Social-emotional competences are critical for positive development and significantly predict educational and occupational attainment, health, and well-being. There is however a lack of consensus about the number of core competences, and how these are defined and operationalized. This divergence in approach challenges future research as well as the scientific usefulness of the construct. In an effort to create an integrative framework, this focused review evaluates different approaches of conceptualizing and assessing social-emotional competences. Building on shared conceptions, an integrative taxonomy “DOMASEC” is introduced, specifying core domains and manifestations of social-emotional competences that bridge across frameworks focusing on social and emotional learning, personality traits (such as the Big Five) and self-determination theory. Core domains include intrapersonal, interpersonal and task-oriented competencies, differentiating between affective, cognitive, and behavioral manifestations of competences across these domains. It is argued that the integrative taxonomy facilitates the conceptual specification of key constructs, that it helps to better organize the multitude of terms and definitions used, and to guide the conceptualization and operationalization of social-emotional competences and their various facets. Social and emotional competences are increasingly recognized as important predictors of valued life outcomes, such as educational and occupational attainment, health and wellbeing OECD, . They arThe conceptualization and measurement of social-emotional competences is not a straightforward task, because the term refers to a set of more specifically delineated competences. The notion of social-emotional competences is generally used as an umbrella term, referring to a range of capabilities that enable individuals to express, regulate and understand their thoughts, emotions, behaviors in every-day situations and interactions with others, and to adjust to changing conditions. Moreover, social-emotional competences are known under different terms, such as “non-cognitive,” “character” or “soft” skills, contrasting them to the more directly assessable cognitive competences  aim to enable the development of core social and emotional competencies that contribute to children's school success and life outcomes. Rooted in theories of progressive education, transactional models of human development, and the emotional intelligence literature , engaging with others (extraversion), collaboration with others (agreeableness), negative emotion regulation (neuroticism), and open-mindedness (openness to experiences)  are conceptually different from academic abilities and subject-matter achievement; (2) originate through reciprocal interactions between biological predispositions and contextual influences; (3) develop progressively as children mature; (4) are shaped through socialization experiences and learning  and are thus understood to be malleable and responsive to intervention; (5) are manifested in more or less consistent patterns of thoughts, feelings and behaviors, although they can vary across contexts and over time; (6) are dependent on situational factors for their expression; and (7) are crucial to success in school, across a wide range of socio-economic outcomes in later life, as well as health and wellbeing Blair, .Previous efforts to create an integrated taxonomy of social-emotional competences argued for the alignment of all existing constructs within a single existing framework, such as the Big Five  which serves to better organize the multiple terms and constructs used in the study of social-emotional competences across disciplines. The DOMASEC model is not intended as a new framework, but as an integrative approach linking across existing frameworks, such as CASEL, the Big Five and others, aligning language with the aim to offer conceptual clarity and to help with the identification and classification of constructs, and where applicable to assess and measure social and emotional competences. The model is guided by developmental-contextual approaches , toward others , and toward developmental tasks . The core domains reflect the ways in which individuals perceive themselves, interact with others, and engage with their environment, e.g., the challenges or tasks they encounter, or the goals they set themselves. Together these domains emphasize the role of the individual as an actor, and the need to engage in and to adapt to different and changing challenges and demands over the life course. At the second level, a differentiation is made between the affective, cognitive, and behavioral manifestations of functioning across different domains. Affective manifestations reflect the positive or negative feelings about the self, others, or different tasks. Cognitions indicate the believes, thoughts and knowledge about the self, others, or different tasks, and behavior the manifest conduct and approach.It is important to take into account different domains and manifestations of social-emotional competences, since some individuals might show effective task-performance and act in correspondence with socially accepted norms and expectations, despite being emotionally unbalanced. Or, they might be well attuned in regulating their interactions with others, but not in concentrating their commitment to specific tasks. The identification of different core domains and manifestations of emotions, thoughts and behaviors within and across these domains is considered necessary to facilitate the conceptual specification of key constructs, directing focus to the most salient aspects of their expression. Considering the multiple domains and manifestations of social-emotional competences enables the assessment of variations in adjustment and the identification of potential competence profiles.The aim of the DOMASEC taxonomy is to be broad enough to integrate social-emotional competences studied across different disciplines, and to be specific enough to enable the grouping of social-emotional competences according to their core domains and their most central manifestations. In particular, the DOMASEC specification of core domains will facilitate the classification of competences recognized across different fields.The DOMASEC taxonomy is not intended to be a grand theory of human development, it rather aims to facilitate the classification of social-emotional competences studied across different disciplines within an integrative framework. One of the central goals of scientific taxonomies is the specification of overarching domains within which large numbers of specific instances can be understood in a simplified way. It is hoped that the DOMASEC framework, as a generally accepted taxonomy, would facilitate the accumulation and communication of empirical findings by offering a standard vocabulary, or nomenclature.mental and experiential life.”  and externalizing adjustment problems as well as prosocial behavior (both reflecting orientation toward others) generally assessed in widely used screening instruments  , or recent work mapping processes associated with executive functioning, a key feature of self-regulation, which also takes into account variations in expression across different developmental stages (Bailey et al., The DOMASEC taxonomy is designed to be broad enough to capture key aspects of different sets of constructs, to classify social-emotional competences studied across different disciplines, and to be specific enough to enable the grouping of social-emotional competences according to their core domains and their most central manifestations. Comparing the DOMASEC taxonomy with some of the frequently used frameworks used in the study of social-emotional learning, personality and character strengths illustrates its potential as an integrative tool. Future research should aim to link the DOMASEC framework to other classification tools with the objective to specify the core constructs and their different facets within the different cells of the grid in more detail, minimizing or eliminating overlap. Good examples of how this can be achieved can be found in the already mentioned online search tool (Explore SEL: The DOMASEC taxonomy also informs the assessment of social-emotional competences. Indeed, the grid structure could serve as a blueprint to facilitate test specification, or the cataloging of existing measurement tools (see also Bailey et al., In developing new assessment instruments aiming for a more comprehensive appraisal of competence profiles, the standard requirements for a reliable and valid assessment should be fulfilled, as well as a number of practical considerations (Campbell et al., Many available assessment instruments were developed for use in small-scale or specialized studies (Halle and Darling-Churchill, Nonetheless, a key message is that social-emotional competences can be measured with relative precision and accuracy. Methods used to quantify the way individuals feel, think and behave across different situations have advanced considerably, in particular through the use of new technologies or involving multi-method multiple-informant approaches (Duckworth and Yeager, Socio-emotional competences are critical for positive development and attainment across multiple domains, including education, employment, health and wellbeing OECD, . HoweverIt is hoped that the proposed taxonomy serves to connect different approaches regarding conceptualization and measurement, and hopefully bring about a consensus regarding the specification and delineation of core socio-emotional competencies and their assessment. Future work should focus in more detail on the specification of the different facets of socio-emotional competences, their comprehensive assessment across cultures, and review variations in the manifestation of distinct socio-emotional competences over time to reflect their formation, growth and possible changes.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.IS conceptualized, drafted, and edited the focused review.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Glycosaminoglycans (GAGs) are linear polysaccharides. In proteoglycans (PGs), they are attached to a core protein. GAGs and PGs can be found as free molecules, associated with the extracellular matrix or expressed on the cell membrane. They play a role in the regulation of a wide array of physiological and pathological processes by binding to different proteins, thus modulating their structure and function, and their concentration and availability in the microenvironment. Unfortunately, the enormous structural diversity of GAGs/PGs has hampered the development of dedicated analytical technologies and experimental models. Similarly, computational approaches  have not been fully exploited in glycobiology, despite their potential to demystify the complexity of GAGs/PGs at a structural and functional level. Here, we review the state-of-the art of computational approaches to studying GAGs/PGs with the aim of pointing out the “bitter” and “sweet” aspects of this field of research. Furthermore, we attempt to bridge the gap between bioinformatics and glycobiology, which have so far been kept apart by conceptual and technical differences. For this purpose, we provide computational scientists and glycobiologists with the fundamentals of these two fields of research, with the aim of creating opportunities for their combined exploitation, and thereby contributing to a substantial improvement in scientific knowledge. In 1902, Hermann Emil Fischer, a German chemistry professor, was awarded the Nobel Prize in Chemistry for his studies on sugar and purine synthesis. Since then, many other scientists have been awarded with the Nobel Prize for glycobiology-oriented studies, including Karl Landsteiner in 1930 for the discovery of human blood groups and Luis F. Leloir in 1970 for the characterization of carbohydrate biosynthesis. Currently, the number of glycobiology-oriented studies is exponentially increasing, showing that sugars are being found to be involved in a growing number of physiological and pathological processes.Among the various classes of sugars, glycosaminoglycans (GAGs) are linear polysaccharides that can attach to core proteins to form proteoglycans (PGs). GAGs and PGs are widely distributed in the bodily fluids, and can be found to be associated with the extracellular matrix (ECM) or expressed on the cell membrane. They are endowed with a mind-boggling diversity of structures, providing a high level of variety and specificity to a wide array of biological functions. Considering the huge amount of data on the functional involvement of GAGs/PGs in physiological and pathological processes, relatively little progress has been made towards truly understanding the molecular mechanism(s) by which GAGs/PGs bind and “tweak” proteins. This is possibly due to the complexity of the structure of GAGs/PGs that has so far prohibited the development of appropriate analytical technologies and experimental models for their study.This problem is well exemplified by considering the “omics” branch of science  aimed at characterizing and quantifying large pools of biomolecules and their interactions, and at translating this information into structures, functions and dynamics. Over the last 30 years, glycomics has not been able to keep up with the rapid progress in genomics and proteomics. Only recently have we witnessed significant advances in new and powerful omics methods that have improved our knowledge of glycomics ,2,3, andAmong the computational methods that can boost the understanding of how GAGs/PGs bind to proteins, particularly promising are molecular modeling, docking and molecular dynamics (MD) simulations. In effect, by working in a virtual environment, these methodologies benefit from a high resilience and potential for high throughput ,8,9,10. Many reviews have been published on GAGs/PGs ,14,15,16The first reported study on a GAG dates back more than 80 years . HoweverGAGs are highly heterogeneous, negatively charged polysaccharides. Different combinations of different hexuronic acids and amino sugars result in five main classes of GAGs, distinguishable by the composition of their disaccharide units ,18: hyalHA is assembled at the plasma membrane, is not linked to core proteins, and remains unsulfated . In contCS, DS and HS contain a common tetrasaccharide (4-mer) linker that is O-linked to specific serine residues in core proteins. KS can instead have three different linkers, either N-linked to asparagine or O-linked to serine/threonine residues in core proteins . MultiplThe process of sulfation of GAGs is of importance to determine their structural heterogeneity and interaction potential  anchor. Syndecans are the most represented family of transmembrane HSPGs [PGs are divided into four major classes, depending on their extracellular and intracellular localization. The only intracellular PG is serglycin, which carries heparin as the polysaccharide chain and is segregated in the granules of mast cells. Importantly, the heparin chains of serglycin can be depolymerized by endoglycosidases to obtain free heparin that is then released to mediate a long list of biological activities . At the ne HSPGs , and thene HSPGs . Glypicane HSPGs . Perlecane HSPGs . Extracene HSPGs .The composition of GAG/PGs changes during cell differentiation , and the− groups in HA or SO3− groups in all the other sulfated GAGs)  and lipids . More ied GAGs) A and strIn general, the long saccharide chains of GAGs/PGs allow multiple bindings with several copies of a protein, inducing effects such as the increase in protein concentration in the microenvironment and the protection from proteolysis and thermal degradation. Additionally, the multivalent binding of a protein to GAGs/PGs can induce its oligomerization  and/or aBy these mechanisms, GAGs/PGs exert functions that range from relatively simple mechanical support functions (mainly when present in the ECMs) to more intricate effects on cellular processes such as cell proliferation, differentiation, adhesion and migration (when associated with the plasma membrane), with consequences in different physiological processes, including development and tissue homeostasis. They are also involved in important pathological processes, such as tumor neovascularization, growth and metastasis, neurodegeneration and viral infection. Finally, GAG/PGs regulate inflammation and the immune responses ,41,45,46In conclusion, the characterization of the chemical structures of GAGs/PGs and of their binding modes to protein partners is mandatory for the comprehension of biological processes involving GAGs/PGs. Furthermore, it is a necessary basis for the design of new drugs aided by molecular modeling, docking and MD simulations.The term “molecular modeling” is commonly understood to comprise all the methods used to model and simulate the behavior of molecules in silico, including molecular docking and MD simulation. Here, we will consider a narrower definition and discuss the three methods separately.The aim of the molecular modeling is to construct models of the three-dimensional structure(s) of molecule systems considering physico-chemical features, such as geometry, energy, and electrostatic potential. Such structures may be determined by experimental techniques including X-ray crystallography , nuclearNevertheless, collecting such structural data for GAGs alone or complexed with proteins remains a challenging task, since GAGs tend to assume a wide distribution of conformational states that make them refractory to X-ray or cryo-EM crystallization. Moreover, NMR, which performs well in the case of flexible structures, has some limits when used to solve long structures such as GAG polysaccharidic chains alone or complexed to proteins.As mentioned above, the lack of appropriate GAG structural data has delayed the exploitation of molecular modeling, docking and MD simulations in glycobiology. However, to compensate for the lack of GAG experimental structures, an increasing number of popular web-based tools with dedicated features for in silico modeling of glycans have been developed and released in the few last years .Although only recently released, web-based tools for in silico GAG modeling have quickly gained prominence with respect to experimental approaches  and in-house libraries, including FDA-approved drugs, pseudo-disaccharide libraries and LOPAC , that prIt goes without saying that the limitations described for molecular modeling of GAGs impact their molecular docking to ligands. Molecular docking computes the configuration of a ligand–receptor complex by calculating the most favorable arrangements. In molecular docking, each of the two molecules involved in the complex is described by its dihedral angles, bond lengths and bond angles, which define its geometry and overall structure . UnfortuOther obstacles are the flexibility of the whole GAG chain (depending upon the 1–4 glycosidic linkage between the monosaccharide units), that of the functional groups on the monosaccharides, and the structural instability of GAG binding sites on the protein partner that can undergo conformational changes (“induced fit”) upon interaction with the GAG. Thus, computational docking of GAGs to proteins remains extremely challenging .The main docking software program used to compute the interaction of small GAGs with proteins is Autodock . Even thNevertheless, all that glitters is not gold. Indeed, even though the quality of the FFs by which GAGs are described has improved, the length and the number of free torsions of longer GAGs still impact the computation time, confining the predictions of GAG/target interactions to short saccharide chains. Notably, novel approaches have been proposed to overcome the “free torsion-limitation” issue, including an incremental docking method in which small GAGs are flexibly docked and connected following a pre-defined path and the final long-GAG/target complex is refined by MD simulation , an autoThe history of MD simulations started more than 60 years ago, when Alder and Wainwright carried out the first simulation of a phase transition in a system of hard spheres . HoweverThen, slowly, the groundwork that made MD simulations a reliable process resulted in the 2013 Nobel prize being given to Karplus, Levitt and Warshel for the development of multiscale models for complex chemical systems . From thThe classical all-atom MD simulation method is mainly used to study GAGs/PGs and consists of numerically solving coupled equations of motion for a system in which the atoms move at defined velocities. The result of these calculations consists of a series of trajectories of the biomolecules, from which thermodynamic and dynamic properties of the system can be extracted. Importantly, the reliability of the prediction of the behavior of a system depends on the assumptions used to describe the interactions within it. Thus, the parameters chosen to describe the systems must be as realistic as possible, considering not only temperature and pressure, but also other relevant features, such as water models, pH and salt concentration of the solution, that are particularly relevant when working with GAGs . The preMany FFs have been developed over the last few years . GLYCAM Shifted textIn conclusion, while molecular modeling and docking provide structures of GAG-protein complexes A,B, the The full potential of molecular modeling, docking and MD simulations can be achieved by following the line of sequential queries schematized in As mentioned above and summarized in (i)a whole set of MD simulations has been performed for a library of HA chains of different lengths complexed to hyaluronan lyase ;(ii)a large array of heparin chains of different lengths has been studied in silico for their capacity to bind up to 20 different viral, animal or human proteins including sulfotransferase, heparinase, immune system-related proteins, protease inhibitors, cell adhesion proteins, blood clotting components, growth factors and their receptors ;(iii)different GAGs (heparin and CS) of different lengths in complex with different glycosidases, chemokines, cell surface receptors and angiogenic growth factors have been subjected to computational studies ;(iv)the in silico combinatorial library screening technology consisting of the automated construction of virtual GAGs has been employed to generate a library of heparins spanning from 2- to 8-mers that have been screened for their binding to thrombin and antithrombin ;Interestingly, some of these papers report multiple computational studies performed on very large libraries of GAGs or GAG-mimetics, supporting the high-through put potential of computational approaches to the study of GAGs and their interaction with proteins, so important in the “omics age”. Here are some examples:(i)the coarse-grained modeling approach, that has been applied to a library of heparin chains spanning from 6- to 68-mers ;(ii)dedicated algorithms have been developed to generate a library of non-sulfated chondroitin spanning from 10- to 200-mer which were compared to MD-generated ensembles for internal validation ;(iii)the same approach was applied to libraries of HA and non-sulfated dermatan, keratan and heparan .To deal with the important issue of GAG length, which still represents a bottleneck and a challenge, different approaches have been described:Despite some important technical progress in computational studies of GAGs , in all the other biologically oriented studies aimed at characterizing the physiological or pathological functions of GAGs/protein interactions , this reSome other important observations can be extracted from Among the large category of GAG interactions with proteins, those with microbial proteins account for 8% of the total. Viruses are the main type of microorganism taken into consideration, with particular attention focused on those proteins exposed on the virus surface that act as determinants of infectivity by interacting with host cell HSPGs . AccordiRegarding human proteins, very few  of the computational studies concern the linking of GAG chains to the core proteins of syndecan , glypicaLast but not least, an important perspective from which to look at the whole body of computational studies of GAGs is their distribution with respect to the type of GAG considered .Not surprisingly, almost half of the computational studies concern heparin. This is easily understandable, given the large array of biological functions played by heparin and the importance of the design of heparin-like drugs for the treatment of coagulation disorders, abnormal inflammatory or immune responses and angiogenesis-dependent diseases. Additionally, the heparin structure is more homogeneous than that of the other GAGs and it is more easily available. Thus, heparin is frequently used as a structural analogue of HS/HSPGs, both in computational and experimental studies. This has surely lowered the number of computational studies of HS, resulting in the number being significantly lower than that of studies of CS, despite the former being more biologically relevant than the latter.A series of features hindered computational studies of GAGs with respect to those of other biological macromolecules . In effeMD simulation has applications as a molecular docking-coupled technique, exploring induced fit mechanisms of GAG–protein binding, evaluating complex stability, and refining and rescoring docking poses . It follAnother remaining obstacle in the field is the absence of well-defined GAG-binding pockets on bound proteins . In effeIn conclusion, molecular modeling, docking and MD simulation of GAGs are being actively pursued but still face challenges due to the length, flexibility and heterogeneity of GAGs. Once exploited at full potential and suitably integrated with biochemical and biological models, computational studies will contribute to a virtuous circle aimed at the deep comprehension of biological and pathological processes involving GAGs .


Aging is an important risk factor for several human diseases such as cancer, cardiovascular disease and neurodegenerative disorders, resulting from a combination of genetic and environmental factors , which, at molecular level, cause changes in gene expression underlying the decline of physiological function. Epigenetics, which include mechanisms regulating gene expression independently of changes to DNA sequence, regulate gene expression by modulating the structure of chromatin or by regulating the binding of transcriptional machinery to DNA. Several studies showed that an impairment of epigenetic mechanisms promotes alteration of gene expression underlying several aging-related diseases. Alteration of these mechanisms is also linked with changes of gene expression that occurs during aging processes of different tissues. In this review, we will outline the potential role of epigenetics in the onset of two age-related pathologies, cancer and cardiovascular diseases. Aging is associated with a progressive decline of numerous physiological processes, which is accompanied by an increase of risk for development of severe diseases such as cancer, cardiovascular disease, senile dementias and type-II diabetes in the elderly. Interestingly, the incidence of many cancers increases after 50 years of age, and diagnoses of heart failure (HF) increases from the age of 60 years, with most patients being over 70 years old. This, coupled with the fact that the average life span has increased, is resulting in aging having a considerable importance at both economic and social levels . DespiteThe aging process of an organism results from a combination of stochastic events including both genetic and environmental factors , which, at the molecular level, cause changes in gene expression underlying the decline of physiological function. For example, aging of the brain is accompanied by changes of expression of genes encoding proteins involved in inflammatory and stress responses and neuropeptide metabolism, while the elderly heart has an altered transcription profile that contributes to impairment of heart function .Nppa, Nppb, Myh7 and Skeletal Alpha-Actin) and repression of adult genes , while cardiac fibrosis is a result of an increase of expression of genes encoding proteins of the extracellular matrix , processes for which the specific underlying mechanisms still remain unknown .Fi–8.Fi6–8]ATP-dependent chromatin-remodeling complexes are multi-protein complexes that regulate gene expression by modifying the nucleosome organization of DNA using energy derived from ATP hydrolysis. Members of these families function as transcriptional activators by promoting the formation of an open and accessible chromatin structure, allowing the recruitment of several proteins involved in transcription. For example, SWI/SNF complexes promote the formation of this structure through a mechanism involving sliding nucleosomes, evicting the H2A/H2B dimers or removing the histone octamers from DNA. Other chromatin-remodeling factors cause gene silencing by organizing the nucleosomes on DNA in a manner that results in the chromatin structure taking a highly compacted form, and thus preventing accessibility to transcription factors .DNA modifications are covalent modifications of DNA bases: the most commonly studied modifications are methylation and hydroxymethylation of cytosine bases. DNA methylation occurs predominantly on the cytosine within CG-dinucleotide-rich genomic regions. These genomic regions are called CpG islands and are found in the majority of promoters in both the human and mouse genomes. The methylation of cytosine promotes transcriptional repression by acting as docking sites of methyl-CpG binding domain (MBD) proteins, a family of proteins that promotes the formation of silent chromatin. In mammals, the DNA methylation pattern is established and maintained by three DNA methyltransferase enzymes (DNMTs): DNMT3A and DNMT3B are essential for de novo DNA methylation during development , while DS-adenosyl-methionine to lysine or arginine residues of histones, and histone demethylases, which catalyze the demethylation of histone tails.Histone modifications are covalent post-translational modifications, which include acetylation, methylation, phosphorylation, ubiquitylation and sumoylation. Among these, the best studied are acetylation and methylation. Acetylation occurs on lysine residues present in the tails of histones, allowing transcription factor accessibility as a result of neutralization of the positive charge of histone tails . The levThe last class of epigenetic mechanisms involves noncoding RNAs (ncRNAs), which include a variety of RNAs that are not translated into proteins. Non-coding RNAs are classified based on their length: short and long. The class of short ncRNAs includes molecules of RNA shorter than 200 nucleotide such as PIWI-interacting RNAs, small interfering RNAs (siRNAs), and microRNAs (miRNAs). In contrast, long ncRNAs (lncRNAs) includes molecules of RNA longer than 200 nucleotides. NcRNAs regulate the expression of proteins at the transcriptional and translational levels. The lack of species conservation of lncRNA renders its study more difficult, although their temporal and spatial expression could be key to understanding the regulation of chromatin structure, recruitment of transcriptional machinery and gene expression. Conversely, microRNAs inhibit the expression of genes by binding to the 3′-UTR (untranslated region) of their target mRNAs, resulting in a degradation of the target mRNA and a subsequent inhibition protein translation .Over the last few decades, the involvement of epigenetic mechanisms has been implicated in several aging-related diseases. In this review, we will focus our attention on two key pathologies, cancer and cardiovascular disease.Cancer is a disease that results from accumulation of genetic and epigenetic alterations, and for several cancers, the most important risk factor is age . PerturbIn an effort to elucidate the role of epigenetic regulation in cancer, several groups over the last few decades have focused their attention on the canonical epigenetic mechanisms that are perturbed during cancer. Dysregulation of DNA methylation is one of the most common epigenetic perturbations in cancer. Loss of DNA methylation at specific regulatory and repetitive elements such as Alu elements (Alu) and long interspersed element-1 (LINE1) has been associated with an increase in genomic instability, making chromosomal arrangements that lead to tumor formation more likely , 16. ConMoreover, aberrant activity of the enzymes catalyzing histone modifications contributes to carcinogenesis . For exaStudies regarding the role of epigenetics in aging have been greatly focused on the role of DNA methylation in this physiological process. Global levels and genomic distribution of 5-methylcytosine change across the genome and at specific loci during aging. Interestingly, DNA methylation has been evaluated as a biomarker for determining the age of cells and tissues, and loci-specific methylation patterns can be very telling as to the age of various tissues. Exposure to ROS, which increases DNA damage, inflammation and the activity and function of DNMTs, has been shown to be correlated with the deposition of 5mC and 5hmc and an increase in mutation frequency . FurtherDysregulation of genes during aging is also linked to an alteration of histone methylation: in murine models, changes in H3K4me3 (activating) and H3K27me3 (repressing) levels have been directly linked to lifespan. Therefore, the DNA and histone modification changes occurring during aging could contribute to the definition of an epigenome more inclined to acquire epigenetic changes responsible for tumor onset.Finally, several non-coding RNAs have been described in regulating cell mechanisms associated with aging, including proliferation, differentiation, apoptosis and senescence, which in turn, have been implicated in potentiation of carcinogenesis . Some exCardiovascular disease (CVD), leading to heart failure, and subsequently death, is the major cause of morbidity and mortality worldwide . There aOf great importance to the proper functioning of the heart is the mitochondria, which is necessary for the metabolic activity of the heart and the production of ATP . CardiacEpigenetic dysregulation has been associated with several cardiovascular pathologies and cardiovascular aging: some of the key epigenetic mechanisms include DNA methylation and hydroxymethylation, chromatin remodeling, aberrant changes in histone modifications, and dysregulation of non-coding RNAs , 50. DNARELA, NOS3, KLF4 and APOE have been linked to progression of atherosclerosis [Chronic inflammation, a key factor of initiation of cardiomyocyte stress and initiation of pathological onset, has been associated with unbalanced lipid levels occurring during atherosclerosis . Studiesclerosis . An impoclerosis . This dyclerosis , collageclerosis  and tranclerosis .MYH7, MYOCD, SRF and KLF4 [MYH6. Furthermore, studies have revealed that in injured adult mouse hearts, there is an alteration of binding of BAF to genomic DNA, thus altering gene expression profiles  is the most abundant modification in eukaryotic messenger RNAs. This chemical modification has been found to be present in intronic regions of messenger RNA, transfer RNA, ribosomal RNA, and noncoding RNAs . RNA metTaken together, these (and other) studies have unveiled several epigenetic mechanisms regulating cardiac homeostasis and revealed how dysregulation of these pathways can lead to onset of cardiovascular pathologies. Many of epigenetic mechanisms involved in CVD are also implicated in aging of several tissues. Despite this, the role of epigenetics in cardiovascular aging and in the onset of cardiovascular disease in the elderly still remains to be elucidated.Over the last decade, our understanding and knowledge of the epigenetic mechanisms involved in cellular homeostasis and disease have greatly increased. Mechanisms involving histone post-translational modifications, chromatin remodeling and non-coding RNA have revealed multi-layered mechanisms regulating the homeostatic state of several cell type ; mechanisms which when dysregulated result in the onset of cancer and cardiac pathologies. Although epigenomic dysregulation in CVD alone is still not fully understood, the role of epigenetics in aging and age-related diseases remains even more elusive. Much progress is still needed to understand changes in the epigenetic landscape of the aged cardiomyocyte , the pathways of which are critical for the maintenance of cardiomyocyte homeostasis, and which are the key factors  that influence chromatin architecture and govern gene expression changes that promote disease.Furthermore, despite decades of study of carcinogenesis, the mechanisms (both genetic and epigenetic) governing the aberrant gene expression changes, cellular identity and responsiveness to cellular and environmental cues, ultimately resulting in cancer, still remain unknown. Studies have revealed that targeting epigenetic mechanisms could play a profound and possibly ubiquitous role in abolishing tumorigenesis. As with other age-related pathologies, there are several unanswered questions with respect to correlating mechanisms of carcinogenesis and aging.Moreover, recent work has shown, using RNA sequencing of whole blood in healthy aged subjects, that there is a small subset of genes that is characterized by changes in expression and splicing and a reduction in genetic regulation, late in life. Quantifying allele-specific gene expression, alternative splicing and genetic regulation, this study showed that there is a strong correlation between genetic effects and the increase in allelic imbalance with age, which is furthermore correlated with increasing environmental variance . Recent Since epigenetic changes have been shown to be reversible, manipulation of epigenomic pathways and epigenetic enzymes using CRISPR/Cas9 technology or targeted pharmacological inhibition could prove to be crucial in reversing epigenetic aberrations that are a hallmark of aging. Currently, there are several epigenetic drugs that are either commercially available, or under clinical phase trials . These dFinally, single-cell transcriptome analysis will be crucial to uncovering epigenomic changes within various cellular and sub-cellular populations to further shed light on the correlation of (epi)transcriptomic changes in aged and diseased tissue. Single-cell RNA sequencing of a murine cardiac pressure-overload HF model revealed that induction of HF leads to an intricate immune activation, whereby a myriad of cells, including neutrophils, B cells, NK cells and mast cells are activated . Using t


Evidence-based approaches to preventing child death require evidence; without data on common causes of child mortality, taking effective action to prevent these deaths is difficult at best. Minimally invasive tissue sampling (MITS) is a potentially powerful, but nascent, technique to obtain gold standard information on causes of death. The Gates Foundation committed to further establishing the methodology and obtain the highest quality information on the major causes of death for children under 5 years. In 2018, the MITS Surveillance Alliance was launched to implement, refine, and enhance the use of MITS across high mortality settings. The Alliance and its members have contributed to some remarkable opportunities to improve mortality surveillance, and we have only just begun to understand the possibilities on larger scales. This supplement showcases studies conducted by MITS Surveillance Alliance members and represents a significant contribution to the cause-of-death literature from high mortality settings. Losing a child is devastating; even worse is losing an infant or child and not knowing why. This tragedy is compounded in poor countries where stillbirth, neonatal, infant, and child mortality is common, but reliable diagnosis of causes of death are rare. Evidence-based approaches to preventing pediatric death require objective data; without data on common causes of child mortality, taking effective action to prevent these deaths is difficult at best.In 2015, the Bill and Melinda Gates Foundation committed to generating more definitive evidence on the causes of child mortality, investing in minimally invasive tissue sampling (MITS), a potentially powerful, but nascent, technique to obtain high-quality information on the causes of death. Conventional medical autopsies remain the gold standard for cause-of-death attribution; however, a growing number of studies provide evidence that MITS is a comparable technique . In MITSAs the value of definitive pathology-based cause of death information in high mortality areas became more apparent, other research groups approached the foundation for technical advice and support for MITS. Therefore, in 2018 the foundation funded the MITS Surveillance Alliance. Built on the experience of ISGlobal, CHAMPS, and the Project to Understand and Research Preterm Pregnancy Outcomes and Stillbirths in South Asia, and facilitated by Research Triangle Institute (RTI) International, the Alliance’s aim was to implement, refine, and enhance the use of MITS across high mortality settings . As the The Alliance and its members have contributed to some remarkable opportunities to improve mortality surveillance. Improvements in tissue sampling practices and application of machine learning techniques to help automate data interpretation may offer substantial efficiencies and can help to solidify the technique as a game-changer for mortality surveillance, within both low-and high-income settings. User-friendly guidance and documentation can increase MITS accessibility and consistency in new sites, and research on acceptability can promote uptake in facility and community-based settings. Improvements in Bayesian methods for predicting underlying causes of death raise the possibility of using MITS-informed causes of death to calibrate verbal autopsy data to improve cause of death attribution and estimation in populations where MITS is not performed . Given tThis supplement showcases studies conducted by MITS Surveillance Alliance members and represents a significant contribution to the cause-of-death literature from high mortality settings. Each MITS case brings us closer to understanding the major causes of mortality. By continuing to invest in techniques that can, with high acceptability, identify causes of death in low-resource settings, and develop solutions to address them we move closer to a world where children, families, and communities no longer needlessly suffer from preventable deaths.


The exponential increase in textile cotton wastes generation and the ineffective processing mechanism to mitigate its environmental impact by developing functional materials with unique properties for geotechnical applications, wastewater, packaging, and biomedical engineering have become emerging global concerns among researchers. A comprehensive study of a processed cotton fibres isolation technique and their applications are highlighted in this review. Surface modification of cotton wastes fibre increases the adsorption of dyes and heavy metals removal from wastewater. Cotton wastes fibres have demonstrated high adsorption capacity for the removal of recalcitrant pollutants in wastewater. Cotton wastes fibres have found remarkable application in slope amendments, reinforcement of expansive soils and building materials, and a proven source for isolation of cellulose nanocrystals (CNCs). Several research work on the use of cotton waste for functional application rather than disposal has been done. However, no review study has discussed the potentials of cotton wastes from source (Micro-Nano) to application. This review critically analyses novel isolation techniques of CNC from cotton wastes with an in-depth study of a parameter variation effect on their yield. Different pretreatment techniques and efficiency were discussed. From the analysis, chemical pretreatment is considered the most efficient extraction of CNCs from cotton wastes. The pretreatment strategies can suffer variation in process conditions, resulting in distortion in the extracted cellulose’s crystallinity. Acid hydrolysis using sulfuric acid is the most used extraction process for cotton wastes-based CNC. A combined pretreatment process, such as sonication and hydrolysis, increases the crystallinity of cotton-based CNCs. The improvement of the reinforced matrix interface of textile fibres is required for improved packaging and biomedical applications for the sustainability of cotton-based CNCs. The demand for textile materials is increasing globally due to population growth and economic development . TextileCotton wastes generated have either been incinerated or landfilled. Few research works on the use of cotton waste for functional application rather than disposal have been done. However, no review has critically discussed research findings and analyses of the state of cotton waste use. In this review, the relevance of our study is benchmarked on three critical aspects including cotton wastes generation and the associated environmental impacts, and functional properties of cotton fibres into functional materials to reduce the environmental impact as a result of disposal and functional biomaterials for sustainable environmental applications. A critical review on this subject is rare. The awareness of functional usage of cotton waste for CNC production has not been fully explored because many studies focus on isolation of CNC from a wood source. Therefore, no review has been written in this respect, which has limited the valorisation of cotton waste for a functional application. This review critically discussed the functional application of cotton waste at micro to nano sizes. This covers cotton fibre and CNC isolation, their application, limitations, and proposed research to combat these limitations. To the best of our knowledge, no review study has discussed the potentials of cotton wastes from source (Micro-Nano) to application. The utilization of the cotton wastes based on its intrinsic functional properties have found wide application in environmental sustainability through dye and heavy metals removal from wastewater as well as geotechnical, packaging, and biomedical applications. The improvement of the reinforced matrix interface of textile fibres is required for improved packaging and biomedical applications for the sustainability of cotton-based CNCs.Over the last decade, 40% of global fibre production is attributed to cotton . China iThe strength of cotton fibres as a functional material is attributed to its rigidity of a cellulose chain, crystalline structure that allows intramolecular and intermolecular hydrogen bonding . Wang, FDuring the processing and production of cotton fibres, cotton wastes are generated. Synthesis of these waste fibres have created potentials and a wide application due to their intrinsic properties. The functionalization of polymers for improved surface properties such as adhesion, surface properties including porosity roughness, surface adsorption, and wettability potentials through active functional groups determines its applicability ,5. The rThe application of cellulose-derived cotton wastes for a wide range of applications, such as environmental including dyes and heavy metal remediation from wastewater, geotechnical, packaging, and biomedical applications, with the potentials of forming composites, is presented in this section.The cost-effectiveness and abundance of cotton wastes can be utilized as the ideal material for the fabrication of highly efficient catalysts and adsorbents for dye and heavy metal removal and for geotechnical applications. For the benefit of the environment, recycling these wastes into value-added products is very significant for environmental sustainability. Çay, Yanık  have recWater TreatmentCotton waste is a very significant textile waste that has found application in water purification and wastewater treatment, especially for the removal of emerging and recalcitrant pollutants from wastewater. The removal of pollutants of emerging concerns such as pharmaceuticals, agrochemical personal care products (PPCPs), and dyes have gained interest in recent times. From an environmental perspective, PPCPs are the excreted drugs by humans, sediments, or pollutants from the treatment plant. Meng, Liu  have conDye Removal2 has good photocurrent activity and chemical stability. Although the light absorption of TiO2 is limited to ultraviolet light, the energy of ultraviolet light accounts for about 4% of solar energy, and, therefore, restricts its practical application. A schematic illustration of adsorption and a photocatalytic process of pollutant removal in solution.The application of cotton wastes for the adsorption of synthetic dyes is economically viable because of the availability and ease of processing the wastes. Cotton wastes have been widely applied for the treatment of cationic dyes ,42. Qin,The efficiency of the processed cotton wastes for the removal of different forms of dyes with a focus on the adsorption method is presented in this review due to its low cost of treatment and high removal capacity from the solution. The investigation revealed that higher sorption capacity was observed on the cotton hull adsorbent than cotton stalk even though the adsorption efficiency for both adsorbents was not very high. The pH of the adsorbate affected the aqueous chemistry and the binding surface of the adsorbents. It was found that cotton wastes, which are predominantly natural cellulosic fibres, are negatively charged as a result of the presence of hydroxyl groups in cellulose. The higher uptakes may likely be obtained at a very acidic pH due to the electrostatic interaction between the positively charged surface of the adsorbent and the negative charge of the Ramazol black B dye anions. Furthermore, Deng, Lu  reportedHeavy metals removalHeavy metal ions are persistent environmental pollutants. They are toxic and hazardous at a low concentration . Heavy mMa, Liu  studied This synergistic interaction implies that competitive adsorption better described the sorption mechanism. Reference  investigThe removal of dyes and heavy metals depends on the chemical composition of the analyte and the nature of the wastes. Spent cotton adsorbents contain toxic substances, which have a severe environmental impact. Desorption of these hazardous wastes is required to ensure environmental sustainability. At the end of the adsorption of dyes on cotton wastes, not all reactive dyes are adsorbed. Consequently, the dyeing baths could generate enormous hazardous effluents.Hu, Shang  have stuGeotechnical applicationsProcessing of cotton waste fibres for the reinforcement is of huge environmental and economic benefits. For building applications, the processing of cotton fibres to form fibre-reinforced composites has been reported by Reference . ReferenHolt, Chow  developeIn another study, Muthuraj, Lacoste  reportedTechnology and engineering sectors are key drivers of innovative waste management strategies to ensure environmental sustainability. Waste engineering and an effective technological approach may well create waste management solutions through recycling of industrial wastes, especially cotton wastes, which are the most generated textile wastes. The concept of bioeconomy has created a sustainable approach to processing cotton wastes into bio-products. Leal Filho, Saari  have repAt a structural level, cellulose derivatives from bio-cellulose composites are an attractive prospect for sheet coating and binders . Fibres The processing of cotton fibres provides an interesting phase in bio-composite applications due to their elasticity and high tensile strength. The application of bio-composites has focused on synthetic thermoplastics or thermosets and other non-biodegradable polymers as a matrix. Cotton fibres have been applied with other fibres to form bio-composites of good thermal and mechanical properties. Reference  have incMeekum and Kingchang  demonstrBiopolymers are often processed for bio-medical packaging, anti-microbial materials, biosensing, and tissue engineered applications . Cotton Antimicrobial MaterialsThe unique physicochemical characteristics of cotton fibres are attributed to the available highly reactive functional groups, such as the hydroxyl groups on the surface of the cellulose-based material, which have the tendency to react with other functional groups such as carboxylic acids amines, and aldehydes, resulting in diverse properties. Hence, the prospect of producing antimicrobial biofilm can be achieved for biomedical packaging applications . The proE. coli. Coradi, Zanetti [Tavakolian, Jafari  have rep Zanetti  have syn Zanetti  reported Zanetti  stated t Zanetti  fabricat Zanetti . The syn Zanetti . Wang, Y Zanetti  evaluateThe authors revealed that the bioactive behaviour of the mesoporous surface has the potentials for attaching red blood cells to the surface of the materials. The modified N-halamine polymer was found to have a higher surface area and pore volume, resulting in the increase of a blood clot index. The synthesis of the membrane from cotton wastes is potential candidates for biomaterial applications, such as coating. The incorporated, extracted cellulose from the cotton into membranes have prospects for biomedical packaging, wound dressing applications, and drug delivery systems.Biosensing and DiagnosticCotton fibres have promising potentials for the integration of biosensors . Idumah The obtained cotton sensor was co-encapsulated in a biopolymer shell by loading the sensor on a pH probe. The sensor system monitored the enzymatic reaction of urease through a pH-responsive tricyanofuran hydrazone chromophore. Under the atmospheric conditions, the encapsulated sensor recorded a detection limit in the range of 0.1 ppm and 250 ppm. The findings revealed that cotton gauze strips that coated the sensor system can be applied for the implantation of a smart bandage. A cotton-derived biosensor was applied for wound dressing. Reference  fabricatAbdelrahman, Fouda  have devTissue EngineeringCotton fibres have been explored for wide applications in tissue engineering through the regeneration of tissues from cell growth supported by biomaterials. Cotton materials have been explored for the fabrication of scaffolds for tissue-engineered applications. King, Chen  reportedSingh, Dutt  stated tThe conversion of cotton wastes into valuable nanomaterials is attracting research attention. From an environmental point-of-view, the recycling of cotton wastes, which is the most generated textile waste, is very significant for the protection of the ecosystem. Cotton fibre is an abundant renewable resource. Therefore, cotton waste remains a suitable candidate for the extraction of cellulose and a precursor for the production of CNC. Cotton fibres consist of three major components, namely, cellulose, hemicellulose, and lignin . The cryHowever, the abundance of cellulose composition in cotton waste has increased the prospect of its utilization for the production of CNC. Due to its inherent properties such as high strength, large surface area, high modulus, unique optical properties, and biodegradability potentials, several extraction methods have been explored for the production of CNC from cotton wastes. The degree and extent of the crystallinity of the isolated CNC from cotton wastes depend on the pretreatment methods and the processing conditions utilized. CNC is often good biodegradable reinforcement materials and has become a focus of attention for producing biodegradable composites due to their excellent mechanical properties. However, an effective processing mechanism of cotton wastes into functional materials for the extraction of CNC is rarely reported. Isolation of CNC from cotton wastes have been rarely explored. Much focus is on wood-based plants for commercialization purposes. The prospect of cotton-derived CNC has been explored as reinforcement material to improve the functional properties of composite films for packaging applications . SimilarCotton wastes have been explored as a suitable precursor for the extraction of cellulose. In the early years of textile production, the extraction of cellulose from cotton wastes was achieved by the removal of nanocellulose (NC) compounds. A significant evolutionary trend has been achieved over the years for the extraction of cellulose from cotton wastes. In earlier studies, several pretreatment methods have been used for the extraction, such as chemical treatment using sulphuric compounds, acids, alkali, thermal treatment using pressing, heating, steam puffing, and decompressing. In some cases, pretreatment methods were combined. The sources and the method of extraction are the two major factors attributed to the production of cellulose from cotton wastes. However, there is still much more progress that is required. In recent years, methods of extraction have focused on different pretreatment methods, such as alkali and acid hydrolysis, including ultrasonication. Cotton production has increased over the years, resulting in the increase in cotton wastes that have been applied in different areas, such as environmental pollution control, soil amendment, reinforcements, and biomedicine. Studies have advanced on the increase in the crystallinity and yield of CNC produced from extracted cellulose from cotton wastes.Recently, hydrolysis pretreatment has been combined with sonication to improve the cellulose content in waste cotton fibre. CNCs from cotton wastes have been used in the biopolymer matrix for reinforcements. The bio-composites have been used for packaging, building materials, and biomedical purposes. The chronological order of cellulose extraction from cotton wastes is presented in The energy requirement and enzymatic hydrolysis were affected by the milling time. The authors reported that the relationship between milling time, enzymatic hydrolysis, and the surface area of biomass determines the extent of crystallinity of cellulose materials. Maciel, Kolodziejski  separateAcid Hydrolysis has been reported for the separation of cellulose from cotton fabric waste. Elazzouzi-Hafraoui, Nishiyama  and Kuo,Ultrasonication is one method that has been used for the isolation of micro and macro fibrils and for the extraction of cellulose. A few studies have combined the process of hydrolysis and sonication for cellulose extraction. Pandi, Sonawane  stated tThe synthesis of cotton wastes on a nanoscale toward pollution management and environmental protection is drawing attention for diverse applications. The characterization of nanocrystals from cotton wastes is attracting significant interest. This can be attributed to its abundance of cellulose, environmentally-friendliness, high crystallinity, biodegradability, low toxicity, and high surface area, including its inherent optical properties and renewability potentials. The extraction of CNCs from cotton wastes can be achieved via chemical, mechanical, or enzymatic processes.The isolation of CNCs from semi-crystalline cellulose is usually achieved through a hydrolytic process whereby the amorphous phase undergoes digestion while, in the process of mechanical disintegration, the crystallites are released. Bahloul, Kassab  reported2SO4. The produced CNC demonstrated high crystalline, biocompatible, and sustainable behaviour. The type of acid used for extracting CNCs can affect the characteristics of the CNC. When sulfuric acid was used, sulphate groups from the acid esterifies the free hydroxyl groups on the surface of the CNC. Conversely, CNCs hydrolyzed by HCl have relatively low concentrations of strong and weak acid groups bound on the surface that allow the crystals to aggregate and flocculate due to van der Waals attraction in aqueous solutions.Maciel, de Carvalho Benini  have rep2SO4 at 45 °C for 1 h. Higher crystallinity of CNC was achieved. This was attributed to the susceptibility of the amorphous region as a result of the effect of hydrolysis, which influenced the removal of amorphous cellulose. Reference [Wang et al. (2019) extracted CNC from cotton wastes by alkali treatment, which is followed by acid hydrolysis. The extracted CNC demonstrated smooth and flat surface morphology, including a high aspect ratio. CNC exhibiting a high aspect ratio have the reinforcing potentials in composites due to good mechanical properties. Reference  stated teference  extracteThe extraction of CNC from cotton wastes, pretreatment methods, and process conditions, including their strength and limitation from the previous studies, is presented in The extraction of CNC from cotton wastes is achieved at a low cost. The wastes are harnessed into value added products with promising potentials for a wide range of application. The functional properties of cotton wastes as a precursor for the extraction of CNCs depend on the extent of its crystallinity. The crystallinity of a material is a function of the hydrolysis reaction time, which is determined by the crystalline index . Ilyas, The findings of the crystallinity indexes in Furthermore, Wang, Yao  reportedThambiraj and Shankaran  synthesiPrevious studies have indicated the significance of the hydrolysis reaction in the extraction of CNC. The effect of chemical hydrolysis in the removal of an amorphous region can be observed in the difference in the morphology of treated and untreated cotton waste fibres, as illustrated in In 2SO4 and HCl produced a very dense, flat, and smooth surface of CNC with good thermal stability. The extracted CNC when used as a reinforcement agent exhibited good surface area, high crystallinity, tensile strength, and modulus of elasticity. However, the CNCs were not well distributed in the polymer matrix at a high concentration. This could be improved using ultrasonic assisted hydrolysis. This process could produce CNC of high crystallinity, a high aspect ratio, and higher thermal stability. However, the dispersibilty for CNCs is caused by hydrolysis of HCl. This problem could be improved by the electrostatic repulsion of sulphate ions during hydrolysis with a mixed acid. The combined effect of sonication and hydrolysis using ultrasonic assisted H2SO4 hydrolysis could enhance the structural and thermal properties of CNC extracted from cotton wastes. This included increased crystallinity due to a combined effect. Enzymatic hydrolysis and sonication could produce high crystallinity CNC from cotton wastes. Low power and short sonication could disrupt the weak linkages of the hydrolyzed cotton for CNC extraction. Lastly, sulfuric acid hydrolysis assisted high pressure of a mechanical homogenizer that could increase crystallinity and a high aspect ratio of CNC from cotton wastes, which has shown to produce composites of high tensile strength.Chemical pretreatment is the most used extraction method for CNC from cotton wastes precursor. However, the techniques applied to extract CNC depends on the chemical composition of the precursor and the pretreatment process conditions of extraction. The extraction procedures involve four major steps, which are washing to remove compounds from cotton wastes, pulping of cotton wastes, then bleaching, and, finally, hydrolysis. The extraction of CNC from cotton wastes using chemical pretreatment mostly applied sulfuric acid hydrolysis to achieve CNC of high crystallinity. Bleaching and sulfuric acid hydrolysis is a highly efficient process of producing CNC of high purity and a high aspect ratio, which can suitably be utilized as reinforcement material in a polymer composite. A combined acid hydrolysis using HWith recent advances in extraction of CNC from cotton wastes using different isolation techniques, there is remarkable interest in advancing its potentials in various applications, which will be a significant benefit in nanotechnology. The utilization of the intrinsic properties of derived CNC from cotton wastes have prospects in advancing applications in areas such as biomedical and packaging. The design of nanocomposite films using cotton-based CNC as reinforcement to enhance films’ properties have attracted significant attention in recent years to improve properties or as a replacement for existing applications.The potential of CNC has been explored for biomedical application, such as anti-cancer activity, drug delivery, and tissue engineering in previous studies . TraditiThe reinforcement potentials of CNCs have often been explored for the improvement of mechanical properties of composites for packaging applications. Reference  comparedCotton wastes is the most generated wastes during textile production. The ineffective disposal mechanism of the wastes causes environmental problems. The valorization of cotton wastes into functional materials is essential, but its sustainability and the potentials of extracted cellulose from the waste streams have not been fully explored even though they have been utilized for some geotechnical, environmental, and biomedical applications. A cotton fiber–biopolymer blend for functional and advanced applications such as biomedical, tissue engineering, etc. still requires further research. Issues of biocompatibility and toxicity of the cotton fibre are still pending. The extraction of CNC from cotton wastes have been widely reported in the literature. However, there still exists a drawback that could limit their applications. The pretreatment strategies can suffer variation in terms of process conditions, which could result in a distortion in the crystallinity of the extracted cellulose. Chemical pretreatment is considered the most efficient process. In some instances, an increase of acid concentration affects the crystalline region of the CNC. The use of ultrasonic techniques for the extraction of CNC from cotton wastes is attracting attention in the area of sonochemistry.In an ultrasonic technique, the exchange of ultrasonic energy to the cellulose chain requires energy for the breaking down of cellulose into nanofibers. Sonication depends on cavitation, whereby the ultrasound energy may likely cause shear-in resulting in breakage of intra-fibrillar bonds due to scission. On a commercial scale, ultrasonication is effective for the extraction of nanofibers from the original, natural fibre by altering the duration and power of the ultrasound. The diameter of the nanocrystal can be increased in the process. Many studies have combined pretreatment methods, such as hydrolysis, alkali treatment, and sonication, to reduce production cost. An increase in the acid hydrolysis affects the crystalline region in some cotton wastes. Therefore, more studies should focus on the best approach to minimize the effect of hydrolysis for an optimal benefit. Mass production of CNCs from cotton wastes have rarely been explored on industrial level even though there are promising potentials for various industrial applications, such as biocompatibility, biodegradability, and high thermal conductivity. The issues and challenges that affect the production of CNC from cotton wastes documented in this review is illustrated in Furthermore, cotton wastes as a precursor for activated carbon have demonstrated high adsorption capacity for the removal of recalcitrant pollutants for dyes and heavy metals including organic pollutants in solution. However, the sorption capacity of the wastes adsorbent depends on the operational conditions of the treatment system and the surface structure of the wastes adsorbent. Surface modification of cotton wastes will improve the extent of attachment of pollutants on the active sites of the adsorbent. The challenge of improvement of reinforced matrix interface using cotton fibre as reinforcement in composites is still a subject of intensive research. According to Claramunt, Ventura , the reiThe possibility of combining biopolymers and cellulose from cotton wastes to obtain a biodegradable plastic can be very useful for packaging applications. The effect of cellulose as filler can significantly impact the mechanical properties of the biopolymer. Masmoudi, Bessadok  reportedThe development of CNCs from cotton wastes have demonstrated vast potentials for various application in our earlier discussions. For the advancement of nanotechnology, enhancement by chemical modification, adding compatibilizers to improve CNC is significant since hydrophilic behaviour of CNC inhibits mixing and dispersal in hydrophobic matrices. PLA obtained from agricultural sources combined with nanocellulose produced cellulose extracted from cotton wastes as reinforcement have the potential to create a functional CNC. The new biomaterials have the prospect of creating new areas of applications in construction and automotive engineering including a sustainable water treatment system, biomedicine, and food packaging. However, the challenge of the dispersal of the reinforcement in the polymer matrix without causing degradation of the biopolymer may limit the application. This limitation can be improved through the nanofibers-matrix compatibility by an interaction or by adopting suitable processing techniques. The technique to be adopted to manufacture a biopolymer/cotton-derived nanocellulose composite should be on the basis of the desired application. This includes the physico-chemical characteristics and the thermal stability of the nanocellulose. For example, the use of nanocellulose as an additive for reinforcement of the biopolymer must have effective binding potential, high molecular strength, and functional surface chemistry that allows reactivity. Cellulose nanocomposites are fibrous in nature with effective mechanical properties including their biocompatibility. They are potentially suitable as components for improved membranes for water treatment systems, conductive thin films, wound dressing, and paper barriers. The incorporation of CNC within the polymer matrix alters the membrane properties. More research attention should focus on the enhancement of the tensile strength from the added CNC and the hydrophilic behaviour, permeability, and resistance to biofouling of the produced bio-nanomaterial.Cotton wastes have been effectively applied due to the high adsorption capacity of the precursor for the removal of dyes and heavy metals from solution. The functional properties of cotton wastes have been utilized for the production of lightweight composite-building materials. Cotton wastes have found application as filler for reinforced structures for geotechnical applications for slope amendments as well as reinforcement of soils and composites with effective binding properties. The cellulosic properties of cotton wastes with other pozolanic materials could be an effective alternative binder to improved flexural strength and physical properties of materials for packaging. Cotton fibres have also been utilized as effective reinforcement materials for packaging, antimicrobial materials, and for the fabrication of scaffolds for tissue-engineered applications. The extraction of CNCs from cotton wastes offer remarkable prospects to produce functional materials for reinforcement applications of composites. The processing of cotton wastes for the extraction of CNCs holds promising potentials for advanced application due to the high crystallinity and thermal stability. Several novel extraction methods including a combination of processes have been reported. Acid hydrolysis using sulphuric acid remains the most used pretreatment method. Cotton gin motes and cotton gin wastes could extract CNCs of high thermal stability and high crystallinity using sulfuric acid hydrolysis. CNCs of high crystallinity could be extracted from cotton wastes by alkali treatment and acid hydrolysis. A combined process of bleaching, acid hydrolysis, and sonication could extract CNC of high thermal conductivity from cotton wastes compared to the raw material. The crystallinity of cotton wastes derived CNC that could increase by 81.23% and the yield by 45%. Reduction in hydrolysis time and enhanced yield of CNC could be achieved by combined extraction methods. Physical and chemical modification of cellulosic sources derived cotton wastes significant for improved functional materials for improved packaging and biomedical applications through improved bonding of the fibre and the matrix of bionanomaterial products. Cotton wastes-extracted CNC have been incorporated as a reinforcement agent in composite films with improved compatibility, homogenous dispersion, and effective fiber-matrix interaction for packaging. CNC derived from cotton wastes have proven to exhibit a non-cytotoxic effect and could be applied as a replacement for carbon nanotubes for biomedical applications. The high crystallinity of CNCs derived from cotton wastes and their properties including high tensile strength and high-water holding capacity create prospects for the production of CNC aerogels/hydrogels for drug delivery, building insulations, and oil and water separation applications. Previous researchers have explored the ideas of producing CNCs. However, effort toward advancing the commercialization potential remains a challenge. Future works to improve on the dispersibility of CNC in the polymer matrix as reinforcements, including the potentials of CNCs from cotton wastes to produce novel bionanomaterials, need to be explored.


Job security influences the ability of nurses to provide high-quality nursing care. The Iranian health system has always faced nursing shortages, and the COVID-19 pandemic has worsened this situation. Although nurses have been labelled ‘heroes’ across the globe, many of them have been hired using insecure employment contracts. This commentary aims to describe issues surrounding job contracts for Iranian nurses during the COVID-19 pandemic and discusses how the current situation can be improved. Iranian nurses are at the frontline of the fight against COVID-19 and need to receive better support in terms of job security and dignity. They should participate more in policymaking activities to improve their job condition and prevent the development and implementation of the short-term and insecure job contracts that lead to job insecurity. Public health has been defined as “the art and science of preventing disease, prolonging life and promoting health through the organized efforts of society” . It aimsThe quality of work life (QWL) of nurses plays an important role in the promotion of public health ,6. QWL iJob security is defined as the employee’s perception that they can maintain their job for as long as they desire, and no mental or objective factor makes them prone to losing their job . Job insWork engagement is a satisfying and positive state of work characterized by vigor, dedication, and absorption . AutonomJob satisfaction has been defined as the sense of pleasantness when job needs or desires are met . It has Nurses’ job insecurity can reduce public health due to dissatisfaction and reduction in QWL . Nurses’A recent study in Spain showed that job security in nursing has worsened in the last decade, mainly due to falling numbers of permanent job contracts . AnotherIn this commentary, we present an overview of the Iranian health system and the nursing profession in Iran based on a thorough review of the literature. We continue with a discussion on the condition of Iranian nurses after the COVID-19 pandemic and the employment contracts in this period. Finally, this paper concludes by proposing some directives about how nurses’ job conditions and security in Iran can be improved.The health system in Iran is primarily an insurance-based system . The MinThe public sector provides primary, secondary, and tertiary healthcare services. Some primary healthcare services, including vaccinations and prenatal care, are provided free of charge. In addition, a significant portion of secondary and tertiary healthcare services in the provinces are provided by the public sector. The private sector also provides secondary and tertiary healthcare in urban areas. Furthermore, non-governmental organizations (NGOs) are active in certain areas such as diabetes, pediatric cancer, thalassemia, and breast cancer. The MoHME is responsible for planning, monitoring, and supervising health-related activities for private and public sectors in Iran ,30,31.On 5 May 2014, the Iranian health system started the implementation of the Health Sector Evolution Plan (HSEP). Its goal was to reduce the co-payment of patients admitted to public hospitals, distribute physicians to less-developed areas of the country, provide incentives to encourage physicians to stay and work in disadvantaged areas, reduce inequalities between different regions of the country, increase equality in access to healthcare services, increase the presence of specialist physicians residing in public hospitals, improve the quality of visiting services, and update healthcare tariffs. In addition, policy making in the fields of prevention and primary healthcare were planned ,33.Currently, due to the shortage of nursing in Iran, most nurses provide services in hospitals. This is because most health officials and those involved in the Iranian health system prefer to employ nurses in the second level of prevention, i.e., clinical care in hospitals ,35. HoweFurthermore, nurses have an important role in the implementation of the HSEP. Indeed, with the implementation of the HSEP and expansion of public health coverage, and the subsequent reduction in treatment tariffs in public centers, referrals to these centers have increased. However, the number of nurses has remained stable, leading to an increased workload for nurses working in public health centers ,38.High-school graduates can enter the nursing program at medical sciences universities across the country based on their interests and rank in the national entrance exam . CurrentClinical placement for undergraduate nursing students begins in the second semester in teaching hospitals. Students should participate in a clinical placement until the end of their third year whilst undertaking theoretical courses. They receive training in their first three years under the direct supervision and guidance of nurse instructors. Their fourth year is dedicated to an internship, which is performed under the supervision of nurse instructors and under the direct guidance of clinical nurses ,43. A baThe nursing shortage for positions in health centers under the supervision of the Iranian health system is a major and multifaceted challenge. The causes of nursing shortages in Iran can be ordered based on priority and importance as follows: unwillingness to enter and stay in the nursing profession, insufficient salaries, low social status, negative perception of nursing being a career primarily for women, low QWL, insufficient support in the workplace, and emigration to other countries ,46. HoweProper salaries are one of the main strategies to attract and retain the workforce . PaymentCultural and contextual diversities and the socio-cultural infrastructure of societies influence the social image of nursing . In the The negative impression of nursing as a woman’s career discourages men from choosing nursing as a career. The male-to-female ratio for nurses in Iran is estimated at 1:7 . One of The findings of a recent study showed that 69.3% of Iranian nurses were dissatisfied with their work life ,60. AnotThe first confirmed cases of COVID-19 were reported by the MoHME in Iran on 19 February 2020 . MeasureThere is a common international notion that pandemics impose a substantial burden on healthcare systems, particularly on human resources , due to Iranian nurses have played various roles during the COVID-19 pandemic to improve people’s health. Most of them provide direct clinical care to patients with COVID-19 in hospitals. Nurses in community health centers contribute to screening for COVID-19, contact tracing and case reporting, provision of education and consultation to the public about basic health measures, quarantine and isolation, risk management, occupational health, mental health support, and vaccination . Iranian nurses who provide direct clinical care and health practice in hospitals or community health centers have experienced many challenges during COVID-19, including anxiety, stress, fear of being judged, frustration, worrying about self/others, feeling abandoned, physical exhaustion, living with uncertainty, and social stigma ,76,77,78Furthermore, the COVID-19 pandemic has driven Iranian nurses to foreign countries that have offered better financial and workplace incentives. Although accurate and official statistics on the migration of Iranian nurses during the COVID-19 pandemic are not available, according to unofficial statistics provided by the Iranian Nursing Organization (INO), the migration of nurses has tripled during COVID-19 and around 100 nurses migrate from Iran every month . TherefoThe COVID-19 pandemic is still one of the most important health issues in Iran. The Iranian health system and society have been severely affected by this pandemic. According to the basics of crisis management science, planning should be done before turning an accident into a crisis as much as possible, but in relation to the COVID-19 pandemic, basic measures in the field of prevention in Iran came after the disease had already turned into a biological crisis .At the beginning of the COVID-19 pandemic, the Iranian health system suffered severely from nursing shortages . In respAfter the formal call to recruit part-time nurses, many nurses were hired in different cities, especially in areas with a red COVID-19 outbreak status, based on insecure employment contracts without granting appropriate job benefits to nurses in hospitals and community health centers. In fact, several nurses who were needed during the COVID-19 crisis were recruited with very low salaries, less than half of the salary of employed nurses, and without job security, leading to job discrimination. At the end of an 89 day period, many nurses must choose to lose their jobs or accept another similar job contract ,84. TherNurses are morally and professionally obliged to provide high-quality care to patients . This obNevertheless, beyond professional and moral commitment, in the context of the COVID-19 crisis, it is unreasonable to employ nurses using inappropriate policies leading to their exploitation.The short-term nature of this type of contract leads to job insecurity for nurses . This feNursing practice in all aspects is regulated by healthcare policies and is influenced by related changes . The proHistorically, nurses have played a limited role in national policies and policy decisions affecting healthcare issues . AlthougThe nursing organization and four nursing associations in Iran, including INO, Iranian Nursing Association (INA), Iranian Cardiac Nursing Association (ICNA), and Iranian Scientific Nursing Association (ISNA), can potentially influence healthcare policies affecting the nursing profession . The polHealthcare systems across the globe act within the framework of healthcare policies. Nurses have the required ability and are well-qualified to participate in health policy development using their knowledge of the healthcare system, as well as their analytical and communication skills . In ordeTo construct a powerful profession that would be able to defend nurses’ rights, the level of membership by nurses to organizations that can develop a stance in social policymaking and advocate for nurses should be increased. Participation in professional nursing organizations or any association that uses a pluralistic advocacy voice provides networking opportunities and collects resources for exercising collective power. Nurses need to adhere to the same value-oriented principles of nursing and develop a united power source that can influence health and nursing policies using a collective voice ,107,108.In addition, INOs and associations should provide opportunities for nurses to enter policymaking initiatives. Nurses can also be engaged directly in policy making by gaining formal leadership positions in the healthcare system and being involved in lobbying and supporting nurse policy makers in professional organizations . In thisThe poor public image of nursing can withdraw nurses from policy making and social activities, reduce their credibility , and redNurses play a key role in the provision of care and optimization of public health, which has become especially prominent during the COVID-19 pandemic. They can provide high-quality healthcare if they receive adequate support and have appropriate QWL and job security. During the current pandemic, the working and employment conditions of many nurses in Iran have been affected due to the imposed insecure employment contracts.Iranian nurses are at the frontline of the fight against COVID-19 and perform important measures not only for individual health outcomes, but also for public health, including community-wide protection, screening, prevention efforts, and vaccination. Therefore, they need to receive recognition and better support, and their employment based on short-term and inappropriate contracts should be stopped. Healthcare officials, nurse managers, and nurse leaders should increase efforts to ensure that the dignity, QWL, and job security of nurses are preserved and nurses’ capacities to provide high-quality care are maintained. Enforceable standards, along with economic policies designed to considerably promote the employment status of Iranian nurses, are required.Appropriate participation in healthcare policy making requires an improvement in nurses’ policymaking competencies. Nurses need to improve their awareness and become equipped with the knowledge and skills of policy making and learn how to develop practical strategies that can have a positive impact on nurses’ job conditions. In addition, coalition and lobbying can help to improve the power of nurses to resist insecure job contracts and ensure their dignity and job security. Increasing organizational membership is suggested to build a strong career for nursing advocates. Nurse leaders and managers should make the most of the opportunities created during COVID-19 to participate in policymaking initiatives and improve the current QWL of nurses.


There has been a growing emphasis on health-related quality of life (HRQoL) as an important outcome in rare disease drug development, although its assessment may be useful outside the drug development context, including in clinical applications or natural history studies. Central to assessing quality of life in health research is utilizing outcome measures that capture symptoms and impacts of the disease and treatment that are important and relevant to patients. Identifying and implementing valid and reliable tools to measure HRQoL in rare diseases poses unique challenges that often require creative solutions.In this commentary, we explore some of the challenges in HRQoL assessment in rare disease, propose solutions, and consider regulatory issues. Some of the solutions discussed entail the use of item banks, adapting existing measures from phenotypically similar disease contexts, use of multi-domain measurement indices, and adapting methods for assessing content validity of existing measures. Current regulatory considerations are discussed and resources outlined.Quality of life may be the most important endpoint for patients with rare diseases, and the challenges of valid assessment require effort and innovative thinking specific to each context to improve measurement and clinical outcomes. In January 2019, the United States (US) Food and Drug Administration (FDA) published revised guidance on rare disease  measures. However, with children and in the light of possible cognitive, speech, or motor dysfunction, traditional self-report may not be useful, and the use of specialized reporting strategies or a caregiver-completed observer-reported outcome (ObsRO) measure may be required. Rare disease may impact multiple organ systems, cause permanent damage to the body, or have a highly heterogeneous presentation, making meaningful treatment benefit unclear in the context of assessment of drugs and biomedical treatments. Accordingly, some researchers may choose to emphasize one or two domains—out of several—where measurement strategy and treatment benefit may be clearer. The natural history studies called for by the FDA in its guidance may not have been completed yet, contributing to an incomplete understanding of rare diseases and their course. Understanding of rare diseases may change rapidly, even during a clinical trial or natural history study, due to new treatments or discoveries about the illness. Pediatric growth and development are challenges for longitudinal assessments. The traditional drug development approach and timeline can be altered considerably . Disease-specific measures often do not exist, while generic measures may be too broad, and traditional guidelines for statistical validation are strongly challenged by very small samples. Factors such as risk and benefit if alternative treatments or new treatment technologies are available may also play a role in the evaluation of treatment benefit.Some of these challenges are illustrated by WHIM syndrome , an ultra-rare primary immunodeficiency , of whicClinical input is a way to provide meaningful insights into rare disease characteristics, outcomes of interest, and interventions. However, individual clinicians may have limited opportunities to observe firsthand the signs of disease in clinical practice. Rare diseases that impact cognition may also alter the patients’ insight into their symptoms, further limiting the clinician’s ability to understand them.n = 30 for stable evaluation of means under the central limit theorem, or n = 10 observations per item for factor analysis or 10 observations per variable in a regression model, simply are impossible to achieve for many ultra-rare diseases.Regarding statistical validation, the rules of thumb of Solutions to the problems outlined above can require considerable creativity as evidenced by recently applied methods.One potential approach to addressing the challenges of rare disease PRO measure development and validation involves harnessing the power of existing item banks to develop PROs that are appropriate for the desired context of use and can be developed relatively rapidly. There are several existing and available item banks that cover a range of HRQoL concepts: the Patient Reported Outcome Measurement System (PROMIS) , QualityIn the application of PROMIS item banks to measuring outcomes in TGCT, significant obstacles were encountered due to the rare nature of the disease, limited prior research, heterogeneity in the types of physical impacts due to varied location of the tumors in each patient, and a large amount of variability in the severity of impacts across patients. The program of research included gathering direct patient input through interviews, patient-completed symptom and impact checklists, clinical expert input, and leveraging item information from PROMIS item banks of relevant concepts using item response theory (IRT) parameters , 8. ThroThe PROMIS PF custom forms simultaneously facilitated the measurement of the construct of interest on a single latent physical functioning scale, while also allowing for an analysis of physical functioning as an outcome in the full sample, regardless of the tumor location or extent of the impact . This isAnother approach to measurement in rare diseases is to adapt existing measures from a phenotypically similar disease to the rare disease context. For example, in one set of studies, the Unified Parkinson’s Disease Rating Scale (UPDRS)-2, originally developed for and widely used in Parkinson’s disease (PD), was adapted for use in pantothenate kinase-associated neurodegeneration (PKAN), a rare disease causing similar motor and speech deficits although with a completely different etiology . In thisAnother approach to measurement could be the use of a multi-domain responder index (MDRI), which the FDA has discussed in its guidance on multiplicity  as a wayIn the third patient-focused drug development guidance , the FDAIn the context of rare disease, assessing the content validity of COAs may require adaptive methods for data collection, using technology, triangulating methods, or mixed methods . To identify more universally experienced symptoms in rare, heterogenous conditions, concept frequency can be assessed within subgroups of patients based on age, sex, or disease severity, for example, to identify commonly experienced concepts across the continuum of disease severity. Likewise, mixed methods of data collection  or different public sources of data collection  can be helpful to provide more data to assess concepts important to patients. Additionally, several other methods can be combined to increase evidence for content validity, including triangulation methods , how treatment benefits are described , descriptive examples of symptom changes , and insightful examples of changes in daily impacts . Other areas of impact can be explored, such as the journey to diagnosis, which is often lengthy and complex for rare conditions, the caregiver burden, unmet medical needs, the patient’s wiliness to take risks with new treatment, treatment preferences, and the way the condition impacts daily life .In each of the first four patient-focused drug development documents from the FDA , 22, 23,When advances in treatment are significant enough to change the patient experience of their condition and influence HRQoL by emphasizing different concepts of interest than were used in the traditional measurement models, qualitative work may need to be repeated to update evidence of content validity. One such example is the new C1-Inhibitors used for prophylaxis in hereditary angioedema (HAE). Patients on these new treatments are now able to engage with life more, live in less fear and anxiety, and they report changes in severity, frequency, and duration of all HAE symptoms. The focus is no longer solely on the swelling attack. These significant changes in overall patient burden and quality of life warrant re-examination of the work substantiating the content validity of HRQoL assessment to ensure the concept coverage is still complete.clinicaltrials.gov. [How a concept is addressed in regulatory guidance documents, as well as how often results for a specific concept are included in label claims, can provide an insight into the level of attention devoted to the concept from the regulatory perspective. Two recent reviews examined the use of PRO measures in approved rare disease labels , 25 demoIn addition to considerations mentioned above, the latest draft FDA guidance for rare disease  emphasizA more detailed guidance on outcome measure development in rare disease was provided by the ISPOR COA Emerging Good Practices Task Force Report . The repOverall, there is an increasing interest and emphasis on including the patient perspective in rare disease drug development, but also a wide recognition that specific challenges exist, which require unique, out-of-the box solutions.An interactive, one-day meeting in 2018 aimed to discuss challenges in developing rare disease regulatory strategies and included 90 leaders with regulatory, biopharmaceutical, and not-for-profit organizations. The meeting report proposed several strategies, including the use of natural history studies, novel approaches to clinical trial design, and novel analytical approaches . RecommeAn alternative strategy focusing specifically on selection of COAs to assess treatment benefit in rare disease trials has been proposed . The autWhile others have noted some challenges and possible solutions for incorporating COA measures in rare disease research, the unique challenges of each patient population persist. In a 2018 Drug Information Association white paper , regulatIn the absence of a detailed regulatory guidance for the selection and validation of COA measures, it seems that the best regulatory strategy includes planning for early communication and collaboration among stakeholders, along with the flexibility to explore novel design and analytic strategies, while building on existing knowledge of COAs in general and HRQoL measures in particular. In a field with over 7000 unique diseases, the development of more specific regulatory guidance to clinical outcome selection and development may indeed not be feasible, but collaborative communication among key stakeholders may ensure that rare disease drug development programs capture the effect of treatments on how patients feel and function.In conclusion, we have elucidated many of the challenges associated with assessing HRQoL in rare diseases, practical barriers, possible solutions, and the regulatory context. In the absence of specific regulatory guidelines, creative application of general principles for design and validation must be relied on to fill the gap, including use of natural history studies, targeted literature reviews, clinical expert input, patient input, and adaptation of item banks, existing measures, and novel statistical approaches where possible. Quality of life may be the most important endpoint of all for many of these patients, and the challenges of assessing it in a valid way are worth the effort, and require innovative thinking suitable for each context.