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Simple Summary The study of cell features has historically been key for the progress of biological sciences and its relevance remains intact. In recent years, mass cytometry has emerged as a promising and powerful technology, capable of studying multiple parameters of cells in the same sample. Mass cytometry has been quickly applied to many research areas, particularly to the study of the immune system for different purposes, in which the simultaneous analysis of a large number of proteins is crucial. However, despite being a technique that is on the rise, its performance in scientific publications has not yet been evaluated. In this work, a bibliometric methodology known as H-Classics was applied to analyse the most relevant articles, known as highly cited papers (HCPs), and determine the main scientific producers (authors, institutions, and countries) and trends around mass cytometry research field. The results confirmed a high interest and application in immunological studies. The identified HCPs came from prestigious institutions and were published in high impact journals. These results may help researchers to expand their knowledge and to establish new valuable collaborative networks around mass cytometry. Abstract Mass cytometry (CyTOF) is a relatively novel technique for the multiparametric analysis of single-cell features with an increasing central role in cell biology, immunology, pharmacology, and biomedicine. This technique mixes the fundamentals of flow cytometry with mass spectrometry and is mainly used for in-depth studies of the immune system and diseases with a significant immune load, such as cancer, autoimmune diseases, and viral diseases like HIV or the recently emerged COVID-19, produced by the SARS-CoV-2 coronavirus. The objective of this study was to provide a useful insight into the evolution of the mass cytometry research field, revealing the knowledge structure (conceptual and social) and authors, countries, sources, documents, and organizations that have made the most significant contribution to its development. We retrieved 937 articles from the Web of Science (2010–2019), analysed 71 Highly Cited Papers (HCP) through the H-Classics methodology and computed the data by using Bibliometrix R package. HCP sources corresponded to high-impact journals, such as Nature Biotechnology and Cell, and its production was concentrated in the US, and specifically Stanford University, affiliation of the most relevant authors in the field. HCPs analysis confirmed great interest in the study of the immune system and complex data processing in the mass cytometry research field.

Simple Summary For the first time, this study investigated the extraction of bioactive substances with different polarities from immature honey pomelo fruit (IPF), a by-product of pomelo planting processing that causes resource waste and environmental pollution, using novel continuous phase transition extraction technology (CPTE). The results showed that CPTE was suitable for extracting essential oil, naringin, and pectin in sequence according to their polarities. The naringin extraction process was optimized by the response surface methodology, resulting in an extract ratio up to 99.47%. Moreover, the pectin extracted from IPF by CPTE showed better quality compared to commercial counterparts, as evidenced by lower protein and ash contents and higher white value. Together, these results suggested that CPTE could be a promising technology to improve the application value of IPF. For instance, the extracted bioactive components can be utilized as nutraceutical food ingredients. The scientific insights from this study will contribute to the development of functional food ingredients and comprehensive utilization of farming by-products. Abstract The immature honey pomelo fruit (IPF) is a huge agro-industrial by-product generated during pomelo planting. Although IPF is rich in nutrients, more than 95% of IPF is discarded annually, which causes resource waste and a serious environmental problem. Here, we report a novel continuous phase transition extraction technology (CPTE) to improve the comprehensive utilization of IPF by sequentially generating high value products and solve pollution problems related to their disposal. First, essential oil was successively extracted by CPTE at a yield of 1.12 ± 0.36%, in which 43 species were identified. Second, naringin extraction parameters were optimized using the response surface methodology (RSM), resulting in a maximum extraction rate of 99.47 ± 0.15%. Finally, pectin was extracted at a yield of 20.23 ± 0.66%, which is similar to the contents of commercial pectin. In conclusion, this study suggested that IPF was an excellent potential substrate for the production of value-added components by CPTE.

Simple Summary Microalgae are increasingly recognized as a source of valuable biomass with numerous health benefits. Cleaning of marine microalgal biomass is very crucial for microalgal studies as the salt on the microalgae cells will lead to overestimation of biomass determination. Incomplete washing of salt from microalgae could also interfere with the nutritional analyses. The biomass, especially dry weight, has been utilized for nutritional or compositional evaluation. Although standard methods of marine microalgal dry weight determination are available, these methods did not provide comprehensive details, and the parameters vary among themselves. Without a standard method, a comparison of results among previous studies can be misleading and unreliable. Therefore, the current study aimed to investigate and determine the ideal setting of several parameters in the marine microalgal dry weight determination for laboratory-scale culture. The present findings could assist in developing a standardized protocol to ensure a high quality of biomass for microalgal studies. Abstract Microalgal biomass is one of the crucial criteria in microalgal studies. Many reported methods, even the well-established protocol on microalgal dry weight (DW) determination, vary greatly, and reliable comparative assessment amongst published results could be problematic. This study aimed to determine the best condition of critical parameters in marine microalgal DW determination for laboratory-scale culture using four different marine microalgal species. These parameters included the washing process, grades of glass microfiber filter (GMF), GMF pretreatment conditions, washing agent (ammonium formate) concentrations, culture: washing agent ratios (v:v) and washing cycles. GMF grade GF/A with precombustion at 450 °C provided the most satisfactory DW and the highest ash-free dry weight (AFDW)/DW ratio. Furthermore, 0.05 M ammonium formate with 1:2 culture: washing agent ratio and a minimum of two washing cycles appeared to be the best settings of microalgal DW determination. The present treatment increased the AFDW/DW ratio of the four respective microalgae by a minimum of 19%. The findings of this study could serve as a pivotal reference in developing a standardized protocol of marine microalgal DW determination to obtain veracious and reliable marine microalgal DW.

Simple Summary The immune system was sculpted in numerous evolutionary battles to protect individuals, societies, and species from novel pathogens. During that time, it had developed highly effective strategies to cope with novel pathogenic challenges and retain immune “memory” following pathogen clearance. We found surprising parallels between person-level immune responses to the virus causing COVID-19 and the society-level responses to the COVID-19 pandemic. Similarly, the events which lead to a life-endangering immune cytokine storm, parallel those leading to a devastating socioeconomic crisis we termed a “social cytokine storm”. This new understanding may help explain why COVID-19, caused by a virus with no “exceptional” epidemiological capabilities, had inflicted such profound social and global toll. Understanding the set of events leading to an immunological and societal cytokine storms may aid scientists and policymakers to adopt more effective strategies that could reduce future disease morbidity and mortality, avert avoidable social cytokine storms, and minimize the socioeconomic toll. Abstract The adaptive immune system was sculpted to protect individuals, societies, and species since its inception, developing effective strategies to cope with emerging pathogens. Here, we show that similar successful or failed dynamics govern personal and societal responses to a pathogen as SARS-CoV2. Understanding the self-similarity between the health-protective measures taken to protect the individual or the society, help identify critical factors underlying the effectiveness of societal response to a pathogenic challenge. These include (1) the quick employment of adaptive-like, pathogen-specific strategies to cope with the threat including the development of “memory-like responses”; (2) enabling productive coaction and interaction within the society by employing effective decision-making processes; and (3) the quick inhibition of positive feedback loops generated by hazardous or false information. Learning from adaptive anti-pathogen immune responses, policymakers and scientists could reduce the direct damages associated with COVID-19 and avert an avoidable “social cytokine storm” with its ensuing socioeconomic damage.

Cancer recurrence has remained a significant challenge, despite advances in therapeutic approaches. In part, this is due to our incomplete understanding of the biology of cancer stem cells and the underlying molecular mechanisms. The phenomenon of differentiation and dedifferentiation (phenotypic switching) is not only unique to stem cells but it is also observed in several other organisms, as well as evolutionary-related microbes. Here, we propose the use of a primitive eukaryotic unicellular organism, Acanthamoeba castellanii, as a model to study the molecular mechanisms of cellular differentiation and dedifferentiation.

Simple Summary Olive oil is the most common vegetable oil used for human nutrition, and its production represents a major economic sector in Mediterranean countries. The milling industry generates large amounts of liquid and solid residues, whose disposal is complicated and costly due to their polluting properties. However, olive mill waste (OMW) may also be seen as a source of valuable biomolecules including plant nutrients, anthocyanins, flavonoids, polysaccharides, and phenolic compounds. This review describes recent advances and multidisciplinary approaches in the identification and isolation of valuable natural OMW-derived bioactive molecules. Such natural compounds may be potentially used in numerous sustainable applications in agriculture such as fertilizers, biostimulants, and biopesticides in alternative to synthetic substances that have a negative impact on the environment and are harmful to human health. Abstract Olive oil production generates high amounts of liquid and solid wastes. For a long time, such complex matrices were considered only as an environmental issue, due to their polluting properties. On the other hand, olive mill wastes (OMWs) exert a positive effect on plant growth when applied to soil due to the high content of organic matter and mineral nutrients. Moreover, OMWs also exhibit antimicrobial activity and protective properties against plant pathogens possibly due to the presence of bioactive molecules including phenols and polysaccharides. This review covers the recent advances made in the identification, isolation, and characterization of OMW-derived bioactive molecules able to influence important plant processes such as plant growth and defend against pathogens. Such studies are relevant from different points of view. First, basic research in plant biology may benefit from the isolation and characterization of new biomolecules to be potentially applied in crop growth and protection against diseases. Moreover, the valorization of waste materials is necessary for the development of a circular economy, which is foreseen to drive the future development of a more sustainable agriculture.

To date, 5-Fluorouracil (5FU) is a major component of several chemotherapy regimens, thus its study is of fundamental importance to better understand all the causes that may lead to chemoresistance and treatment failure. Given the evident differences between prognosis in Asian and Caucasian populations, triggered by clear genetic discordances and given the extreme genetic heterogeneity of gastric cancer (GC), the evaluation of the most frequent mutations in every single member of the 5FU conversion and activation pathway might reveal several important results. Here, we exploited the cBioPortal analysis software to query a large databank of clinical and wide-genome studies to evaluate the components of the three major 5FU transformation pathways. We demonstrated that mutations in such ways were associated with a poor prognosis and reduced overall survival, often caused by a deletion in the TYMP gene and amplification in TYMS. The use of prodrugs and dihydropyrimidine dehydrogenase (DPD) inhibitors, which normally catabolizes 5FU into inactive metabolites, improved such chemotherapies, but several steps forward still need to be taken to select better therapies to target the chemoresistant pools of cells with high anaplastic features and genomic instability.

A laboratory based microflotation rig termed efficient FLOtation of Algae Technology (eFLOAT) was used to optimise parameters for harvesting microalgal biomass from eutrophic water systems. This was performed for the dual objectives of remediation (nutrient removal) and resource recovery. Preliminary experiments demonstrated that chitosan was more efficient than alum for flocculation of biomass and the presence of bacteria could play a positive role and reduce flocculant application rates under the natural conditions tested. Maximum biomass removal from a hyper-eutrophic water retention pond sample was achieved with 5 mg·L−1 chitosan (90% Chlorophyll a removal). Harvesting at maximum rates showed that after 10 days, the bacterial diversity is significantly increased with reduced cyanobacteria, indicating improved ecosystem functioning. The resource potential within the biomass was characterized by 9.02 μg phosphate, 0.36 mg protein, and 103.7 μg lipid per mg of biomass. Fatty acid methyl ester composition was comparable to pure cultures of microalgae, dominated by C16 and C18 chain lengths with saturated, monounsaturated, and polyunsaturated fatty acids. Finally, the laboratory data was translated into a full-size and modular eFLOAT system, with estimated costs as a novel eco-technology for efficient algal bloom harvesting.

A point source is the central and most important point or place for any group of cohering phenomena. Evolutionary development presumes that biological processes are sequentially linked, but neither directed from, nor centralized within, any specific biologic structure or stage. However, such an epigenomic entity exists and its transforming effects can be understood through the obligatory recapitulation of all eukaryotic lifeforms through a zygotic unicellular phase. This requisite biological conjunction can now be properly assessed as the focal point of reconciliation between biology and quantum phenomena, illustrated by deconvoluting complex physiologic traits back to their unicellular origins.

Heterochrony is an enabling concept in evolution theory that metaphorically captures the mechanism of biologic change due to mechanisms of growth and development. The spatio-temporal patterns of morphogenesis are determined by cell-to-cell signaling mediated by specific soluble growth factors and their cognate receptors on nearby cells of different germline origins. Subsequently, down-stream production of second messengers generates patterns of form and function. Environmental upheavals such as Romer's hypothesized drying up of bodies of water globally caused the vertebrate water-land transition. That transition caused physiologic stress, modifying cell-cell signaling to generate terrestrial adaptations of the skeleton, lung, skin, kidney and brain. These tissue-specific remodeling events occurred as a result of the duplication of the Parathyroid Hormone-related Protein Receptor (PTHrPR) gene, expressed in mesodermal fibroblasts in close proximity to ubiquitously expressed endodermal PTHrP, amplifying this signaling pathway. Examples of how and why PTHrPR amplification affected the ontogeny, phylogeny, physiology and pathophysiology of the lung are used to substantiate and further our understanding through insights to the heterochronic mechanisms of evolution, such as the fish swim bladder evolving into the vertebrate lung, interrelated by such functional homologies as surfactant and mechanotransduction. Instead of the conventional description of this phenomenon, lung evolution can now be understood as adaptive changes in the cellular-molecular signaling mechanisms underlying its ontogeny and phylogeny.

Evolutionary developmental genetics has traditionally been conducted by two groups: Molecular evolutionists who emphasize divergence between species or higher taxa, and quantitative geneticists who study variation within species. Neither approach really comes to grips with the complexities of evolutionary transitions, particularly in light of the realization from genome-wide association studies that most complex traits fit an infinitesimal architecture, being influenced by thousands of loci. This paper discusses robustness, plasticity and lability, phenomena that we argue potentiate major evolutionary changes and provide a bridge between the conceptual treatments of macro- and micro-evolution. We offer cryptic genetic variation and conditional neutrality as mechanisms by which standing genetic variation can lead to developmental system drift and, sheltered within canalized processes, may facilitate developmental transitions and the evolution of novelty. Synthesis of the two dominant perspectives will require recognition that adaptation, divergence, drift and stability all depend on similar underlying quantitative genetic processes—processes that cannot be fully observed in continuously varying visible traits.

The conventional understanding of phenotype is as a derivative of descent with modification through Darwinian random mutation and natural selection. Recent research has revealed Lamarckian inheritance as a major transgenerational mechanism for environmental action on genomes whose extent is determined, in significant part, by germ line cells during meiosis and subsequent stages of embryological development. In consequence, the role of phenotype can productively be reconsidered. The possibility that phenotype is directed towards the effective acquisition of epigenetic marks in consistent reciprocation with the environment during the life cycle of an organism is explored. It is proposed that phenotype is an active agent in niche construction for the active acquisition of epigenetic marks as a dominant evolutionary mechanism rather than a consequence of Darwinian selection towards reproductive success. The reproductive phase of the life cycle can then be appraised as a robust framework in which epigenetic inheritance is entrained to affect growth and development in continued reciprocal responsiveness to environmental stresses. Furthermore, as first principles of physiology determine the limits of epigenetic inheritance, a coherent justification can thereby be provided for the obligate return of all multicellular eukaryotes to the unicellular state.

Life originated from unicellular organisms by circumventing the Second Law of Thermodynamics using the First Principles of Physiology, namely negentropy, chemiosmosis and homeostatic regulation of calcium and lipids. It is hypothesized that multicellular organisms are merely contrivances or tools, used by unicellular organisms as agents for the acquisition of epigenetic inheritance. The First Principles of Physiology, which initially evolved in unicellular organisms are the exapted constraints that maintain, sustain and perpetuate that process. To ensure fidelity to this mechanism, we must return to the first principles of the unicellular state as the determinants of the primary level of selection pressure during the life cycle. The power of this approach is reflected by examples of its predictive value. This perspective on life is a “game changer”, mechanistically rendering transparent many dogmas, teleologies and tautologies that constrain the current descriptive view of Biology.

Simple Summary Cutaneous vascular neoplasms of uncertain biological behavior present a diagnostic and therapeutic challenge to physicians. The rarity of these lesions and the recent recognition of such entities suggests an extensive amount of knowledge remains lacking concerning effective treatments, accurate prognosis, and follow-up recommendations for patients with superficial vascular tumors. The objective of this manuscript is to compile a comprehensive summary of the current literature on neoplasms limited to the skin and of vascular origin that are currently categorized as indeterminate biological potential. By compiling numerous studies and summarizing the aggregate findings, this paper aims to offer providers a condensed yet detailed report of the entirety of what is known regarding these lesions. The information will aid physicians in the process of diagnosing, treating, prognosticating, and following up these rare tumors. Abstract Neoplasms of uncertain biological behavior present physicians with a genuine conundrum in practice. Cutaneous vascular neoplasms within this category are exceedingly rare, possessing significant gaps and uncertainty in many facets of clinical practice. Firstly, lesions were selected for review based on their categorization as indeterminate behavior, indicating the potential for local recurrence and rarely metastasize. After identification of the target lesions, a comprehensive review of the literature using national databases produced several landmark studies and case series regarding these neoplasms. Limiting the review to only cutaneous limited tumors narrowed the pool of studies; however, quite a large sum of papers remained. Examination of each paper yielded beneficial results on diagnosing, effective treatments, follow-up findings, and prognosis for each indeterminate lesion discussed. Overall, the literature search combined the molecular, histologic, immunohistochemical, surgical strategies to develop an up-to-date and comprehensive framework to guide physicians when encountering such lesions. The tumors reviewed include: kaposiform hemangioendothelioma, endovascular papillary angioendothelioma, pseudomyogenic hemangioendothelioma, retiform hemangioendothelioma, epithelioid hemangioendothelioma, and composite hemangioendothelioma.

Simple Summary Sugarcane ratooning ability is directly related to sugarcane production costs and planting benefits. There are several questions within the field that we have explored in this review and that remain to be answered. What is the genetic basis of ratooning ability? How do these traits form and evolve? How does the environment affect the ratooning ability? Where should the research focus of sugarcane ratooning ability be placed in the future? How can technical methods be optimized for breeding sugarcane with strong ratooning ability? In this paper, we reviewed previous studies in terms of the definition, phenotypic traits, major influencing factors, genetic basis, and the physiology associated with sugarcane ratooning ability. We also highlighted the shortcomings of existing research on ratooning ability and suggested the focuses of future studies. Abstract Sugarcane is an important sugar crop and it can be subjected to ratooning for several years. The advantages of ratooning include quality improvement, efficiency enhancement, and reduced costs and energy use. The genotype, environment, cultivation management, and harvesting technology affect the productivity and longevity of ratoon cane, with the genetic basis being the most critical factor. However, the majority of research has been focused on only limited genotypes, and a few studies have evaluated up to 100 sugarcane germplasm resources. They mainly focus on the comparison among different genotypes or among plant cane, different selection strategies for the first and second ratoon crops, together with screening indicators for the selection of stronger ratooning ability. In this paper, previous studies are reviewed in order to analyze the importance of sugarcane ratooning, the indicative traits used to evaluate ratooning ability, the major factors influencing the productivity and longevity of ratooning, the genetic basis of variation in ratooning ability, and the underlying mechanisms. Furthermore, the shortcomings of the existing research on sugarcane ratooning are highlighted. We then discuss the focus of future ratoon sugarcane research and the technical methods that will shorten the selection cycle and increase the genetic gain of ratooning ability, particularly the development of linked markers. This review is expected to provide a reference for understanding the mechanisms underlying the formation of ratooning ability and for breeding sugarcane varieties with a strong ratooning ability.

Simple Summary One of the hottest areas in deep learning is computerized tumor diagnosis and treatment. The identification of tumor markers, the outline of tumor growth activity, and the staging of various tumor kinds are frequently included. There are several deep learning models based on convolutional neural networks that have high performance and accurate identification, with the potential to improve medical tasks. Breakthroughs and updates in computer algorithms and hardware devices, and intelligent algorithms applied in medical images have a diagnostic accuracy that doctors cannot match in some diseases. This paper reviews the progress of tumor detection from traditional computer-aided methods to convolutional neural networks and demonstrates the potential of the practical application of convolutional neural networks from practical cases to transform the detection model from experiment to clinical application. Abstract Tumors are new tissues that are harmful to human health. The malignant tumor is one of the main diseases that seriously affect human health and threaten human life. For cancer treatment, early detection of pathological features is essential to reduce cancer mortality effectively. Traditional diagnostic methods include routine laboratory tests of the patient’s secretions, and serum, immune and genetic tests. At present, the commonly used clinical imaging examinations include X-ray, CT, MRI, SPECT scan, etc. With the emergence of new problems of radiation noise reduction, medical image noise reduction technology is more and more investigated by researchers. At the same time, doctors often need to rely on clinical experience and academic background knowledge in the follow-up diagnosis of lesions. However, it is challenging to promote clinical diagnosis technology. Therefore, due to the medical needs, research on medical imaging technology and computer-aided diagnosis appears. The advantages of a convolutional neural network in tumor diagnosis are increasingly obvious. The research on computer-aided diagnosis based on medical images of tumors has become a sharper focus in the industry. Neural networks have been commonly used to research intelligent methods to assist medical image diagnosis and have made significant progress. This paper introduces the traditional methods of computer-aided diagnosis of tumors. It introduces the segmentation and classification of tumor images as well as the diagnosis methods based on CNN to help doctors determine tumors. It provides a reference for developing a CNN computer-aided system based on tumor detection research in the future.

Simple Summary Currently, only a few label-free methods for cell viability assessment are described in the literature. This paper covers a new label-free method based on the laser interference microscopy (LIM) to monitor the viability of single cells in real-time without dye incorporation. The metabolic activity of cells has been a key sign in assessing their viability with use of the LIM-aided method. On this basis, LIM allows the level of cell dynamics to be evaluated. We have analyzed the viability of attached and suspended cells by several spectral techniques of the LIM data processing and selected universal parameters for assessing their condition. Thus, LIM, as a highly sensitive quantitative phase imaging method, is applicable for assessing cell viability by a non-invasive mode combined with other cell assays. Abstract Laser interference microscopy (LIM) is a promising label-free method for single-cell research applicable to cell viability assessment in the studies of mammalian cells. This paper describes the development of a sensitive and reproducible method for assessing cell viability using LIM. The method, based on associated signal processing techniques, has been developed as a result of real-time investigation in phase thickness fluctuations of viable and non-viable MCF-7 cells, reflecting the presence and absence of their metabolic activity. As evinced by the values of the variable vc, this variable determines the viability of a cell only in the attached state (vc exceeds 20 nm2 for viable attached cells). The critical value of the power spectrum slope βc of the phase thickness fluctuations equals 1.00 for attached MCF-7 cells and 0.71 for suspended cells. The slope of the phase fluctuations’ power spectrum for MCF-7 cells was determined to exceed the threshold value of βc for a living cell, otherwise the cell is dead. The results evince the power spectrum slope as the most appropriate indicator of cell viability, while the integrated evaluation criterion (vc and βc values) can be used to assay the viability of attached cells.

Simple Summary Extracellular vesicles (EVs) have been recently considered one of the main characters for liquid biopsy (biomarkers) and therapeutic application. Particularly, the therapeutic application of EVs is involved in the bone regeneration, thanks to the regulation of immune environments, enhancement of angiogenesis, differentiation of osteoblasts and osteoclasts, and promotion of bone mineralization. In the past 15 years, researchers have focused on the application of EVs derived from different types of mesenchymal stem cells (MSCs) in the field of bone regenerative medicine. This systematic review aims to analyze in vitro and in vivo studies that report the effects of EVs combined with scaffolds in bone regeneration. A methodical review of the literature was performed on PubMed and Embase from 2012 to 2020. Sixteen papers were analyzed; of these, one study was in vitro, eleven were in vivo, and four were both in vitro and in vivo studies. This analysis shows a growing interest in this upcoming field, with overall positive results. Promising in vitro results have been discussed in terms of bone regeneration and pro-angiogenetic processes. The positive in vitro findings were confirmed in vivo, with studies showing positive effects on several critical-size defects. However, some aspects remain to be elucidated, like the different effects induced by EVs and secretome, the most suitable cell source, the EV production protocol and concentration, and the clinical use that may benefit from this new biological approach. Abstract Scaffolds associated with mesenchymal stem cell (MSC) derivatives, such as extracellular vesicles (EVs), represent interesting carriers for bone regeneration. This systematic review aims to analyze in vitro and in vivo studies that report the effects of EVs combined with scaffolds in bone regeneration. A methodical review of the literature was performed from PubMed and Embase from 2012 to 2020. Sixteen papers were analyzed; of these, one study was in vitro, eleven were in vivo, and four were both in vitro and in vivo studies. This analysis shows a growing interest in this upcoming field, with overall positive results. In vitro results were demonstrated as both an effect on bone mineralization and proangiogenic ability. The interesting in vitro outcomes were confirmed in vivo. Particularly, these studies showed positive effects on bone regeneration and mineralization, activation of the pathway for bone regeneration, induction of vascularization, and modulation of inflammation. However, several aspects remain to be elucidated, such as the concentration of EVs to use in clinic for bone-related applications and the definition of the real advantages.

Simple Summary The LI-RADS system is nowadays the mainstream system used in classifying liver nodules in cirrhotic liver according to their risk of malignancy. Two main LI-RADS documents have been released—the CEUS LI-RADS v2017 document, and the CT/MRI LI-RADS v2018 document. In some circumstances, a nodule can be differently classified when using CEUS versus when using CT or MRI. In this paper, we also focus on the existing similitudes between the two documents but, essentially, on the differences between the two main documents and the complementarities between imaging techniques in characterizing liver nodules in cirrhotic livers. Awareness of the complementarity of imaging techniques may lead to an improvement in the characterization and classification of liver nodules and will reduce the number of liver biopsies. This paper proposes practical solutions in order to better classify and manage observations or nodules detected in cirrhotic livers. Abstract Different LI-RADS core documents were released for CEUS and for CT/MRI. Both documents rely on major and ancillary diagnostic criteria. The present paper offers an exhaustive comparison of the two documents focusing on the similarities, but especially on the differences, complementarity, and added value of imaging techniques in classifying liver nodules in cirrhotic livers. The major diagnostic criteria are defined, and the sensitivity and specificity of each major diagnostic criteria are presented according to the literature. The existing differences between techniques in assessing the major diagnostic features can be then exploited in order to ensure a better classification and a better clinical management of liver nodules in cirrhotic livers. Ancillary features depend on the imaging technique used, and their presence can upgrade or downgrade the LI-RADS score of an observation, but only as far as LI-RADS 4. MRI is the imaging technique that provides the greatest number of ancillary features, whereas CEUS has fewer ancillary features than other imaging techniques. In the final part of the manuscript, some recommendations are made by the authors in order to guidephysicians as to when adding another imaging technique can be helpful in managing liver nodules in cirrhotic livers.

Simple Summary Computational simulations of biological systems are an intrinsic element of engineering in medicine, allowing physicians the ability to visualize the pathophysiology behind a disease. Many biomedical applications require fluid–structure interaction analyses. This paper provides a review of fluid–structure interaction methods using smoothed-particle hydrodynamics to analyze the dynamics of biological processes. Abstract Due to the inherent complexity of biological applications that more often than not include fluids and structures interacting together, the development of computational fluid–structure interaction models is necessary to achieve a quantitative understanding of their structure and function in both health and disease. The functions of biological structures usually include their interactions with the surrounding fluids. Hence, we contend that the use of fluid–structure interaction models in computational studies of biological systems is practical, if not necessary. The ultimate goal is to develop computational models to predict human biological processes. These models are meant to guide us through the multitude of possible diseases affecting our organs and lead to more effective methods for disease diagnosis, risk stratification, and therapy. This review paper summarizes computational models that use smoothed-particle hydrodynamics to simulate the fluid–structure interactions in complex biological systems.

Simple Summary Periodontal disease consists of a wide range of inflammatory conditions that affect the supporting apparatus of teeth, and is highly prevalent in adults worldwide. Tobacco use is currently recognized as the most important risk factor for periodontal disease as it negatively affects both disease evolution and therapeutic strategies. Given close contact with tobacco products, oral microcirculation becomes dysfunctional which, in turn, aggravates periodontal disease. This paper intends to provide a comprehensive review about the impact of tobacco use on oral microcirculation and the mechanisms underlying periodontal disease aggravation. Acute nicotine administration or tobacco use increases oral perfusion (gingiva, lip, tongue) of healthy subjects due to local irritation and increased blood pressure, which overcome neural- and endocrine-mediated vasoconstriction. Chronic tobacco use, particularly smoking, causes several morphological changes to oral microcirculation, namely, increased vascular density and tortuosity, despite a decrease in capillary diameter, and decreased perfusion due to the multiple vasoconstrictive insults. Periodontal disease involves considerable gingival inflammation and angiogenesis in non-smokers which, in chronic smokers, are considerably suppressed, in part due to local immune suppression and oxidative stress. Tobacco exposure, irrespective of form of use, causes long-term microvascular dysfunction which may not be completely reversible upon cessation, and increases the risk of complications due to the natural disease course or secondary to therapeutic strategies. Abstract Periodontal disease consists in highly prevalent wide-ranging inflammatory conditions that affect the supporting apparatus of teeth. Tobacco use is the most important risk factor for periodontal disease as it increases disease severity and periodontal surgery complications. Tobacco use is harmful for the vasculature by causing microvascular dysfunction, which is known to negatively affect periodontal disease. To the author’s knowledge this paper is the first comprehensive review on the mechanisms by which tobacco use affects oral microcirculation and impacts the pathophysiology of periodontal disease. In healthy subjects, acute nicotine administration or tobacco use (smoking/smokeless forms) increases the blood flow in the oral mucosa due to local irritation and increased blood pressure, which overcome neural- and endocrine-mediated vasoconstriction. Chronic tobacco smokers display an increased gingival microvascular density, which is attributed to an increased capillary recruitment, however, these microcirculatory units show higher tortuosity and lower caliber. These morphological changes, together with the repetitive vasoconstrictive insults, contribute to lower gingival perfusion in chronic smokers and do not completely regress upon smoking cessation. In periodontal disease there is considerable gingival inflammation and angiogenesis in non-smokers which, in chronic smokers, are considerably suppressed, in part due to local immune suppression and oxidative stress. Tobacco exposure, irrespective of the form of use, causes long-term microvascular dysfunction that increases the risk of complications due to the natural disease course or secondary therapeutic strategies.

Simple Summary Isoflavones are naturally-occurring phytoestrogens, highly prevalent in soybeans, and known to improve cardiovascular health in populations with a high isoflavone dietary intake. Most clinical studies have assessed the impact of dietary intake or supplementation with mixtures of isoflavones, with few studies dedicated to the effects of isolated compounds (i.e., genistein, daidzein, glycitein, formononetin, biochanin A, and equol). This paper reviews the main actions of isolated isoflavones on the vasculature, with particular focus on the determinants of blood pressure regulation. Isoflavones evoke relaxation of different vascular beds by acting on several signaling pathways in the endothelium, where they potentiate the release of important vasorelaxant mediators, and in vascular smooth muscle cells, where relaxation is attained mainly through hyperpolarization. Some of these effects are attributed to their ability to modulate estrogen receptors. These vascular effects occur at plasma concentrations in the micromolar range, attained only through dietary supplementation. This paper highlights isolated isoflavones as potentially suitable alternatives to soy-based foodstuffs and supplements and which could enlarge the current therapeutic arsenal. Abstract Isoflavones are phytoestrogen compounds with important biological activities, including improvement of cardiovascular health. This activity is most evident in populations with a high isoflavone dietary intake, essentially from soybean-based products. The major isoflavones known to display the most important cardiovascular effects are genistein, daidzein, glycitein, formononetin, and biochanin A, although the closely related metabolite equol is also relevant. Most clinical studies have been focused on the impact of dietary intake or supplementation with mixtures of compounds, with only a few addressing the effect of isolated compounds. This paper reviews the main actions of isolated isoflavones on the vasculature, with particular focus given to their effect on the determinants of blood pressure regulation. Isoflavones exert vasorelaxation due to a multitude of pathways in different vascular beds. They can act in the endothelium to potentiate the release of NO and endothelium-derived hyperpolarization factors. In the vascular smooth muscle, isoflavones modulate calcium and potassium channels, leading to hyperpolarization and relaxation. Some of these effects are influenced by the binding of isoflavones to estrogen receptors and to the inhibition of specific kinase enzymes. The vasorelaxation effects of isoflavones are mostly obtained with plasma concentrations in the micromolar range, which are only attained through supplementation. This paper highlights isolated isoflavones as potentially suitable alternatives to soy-based foodstuffs and supplements and which could enlarge the current therapeutic arsenal. Nonetheless, more studies are needed to better establish their safety profile and elect the most useful applications.

A dye exclusion test (DET) was performed to determine the viability of human breast cancer cells MCF-7, using natural food pigments as compared with trypan blue (TB), a typical synthetic dye for DET known to exhibit teratogenicity and cytotoxicity. We demonstrated that Monascus pigment (MP) is noninvasive to living cells and can effectively stain only dead cells. This study is the first verification of the applicability of MP to cancer cells. The appropriate MP concentration was 0.4% (0.02% as the concentration of pure MP) and all the dead cells were stained within 10 min. We found that the cell proliferation or the reduced nicotinamide adenine dinucleotide (NADH) activity of living cells was maintained over 48 h. Although 0.1% TB did not show an increase in dead cells, a marked decrease in NADH activity was confirmed. In addition, even when MP coexisted with cisplatin, staining of dead cells was maintained for 47 h, indicating stability to drugs (reagents). The cost of MP is estimated to be about 1/10 of TB. The fact that MP can be used as a cell viability determination reagent for Euglena and Paramecium, as shown in preceding papers, and also for MCF-7, as shown in this paper, indicates the possibility of application in more cells of different species.

Blue gourami belongs to the Labyrinithici fish and the Anabantiform order. It is characterized by a specific organ located above its gills for the respiration of atmospheric oxygen. This specific adaptation to low oxygen levels affects reproduction that is controlled by the brain, which integrates different effects on reproduction mainly through two axes—the gonadotropic brain pituitary gonad axis (BPG) and the hypothalamic-pituitary-somatotropic axis (HPS axis), including the interactions between them. This brain control reproduction of the Anabantoidei suborder summarizes information that has been published on the hormones involved in controlling the reproduction system of a model female blue gourami fish (Trichogaster trichopterus), including unpublished data. In the whole-brain transcriptome of blue gourami, 17 transcription genes change during vitellogenesis in the brain. The hormones involved in reproduction in blue gourami described in the present paper include: Kisspeptin 2 (Kiss 2) and its receptors 1 and 2 (KissR 1 and 2); gonadotropin-releasing hormone 1, 2 and 3 (GnRH1, 2 and 3); GnRH receptor; pituitary adenylate cyclase-activating polypeptide (PACAP) and its related peptide (PRP); somatolactin (SL); follicle-stimulating hormone (FSH); luteinizing hormone (LH); growth hormone (GH); prolactin (PRL), 17β-estradiol (E2); testosterone (T); vitellogenesis (VTL); and 17α,20β- dihydroxy-4-pregnen-3-one (17,20P). A proposed quality model is presented regarding the brain control oogenesis in blue gourami that has a Labyrinth organ about which relatively little information has been published. This paper summarizes the complex various factors involved in the interactions between external and internal elements affecting the brain of fish reproduction in the Anabantiform order. It is suggested to study in the future the involvement of receptors of hormones, pheromones, and genome changes in various organs belonging to the reproduction system during the reproduction cycles about which little is known.

Simple Summary Forensic anthropology in the United States is a specialization within the overall field of anthropology. Forensic anthropologists are specially educated and trained to search, recover, and examine human remains within a medicolegal context. Over time, forensic anthropology has become increasingly specialized and distinct from other specializations within anthropology. As such, we argue that forensic anthropology should be considered its own discipline, with a unique knowledge base, separate from other similar forms of anthropology, such a bioarchaeology. We argue that forensic anthropologists have unique expertise, making them the only type of anthropologist qualified to perform medicolegal examinations of human remains. Finally, we contend that to perform or represent yourself as a forensic anthropologist without the appropriate expertise is ethical misconduct. The value of this paper is that it explains the importance of expertise and knowledge, and how forensic anthropology has diverged from other specializations of anthropology enough to be considered its own discipline. Abstract This paper explores the current state of forensic anthropology in the United States as a distinct discipline. Forensic anthropology has become increasingly specialized and the need for strengthened professionalization is becoming paramount. This includes a need for clearly defined qualifications, training, standards of practice, certification processes, and ethical guidelines. Within this discussion, the concept of expertise is explored in relation to professionalization and practice, as both bioarchaeology and forensic anthropology have different areas of specialist knowledge, and therefore unique expertise. As working outside one’s area of expertise is an ethical violation, it is important for professional organizations to outline requisite qualifications, develop standards and best practice guidelines, and enforce robust preventive ethical codes in order to serve both their professional members and relevant stakeholders.

Evolutionary change comes from natural and other forms of selection acting on existing anatomical and physiological variants. While much is known about selection, little is known about the details of how genetic mutation leads to the range of heritable anatomical variants that are present within any population. This paper takes a systems-based view to explore how genomic mutation in vertebrate genomes works its way upwards, though changes to proteins, protein networks, and cell phenotypes to produce variants in anatomical detail. The evidence used in this approach mainly derives from analysing anatomical change in adult vertebrates and the protein networks that drive tissue formation in embryos. The former indicate which processes drive variation—these are mainly patterning, timing, and growth—and the latter their molecular basis. The paper then examines the effects of mutation and genetic drift on these processes, the nature of the resulting heritable phenotypic variation within a population, and the experimental evidence on the speed with which new variants can appear under selection. The discussion considers whether this speed is adequate to explain the observed rate of evolutionary change or whether other non-canonical, adaptive mechanisms of heritable mutation are needed. The evidence to hand suggests that they are not, for vertebrate evolution at least.

This article belongs to the Section Evolutionary Biology., This paper presents an Evolutionary Cellular Automaton (ECA) that simulates the evolutionary dynamics of biological interactions by manipulating strategies of dispersion and associations between digital organisms. The parameterization of the different types of interaction and distribution strategies using configuration files generates easily interpretable results. In that respect, ECA is an effective instrument for measuring the effects of relative adaptive advantages and a good resource for studying natural selection. Although ECA works effectively in obtaining the expected results from most well-known biological interactions, some unexpected effects were observed. For example, organisms uniformly distributed in fragmented habitats do not favor eusociality, and mutualism evolved from parasitism simply by varying phenotypic flexibility. Finally, we have verified that natural selection represents a cost for the emergence of sex by destabilizing the stable evolutionary strategy of the 1:1 sex ratio after generating randomly different distributions in each generation., This work has been supported by Generalitat Valenciana, Spain (project Prometeo/2018/A/133), Ministerio de Ciencia, Innovación y Universidades, Spain (project PID2019-105969GB-I00) and co-financed by the European Regional Development Fund (ERDF) to A.M.

Simple Summary Owing to climate change and human overdevelopment, the number of endangered species has been increasing. To face this challenge, the CITES treaty has been adopted by many countries worldwide to prevent the extinction of endangered plants and animals. Additionally, since customs clearance inspections for goods at airports and ports take a long time, and due to the difficulty of distinguishing such species by nonexperts, smugglers have been exploiting this vulnerability to illegally import or export endangered parrot species. If these cases continue to increase, the extinction of species with fewer populations can be accelerated by illegal trade. To tackle this problem, in this study, we constructed an object detection model using convolutional neural networks (CNNs) to classify 11 endangered species of parrots. Utilizing artificial intelligence techniques, the procedures for inspection of goods can be simplified and the customs clearance inspection systems at airports and ports can be enhanced, thus protecting endangered species. Abstract Owing to climate change and human indiscriminate development, the population of endangered species has been decreasing. To protect endangered species, many countries worldwide have adopted the CITES treaty to prevent the extinction of endangered plants and animals. Moreover, research has been conducted using diverse approaches, particularly deep learning-based animal and plant image recognition methods. In this paper, we propose an automated image classification method for 11 endangered parrot species included in CITES. The 11 species include subspecies that are very similar in appearance. Data images were collected from the Internet and built in cooperation with Seoul Grand Park Zoo to build an indigenous database. The dataset for deep learning training consisted of 70% training set, 15% validation set, and 15% test set. In addition, a data augmentation technique was applied to reduce the data collection limit and prevent overfitting. The performance of various backbone CNN architectures (i.e., VGGNet, ResNet, and DenseNet) were compared using the SSD model. The experiment derived the test set image performance for the training model, and the results show that the DenseNet18 had the best performance with an mAP of approximately 96.6% and an inference time of 0.38 s.

Simple Summary The incidence and developing status of multidrug-resistant bacteria and fungi, as well as their related mortality, is reviewed by a systematic published literature search from nine countries in the Arabian Peninsula. In order to analyse the emerging status and mortality, a total of 382 research articles were selected from a comprehensive screening of 1705 papers. More than 850 deaths reported since 2010 in the Arabian Peninsula due to the infection of multidrug-resistant bacteria and fungi. Multidrug-resistant bacteria Acinetobacter baumannii, Mycobacterium tuberculosis, Staphylococcus aureus, and fungi Candida auris are the most prevalent and causing high deaths. To control these infections and associated deaths in the Arabian Peninsula, continuous preventive measures, accurate methods for early diagnosis of infection, active surveillance, constant monitoring, developing vaccines, eradicating multidrug resistance modulators, and data sharing among countries are required. Abstract We aimed to identify the prevalence and emerging status of multidrug-resistant bacteria and fungi and their associated mortality in nine countries in the Arabian Peninsula. Original research articles and case studies regarding multidrug-resistant bacteria and fungi in the Arabian Peninsula, published during the last 10 years, were retrieved from PubMed and Scopus. A total of 382 studies were included as per the inclusion and exclusion criteria, as well as the PRISMA guidelines, from a thorough screening of 1705 articles, in order to analyse the emerging status and mortality. The emerging nature of >120 multidrug-resistant (MDR) bacteria and fungi in the Arabian Peninsula is a serious concern that requires continuous monitoring and immediate preventive measures. More than 50% (n = 453) of multidrug-resistant, microbe-associated mortality (n = 871) in the Arabian Peninsula was due to MDR Acinetobacter baumannii, Mycobacterium tuberculosis and Staphylococcus aureus infection. Overall, a 16.51% mortality was reported among MDR-infected patients in the Arabian Peninsula from the 382 articles of this registered systematic review. MDR A. baumannii (5600 isolates) prevailed in all the nine countries of the Arabian Peninsula and was one of the fastest emerging MDR bacteria with the highest mortality (n = 210). A total of 13,087 Mycobacterium tuberculosis isolates were reported in the region. Candida auris (580 strains) is the most prevalent among the MDR fungal pathogen in the Arabian Peninsula, having caused 54 mortalities. Active surveillance, constant monitoring, the development of a candidate vaccine, an early diagnosis of MDR infection, the elimination of multidrug resistance modulators and uninterrupted preventive measures with enhanced data sharing are mandatory to control MDR infection and associated diseases of the Arabian Peninsula. Accurate and rapid detection methods are needed to differentiate MDR strain from other strains of the species. This review summarises the logical relation, prevalence, emerging status and associated mortality of MDR microbes in the Arabian Peninsula.

Simple Summary To function correctly, most proteins need to fold into well-defined three-dimensional structures. Destabilization of these structures may not only lead to the loss of function, but also to toxic aggregation and fibril formation. These pathological processes have been linked to a number of neurodegenerative diseases. To prevent such processes, it is important to describe factors causing protein destabilization and identify misfolded structures that are at the origin of the toxic behavior. From the experimental point of view, in many cases, it is useful to construct protein models to better investigate the issues of stability, misfolding, and aggregation. Here, indeed, we focus on a mutant model of superoxide dismutase 1, a protein implicated in amyotrophic lateral sclerosis. We apply a state-of-the-art molecular simulation method to verify whether the current computational machinery is able to describe the features of the biochemical model. Namely, our paper provides a microscopic insight into the unfolding of the superoxide dismutase 1 model while highlighting the strengths and limitations of the computational approach. Overall, our investigation opens the route to the computational study of pathological mutants of the superoxide dismutase 1 protein. Abstract In this work, we investigate the β-barrel of superoxide dismutase 1 (SOD1) in a mutated form, the isoleucine 35 to alanine (I35A) mutant, commonly used as a model system to decipher the role of the full-length apoSOD1 protein in amyotrophic lateral sclerosis (ALS). It is known from experiments that the mutation reduces the stability of the SOD1 barrel and makes it largely unfolded in the cell at 37 degrees Celsius. We deploy state-of-the-art computational machinery to examine the thermal destabilization of the I35A mutant by comparing two widely used force fields, Amber a99SB-disp and CHARMM36m. We find that only the latter force field, when combined with the Replica Exchange with Solute Scaling (REST2) approach, reproduces semi-quantitatively the experimentally observed shift in the melting between the original and the mutated SOD1 barrel. In addition, we analyze the unfolding process and the conformational landscape of the mutant, finding these largely similar to those of the wildtype. Nevertheless, we detect an increased presence of partially misfolded states at ambient temperatures. These states, featuring conformational changes in the region of the β-strands β4−β6, might provide a pathway for nonnative aggregation.

In response to the current state of the COVID-19 pandemic, healthcare providers are using common surgical masks and filtering respirators in conjunction with the presence of facial hair, which could lead to a large number of particles passing into their respiratory system. The purpose of this study was to determine the fit factor effectiveness of filtering respirators and surgical masks in bearded versus non-bearded healthcare providers. A controlled randomized clinical trial (NCT04391010) was carried out, analyzing a sample of 63 healthcare providers. The fit factors of surgical masks and FFP3 filtering respirators for healthcare providers with (n = 32) and without (n = 31) facial hair were compared. Fit factors were measured during an exercises protocol in which healthcare providers wore surgical masks and FFP3 filtering respirators. Surgical mask fit factor comparisons did not show significant differences (p &gt, 0.05) between healthcare providers with and without facial hair. In contrast, filtering respirator fit factor comparisons showed statistically significant differences (p &lt, 0.01) between both groups, indicating that healthcare providers with facial hair showed lower fit factor scores, which implies a worse fit factor with respect to healthcare providers without facial hair. The fit factor effectiveness of filtering respirators was reduced in healthcare providers with facial hair. The authors of this paper encourage healthcare providers to trim their beards during filtering respirator use or wear full-mask filtering facepiece respirators, especially during the COVID-19 pandemic.

Simple Summary Studies describing the effects of various forms of exercise and age on muscle regeneration were reviewed. Satellite cells are a heterogeneous group of cells that includes stem cells and skeletal muscle progenitor cells. Each skeletal muscle fiber has its own pool of satellite cells that remain inactive until the muscle is damaged. Minor damage within the cell membrane of muscle fibers is patched by fusing intracellular vesicles with the damaged sarcolemma. More severe muscle damage initiates a multistep regeneration process in which satellite cells play an essential role. The condition that initiates the cascade of reactions is the formation of inflammation at the structural discontinuity site, resulting in satellite cell activation. The multitude of reactions and pathways occurring during this process means that many different substances are involved in it and control it. Not all of them are well-understood yet. In parallel, the body’s own population of satellite cells is being rebuilt so that more fibers can be regenerated in the future. Athletes and the elderly are primarily at risk for muscle damage, and pathologies in muscle fiber regeneration cause serious diseases. Abstract The population of satellite cells (mSCs) is highly diversified. The cells comprising it differ in their ability to regenerate their own population and differentiate, as well as in the properties they exhibit. The heterogeneity of this group of cells is evidenced by multiple differentiating markers that enable their recognition, classification, labeling, and characterization. One of the main tasks of satellite cells is skeletal muscle regeneration. Myofibers are often damaged during vigorous exercise in people who participate in sports activities. The number of satellite cells and the speed of the regeneration processes that depend on them affect the time structure of an athlete’s training. This process depends on inflammatory cells. The multitude of reactions and pathways that occur during the regeneration process results in the participation and control of many factors that are activated and secreted during muscle fiber damage and at different stages of its regeneration. However, not all of them are well understood yet. This paper presents the current state of knowledge on satellite cell-dependent skeletal muscle regeneration. Studies describing the effects of various forms of exercise and age on this process were reviewed.

Simple Summary Treatment regimens for patients with advanced disease are limited and the mortality rate is high in these patients. A better understanding on pathogenesis and progression of cancer is critical for the development of new treatment strategies. In colorectal cancer (CRC), exosomes (secreted vesicles from cells) and long non-coding RNAs (lncRNAs) have been shown to play significant roles in disease development and progression. Long non-coding RNAs (lncRNAs) are present in the exosomes of serum and their profiles may potentially be useful as novel biomarkers for CRC patients and may provide a new insight in the pathogenesis and progression of CRC. Here, we compared the expression profiles of exosomal lncRNAs between non-cancer individuals and patients with colorectal carcinoma. The relative expression level of LINC00152 was found to be significantly lower in exosomes from sera of CRC patients as compared to non-cancer individuals whereas lncRNA H19 was significantly up-regulated in advanced-stages (stage III and IV) of CRC as compared to early-stages (stage I and II). Our data suggest that LINC00152 and H19 may play important roles in pathogenesis and progression of CRC. Abstract Long non-coding RNAs (lncRNAs) are non-coding RNAs consisting of more than 200 nucleotides in length. LncRNAs present in exosomes may play a critical role in the cellular processes involved in cancer pathogenesis and progression including proliferation, invasion, and migration of tumor cells. This paper aims to identify the differential expression of exosomal lncRNAs derived from the sera of non-cancer individuals and patients diagnosed with colorectal carcinoma. These differentially-expressed exosomal serum lncRNAs may provide an insight into the pathogenesis and progression of colorectal cancer (CRC). Serum exosomes and exosomes from SW480-7 cell culture supernatants were isolated and viewed by transmission electron microscope (TEM). The particle size distribution and protein markers of exosomes derived from SW480-7 were further analyzed using the Zetasizer Nano S instrument and western blotting technique. TEM showed that exosomes derived from serum and SW480-7 cells were round vesicles with sizes ranging from 50–200 nm. The exosomes derived from SW480-7 had an average diameter of 274.6 nm and contained the exosomal protein, ALIX/PDCD6IP. In our clinical studies, six lncRNAs, namely GAS5, H19, LINC00152, SNHG16, RMRP, and ZFAS1 were detected in the exosomes from sera of 18 CRC patients. Among these six lncRNAs, the expression level of LINC00152 was found to be significantly lower in CRC patients as compared to non-cancer individuals (p = 0.04) while lncRNA H19 was significantly up-regulated in advanced-stages (stage III and IV) of CRC (p = 0.04) as compared to early-stages (stage I and II). In conclusion, the detection of lower LINC00152 in exosomes of sera from CRC patients versus non-cancer individuals and H19 upregulation in advanced stages suggests that they may play important roles in pathogenesis and progression of CRC.

Simple Summary There is limited information on how SARS-CoV-2 reaches the brain. Thus, this paper examines how, during co-infection, a protease-secreting microbe may facilitate brain invasion by SARS-CoV-2. An understanding of this potential invasion mechanism could lead to better SARS-CoV-2 intervention measures. Abstract SARS-CoV-2 has been shown to display proclivity towards organs bearing angiotensin-converting enzyme (ACE2) expression cells. Of interest herein is the ability of the virus to exhibit neurotropism. However, there is limited information on how this virus invades the brain. With this contribution, we explore how, in the context of a microbial co-infection using a cryptococcal co-infection as a model, SARS-CoV-2 could reach the brain. We theorise that the secretion of proteases by disseminated fungal cells might also activate the S2 domain of the viral spike glycoprotein for membrane fusion with brain endothelial cells leading to endocytosis. Understanding this potential invasion mechanism could lead to better SARS-CoV-2 intervention measures, which may also be applicable in instances of co-infection, especially with protease-secreting pathogens.

Simple Summary Our work is motivated by the increasing production of chemicals with environmentally harmful effects to our aquatic ecosystems. We show that it is possible to detect and distinguish the presence of several different emerging contaminants, using the photochemical responses of a microalgae species, which is among the most abundant phytoplankton group in the oceans. We use several machine learning and deep learning models that operate on chlorophyll fluorescence induction curves, which are composed of fluorescence values taken at different time steps from the microalgae exposure trials, achieving up to 97.65% accuracy when predicting the type of contaminant, and up to 100% in several cases when predicting the exposure concentration. Our results show the combination of these models with the fluorescence induction curves creates a powerful tool for ecotoxicity assessment, capable of classifying model organisms for their contaminant exposure, both in terms of type and concentration, opening new doors for toxicophenomics developments. Abstract Over recent decades, the world has experienced the adverse consequences of uncontrolled development of multiple human activities. In recent years, the total production of chemicals has been composed of environmentally harmful compounds, the majority of which have significant environmental impacts. These emerging contaminants (ECs) include a wide range of man-made chemicals (such as pesticides, cosmetics, personal and household care products, pharmaceuticals), which are of worldwide use. Among these, several ECs raised concerns regarding their ecotoxicological effects and how to assess them efficiently. This is of particular interest if marine diatoms are considered as potential target species, due to their widespread distribution, being the most abundant phytoplankton group in the oceans, and also being responsible for key ecological roles. Bio-optical ecotoxicity methods appear as reliable, fast, and high-throughput screening (HTS) techniques, providing large datasets with biological relevance on the mode of action of these ECs in phototrophic organisms, such as diatoms. However, from the large datasets produced, only a small amount of data are normally extracted for physiological evaluation, leaving out a large amount of information on the ECs exposure. In the present paper, we use all the available information and evaluate the application of several machine learning and deep learning algorithms to predict the exposure of model organisms to different ECs under different doses, using a model marine diatom (Phaeodactylum tricornutum) as a test organism. The results show that 2D convolutional neural networks are the best method to predict the type of EC to which the cultures were exposed, achieving a median accuracy of 97.65%, while Rocket is the best at predicting which concentration the cultures were subjected to, achieving a median accuracy of 100%.

Simple Summary Mitochondria are essential intracellular organelles that generate energy within the cell. Mitochondria are present in all organs, and organs are powered by the energy produced by mitochondria. Mitochondria are composed of proteins encoded by nuclear and mitochondrial DNA. It is possible that mutations in nuclear and mitochondrial DNA cause alterations in proteins that make up mitochondria, resulting in mitochondrial dysfunction. Since cellular and organ functions depend on mitochondrial function, this mitochondrial dysfunction can lead to tissue dysfunction, namely mitochondrial diseases. In recent years, there have been many reports of the multifaceted functions of mitochondria. However, there is still little knowledge about the diseases. This problem arises because there is no suitable model to mimic mitochondrial diseases. In this paper, we introduce mitochondrial cardiomyopathy models that mimic patients’ cardiomyocytes using human induced pluripotent stem cells (iPSCs). The use of human iPSCs will advance the understanding of the pathogenesis of mitochondrial cardiomyopathy and the development of new drugs. Abstract Mitochondrial cardiomyopathy (MCM) is characterized as an oxidative phosphorylation disorder of the heart. More than 100 genetic variants in nuclear or mitochondrial DNA have been associated with MCM. However, the underlying molecular mechanisms linking genetic variants to MCM are not fully understood due to the lack of appropriate cellular and animal models. Patient-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) provide an attractive experimental platform for modeling cardiovascular diseases and predicting drug efficacy to such diseases. Here we introduce the pathological and therapeutic studies of MCM using iPSC-CMs and discuss the questions and latest strategies for research using iPSC-CMs.

The evolutionary processes responsible for the extraordinary diversity in the middle elevation montane forests of the Tropical Andes (MMF, 1000–3500 m) remain poorly understood. It is not clear whether adaptive divergence, niche conservatism or geographical processes were the main contributors to the radiation of the respective lineages occurring there. We investigated the evolutionary history of plant lineages in the MMF. We used the vascular plant genus Macrocarpaea (Gentianaceae) as a model, as it consists of 118 morphologically diverse species, a majority of which are endemic to the MMF. We used a time-calibrated molecular phylogeny and morphological and climatic data to compare a set of evolutionary scenarios of various levels of complexity in a phylogenetic comparative framework. In this paper, we show that the hypothesis of adaptive radiation for Macrocarpaea in the MMF is unlikely. The genus remained confined to the upper montane forests (UMF &gt, 1800 m) during more than a half of its evolutionary history, possibly due to evolutionary constraints. Later, coinciding with the beginning of the Pleistocene (around 2.58 Ma), a phylogenetically derived (recently branching) clade, here referred to as the M. micrantha clade (25 species), successfully colonized and radiated in the lower montane forests (LMF &lt, 1800 m). This colonization was accompanied by the evolution of a new leaf phenotype that is unique to the species of the M. micrantha clade that likely represents an adaptation to life in this new environment (adaptive zone). Therefore, our results suggest that niche conservatism and geographical processes have dominated most of the diversification history of Macrocarpaea, but that a rare adaptive divergence event allowed a transition into a new adaptive zone and enabled progressive radiation in this zone through geographical processes.

Dengue fever is a viral mosquito-borne infection and a major international public health concern. With 2.5 billion people at risk of acquiring the infection around the world, disease severity is influenced by the immunological status of the individual, seronegative or seropositive, prior to natural infection. Caused by four antigenically related but distinct serotypes, DENV-1 to DENV-4, infection by one serotype confers life-long immunity to that serotype and a period of temporary cross-immunity (TCI) to other serotypes. The clinical response on exposure to a second serotype is complex with the so-called antibody-dependent enhancement (ADE) process, a disease augmentation phenomenon when pre-existing antibodies to previous dengue infection do not neutralize but rather enhance the new infection, used to explain the etiology of severe disease. In this paper, we present a minimalistic mathematical model framework developed to describe qualitatively the dengue immunological response mediated by antibodies. Three models are analyzed and compared: (i) primary dengue infection, (ii) secondary dengue infection with the same (homologous) dengue virus and (iii) secondary dengue infection with a different (heterologous) dengue virus. We explore the features of viral replication, antibody production and infection clearance over time. The model is developed based on body cells and free virus interactions resulting in infected cells activating antibody production. Our mathematical results are qualitatively similar to the ones described in the empiric immunology literature, providing insights into the immunopathogenesis of severe disease. Results presented here are of use for future research directions to evaluate the impact of dengue vaccines., A.S, H.F., and E.S. E.S. has received funded from the Indonesian RistekBrin Grant No. 122M/IT1.C02/TA.00/2021, 2021 (previously RistekDikti 2018-2021). M.A. received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 792494.

Simple Summary The coronavirus disease 2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first encountered in December of 2019 in Wuhan, China. As of now, there have been over 200 million infections and 4 million deaths attributed to the virus. Due to this, it has been a priority to find an effective preventative measure, and numerous vaccines have been developed. Although the developed vaccines share the target of blocking viral entry by the spike protein, their pharmacology and efficacy differs. As such, the mechanism of action and the elicited immune response of the most common COVID-19 vaccines have been compared to help determine which vaccine is most efficacious and is best suited to prevent reinfection and address viral mutations. Abstract It has been over a year since SARS-CoV-2 was first reported in December of 2019 in Wuhan, China. To curb the spread of the virus, many therapies and cures have been tested and developed, most notably mRNA and DNA vaccines. Federal health agencies (CDC, FDA) have approved emergency usage of these S gene-based vaccines with the intention of minimizing any further loss of lives and infections. It is crucial to assess which vaccines are the most efficacious by examining their effects on the immune system, and by providing considerations for new technological vaccine strategies in the future. This paper provides an overview of the current SARS-CoV-2 vaccines with their mechanisms of action, current technologies utilized in manufacturing of the vaccines, and limitations in this new field with emerging data. Although the most popular COVID-19 vaccines have been proven effective, time will be the main factor in dictating which vaccine will be able to best address mutations and future infection.

Simple Summary High nitrogen use efficiency (NUE) in wheat (Triticum aestivum L.) is the key to ensure high yield and reduce pollution. Understanding the physiological and molecular changes that regulate NUE is important for the breeding of high-NUE wheat varieties. Carbon and nitrogen metabolism are the basic metabolic pathways in plants. It becomes important to reveal the underlying molecular mechanisms related to carbon and nitrogen metabolism, which may be helpful to improve NUE. In this paper, two wheat near-isogenic lines (NILs) with contrasting NUE were performed RNA-Sequencing (RNA-Seq) to identify candidate genes associated with carbon/nitrogen metabolism under normal nitrogen conditions. Our research may provide new insights into the comprehensive understanding of the molecular mechanism underlying NUE. Abstract Nitrogen (N) is an essential nutrient element for crop productivity. Unfortunately, the nitrogen use efficiency (NUE) of crop plants gradually decreases with the increase of the N application rate. Nevertheless, little has been known about the molecular mechanisms of differences in NUE among genotypes of wheat. In this study, we used RNA-Sequencing (RNA-Seq) to compare the transcriptome profiling of flag leaves at the stage of anthesis in wheat NILs (1Y, high-NUE, and 1W, low-NUE) under normal nitrogen conditions (300 kg N ha−1, corresponding to 1.6 g N pot−1). We identified 7023 DEGs (4738 upregulated and 2285 downregulated) in the comparison between lines 1Y and 1W. The responses of 1Y and 1W to normal N differed in the transcriptional regulatory mechanisms. Several genes belonging to the GS and GOGAT gene families were upregulated in 1Y compared with 1W, and the enhanced carbon metabolism might lead 1Y to produce more C skeletons, metabolic energy, and reductants for nitrogen metabolism. A subset of transcription factors (TFs) family members, such as ERF, WRKY, NAC, and MYB, were also identified. Collectively, these identified candidate genes provided new information for a further understanding of the genotypic difference in NUE.

Simple Summary The collaboration between periodontics and orthodontics has the potential to allow safer orthodontic tooth movement and improve vulnerable oral conditions especially for patients with very thin bone and soft tissue. By providing this interdisciplinary surgical approach where thin bone and soft tissue are surgically augmented to convert a fragile-thin to a robust-thick tissue phenotype, this permits orthodontic treatment in these previously thin tissue cases to proceed without iatrogenically induced adverse effects. This is an infrequently performed procedure with few clinical recommendations. This review paper provides the rationale and the currently available evidence on the benefits of this novel surgical approach. Abstract Purpose: This systematic review compares the clinical and radiographic outcomes for patients who received only a corticotomy or periodontal accelerated osteogenic orthodontics (PAOO) with those who received a conventional orthodontic treatment. Methods: An electronic search of four databases and a hand search of peer-reviewed journals for relevant articles published in English between January 1980 and June 2021 were performed. Human clinical trials of ≥10 patients treated with a corticotomy or PAOO with radiographic and/or clinical outcomes were included. Meta-analyses were performed to analyze the weighted mean difference (WMD) and confidence interval (CI) for the recorded variables. Results: Twelve articles were included in the quantitative analysis. The meta-analysis revealed a localized corticotomy distal to the canine can significantly increase canine distalization (WMD = 1.15 mm, 95% CI = 0.18–2.12 mm, p = 0.02) compared to a conventional orthodontic treatment. In addition, PAOO also showed a significant gain of buccal bone thickness (WMD = 0.43 mm, 95% CI = 0.09–0.78 mm, p = 0.01) and an improvement of bone density (WMD = 32.86, 95% CI = 11.83–53.89, p = 0.002) compared to the corticotomy group. Conclusion: Based on the findings of the meta-analyses, the localized use of a corticotomy can significantly increase the amount of canine distalization during orthodontic treatment. Additionally, the use of a corticotomy as a part of a PAOO procedure significantly increases the rate of orthodontic tooth movement and it is accompanied by an increased buccal bone thickness and bone density compared to patients undergoing a conventional orthodontic treatment.

Simple Summary The Duvalius cave beetles have a wide distribution in the Palearctic region. They have distinct adaptations to life in soil and subterranean habitats. Our present study intends to extend the knowledge on the morphology of cave Carabidae by describing two larvae belonging to different species of Duvalius and the ultrastructural details with possible implications in taxonomy and ecology. These two species are endemic for limited areas in the northern and north-western Romanian Carpathians. Our study provides knowledge on the biology and ecology of the narrow endemic cave beetles and their larvae are important in conservation and to establish management measures. Endemic species are vulnerable to extinction and, at the same time, an important target of global conservation efforts. Abstract The morphological and ultrastructural descriptions of the larvae of two cave species of Trechini—Duvalius (Hungarotrechus) subterraneus (L. Miller, 1868) and Duvalius (Biharotrechus) paroecus (J. Frivaldszkyi, 1865)—are presented in this paper. The interest in studying these larvae lays in their rarity and the limited distribution of the Duvalius species. The larvae were collected from caves in the Romanian Carpathians and were examined under a stereomicroscope and scanning electron microscopy. New important taxonomical and fine morphological characteristics are discussed together with conclusions on the larvae microhabitat as part of the measures to be taken by a proper management of caves.

Simple Summary Although renal-transplant-recipients can lead much more comfortable life in comparison to patients on dialysis, they need to face other problems. One of them is lifetime immunosuppressive therapy on daily basis. Immunosuppressive regimen contains usually three different drugs and although each one of them is crucial to keep graft in good condition and to suppress immune response against the transplanted organ, they influence, among the other, reproductive system. In current paper we have observed that immunosuppressive therapy based on tacrolimus significantly affected the hormonal balance of sex hormones in both men and women. It is of great importance, as nowadays infertility is rising problem even in health people, therefore more attention should be paid to choose the best suitable immunosuppressive regiment for recipient in reproductive age. Abstract It is estimated that approximately 20% of couples suffer from infertility worldwide and within renal-transplant recipients, this problem is 10 times more common. An intake of immunosuppressants may lead to hormonal imbalance. The aim of the study was to investigate the influence of tacrolimus-based therapy on the hormonal status of grafted patients. Blood samples were obtained from patients from the Department of Nephrology, Transplantology, and Internal Medicine of Independent Public Clinical Hospital No. 2, Pomeranian Medical University. All 121 patients had stable graft function for over 6 months. The blood plasma concentrations of luteinizing hormone, follicle-stimulating hormone, prolactin, testosterone, estradiol, cortisol were assessed by the electrochemiluminescence method. We observed decreased levels of prolactin (11.9 ng/mL) and cortisol (87.4 μg/mL) in patients under tacrolimus-based therapy. Tacrolimus-based therapy was also associated with increased testosterone and follicle-stimulating hormone in males, 4.04 ng/mL and 6.9 mLU/mL, respectively, and decreased testosterone levels in females, 0.121 ng/mL. We also assessed that immunosuppressive therapy based on tacrolimus is less nephrotoxic in comparison to other regimens. Concluding, tacrolimus-based therapy may influence the hormonal status of transplant recipients in the current study. Results presented here are believed to be helpful for clinicians and patients, especially within the aspect of willingness for biological offspring.

Among the diverse and important applications that networks currently have is the modeling of infectious diseases. Immunization, or the process of protecting nodes in the network, plays a key role in stopping diseases from spreading. Hence the importance of having tools or strategies that allow the solving of this challenge. In this paper, we evaluate the effectiveness of the DIL-Wα ranking in immunizing nodes in an edge-weighted network with 3866 nodes and 6,841,470 edges. The network is obtained from a real database and the spread of COVID-19 was modeled with the classic SIR model. We apply the protection to the network, according to the importance ranking list produced by DIL-Wα, considering different protection budgets. Furthermore, we consider three different values for α, in this way, we compare how the protection performs according to the value of α.

Simple Summary The brain is an incredibly complex system possessing outstanding abilities to perform difficult tasks through a vast number of densely interconnected neurons. Aimed at discovering the underlying mechanisms of the brain, a number of spiking neural networks have been proposed to mimic biological neural dynamics. Subsequently, to perceive how the neural networks in the brain work, simulation and hardware realization of large-scale systems, similar to the brain, is an essential requirement. Behavior of a single neuron can be described by the mathematical equations in different levels of computing and biological accuracy. In this approach, a new modified ADEX model is presented based on sampling frequency by the nonlinear functions of the original model. This new model is capable for reproducing all aspects of the original model in low-error and high-degree of similarity conditions. Finally, the proposed model can be implemented on digital hardware platforms to have a real digital system. Digital results show the increase in system speed (frequency) and overall saving in hardware resources (compared by the original model and other similar works). This low-cost digital hardware is applied in large-scale neuronal networks. Design and implementation of biological neural networks is a vital research field in the neuromorphic engineering. This paper presents LUT-based modeling of the Adaptive Exponential integrate-and-fire (ADEX) model using Nyquist frequency method. In this approach, a continuous term is converted to a discrete term by sampling factor. This new modeling is called N-LUT-ADEX (Nyquist-Look Up Table-ADEX) and is based on accurate sampling of the original ADEX model. Since in this modeling, the high-accuracy matching is achieved, it can exactly reproduce the spiking patterns, which have the same behaviors of the original neuron model. To confirm the N-LUT-ADEX neuron, the proposed model is realized on Virtex-II Field-Programmable Gate Array (FPGA) board for validating the final hardware. Hardware implementation results show the high degree of similarity between the proposed and original models. Furthermore, low-cost and high-speed attributes of our proposed neuron model will be validated. Indeed, the proposed model is capable of reproducing the spiking patterns in terms of low overhead costs and higher frequencies in comparison with the original one. The properties of the proposed model cause can make it a suitable choice for neuromorphic network implementations with reduced-cost attributes.

Simple Summary With the emergence of novelty regeneration techniques in the implant dentistry field, the professional may have some queries about which one to use in their daily practice. No systematic review, to date, analyzes the horizontal gains achievable with the two main procedures for bone regeneration: the Khoury technique, which uses split blocks obtained from the patient himself, or the Urban technique, which employs membranes to contain the biomaterials. Regarding this paper, the reader will be able to decide if any of these options is adequate for the indication required. Abstract Purpose. The objective of this systematic review was to evaluate and compare the clinical efficacy of horizontal alveolar ridge augmentation techniques described by Khoury and Urban. Methods. A systematic electronic search in the MEDLINE databases, SCOPUS, WOS, and the Cochrane Central Register of Controlled Trials (CENTRAL) as well as a manual search, were conducted independently by two reviewers up to July 2021. Results. Six studies met the pre-established inclusion criteria and were included in the descriptive analysis. Due to the heterogeneity found across the included studies, meta-analysis could not be performed. Horizontal bone gain was between 3.93 ± 0.9 mm and 5.02 ± 0.8 mm with the Khoury technique and between 3.9 ± 0.9 mm and 5.68 ± 1.42 mm with the Urban technique. Similar complication rates were reported in both groups: infection (7%), in the Khoury technique, and membrane exposure (3.2–13.6%), in the Urban technique, being the most frequent events. Conclusions. Both techniques were found to be effective, in terms of clinical bone gain, for horizontal alveolar ridge gain. Nevertheless, available literature is limited, and there is a lack of comparative studies to better evaluate the results.

Copy number variation (CNV) is a common type of structural variation in the human genome. Accurate detection of CNVs from tumor genomes can provide crucial information for the study of tumor genesis and cancer precision diagnosis. However, the contamination of normal genomes in tumor genomes and the crude profiles of the read depth make such a task difficult. In this paper, we propose an alternative approach, called CIRCNV, for the detection of CNVs from sequencing data. CIRCNV is an extension of our previously developed method CNV-LOF, which uses local outlier factors to predict CNVs. Comparatively, CIRCNV can be performed on individual tumor samples and has the following two new features: (1) it transfers the read depth profile from a line shape to a circular shape via a polar coordinate transformation, in order to improve the efficiency of the read depth (RD) profile for the detection of CNVs, and (2) it performs a second round of CNV declaration based on the truth circular RD profile, which is recovered by estimating tumor purity. We test and validate the performance of CIRCNV based on simulation and real sequencing data and perform comparisons with several peer methods. The results demonstrate that CIRCNV can obtain superior performance in terms of sensitivity and precision. We expect that our proposed method will be a supplement to existing methods and become a routine tool in the field of variation analysis of tumor genomes.

Branching morphogenesis and seamless tube formation in Drosophila melanogaster are essential for the development of vascular and tracheal systems, and instructive in studying complex branched structures such as human organs. Zipper is a myosin II’s actin-binding heavy chain, hence, it is important for contracting actin, cell proliferation, and cell sheet adhesion for branching of the tracheal system in post-larval development of the D. melanogaster. Nevertheless, the specific role of Zipper in the larva is still in question. This paper intended to investigate the specific role of Zipper in branching morphogenesis and lumenogenesis in early developmental stages. It did so by checking the localization of the protein in the cytoplasm of the terminal cells and also by analyzing the morphology of zipper RNAi loss-of-function mutants in regard to branching and lumen formation in the terminal cells. A rescue experiment of RNAi mutants was also performed to check the sufficiency of Zipper in branching morphogenesis. Confocal imaging showed the localization of Zipper in the cytoplasm of the terminal cells, and respective quantitative analyses demonstrated that zipper RNAi terminal cells develop significantly fewer branches. Such a result hinted that Zipper is required for the regulation of branching in the terminal cells of D. melanogaster. Nevertheless, Zipper is not significantly involved in the formation of seamless tubes. One hypothesis is that Zipper’s contractility at the lateral epidermis’ leading edge allows cell sheet movement and respective elongation, as a result of such an elongation, further branching may occur in the elongated region of the cell, hence defining branching morphogenesis in the terminal cells of the tracheal system.

Simple Summary This review was aimed at exploring the potentiality of drugging the endocannabinoid system as a therapeutic option for Alzheimer’s disease (AD). Recent discoveries have demonstrated how the modulation of cannabinoid receptor 1 (CB1) and receptor 2 (CB2) can exert neuroprotective effects without the recreational and pharmacological properties of Cannabis sativa. Thus, this review explores the potential of cannabinoids in AD, also highlighting their limitations in perspective to point out the need for further research on cannabinoids in AD therapy. Abstract Alzheimer’s disease (AD) is a detrimental brain disorder characterized by a gradual cognitive decline and neuronal deterioration. To date, the treatments available are effective only in the early stage of the disease. The AD etiology has not been completely revealed, and investigating new pathological mechanisms is essential for developing effective and safe drugs. The recreational and pharmacological properties of marijuana are known for centuries, but only recently the scientific community started to investigate the potential use of cannabinoids in AD therapy—sometimes with contradictory outcomes. Since the endocannabinoid system (ECS) is highly expressed in the hippocampus and cortex, cannabis use/abuse has often been associated with memory and learning dysfunction in vulnerable individuals. However, the latest findings in AD rodent models have shown promising effects of cannabinoids in reducing amyloid plaque deposition and stimulating hippocampal neurogenesis. Beneficial effects on several dementia-related symptoms have also been reported in clinical trials after cannabinoid treatments. Accordingly, future studies should address identifying the correct therapeutic dosage and timing of treatment from the perspective of using cannabinoids in AD therapy. The present paper aims to summarize the potential and limitations of cannabinoids as therapeutics for AD, focusing on recent pre-clinical and clinical evidence.