPSs, ,48,49. OThe impairment of the autophagic flux has been recognized as important pathogenetic factor for neurodegeneration in lysosomal storage diseases, including MPSs ,55. In nIn addition, impairment of lysosome/autophagy pathway affects extracellular matrix formation and skeletal development and growth in MPSs ,59.Deregulation of mTORC1 signaling arrests bone growth in lysosomal storage disorders. In the mouse model of MPS VII lysosomal dysfunction induced a constitutive activation of mTORC1 in chondrocytes. As a consequence, chondrocytes fail to properly secrete collagens, the main components of the cartilage extracellular matrix. Rescue of the autophagy flux resulted in restored collagen levels in cartilage and ameliorated the bone phenotype .A primary function of autophagy is to mediate mitochondrial turnover . This sePerturbations in mitochondrial function and homeostasis caused by impaired autophagy have been recognized in several LSDs, including some MPSs , and havPathological findings have been described in detail in the murine model of MPS IIIC, in which accumulation of pleomorphic, swollen mitochondria containing disorganized or reduced cristae, was observed in neurons in all parts of the brain. These abnormalities appeared to be progressive. Some neurons containing swollen mitochondria were already detectable at 5 months of age, while by the age of 12 months mitochondrial damage was seen in the majority of neurons ,63.Increased oxidative stress and enhanced susceptibility of cells to mitochondria-mediated apoptotic insults are obvious consequences of defects in mitophagy and mitochondrial dysfunction. Elevation of reactive oxygen species (ROS) and accumulation of damaged mitochondria has been observed in some MPSs .Some studies performed in animal models have linked oxidative stress to MPSs ,69. ThesNon-physiologic activation of signaling cascades is an important and intriguing aspect of MPS pathophysiology that in recent years is attracting growing interest. Indeed, aberrant signaling may be directly implicated in the pathophysiology of some of the most prominent and most debilitating clinical manifestations of these disorders, such as pain, physical disability, neurodegeneration, skeletal abnormalities, and heart involvement. Several factors contribute to signaling dysregulation. One of them is the synthesis of aberrant GAGs that interferes with normal GAG interactions with different receptors, such as the fibroblast growth factors (FGFs), and with morphogens such as those implicated in neurogenesis, axonal guidance, and synaptogenesis. In addition, several of the secondary events triggered by storage  may affect the internalization and trafficking of signaling molecules . NeurodeSevere neuroinflammation is a consistent finding in MPS animal models and may be a factor implicated in the progression of neurodegeneration. Accumulation of GAG-related oligosaccharides in microglia, likely released by lysosomal exocytosis, are thought to induce inflammation in the brain by activating toll-like receptor (TLR) receptors of microglia cells, and to induce release of inflammatory cytokines. Evidence of neuroinflammation in MPSs has been obtained both in vitro and in vivo. In vitro lipopolysaccharide (LPS)-TLR4 activated microglia has been shown to express and secrete inflammatory cytokines and chemokines such as tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6), and macrophage inflammatory chemochine ligand-3 (CCL3) . In in vThe characterization of the molecular pathways underlying neuroinflammation in MPSs has possible therapeutic implications. The TLR4-TNFa pathway has been recognized as a potential therapeutic target. Preclinical studies with pentosan-sulfate, an FDA-approved drug with anti-inflammatory and pro-chondrogenic properties, showed clinical improvements in MPS VI rats and in MPS I dogs, with a reduction of pro-inflammatory cytokines in tissues and in the cerebrospinal fluid ,83,84. AAberrant signaling also plays an important role in the pathophysiology of bone and skeletal involvement in MPSs. In this case excess of extracellular, rather than intracellular GAGs, appear to be most significant. In fact, chondrogenesis, the earliest phase of skeletal formation, is mostly controlled by cellular interactions between the extracellular matrix (of which GAGs are important components) and differentiation factors, other signaling molecules and transcription factors . Recent Much attention has been paid to fibroblast growth factors (FGFs) signaling pathway. FGFs are a cytokine family that modulates cell growth, migration, differentiation, and neuroectodermal development . AbnormaStudies performed in the MPS VII canine model showed failed initiation of secondary ossification in vertebrae and long bones at the appropriate postnatal developmental stage and suggested dysregulation of signaling pathways modulating bone development and ossification. Epiphyseal chondrocytes showed abnormal persistence of Sox9 protein and were unable to successfully transition from proliferation to hypertrophy . TargeteProteomic studies in the murine MPS I model revealed significant decreases in key structural and signaling extracellular matrix proteins, such as biglycan, fibromodulin, PRELP, type I collagen, lactotransferrin, and SERPINF1. Genome-wide expression analysis in the same mouse model identified several significantly dysregulated mRNAs  .It has also been suggested that in MPS II perturbations of GAG catabolism may affect morphogens release and activity, such as sonic hedgehog (Shh) distribution and signaling. Uncleared GAGs may interfere extracellularly with Shh binding to Patched, therefore blocking Shh pathway transduction . DysreguImpaired calcium homeostasis and signaling has been demonstrated in some LSDs, such as Niemann-Pick disease type C ,96. ThesThe characterization of the cellular processes that are involved in the pathophysiology of lysosomal diseases has important implications for the treatment of LSDs, including MPSs. Some of the pathways that are dysregulated in these disorders may be pharmacologically or genetically manipulated and may represent novel and promising therapeutic targets. It is reasonable to think that future research will focus on these aspects, possibly developing complementary strategies to improve the outcome of traditional therapies aimed at restoring the function of defective enzymes.


Learning opportunities beyond the classroom create lasting and positive effects on students’ academic and professional growth. When faculty members participate in engaged scholarship in their local communities, out-of-classroom learning opportunities for students likewise expand. In the context of aging, the array of opportunities for students to engage with community partners is vast, from interactive course assignments to research opportunities, clinical experience, local policy efforts, and more. This paper builds on previous theoretical and empirical work from scholars (including AGHE and GSA Fellows) in the science of engagement, and integrates case examples of campus-community relationships from our collective years in the academy. Examples will showcase how engaged teaching, engaged research, and engaged service collectively informs and enriches our students’ experiences. In the spirit of the 2020 conference theme, we will discuss opportunities for university-community engagement as a way to strengthen and inspire current and future gerontological pedagogy.


The porosity parameter increased the Bejan number while the Eckert and Prandtl numbers decreased the Bejan number. Skin friction was enhanced with increasing the Casson, porosity, and magnetic parameters while it decreased with enhancing rotation and squeezing parameters. All these impacts have been shown via graphs. The influences by fluid flow parameters over skin friction and Nusselt number are accessible through tables. In this research article, the investigation of the three-dimensional Casson nanofluid flow in two rotating parallel plates has been presented. The nanofluid has been considered in steady state. The rotating plates have been considered porous. The heat equation is considered to study the magnetic field, joule heating, and viscous dissipation impacts. The nonlinear ordinary system of equations has been solved analytically and numerically. For skin friction and Nusslt number, numerical results are tabulated. It is found that velocity declines for higher values of magnetic and porosity parameter while it is heightened through squeezing parameter. Temperature is an enhancing function for Eckert number and nanoparticles volume fraction. Entropy generation is augmented with radiation parameter, Prandtl, and Eckert numbers. The Casson, porosity, magnetic field, and rotation parameters were reduced while the squeezing and suction parameters increased the velocity profile along  In the modern world of science and technology, we need more development in the direction of the exhaustion of energy in engineering and industrial fields. Thus, for the exhaustion and transfer of heat, the study of nanofluids discloses extraordinary thermal conductivity and heat transfer coefficients compared to conventional fluids. These specific aspects of nanofluids make them appropriate for the succeeding generation of flow and heat transfer fluids. Therefore, the revolutionary nanofluids investigation has encouraged researchers and engineers all over the world. Problems related to the heat and mass transfer via nanofluid flow between two permeable walls/plates has remained under discussion since last few years. This is because heat and mass transfer have numerous applications in the industries of petroleum supplies, oil conveyance, and separation processes in chemical companies, etc. The advancement of power energy in technology is the essential objective of scientists and engineers. This is because of the extreme interest in cooling/heating in modern systems. Very high thermal conductivity of the nanofluid separates them from the other ordinary fluids as an ideal fluid. Since nanofluids have ideal thermal conductivity, they are used as cooling agents in computers, nuclear reactors, cancer therapy, to lower the level of cholesterol in blood, make surgeries safer, electronics, micro channels in defence sector, printing and press systems, food and drinks industries, as well as in oil, gas, and chemicals industries.A key test for analysts is to upgrade the thermal conductivity applications of usual coolants corresponding to oil, ethylene glycol, and water, which have low thermal conductivity. Because of such inspiration, the first endeavor made by Choi  on this The measure of disorder in a system or unavailable energy in a closed thermodynamically system is known as entropy. The entropy generation is derived from second law of thermodynamics. In 1980, the entropy production rate was introduced by Bejan . Hayat eIn this research article, the investigation of the three-dimensional Casson nanofluid flow in two rotating parallel plates has been presented. The nanofluid has been considered in a steady state. The rotating plates have been considered porous. The heat equation is considered to study the magnetic field, joule heating, and viscous dissipation impacts. The nonlinear ordinary system of equations has been solved analytically. Here, we assumed 3D unsteady flow of Casson nanofluid to have viscous dissipation, joule heating, and entropy generation properties in two rotating parallel plates. Both plates are permeable. The suction velocity of the fluid via upper porous plate is Nanofluid flow governing equations are ,54,55,56Problem constrains at the boundary is of the form:The applied two forces are equal in measurement but reverse in direction, keeping the plates stretched. The lower plate is extended because of these equivalent forces in size and inverted direction, while the lower plate is squeezed down with velocity The transformation variables are demarcated:Obviously, Equation (1) satisfies, and Equations (2)–(6) becomes:Satisfying the succeeding boundary conditions:Here the following ratios are defined between the nanofluid and base fluid. Also, The skin friction and Nusselt number of the nanofluid can be characterized as:Substituting Equation (14) in Equation (13), in a simple way, isThe rate of entropy production EUsing Equations (8) and (16) reduced as:The entropy generation rate is reduced as:In components form, Equation (18) is expressed as:The complete volumetric entropy production is demarcated as: The non-dimensional total entropy generation is reduced as:The Bejan number shows the quotient of entropy production rate for heat transfer to entire entropy production. It is characterized as:The Bejan number permanently lies in the range of 0 and 1. The To solve the proposed model by analytical method called HAM ,50,51,52The linear operators are defined as:The initial solutions are: Here, When we compute the series solutions of the velocity and temperature functions in order to use HAM, the assisting parameters This segment treaties with the physical impacts of concerned factors of the nanofluid flow on velocity profiles The impact of Casson parameter The impressions of Casson parameter We solve the system the model Equations (9)–(11) with boundary conditions (12) by ND Solve in Mathematica 10 package. Comparison between analytical and numerical techniques is shown in The squeezing Casson nanofluid flow with viscous dissipation and entropy generation between two parallel stretching plates has been presented in this paper. The stretching plates are considered porous. The impact of magnetic field is also reflected in the proposed model. The impacts of embedded parameters are shown through figures and tables. The Casson parameter, porosity parameter, magnetic field parameter, and rotation parameter reduced the velocity profile The Casson parameter, porosity parameter, magnetic field parameter, and rotation parameter showed dual behavior in the velocity profile The squeezing parameter \ increased the velocity profile The Eckert numbers and squeezing parameter increased the temperature profile The Prandtl number, porosity parameter, and Eckert numbers increased the Entropy generation rate The porosity parameter increased the Bejan number The significant facts of the presented model are as follows: