Neural precursors (NPs) present in the hippocampus can be modulated by several neurogenic stimuli including environmental enrichment (EE) and antidepressant treatment acting through BDNF-TrkB signaling. We have recently identified NPs in meninges, however menigneal niche response to pro-neurogenic stimuli has never been investigated. To this aim, we analyzed the effects of 4 weeks fluoxetine administration or 1 week EE treatment on NP distribution in mouse brain meninges. Following neurogenic stimuli, although we did not detect modification of meningeal cell number and proliferation, we observed, in meninges, an increased number of β3-Tubulin⁺ immature neuronal cells. Lineage-tracing experiment confirmed that EE-induced β3-Tubulin⁺ immature neuronal cells present in meninges originated from GLAST⁺ radial glia cells. To investigate the molecular mechanism responsible for this response, we studied the BDNF-TrkB interaction. Treatment with ANA-12, a TrkB non-competitive inhibitor, abolished the EE-induced increase of β3-Tubulin⁺ immature neuronal cells in meninges.Overall these data showed, for the first time, that the meningeal niche responded to neurogenic stimuli by increasing the immature neuronal population through TrkB-mediated signaling. A better understanding of the neurogenic stimuli effects on NPs in meninges may be useful to improve the effectiveness of depression and mood disorders treatments.

In the present era, infertility is one of the major issues which restricts many couples to have their own kids. Infertility is the inability to achieve a clinical pregnancy after regular unprotected sexual intercourse for the period of one year or more. Various factors including defective male or female germ cell development, unhealthy and improper lifestyles, diseases like cancer and associated chemo-or-radiation therapies, congenital disorders etc. may be responsible for infertility. Therefore, it is highly important to understand the basic concepts of germ cell development including primordial germ cell (PGC) formation, specification, migration, entry to genital ridges and their molecular mechanisms, activated pathways, paracrine and autocrine signaling, along with possible alteration which can hamper germ cell development and can cause adversities like cancer progression and infertility. Knowing all these aspects in a proper way can be very much helpful in improving our understanding about gametogenesis and finding possible ways to cure related disorders. Here in this review, various aspects of gametogenesis especially female gametes and relevant factors causing functional impairment have been thoroughly discussed.

As Christopher Alexander conceived and defined through his life’s work – The Nature of Order – wholeness is a recursive structure that recurs in space and matter and is reflected in human minds and cognition. Based on the definition of wholeness, a mathematical model of wholeness, together with its topological representation, has been developed, and it is able to address not only why a structure is beautiful, but also how much beauty the structure has. Given the circumstance, this paper is attempted to argue for the wholeness as the scientific foundation of sustainable urban design and planning, with the help of the mathematical model and topological representation. We start by introducing the wholeness as a mathematical structure of physical space that pervasively exists in our surroundings, along with two fundamental laws – scaling law and Tobler’s law – that underlie the 15 properties for characterizing and making living structures. We argue that urban design and planning can be considered to be wholeness-extending processes, guided by two design principles of differentiation and adaptation, to transform a space – in a piecemeal fashion – into a living or more living structure. We further discuss several other urban design theories and how they can be justified by and placed within the theory of wholeness. With the wholeness as the scientific foundation, urban design can turn into a rigorous science with creation of living structures as the primary aim.

The societies of Western Europe, following the territorial delimitation of the corresponding State, have gone through different historical processes of internal homogenization. After the Peace of Westphalia (1648) the application of the principle cuius regio eius religio induced the religious homogenization of the population. Then, due to the ethnic diversity of its population, the State tried to homogenize it from the cultural point of view; it was the process of nationalization and democratization of the State. This process lead to the separation of religion from politics and from culture. After the two world wars, national reconstruction needed a foreign population: this need for labor was filled in the most developed countries by population of the countries that were least (Portuguese, Spanish, Italian ...) and also by population flows coming from the old colonies. The cultural and religious homogeneity of these countries began to lose force. With the oil crisis of the 1970s, a period of major economic fluctuations began in Europe. In those years, the second generation of the population of immigrant origin began to go to a job market that was not in good health. The religion and culture of their predecessors became autonomous resources for the reconstruction of their identity and to achieve a personal and social esteem. This process is necessarily leading States to rethink the relations between politics, culture and religion.

As a result of the COVID 19 outbreak that has affected the whole world, teacher leadership has gained more significance. Teacher leadership is a multidimensional concept. While some teachers exercise leadership only at the classroom level, others exercise leadership at macro level. This level of leadership enactment is directly related to how teachers construct their professional identity in relation to leadership. This study aims to explore the leadership-related professional identities of teachers who came to the fore especially during the COVID 19 pandemic period by using the latent profile analysis method. The data were collected a sample of 710 teachers. Teachers completed Teacher Leadership Behavior Scale that measures teacher leadership behaviors at four levels: classroom, parental, micro-level, macro-level. Participants also completed Rosenberg Self-Esteem Scale, Teacher Self-Efficacy Scale, Openness to Authority Scale, and Job Satisfaction Scale. As a result of latent profile analysis, three distinct profiles of teacher leadership identity emerged: those who exercise leadership at a minimum level, an intermediate level and a maximum level across all four levels of teacher leadership. These profiles were labeled as "extended professionality," "intermediate professionality," and "restricted professionality," drawing upon Hoyle's (1974) conceptualization of teacher professional identity. These findings suggest that teachers construct their identity differently about teacher leadership. It is essential for school leaders to first explore those different levels of professional identity and tailor their professional development activities accordingly.

Since the outbreak of the Covid-19, working from home has become the norm for millions of workers worldwide. The current research focuses on the benefits and challenges of teleworking in the administrative sectors of greek healthcare units, with a view to harnessing the knowledge gained through experience, in order to create the frame for sustainable behaviors. Anyways, the implementation of teleworking requires complex and dynamic changes in technical and behavioral aspects. Therefore, a systematic review was also conducted to identify the relationships between telecommuting and organizational behavior, with the aim of achieving sustainable development in businesses. Moreover, an important positive aspect of telework that emerged from this literature review appears to create opportunities for potential direct or indirect linkages between telework and many SDGs areas, based on the fact that telework appears to be a community-friendly form of work. In summary, this research strongly suggests that leaders facilitate telecommuters to adopt green practices and volunteerism that can consequently contribute to the SDGs. However, in order to meet the challenges arising from unprecedented times, the leaders of the organizations will have to redesign their policies, while the states will have to focus on guaranteeing the rights and freedoms of the workers.

Weighted Student Funding (WSF) systems have been implemented in various countries to give schools more autonomy over how to allocate their funding. School principals use funding to maintain school operations and foster innovation for achieving educational goals. However, despite the importance of this process, scholarly research has largely overlooked how principals make decisions about their financial resources. Accordingly, this study seeks to provide practical insights into the strategies used by one school by highlighting their staff’s perceptions about using their WSF to maintain school operations and spur innovation. Using a case study approach, we investigated a principal who effectively used a school’s WSF to transform a failing school into an innovative one. The findings revealed that the principal strategically implemented financial management mechanisms in a way that inspired teachers to deeply consider how a school's WSF can help achieve educational goals. The principal fostered consensus on the school's direction, encouraged innovation through hands-on experiential learning and strategic planning, and facilitated funding for innovative teachers by guiding proposal development. Insights into the shifting cultural and practical landscape of financial resource utilization within schools are discussed.

Attracting and retaining international students has been widely discussed in higher education settings. Increasing the number of international students has become an indispensable strategy for national and global competition. This study focuses on effective strategies and international students' issues regarding satisfaction in the most popular STEM (science, technology, engineering, and mathematics) programs. We designed a structural equation modeling (SEM) method to determine the effect of institutional mediation between push factors and satisfaction factors for the development of better strategies by which to attract and retain international students. Taking Taiwan as an example, this study employed a self-designed questionnaire to collect data: 485 degree-seeking international students in STEM programs were invited and successfully participated in this study during spring 2021. IBM SPSS 26 and AMOS 26 (Analysis of Moment Structure) were used to carry out the data analysis. We employed reliability, factor, and SEM analyses. This study assumed that the impact of push factors can be modified by institutional situations and result in international students’ satisfaction with their learning and environment and regarding migration policy. The results revealed that the predictors, mediation, and criteria were significant at the 0.05 or 0.01 levels. The findings suggest that push factors impact international students’ satisfaction when using institutional leadership and international strategy. The results of the bootstrap with a generalized least square method showed that the SEM model fit in 2000 bootstrap samples. The effect of institutional mediation can provide useful information for STEM programs to boost their future recruitment and retention strategies. This study provides an innovative approach to the detection of issues among international students in specific programs. These findings can enrich our knowledge regarding attracting and retaining global students in higher education settings.

Studies of discrete pride in the workplace are both few and on the rise. We examined what has, to date, been yet unstudied: the impact that a leader’s expressions of authentic and hubristic pride can have on the followers at that moment, and on their feelings about their task, leader, and group. Students working in groups building Lego structures rated their perceived leader regarding expressions of pride, both authentic and hubristic. Students who perceived the leader as expressing more authentic pride rated the task, group (satisfaction and cohesion), and leader more positively; while the reverse was generally true for perceptions of expressions of hubristic pride. We found these effects both at the individual level, and at the group level. We also predicted and found moderation for the type of task worked on, creative or detailed. Implications abound for leader emotional labor and emotion management.

Xinjiang, as a climate-sensitive region in northwest China, holds significant importance in studying extreme weather events for agricultural production and socioeconomic development. Based on data from 52 meteorological stations and 23 extreme climate indicators in Xinjiang from 1960 to 2021, the 5a moving average, linear trend estimation, climate tendency rate, and GIS spatial analysis methods are used to analyze the distribution and change characteristics of extreme climate. The results revealed that from 1960 to 2021, TXx, TNx, TXn, TNn, FD, ID, TN10p, TX10p, and WSDI showed a significant upward trend, while SU, TR, TN90p, TX90p, and CSDI showed a significant downward trend. What is more, the range of changes in the extreme temperature indexes from 1990 to 2021 is higher than that of 1960 to 1989. The high-value areas of extreme indexes are primarily concentrated in the northern part, while the high-value areas of cold event indexes are mainly distributed in the southern part. The upward/downward trends all accounting for over 80.00% of the entire region. The Rx1day, Rx5day, PRCPTOT, R95p, R99p, R10, R20, and R25 showed a significant growth trend from 1960 to 2021, and the range of change in the extreme precipitation indexes from 1990 to 2021 was lower than that from 1960 to 1989. Moreover, their high-value areas and high climate tendency areas are mainly concentrated in the northern and western parts of Xinjiang, with upward trends all accounting for over 71.00% of the entire region. The research results provide theoretical foundations for formulating climate risk strategies in the northwest region of China.

Background: Since cytokine receptor like factor 1 (CRLF1) has been implicated in tissue regeneration, we hypothesized that CRLF1 released by mesenchymal stem cells can promote the repair of osteochondral defects. Methods: The degree of a femoral osteochondral defect repair in rabbits after intra-articular injections of bone marrow derived mesenchymal stem cells (BMSCs) that were transduced with empty adeno associated virus (AAV) or AAV containing CRLF1 was determined by morpholog-ical, histological and microCT analyses. The effects of CRLF1 on chondrogenic differentiation of BMSCs or catabolic events of interleukin-1beta-treated chondrocyte cell line TC28a2 were deter-mined by alcian blue staining, gene expression levels of cartilage and catabolic marker genes us-ing real time PCR analysis, and immunoblot analysis of Smad2/3 and STAT3 signaling. Results: Intra-articular injections of BMSCs overexpressing CRLF1 markedly improved repair of a rabbit femoral osteochondral defect. Overexpression of CRLF1 in BMSCs resulted in the release of a homodimeric CRLF1 complex that stimulated chondrogenic differentiation of BMSCs via enhancing Smad2/3 signaling, whereas the suppression of CRLF1 expression inhibited chondro-genic differentiation. In addition, CRLF1 inhibited catabolic events in TC28a2 cells cultured in an inflammatory environment, while a heterodimeric complex of CRLF1 and Cardiotrophin like Cytokine (CLC) stimulated catabolic events via STAT3 activation. Conclusion: A homodimeric CRLF1 complex released by BMSCs enhanced the repair of osteochondral defects via the inhibition of catabolic events in chondrocytes and the stimulation of chondrogenic differentiation of precursor cells.

Glycosphingolipids (GSLs), a subtype of glycolipids containing sphingosine, are critical components of vertebrate plasma membranes, playing a pivotal role in cellular signaling and interactions. In human articular cartilage in osteoarthritis (OA), GSL expression is known notably to decrease. This review focuses on the roles of gangliosides, a specific type of GSL, in cartilage degeneration and regeneration, emphasizing their regulatory function in signal transduction. The expression of gangliosides, whether endogenous or augmented exogenously, is regulated at the enzymatic level, targeting specific glycosyltransferases. This regulation has significant implications for the composition of cell surface gangliosides and their impact on signal transduction in chondrocytes and progenitor cells. Different levels of ganglioside expression can influence signaling pathways in various ways, potentially affecting cell properties, including malignancy. Moreover, gene manipulations against gangliosides have been shown to regulate cartilage metabolism and chondrocyte differentiation in vivo and in vitro. This review highlights the potential of targeting gangliosides in the development of therapeutic strategies for osteoarthritis and cartilage injury and addresses promising directions for future research and treatment.

The increasing residential space differentiation is an important practical problem for Chinese cities. The different choice of living space for urban residents is a concrete reflection of social class divide, which reflects the differences in the choices and demands of different social groups for urban housing. Taking Wuhan, an important city in central China, as an example, this research divides the residential space based on the social resource structure, and analyzes and compares the spatial differentiation and influencing factors of different residential areas and houses with different prices in Wuhan by spatial differentiation indicators and geographic detector. The results show clear differences in resource structure among residential areas, and there are few high-quality residential areas with a concentrated distribution. The spatial differentiation levels of different residential areas are distinct, and the pursuit of high-quality and scarce resources is the key to the residential space differentiation of most large cities in China. In addition, residential space differentiation can lead to inter-generational problems such as housing wealth inequality, resource deprivation and solidified class identity. Exploring the mechanisms and social effect of residential space differentiation in most large cities in China can provide some reference for China's urban space planning and real estate market regulation in the new era.

Defects in low-density lipoprotein receptor (LDLR) are associated with familial hypercholesterolemia (FH), manifested by atherosclerosis and cardiovascular disease. Defective LDLR in hepatocytes leads to increased blood cholesterol level that damage vascular cells, especially endothelial cells, through oxidative stress and inflammation. However, the distinctions between endothelial cells from individuals with normal and defective LDLR are not yet fully comprehended. In this study, we obtained and examined endothelial derivatives of induced pluripotent stem cells (iPSC) generated previously from conditionally healthy donors and compound heterozygous FH patients carrying pathogenic LDLR alleles. In normal iPSC-derived endothelial cells (iPSC-EC), we detected the LDLR protein predominantly in its mature form, while iPSC-EC from patients with FH display reduced level of mature LDLR and show abolished low-density lipoprotein uptake. RNA-seq of iPSC-EC with mutant LDLR revealed a unique transcriptome profile comprising downregulated genes related to monocarboxylic acid transport, exocytosis and cell adhesion, as well as upregulated signaling pathways of cell secretion and leukocyte activation. Overall, these findings suggest that LDLR defects increases susceptibility of endothelial cells to inflammation and oxidative stress. This, combined with elevated extrinsic cholesterol levels, may result in accelerated endothelial dysfunction, contributing to early progression of atherosclerosis and other cardiovascular pathologies related to FH.

This study aims to explore the potential inhibition effects of staurosporine isolated from a Strepto-myces sp. SNC087 strain obtained from seawater on nasal polyps. Staurosporine possesses antimi-crobial and antihypertensive activities. This research focuses on investigating the effects of stau-rosporine on suppressing the growth and development of nasal polyps and elucidating the un-derlying mechanisms involved. The experimental design includes in vitro and ex vivo evaluations to assess the inhibition activity and therapeutic potential of staurosporine against nasal polyps. Nasal polyp-derived fibroblasts (NPDFs) were stimulated with TGF- β1 in the presence of staurosporine. The levels of -smooth muscle actin (-SMA), collagen type-I (Col-1), fibronectin, and phosphory-lated (p)-Smad 2 were investigated using western blotting. VEGF expression levels were analyzed in nasal polyp organ cultures treated with staurosporine. TGF-β1 stimulated the production of Col-1, fibronectin, and -SMA and was attenuated by staurosporine pretreatment. Furthermore, these inhibitory effects were mediated by modulation of the signaling pathway of Smad 2 in TGF-β1-induced NPDFs. Staurosporine also inhibits the production of VEGF in ex vivo NP tissues. The findings from this study will contribute to a better understanding of staurosporine’s role in nasal polyp management and provide insights into its mechanisms of action.

Still, the most common in vitro model for absorption, distribution, metabolism and excretion (ADME) purposes is the Caco-2 cell line. However, clear differences in gene- and protein expression towards the small intestine and an at best fair prediction accuracy of intestinal drug absorption restrict the usefulness as model for intestinal epithelial cells. To overcome these limitations, we evaluated a panel of low-passaged patient-derived colorectal cancer cell lines of the HROC collection concerning similarities to small intestinal epithelial cells and their potential to predict intestinal drug absorption. After initial screen of a larger panel, ten cell lines with confluent outgrowth and long-lasting barrier forming potential were further characterized in close detail. Tight junctional complexes and microvilli structures were detected in all lines, differentiated epithelial cells were abundant in 7/10. All lines expressed multiple transporter molecules, with expression levels in three lines being close to those of small intestinal epithelial cells. Compared to the Caco-2 model, three HROC lines demonstrated both higher similarity to jejunal epithelial tissue cells and higher regulatory potential of relevant drug transporters. In sum, these lines would be better suited human small intestinal epithelium models for basic and translational research; especially for ADME studies.

Matrix vesicles (MVs) are nano-sized extracellular vesicles that are anchored in the extracellular matrix (ECM). In addition to playing a role in biomineralization, osteoblast-derived MVs were recently suggested to have regulatory duties. The aims of this study were to: establish the characteristics of osteoblast-derived MVs in the context of extracellular vesicles like exosomes, assess their role in modulating osteoblast differentiation, and examine their mechanism of uptake. MVs were isolated from the ECM of MG-63 human osteoblast-like cell cultures and characterized via enzyme activity, transmission electron microscopy, nanoparticle tracking analysis, western blot, and small RNA sequencing. Osteoblasts were treated with MVs from two different culture conditions (growth media [GM]; osteogenic media [OM]) to evaluate their effects on differentiation and production of inflammatory markers and on macrophage polarization. MV endocytosis was assessed using a lipophilic, fluorescent dye and confocal microscopy with the role of caveolae determined using methyl-β-cyclodextrin. MVs exhibited a four-fold enrichment in alkaline phosphatase specific activity compared to plasma membranes, were 50-150nm in diameter, possessed exosomal markers CD63, CD81, and CD9 and endosomal markers ALIX, TSG101, and HSP70, and were selectively enriched in microRNA linked to an anti-osteogenic effect and to M2 macrophage polarization. Treatment with GM or OM MVs decreased osteoblast differentiation. Osteoblasts endocytosed MVs by a mechanism that involves caveolae. These results support the hypothesis that osteoblasts produce MVs that participate in the regulation of osteogenesis.

Human induced pluripotent stem cells (hiPSCs) have two characteristic abilities 1) self-renewal and 2) differentiation into all cell types in the human body. It is this ability of iPSCs to differentiate into any desired cell type that makes them amenable to disease modeling. iPSCs can further be engineered to carry a disease-specific mutation or be derived from patients to phenocopy the disease. To model neurodegenerative/neurodevelopmental disorders iPSCs are differentiated into neurons. This chapter describes protocols for two different approaches to generate neurons from iPSCs, first using dual SMAD inhibition to generate neural progenitor cells which are then differentiated into neurons, and second using single transcription factor (NGN2) over-expression to drive differentiation of iPSCs directly into neurons.

The quality of underground space information has become a major problem that endangers the safety of underground spaces. Currently, the main methods for the high-precision and long-distance transmission of detection information are radar and optical methods. However, in practical applications, we found that the radar method has the shortcomings of large energy loss and poor anti-jamming ability, which limit the accuracy of information data transmission and distance. The optical method has the shortcomings that the weather has a great impact on its accuracy and can only be applied to static objects above ground; therefore, it has the limitation of application objects and use environment. More importantly, the current high-precision information remote detection methods are limited to the detection of overground space objects and are not applicable to the detection of various information data in underground space. In this study, we analyze the spectral properties of the fractional differential operator and find that it is suitable for studying non-linear, non-causal, and non-stationary signals. The theory of fractional calculus is applied to the field of data processing, and a mathematical model of remote transmission and high-precision detection of information based on fractional difference is established, which realizes the functions of high-precision and remote detection of information. By fusing the information data to detect the mathematical model over a long distance and with high accuracy, a mathematical model for stratum data processing used to provide long-distance and high-accuracy data was established. Through application in engineering practice, the effectiveness of this method for underground space information data detection was verified.

Heating has been recently used as an alternative application to electrical stimulation to modulate excitability and to induce neuritogenesis and the expression of neuronal markers, but a long-term functional differentiation has not been described so far. Here we present the results obtained by a new approach for scalable thermal stimulation on the behavior of a model of dorsal root ganglion neurons, the F-11 cell line. Initially, we performed experiments of bulk stimulation in incubator for different time intervals and temperatures, and significant differences in neurite elongation and in electrophysiological properties were observed in cultures exposed at 41,5°C for 30 minutes. Thus, we exposed the cultures to the same temperature increase by irradiating, with a near infrared laser, a disc of Prussian Blue nanoparticles and poly-vinyl alcohol, that we stuck on the outer surface of the petri dish. In irradiated cells neurites were significantly longer and the electrophysiological properties (action potential firing frequency and spontaneous activity) were significantly increased compared to the control. These results suggest that a targeted thermal stimulation could be a promising technique to induce differentiation and support the future application of this method as a strategy to modify neuronal behavior in vivo.

leaf beetle (BLB) (Ootheca mutabilis) has emerged as an important bean pest in Uganda, leading to devastating crop losses. There is limited information on the population genetic structure of BLB despite their importance. In this study, novel microsatellite markers and the partial mitochondrial cytochrome oxidase subunit I (mtCOI) gene sequences were used to analyze the spatial population genetic structure, genetic differentiation, gene flow and haplotype diversity of 87 O. mutabilis samples from five populations. We identified 19,356 simple sequence repeats (SSRs) (mono, di, tri, tetra, penta, and hexa-nucleotides) of which 81 di, tri and tetra-nucleotides were selected for primer synthesis. Five highly polymorphic SSR markers (4-21 alleles, heterozygosi-ty 0.59-0.84, polymorphic information content (PIC) 50.13-83.14%) were used for this study. Analyses of the five O. mutabilis populations with these five novel SSRs found 89% of genetic variation occurring within individuals, 9% among individuals and 2% among populations. Genetic differentiation was low but significant for SSR and insignificant for mtCOI partial sequence data while gene flow was high across the populations. There was no evidence of isolation by distance between geographical and genetic distances. Bayesian clustering identified signature of admixture that suggests genetic contributions from two ancestral genetic lineages, and the median-joining haplotype network showed low differentiation of many different haplotypes from the most common haplotype. Low genetic differentiation and high gene flow indicates unrestricted migrations between populations. This information will contribute to the design of BLB control strategies.

Choline and choline metabolites are essential for all cellular functions. They have also been reported to be crucial for neural development. In this work, we studied the functional characteristics of the choline uptake system in human neural stem cells (hNSCs). Additionally, we investigated the effect of extracellular choline uptake inhibition on the cellular activities in hNSCs. We found that the mRNAs and proteins of choline transporter-like protein 1 (CTL1) and CTL2 were expressed at high levels. Immunostaining showed that CTL1 and CTL2 were localized in the cell membrane and partly in the mitochondria, respectively. The uptake of extracellular choline was saturable and performed by a single uptake mechanism, which was Na+-independent and pH-dependent. We conclude that CTL1 is responsible for extracellular choline uptake, and CTL2 may uptake choline in the mitochondria and be involved in DNA methylation via choline oxidation. Extracellular choline uptake inhibition caused intracellular choline deficiency in hNSCs, which suppressed cell proliferation, cell viability, and neurite outgrowth. Our findings contribute to the understanding of the role of choline in neural development as well as the pathogenesis of various neurological diseases caused by choline deficiency or choline uptake impairment.

Flow cytometric detection of intracellular (IC) signaling proteins and transcription factors (TFs) will help elucidate the regulation of B cell survival, proliferation and differentiation. However, simultaneous detection of signaling proteins or TFs, with membrane markers (MM) can be challenging as required fixation and permeabilization procedures can affect functionality of conjugated antibodies. Here, a phosphoflow method is presented for detection of activated NF-κB p65 and phosphorylated STAT1, STAT3, STAT5 and STAT6 together with B cell differentiation MM CD19, CD27 and CD38. Additionally, a TF-flow method is presented that allows detection of B cell TFs; PAX5, c-MYC, BCL6, AID and antibody-secreting cell (ASC) TFs BLIMP1 and XBP-1s together with MM. Applying these methods on in vitro induced human B cell differentiation cultures showed significantly different steady-state levels, and responses to stimulation, of phosphorylated signaling proteins in CD27-expressing B cell and ASC populations. The TF-flow protocol and UMAP analysis revealed heterogeneity in TF-expression within stimulated CD27 or CD38-expressing B cell subsets. The methods presented here allow for sensitive analysis of STAT and NF-κB p65 signaling and TFs together with B cell differentiation MM at single-cell resolution. This will aid further investigation of B cell responses in both health and disease.

Individual plant cells are the building blocks for all plantae and artificially constructed plant biomaterials, like biocomposites. Secondary cell walls (SCWs) are a key component for mediating mechanical strength and stiffness in both living vascular plants and biocomposite materials. In this paper, we study the structure and biomechanics of cultured plant cells during the cellular developmental stages associated with SCW formation. We use a model culture system that induces transdifferentiation of Arabidopsis thaliana cells to xylem vessel elements, upon treatment with dexamethasone (DEX). We group the transdifferentiation process into three distinct stages, based on morphological observations of the cell walls. The first stage includes cells with only a primary cell wall (PCW), the second covers cells that have formed a SCW, and the third stage includes cells with a ruptured tonoplast and partially or fully degraded PCW. We adopt a multi-scale approach to study the mechanical properties of cells in these three stages. We perform large-scale indentations with a micro-compression system and nanoscale indentations through atomic force microscopy (AFM), in three different osmotic conditions. We introduce a spring-based model to deconvolve the competing stiffness contributions from turgor pressure, PCW, SCW and cytoplasm in the stiffness of differentiating cells. Prior to triggering differentiation, cells in hypotonic pressure conditions are significantly stiffer than cells in isotonic or hypertonic conditions, highlighting the dominant role of turgor pressure. Plasmolyzed cells with a SCW reach similar levels of stiffness as cells with maximum turgor pressure. The stiffness of the PCW in all of these conditions is lower than the stiffness of the fully-formed SCW. Our results provide the first experimental characterization of the mechanics of SCW formation at single cell level.

Trophoblasts are the first cell-type to be specified during embryogenesis, and they are essential for placental morphogenesis and function. Trophoblast stem (TS) cells are the progenitor cells for all trophoblast lineages; control of TS cell differentiation into distinct trophoblast subtypes is not well understood. Mice lacking the transcription factor OVO-like 2 (OVOL2) fail to produce a functioning placenta, and die around embryonic day 10.5, suggesting that OVOL2 may be critical for trophoblast development. Therefore, our objective was to determine the role of OVOL2 in mouse TS cell fate. We found that OVOL2 was highly expressed in mouse placenta and differentiating TS cells. Placentas and TS cells lacking OVOL2 showed poor trophoblast differentiation potential, including increased expression of stem-state associated genes (Eomes, Esrrb, Id2) and decreased levels of differentiation-associated transcripts (Gcm1, Tpbpa, Prl3b1, Syna). Ectopic OVOL2 expression in TS cells elicited precocious differentiation. OVOL2 bound proximate to the gene encoding inhibitor of differentiation 2 (ID2), a dominant negative helix-loop-helix protein, and directly repressed its activity. Overexpression of ID2 was sufficient to reinforce the TS cell stem state. Our findings reveal a critical role of OVOL2 as a regulator of TS cell differentiation and placental development, in-part by coordinating repression of ID2.

Computational simulation using mathematical models is a useful method for understanding the complex behavior of a living system. The majority of studies using mathematical models to reveal biological mechanisms uses one of the two main approaches: the bottom-up or the top-down approach. When we aim to analyze a large-scale network, such as a comprehensive knowledge-integrated model of a target phenomenon, for example a whole-cell model, the variation of analyses is limited to particular kind of analysis because of the size and complexity of the model. To analyze a large-scale regulatory network of neural differentiation, we developed a hybrid method that combines both approaches. To construct a mathematical model, we extracted network motifs, subgraph structures that recur more often in a metabolic network or gene regulatory network than in a random network, from a large-scale regulatory network, detected regulatory motifs among them, and combined these motifs. We confirmed that the model reproduced the known dynamics of HES1 and ASCL1 before and after differentiation, including oscillation and equilibrium of their concentrations. The model also reproduced the effects of overexpression and knockdown of the Id2 gene. Our model suggests that the characteristic change in HES1 and ASCL1 expression in the large-scale regulatory network is controlled by a combination of four feedback loops, including a large loop which has not been focused on. The model extracted by our hybrid method has the potential to reveal the critical mechanisms of neural differentiation. The hybrid method is applicable to other biological events.

Integrated information theory (IIT) proposes a measure of integrated information (Φ) to capture the level of consciousness for a physical system in a given state. Unfortunately, calculating Φ itself is currently only possible for very small model systems, and far from computable for the kinds of systems typically associated with consciousness (brains). Here, we consider several proposed measures and computational approximations, some of which can be applied to larger systems, and test if they correlate well with Φ. While these measures and approximations capture intuitions underlying IIT and some have had success in practical applications, it has not been shown that they actually quantify the type of integrated information specified by the latest version of IIT. In this study, we evaluated these approximations and heuristic measures, based not on practical or clinical considerations, but rather based on how well they estimate the Φ values of model systems. To do this, we simulated networks consisting of 3–6 binary linear threshold nodes randomly connected with excitatory and inhibitory connections. For each system, we then constructed the system’s state transition probability matrix (TPM), as well as its state transition matrix (STM) over time for all possible initial states. From these matrices, we calculated, approximations to Φ, and measures based on state differentiation, state entropy, state uniqueness, and integrated information. All measures were correlated with Φ in a state dependent and state independent manner. Our findings suggest that Φ can be approximated closely in small binary systems by using one or more of the readily available approximations (r > 0.95), but without major reductions in computational demands. Furthermore, Φ correlated strongly with measures of signal complexity (LZ, r_s = 0.722), decoder based integrated information (Φ*, r_s = 0.816), and state differentiation (D1, r_s = 0.827), on the system level (state independent). These measures could allow for efficient estimation of Φ on a group level, or as accurate predictors of low, but not high, Φ systems. While it’s uncertain whether the results extend to larger systems or systems with other dynamics, we stress the importance that measures aimed at being practical alternatives to Φ are at a minimum rigorously tested in an environment where the ground truth can be established.

Adipose-derived stem cells (ADSCs) were suggested for treating degenerative osteoarthritis, suppressing inflammatory responses, and repairing damaged soft tissues. Moreover, the ADSCs have the potential to undergo self-renewal and differentiate into bone, tendon, cartilage, and ligament. Recently, investigation of the self-renewal and differentiation of the ADSCs becomes an attractive area. In this work, a pneumatic microdevice has been developed to study the gene expression of the ADSCs after the stimulation of multi-axial tensile strain. The ADSCs were cultured on the microdevice and experienced multi-axial tensile strain during a 3-day culture course. Self-renewal and differentiation abilities were investigated by mRNA expressions of NANOG, SOX2, OCT4, SOX9, PPAR-γ, and RUNX2. The result showed that the genes related self-renewal were significantly up-regulated after the tensile stimulation. Higher proliferation ratio of the ADSCs was also shown by cell viability assay. The microdevice provides a promising platform for cell-based study under mechanical tensile stimulation.

Enamel matrix derivative (EMD) is used for periodontal tissue regeneration therapy, and can induce mineralization in dental pulp cells (DPCs). We designed a synthetic peptide (SP) derived from the response of cells to EMD, and investigated the effect of the SP on potentiating osteogenesis in DPCs, which have a critical role of dental pulp homeostasis. DPCs were treated with 0, 10, 100, or 1000 ng/mL SP to determine its effect on cell proliferation, cell migration, cell differentiation, and mineralization. We then examined the molecular effects of the SP, focusing on changes in the mitogen-activated protein kinases (MAPK) signaling pathway in these cells. The SP significantly promoted DPC proliferation and migration. Cultures treated with the SP also showed an enhanced expression of markers of osteogenic differentiation and mineralization. The SP also induced the activation of MAPK signaling pathway components. These results suggest that our SP could promote the dental pulp tissue repair by hard tissue formation and the mineralization through activating MAPK signaling pathway. This study provides the first evidence that SP might be a new material for dental pulp tissue treatment.

According to some authors, the serum selenium level is strongly associated with the severity of liver diseases including liver cirrhosis. The aim of the study was to determine the relationship between the concentration of selenium and pro-inflammatory and profibrotic cytokines – interleukin-6 (IL-6) and growth differentiation factor 15 (GDF-15) in patients with alcoholic liver cirrhosis. The parameters studied were determined in serum of 99 alcoholic liver cirrhosis patients divided based on the severity of disease according to the Child-Turcotte-Pugh criteria. In patients with liver cirrhosis, the serum selenium concentration was statistically lower whereas serum IL-6 and GDF-15 concentrations were higher than those in the control group. Moreover, the concentration of selenium negatively correlated with the levels of GDF-15 and IL-6. The above results may indicate a role of selenium deficiency in the pathogenesis and progression of alcoholic liver disease.

Abstruct Green Human Resource Management (GHRM) has emerged as an essential strategy for achieving environmental sustainability within organizations. However, there remains a significant gap in understanding its direct impact on sustainable performance. This study seeks to address these gaps by investigating the relationship between GHRM and sustainable performance, with a focus on the mediating role of green innovation and the moderating influence of transformational leadership. A cross-sectional study was conducted among Malaysian small and medium-sized enterprises (SMEs) to explore the interrelationships between Green HRM, green process and product innovation, sustainability, and the role of sustainable leadership. The study's findings reveal a positive and significant relationship between green HRM practices and sustainability, encompassing environmental, economic, and social aspects. The findings suggest that management support for environmental initiatives is a critical factor in enhancing the effectiveness and spread of green innovations, emphasizing the importance of GHM in the broader context of organizational change and sustainability. In addition, the study underscores the critical role of transformative leadership in fostering sustainable practices, particularly the significant moderator role of responsible leadership in driving sustainable business practices. In summary, this study provides a roadmap for businesses, particularly SMEs, to leverage HGRM as a strategic tool in their pursuit of sustainability.

This paper presents a brief account and rationale for implementation of competency-based learning in any form of management and leadership development programmes in South Africa. The fact that competency-based learning (CBL), also known as outcomes-based learning has been scrapped from the schooling system in South Africa is unfortunate as this method enhances critical thinking skills and practical problem-solving skills. This paper presents CBL as a model of meta-cognitive approach to learning that integrates both theory and practice into experiential learning through six dimensions, namely, active learning, constructive learning, cumulative learning, goal-oriented learning, learner-centred and curriculum design strategies. In the advent of the fast-paced global economy, managers and leaders need to seek those business schools that value real-time practical approach to curriculum for relevance and to maximize shareholder value through human resource development. This brief presentation ends by recommending an approach through CBL that fosters three critical pillars of leadership development, namely: intellectual, behavioural and emotional agenda.

Abstract. Graphene family (GF)-Calcium phosphate (CaP) composites, holds great potential as components of bone regeneration materials. GF nanomaterials can be modified physically as well as chemically, which are to be biomimetic, mechanically to be hard due to their capability to support exceptional mechanical, thermal and electronic properties. These biocompatible GF composites coated on the calcium phosphate can enhance and tolerate stem cell growth and differentiation, proliferation into various lineages or interact with bioorganisms. The development in CF-CaP materials and their physicochemical/biointeractions and strategies towards osteoblasts is a great concern to promote faster healing and reconstructions of large bone imperfections or defects. In this review, we explain the influence of the CF-CaP and summarize recent developments on designing CF-CaP architectures as multifunctional bone regeneration platforms. We have also explored the typical biological applications concerning these CF-CaP based bioactive nanocomposites. Furthermore, the future viewpoints and evolving challenges will also be emphasized. Due to the shortage of full-length reviews in this emerging research field, this review would be caught great attention and encourage various new chances across a wider range of disciplines.

The corneal epithelium (CE) is spread between two domains, the outer vascularized limbus and the avascular cornea proper. Epithelial cells undergo constant migration from the limbus to the vision-critical central cornea. Coordinated with this migration the cells undergo differentiation changes where a pool of unique stem/precursor cells at the limbus yields the mature cells that reach the corneal center. Differentiation is heralded by the expression of the corneal-specific Krt12. Processing data acquired by scRNA-Seq we found that the increase of Krt12 expression occurs in four distinct steps within the limbus plus a single continuous increase in the cornea. Differential gene analysis demonstrated that these domains reflect discreet stages of CE differentiation and yielded extensive information of the genes undergoing down or up regulation in the sequential transition from less to more differentiate conditions. The approach allowed the identification of multiple gene cohorts, including a) the genes that have maximal expression in the most primitive, Krt12-negative cell cohort, which is likely to include the stem/precursor cells; b) the sets of genes that undergo continuous increase or decrease along the whole differentiation path, and c) and the genes showing maximal positive or negative correlation with the changes in Krt12.

Epigenetic modifications play a significant role in determining the fate of AFSC in terms of differentiation into multiple lineages. There is a tight correlation among DNA methylation, histone modifications, and small noncoding RNAs during the epigenetic control of stem cells differentiation. The present study investigates the role of miRNAs in differentiation of AFSC and addresses how their unique signatures contribute to lineage-specific differentiation. miRNAs profile was assessed in AFSC after 4 weeks of endothelial and muscular differentiation. Our results showed a decreased expression of for 5 miRNAs (miR-125b-5p, hsa-miR-18a-5p, hsa-miR-137, hsa-miR-21-5p and hsa-let-7a-5p) and an increased expression for 12 miRNAs (miR-134-5p, miR-103a-3p, let-7i-5p, miR-214-3p, let-7c-5p, miR-129-5p, miR-210-3p, let-7d-5p, miR-375, miR-181-5p, miR-125a-5p, hsa-let-7e-5p) in EPC compared with undifferentiated AFSC. Smooth muscle differentiation of AFSC revealed significant changes in 9 miRNAs from total of 84 tested; 3 were downregulated (miR-18a-5p, miR-137, sa-miR-21-5p) and 6 were upregulated (miR-155-5p, miR-20a-5p, let-7i-5p, hsa-miR-134-5p, hsa-miR-214-3p, hsa-miR-375). miRNAs are molecular regulators of cell fate and differentiation, recent advances in molecular biology techniques revealed miRNA regulatory networks that can provide us information of endothelial and muscle cell biology in terms of homeostasis, growth, differentiation, and vascular function.

This study investigated clinical nurses’ knowledge and visual differentiation ability of the pressure injury classification system (PICS) and incontinence-associated dermatitis (IAD), additionally analyzing possible influencing factors. A convenience sample of 248 nurses took the PICS and IAD knowledge test (KT) and completed the visual differentiation ability test (VDAT), consisting of 21 photographs with clinical information. The overall mean score for correct answers was 12.65±2.90 points in PICS & IAD KT and 11.43±4.57 points in VDAT. Incorrect responses were most common for statements related to stage Ⅱ, Ⅲ, IAD for PICS & IAD KT, and deep tissue pressure injury (DTPI), unstageable, and stage Ⅲ for VDAT. Significant correlations were found between PICS & IAD KT and VDAT (r=.252, p<.001). Factors affecting scores for VDAT were the scores of PICS & IAD KT, debridement experience in nursing patients with PI, and the management frequency of PI and IAD. Results indicate that nurses have an overall understanding of PICS and IAD, but low visual differentiation ability regarding stage Ⅲ, DTPI, and unstageable PI. Continuing education is needed to further improve knowledge and visual differentiation ability for PICS and IAD.

Brain stem cells (neural stem cells or NSCs) and neurons of a chosen kind reprogramming is a potential technique for cell therapy. It is possible to reprogram non-neuronal cells, for example, by using a predetermined group of factors, nuclear transfer, and the induced transcriptional factors (TFs) expression in a related lineage of cells, and non-coding microRNAs (miRNAs). Researchers have additionally been attempting to improve reprogramming methods, whether it is by employing unique sets of biomolecules and particular TFs or by delivering relevant miRNA and Biomolecules. The technique of miRNA mediated is intriguing for its capability to quickly create a range of biologically desirable cell types for therapy from different lineages of cells. Current findings have made significant advancements towards changing the somatic cells to diverse particular neuronal subgroups with greater efficiency, using reprogramming of miRNA-mediated neural cells, despite the fact that the precise processes need to be discovered. To further understand how miRNAs might direct somatic cells to become neural, we need to look at the latest research on their function in neural reprogramming over the differentiated cells. Recent findings on the role of miRNAs in the initiation of cell reprogramming and the determination of the neuronal subtype's destiny are the primary focus of this comprehensive overview. Furthermore, we cover the far more latest results concerning certain miRNAs' activity in controlling different phases of neuronal differentiation, which contributes in comprehending the interaction network of miRNAs and their receptors.

Different types of engineered cardiac constructs are being developed nowadays by many research groups. However, the immunological properties of such artificial tissues are not yet clearly understood. Previously, we have studied microfiber scaffolds carrying iPSC-derived cardiomyocytes. In this work, we evaluated the ability of these tissue-engineered constructs to activate the expression of CD28 and CTLA-4 proteins in T-lymphocytes which are early markers of the immune response. For this purpose electrospun PLA nanofibrous scaffolds were seeded with human iPSCs-CM and cultivated for 2 weeks. After, allogeneic mononuclear cells were co-cultured during 48 hours with 3 groups of samples that were tissue-engineered constructs, pure culture of cardiomyocytes and bare scaffolds followed by analysis of CD28/CTLA-4 expression on T-lymphocytes via flow cytometry. PLA scaffolds and concanavalin A (positive control) stimulation statistically significantly increased CD28 expression on CD4+ cells (up to 61.3% and 66.3%) and on CD8+ cells (up to 17.8% and 21.7%). CD28/CTLA-4 expression didn’t increase during co-cultivation of T-lymphocytes with cardiac engineered constructs and iPSC-CM monolayers. Thus, iPSCs-CM in monolayers and on PLA nanofibrous scaffolds didn’t cause T-cell activation, which allows us to expect that such cardiac constructs are not a cause of rejection after implantation.

Abstract: Remarkably, the p53 transcription factor, referred to as “the guardian of the genome”, is not essential for mammalian development. Moreover, efforts to identify p53‑dependent developmental events have produced contradictory conclusions. Given the importance of pluripotent stem cells as models of mammalian development, and their applications in regenerative medicine and disease, resolving these conflicts is essential. Here we attempt to reconcile disparate data into justifiable conclusions predicated on reports that p53‑dependent transcription is first detected in late mouse blastocysts, that p53 activity first becomes potentially lethal during gastrulation, and that apoptosis does not depend on p53. Furthermore, p53 does not regulate expression of genes required for pluripotency in embryonic stem cells (ESCs); it contributes to ESC genomic stability and differentiation. Depending on conditions, p53 accelerates initiation of apoptosis in ESCs in response to DNA damage, but cell cycle arrest as well as the rate and extent of apoptosis in ESCs are p53-independent. In embryonic fibroblasts, p53 induces cell cycle arrest to allow repair of DNA damage, and cell senescence to prevent proliferation of cells with extensive damage.

Chronic obstructive pulmonary disease (COPD) is associated with high morbidity and mortality globally. Studies show that airway mucus hypersecretion strongly compromises lung function, leading to frequent hospitalization and mortality, highlighting an urgent need for effective COPD treatments. MUC5AC is known to contribute to severe muco-obstructive lung diseases, worsening COPD pathogenesis. Various pathways are implicated in the aberrant MUC5AC production and secretion MUC5AC. These include signaling pathways associated with mucus-secreting cell differentiation [ nuclear factor-κB (NF-кB)and IL-13-STAT6- SAM pointed domain containing E26 transformation-specific transcription factor (SPDEF), as well as epithelial sodium channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR)], and signaling pathways related to mucus transport and excretion-ciliary beat frequency (CBF). Various inhibitors of mucus hypersecretion are in clinical use but have had limited benefits against COPD. Thus, novel therapies targeting airway mucus hypersecretion should be developed for effective management of muco-obstructive lung disease. Here, we systematically review the mechanisms and pathogenesis of airway mucus hypersecretion, with emphasis on multi-target and multi-link intervention strategies for the elucidation of novel inhibitors of airway mucus hypersecretion.

Corundum-rich (up to 55 vol.%) felsic dykes formed by albite, ±K-feldspar, ±hercynite and ±biotite-siderophyllite cut the lower crustal rocks exposed in the Ivrea-Verbano Zone (NW Italy). Zircon is an abundant accessory mineral and its investigation through LA-ICP-(MC)MS has allowed to directly constrain the timing of emplacement, as well as petrology and geochemistry of parental melts. Zircons are characterised by very large concentration in REE, Th, U, Nb and Ta, and negative Eu anomaly. U–Pb analysis points to Norian emplacement ages (223±7 Ma and 224±6 Ma), whereas large positive εHf(t) values (+13 on average) indicate a derivation from depleted to mildly enriched mantle source. The mantle signature and the corundum oversaturation were preserved thanks to limited crustal contamination of the host, HT refractory granulites and mafic intrusives. According to the geochemical data and to the evidence of the development of violent explosions into the conduits, it is proposed that dykes segregated from peraluminous melts produced by exsolution processes affecting volatile-rich differentiates during alkaline magmatism. This work provides robust evidence about the transition of the geochemical affinity of Southern Alps magmatism from orogenic-like to anorogenic during Norian, linked to a regional uprising of the asthenosphere and change of tectonic regime.

Bacteria participate in a wide diversity of symbiotic associations with eukaryotic hosts that require precise interactions for bacterial recognition and persistence. Most commonly, host-associated bacteria interfere with host gene expression to modulate the immune response to the infection. However, many of these bacteria also interfere with host cellular differentiation pathways to create a hospitable niche, resulting in the formation of novel cell types, tissues, and organs. In both of these situations, bacterial symbionts must interact with eukaryotic regulatory pathways. Here, we detail what is known about how bacterial symbionts, from pathogens to mutualists, control host cellular differentiation across the central dogma, from epigenetic chromatin modifications, to transcription and mRNA processing, to translation and protein modifications. We identify four main trends from this survey. First, mechanisms for controlling host gene expression appear to evolve from symbionts co-opting cross-talk between host signalling pathways. Second, symbiont regulatory capacity is constrained by the processes that drive reductive genome evolution in host-associated bacteria. Third, the regulatory mechanisms symbionts exhibit correlate with the cost/benefit nature of the association. And, fourth symbiont mechanisms for interacting with host genetic regulatory elements are not bound by native bacterial capabilities. Using this knowledge, we explore how the ubiquitous intracellular Wolbachia symbiont of arthropods and nematodes may modulate host cellular differentiation to manipulate host reproduction. Our survey of the literature on how infection alters gene expression in Wolbachia and its hosts revealed that, despite their intermediate-sized genomes, different strains appear capable of a wide diversity of regulatory manipulations. Given this and Wolbachia’s diversity of phenotypes and eukaryotic-like proteins, we expect that many symbiont-induced host differentiation mechanisms will be discovered in this system.

The tumor suppressor protein p53 is considered a guardian of genome integrity, regulating the induction of apoptosis and cell cycle arrest in response to irradiation to block the transmission of teratogenic mutations to progeny cells. We examined the function of p53 in highly radiosensitive tissues, the developing brain and mature testis, using a small fish model, medaka (Oryzias latipes). Medaka offer advantages as a vertebrate model system, as the transparency and small size of the embryos enables clear detection of apoptotic cells in the developing brain. In addition, the simple architecture of medaka testes enables more precise identification of the differentiating spermatogenic stages compared with mammals. We found that in irradiated p53-deficient embryonic brain, diminished induction of apoptosis facilitated tissue regeneration earlier compared to irradiated wild-type embryos, which remained structural abnormalities in the retina at hatching. Moreover, the prominent delay in apoptotic induction in irradiated p53-deficient testes could induce transient mis-differentiation during spermatogenesis, such as the formation of ovum-like cells (testis-ova). However, all testis-ova cells were eliminated via p53-independent apoptosis, and spermatogenesis was completely restored within 1 month after irradiation. Collectively, these data indicate that p53 is not indispensable for the restoration of irradiation-induced damaged tissues.

The ongoing growth of international occurrence of depression and its ability to co-occur with other serious medical disorders such as heart disease, cancer, diabetes, and Parkinson’s disease is a current public health problem. Inhibitor of DNA-Binding/Differentiation (ID) proteins are part of a group of transcriptional factors that have been seen to be involved in neurocognitive disorders and therefore, may have influence on depressive disorders. Previously, it has been established that environmental estrogenic endocrine disruptors (EEDs) such as polychlorinated biphenyls (PCBs) & bisphenol A (BPA) have played an important role in the impact of depressive disorders. Hence, based on many studies, we consider the impact of these environmental pollutants on the group of ID proteins. Improved understanding of how the interaction of ID proteins by EED exposure can influence depressive disorders will contribute essential evidence that can further benefit our public health community with innovative knowledge to prevent these types of mental illnesses.

Plant life-long organogenesis involves sequential, time and tissue specific expression of developmental genes. This requires activities of Polycomb Group (PcG) and trithorax Group complexes, respectively responsible for repressive Histone 3 trimethylation at lysine 27 (H3K27me3) and activation-related H3K4me3. However, the genome-wide dynamics in histone modifications that occur during developmental processes have remained elusive. Here, we report the distributions of H3K27me3 and H3K4me3 along with transcriptional changes, in a developmental series including Arabidopsis leaf and three stages of flower development. We found that chromatin mark levels are highly dynamic over the time series on nearly half of all Arabidopsis genes. Moreover, during early flower morphogenesis, changes in H3K4me3 prime over changes in H3K27me3 and quantitatively correlate with transcription changes, while H3K27me3 changes occur after prolonged expression changes. Notably, early activation of PcG target genes is dominated by increases in H3K4me3 while H3K27me3 remains present at the locus. Our results reveal H3K4me3 as greater predictor over H3K27me3 for transcription dynamics, unveil unexpected chromatin mechanisms at gene activation and underline the relevance of tissue-specific temporal epigenomics.

The study aimed to investigate how distributed leadership influences adolescents' social and emotional competence, considering the roles of student-centered instructional practices and teacher self-efficacy. Utilizing survey data from 7,246 Suzhou adolescents enrolled in the SESS program, the study employed multilevel structural equation modeling for analysis. The findings indicated a positive correlation between distributed leadership and adolescents' social and emotional competence, as evaluated by teachers. Moreover, distributed leadership was observed to exert an indirect impact on adolescents' self-assessment and teacher-rated social and emotional competence. This influence operated through several mediators: student-centered instructional practices, teacher self-efficacy, and the sequential mediating pathway of student-centered instructional practices → teacher self-efficacy. This study underscores the significance of supportive elements in fostering students' social and emotional competence. It offers valuable insights into the everyday practices of teachers, principals, and administrators. Additionally, it sheds light on how distributed leadership contributes to enhancing adolescents' overall social and emotional development.

The concept of supply chain leadership strategy has garnered increasing interest from policymakers and experts, because it is among the most dependable practices to sustainable innovation and competitiveness for large firms across developing economies. Effective implementation of supply chain leadership strategic actions at each level in the company can create sustainable innovative and competitiveness. The study collected statistical data using an online Survey- Monkey questionnaire from 46 of top 100 JSE-listed companies with the intention to discover supply chain leadership strategic actions that drive sustainable innovation and competitiveness in the company. The findings expose a significant empirical insight for companies to understand and leverage supply chain leadership strategic actions to influence sustainable innovative position in a developing economy. These results suggest that firms operating within emerging markets should embrace and acknowledge the importance of sustainable innovation in business practices in the provision of goods and services. This study therefore delivers major contributions to the literature to assist in planning sustainable innovation and supply chain practices in a developing economy to survive in a competitive global environment. The paper also offers a vigorous awareness and knowledge of the common characteristics and strategies for supply chain management that needs to be prioritized by the JSE-listed companies.

The world is looking towards organizations for social responsibility to contribute to a sustainable environment. Employees’ organizational citizenship behavior for the environment (OCBE) is a voluntary environmental-oriented behavior that is important for organizations’ environmental performance. Based on social learning theory, the study examined the effects of responsible leadership in connection with OCBE by using a sample of 520 employees of manufacturing and service sector including engine manufacturing, petroleum plants banking and insurance sector organizations of China. Further, the role of psychological ownership and employee environmental commitment were used as mediators and moderators simultaneously. The direct, mediation, and moderation model results exposed a positive relationship between responsible leadership and OCBE via employee psychological ownership and employee environmental commitment. The study also revealed that the indirect effect is stronger when employees hold higher employee environmental commitment. The theoretical and practical implications for environmental sustainability in respect of organizations as well as future research directions are discussed.

The World economy after global crisis of 2008–2009 entered a restructuring era. It defines relevance of researches of its directions and patterns. The principles of determinism and systemic analysis are methodological basis of article. In research were used the methods of processing Big Date, as of continuous changes and the symmetric analysis of macroeconomic indicators according to databases of the IMF, WB, BIS, the Central banks and treasuries. As a result of the research it is proved that depth and globalism of recessionary processes are caused by a combination of crisis of world financial system and civilization problems. Intrinsic signs of risks in the modern economy caused by the duality of the nature of global crises have been identified. There are analyzes: the deficit of resources of the international financial institutions, a negative role of a fixed rate of Yuan, a big share of derivatives and off-balance obligations of banks, use of SPV in structures of deals, growth of debt obligations, trade wars, slowdown in the growth of the Chinese economy, aggravation of contradictions between global and national finances. The thesis is reasonable that deglobalization and dedollarization deepened this conflict, started the rollback mechanism from achievements of globalization, led to tariff wars. By means of a systematization it is proved the key directions of the restructuring of global economy: legal basis, leadership and reserve currency. On the basis of SWOT-analysis of the USA and China it was concluded that the question of leadership of one country should be excluded, but slow transition to use SDR (with a basket from 15–20 currencies) as a reserve.

The differentiation of ESCs into cardiomyocytes in vitro is an excellent and reliable model system for studying normal cardiomyocyte development in mammals, modeling cardiac diseases, and for use in drug screening. Mouse ESC differentiation still provides relevant biological information about cardiac development. However, the current methods for efficiently differentiating ESCs into cardiomyocytes are limiting. Here, we describe a “WNT Switch” method to efficiently commit mouse ESCs into cardiomyocytes using the small molecule WNT signaling modulators CHIR99021 and XAV939 in vitro. This method significantly improves the yield of beating cardiomyocytes, reduces number of treatments, and is less laborious.

The COVID-19 pandemic stimulated attention to the medicinal applications of messenger RNA (mRNA). mRNA is expected to be applied not only to vaccines but also to regenerative medicines. The purity of mRNA is important for its medicinal application. However, the current mRNA synthesis techniques have problems, e.g., contamination of undesired 5’-uncapped mRNA and double-stranded RNAs. Recently, our group developed a completely capped mRNA synthesis technology that contributed to the progress of mRNA research. The introduction of chemically modified nucleosides, e.g., N1-methylpseudouridine and 5-methylcytidine, have been demonstrated by Dr. Karikó and Dr. Weissman which opened the practical application of mRNA for vaccines and regenerative medicines. Dr. Yamanaka reported the production of Induced Pluripotent Stem Cells (iPSCs) by the introduction of 4 types of genes using a retrovirus vector. iPSCs are widely used for research about regenerative medicines and the preparation of disease models to screen new drug candidates. Of the Yamanaka factors, Klf4 and c-Myc are oncogenes, and there is a tumor development risk if these are integrated into genomic DNA. Therefore, regenerative medicines using mRNA, which has no risk of genome insertion, have attracted attention. In this review, we summarized the synthesis of mRNA and its application for regenerative medicine.

Bone fractures are very common in the geriatric population and poses a great economic burden worldwide. While traditional methods for repairing bone defects have primarily been autografts, there are several drawbacks limiting its use. Bone graft substitutes have been used as alternative strategies to improve bone healing. However, there remains several impediments to achieving the desired healing outcomes. Injectable hydrogels have become attractive scaffold materials for bone regeneration given their high performance in filling irregularly sized bone defects, ability to encapsulate cells and bioactive molecules, and mimic the native ECM of bone. We investigated the use of an injectable chitosan-based hydrogel scaffold to promote differentiation of preosteoblasts in vitro. The hydrogels were characterized by evaluating cell homogeneity, cell viability, rheological and mechanical properties, and differentiation ability of preosteoblasts in hydrogel scaffolds. Cell-laden hydrogel scaffolds exhibited shear thinning behavior and the ability to maintain shape fidelity after injection. The CNC-CS hydrogels exhibited higher mechanical strength and significantly upregulated the osteogenic activity and differentiation of preosteoblasts as shown by ALP activity assays and histological analysis of hydrogel scaffolds. These results suggest that this injectable hydrogel is suitable for cell survival, can promote osteogenic differentiation of preosteoblasts, and structurally support new bone growth.

Background: The major histocompatibility complex (MHC) plays a key role in the adaptive immune response to pathogens due to its extraordinary polymorphism. However, the spatial patterns of MHC variation in the striped hamster remain unclear, particularly regarding the relative contribution of balancing selection in shaping MHC population and diversity compared to neutral forces. Methods: In this study, we investigated the immunogenic variation of the striped hamster in four wild populations in Inner Mongolia, which experience heterogeneous parasitic stress. Our goal was to identify local adaptation by comparing the genetic structure at MHC with that at seven microsatellite loci, taking into account neutral processes. Results: We observed significant variation in parasite pressure among sites, with parasite burden showing a correlation with temperature and precipitation. Molecular analysis revealed a similar co-structure between MHC and microsatellite loci. We observed lower genetic differentiation at MHC loci compared to microsatellite loci, and no correlation was found between the two. Conclusions: Overall, these results suggest a complex interplay between neutral evolutionary forces and balancing selection in shaping the spatial patterns of MHC variation. Local adaptation was not detected at a small scale but may be applicable at a larger scale.

The capability of radially polymerized bio-dendrimers and hyperbranched polymers for medical applications is well established. Among them, perhaps the most important are those that involve interactions with the regenerative mechanisms of cells. Dendritic polymers due to their distinctive architecture may play a multitude of roles such as protein biomimicry (collagen, elastin, hydroxy apatite production), gene and drug delivery (cell differentiation, antimicrobial protection), surface chemistry and charge modulation (adhesion to cells and tissues), polymer cross-linking (eye, skin and internal organ wound healing). The review highlights all the different categories of hard and soft tissues that may be remediated with their contribution. The reader will be also exposed to the incorporation methods to established biomaterials such as scaffolds, the functionalization strategies, and the synthetic paths for the assembly from biocompatible building blocks and natural metabolites.

Reliable quantification of pulmonary arterial pressure is essential in the diagnostic and prognostic assessment of a range of cardiovascular pathologies including rheumatic heart disease, yet an accurate and routinely available method for its quantification remains elusive. This work proposes an approach to infer pulmonary arterial pressure based on scientific machine learning techniques and non-invasive, clinically available measurements. A 0-D multicompartment model of the cardiovascular system was optimized using several optimization algorithms, subject to forward-mode automatic differentiation. Measurement data were synthesized from known parameters to represent the healthy, mitral regurgitant, aortic stenosed and combined valvular disease situations with and without pulmonary hypertension. Eleven model parameters were selected for optimization based on 95 % explained variation in mean pulmonary arterial pressure. A hybrid Adam and limited-memory Broyden-Fletcher-Goldfarb-Shanno optimizer yielded the best results with input data including valvular flow rates, heart chamber volume changes and systematic arterial pressure. Mean absolute percentage errors ranged from 1.8 % to 3.78 % over the simulated test cases. The model was able to capture pressure dynamics under hypertensive conditions with pulmonary arterial systole, diastole, and mean pressure average percentage errors of 1.12 %, 2.49 % and 2.14 %, respectively. The relatively low errors highlight the potential of the proposed model to recover pulmonary pressures for diseased heart valve and pulmonary hypertensive conditions.

By reviewing the research of development economics in recent years, five key terms of ‘innovation, coordination, green, openness and sharing’ are extracted, corresponding to the five dimensions of the New Development Concept advocated by China. Based on this, an evaluation index system of the development quality of China's fishery industry is constructed. The spatio-temporal characteristics of China's fishery industry development quality were analyzed by using the provincial panel data from 2007 to 2017. The results show that: i) China's fishery industry overall development quality continues to grow, while the variation of provincial quality is also increasing, and the contribution of innovation quality and sharing quality is increasing, becoming an important sub-dimension leading the overall development quality.ii) there is a significant spatial dependence among provincial quality, and the significance is further strengthening. The Hangzhou Bay area and Bohai Bay area have gradually become a dual-core area where the high-quality development of China's fishery industry agglomeration, and the radiation from the dual-core area to the peripheral areas may still be in the process of enhancement. The spatial and temporal distribution of China’s fishery industry development quality keeps the trend of ‘from northeast to southwest’, which is almost parallel to Hu Huanyong line. The gravity center of its distribution is close to the gravity center of Chinese population and economy, and the development quality experienced a process from relatively concentrated to dispersed and then returned to concentrated, and the development speed in the later period was higher than that in the earlier period. iii) Capital accumulation level is the dominant positive influencing factors, while government support level is the dominant negative influencing factors respectively, and both have significant spatial differentiation among provinces.

Objective: To investigate the protein expression levels of cyclin‑dependent kinase subunit 2 (CKS2) and cluster of differentiation (CD) 47 in gastric cancer (GC) and their clinical significances. Methods: A total of 126 GC patients who underwent radical resection were selected as study subjects. Additionally, 32 patients with benign gastric tumor, 42 patients with low-grade intraepithelial neoplasia (LGIEN), and 49 patients with high-grade intraepithelial neoplasia (HGIEN) who underwent surgery were selected as the control groups. Immunohistochemistry was used to detect the expression of CKS2 and CD47 in surgical specimens. We statistically analyzed the clinical significance of the expression of the two factors. Results: (1) The positivity rates for CKS2 in benign gastric tumor tissue, LGIEN tissue, HGIEN tissue, and GC tissue gradually increased, i.e., 6.3% (2/32), 30.9% (13/42), 38.8% (19/49), and 60.3% (76/126), respectively, and the positivity rates for CD47 were 18.8% (6/32), 38.1% (16/42), 46.9% (23/49), and 65.9% (83/126), respectively. (2) High expression of CKS2 and CD47 were associated with tumor diameter, Lauren classification, number of lymph node metastases, and TNM stage. In addition, the immunohistochemical scores for CKS2 and CD47 were positively correlated (r=0.625, P=0.000). (3) The median follow-up time of 126 patients was 46.5 months, and the overall survival rate was 40.5% (51/126). Survival analysis showed that compared with that in the CKS2 (-) group, the overall survival rate for patients in the CKS2 (+) group was significantly worse (25.0% vs 64.0%, 2=15.67, P=0.000) and that compared with the CD47 (-) group, the CD47 (+) group had significantly worse overall survival (30.1% vs 60.5%, 2=15.67, P=0.000). (4) The overall survival rates of CKS2(+)CD47(+) group, CKS2(+)CD47(-) group, CKS2(-)CD47(+) group, and CKS2 (-)CD47 (-) group were 20.0%(13/65), 58.3%(7/12), 57.1%(8/14), 65.7% (23/35), respectively, the prognosis of patients in CKS2(+)CD47(+) group was significantly poor. Conclusion: High expression levels of CKS2 and CD47 were closely related to the occurrence of GC and can be used as independent risk factors to assess the prognosis of patients.

Mesenchymal stem cells (MSCs) showed in vitro mesoderm-lineage differentiation and self-renew capacity. However, no comparative study was reported on the biological characteristics of stem cells derived from skeletal muscle (SM-MSCs), dermal skin (DS-MSCs), and adipose tissues (A-MSCs) from a single donor in camels. The present study aimed to evaluate the influence of MSCs source on stem cell characteristics. We evaluated proliferation capacity and mesoderm-lineage differentiation potential from SM-MSCs, DS-MSCs, and A-MSCs. They showed spindle-like morphology after homogenization. The proliferation ability was no significant difference in all groups. Furthermore, the portion of the cell cycle and expression of pluripotent markers (Oct4, Sox2, and Nanog) were similar in all cell lines at passage 3. The differentiation capacity of A-MSCs into adipocytes was significantly higher than that of SM-MSCs and DS-MSCs. However, the osteoblast differentiation capacity of A-MSCs was significantly lower than that of SM-MSCs and DS-MSCs. Additionally, after osteoblast differentiation, the ALP activity and calcium content was significantly decreased in A-MSCs as compared to SM-MSCs and DS-MSCs. To the best of our knowledge, we primally established MSCs from the single camel and demonstrated their comparative characteristics including expression of pluripotent factors and proliferation, and in vitro differentiation capacity into adipocytes and osteoblasts.

Background Human parvovirus B19, a human pathogen of the erythroparvovirus genus, is responsible for a variety of diseases. Despite less symptoms caused by B19 infection in healthy individuals, this pathogen can not be neglected in specific groups who exhibit severe anemia. Main body of abstract Transient aplastic crisis and pure red cell aplasia are two kinds of anemic hemogram respectively in acute phase and chronic B19 infection, especially occur in individuals with a shortened red cell survival or immunocompromised patients. In addition, B19 infected pregnant women may suffer risks of hydrops fetalis secondary to severe anemia and fetal loss. B19 possesses high affinity to bone marrow and fetal liver due to its extremely restricted cytotoxicity to erythroid progenitor cells mediated by viral proteins. The nonstructural protein NS1 is considered to be the major pathogenic factor, which takes parts in differentiational inhibition and apoptosis of erythroid progenitor cells through inducing viral DNA damage responses and cell cycle arrest. The time phase property of NS1 activity during DNA replication and conformity to transient change of hemogram are suggestive of its role in regulating differentiation of hematopoietic cells, which is not completely understood. Conclusion In this review, we set up a hypothetic bridge between B19 NS1 and Notch signaling pathway or transcriptional factors GATA which are essential in hematopoiesis, to provide a new insight of the potential mechanism of B19-induced differentiational inhibition of erythroid progenitor cells.

Abstract: Periodontal disease is the main reason for tooth loss in adults. Tissue engineering and regenerative medicine are the advanced technologies used to manage soft and hard tissue defects caused by periodontal disease. We developed a transforming growth factor-β3 chitosan sponge (TGF-β3/CS) to repair periodontal soft and hard tissue defects. We investigated the proliferation and osteogenic differentiation behaviors of primary human periodontal ligament stem cells (hPDLSCs) to discuss the bioactivity and application of TGF-β3 in periodontal disease. We separately used Calcein-AM/PI double-labeling or CM-Dil-labeling coupled with fluorescence microscopy to trace the survival and function of the cells after implantation in vitro or in vivo. The mineralization of osteogenic differentiated hPDLSCs was confirmed by measuring ALP activity and calcium content. The levels of COL I, ALPL, TGF-βRI, TGF-βRII, and Pp38/t-p38 were tested using Western blot to explore the mechanism of bone repair prompted by TGF-β3. When hPDLSCs were inoculated with different concentrations of TGF-β3/CS (62.5–500 ng/mL), ALP activity was the highest in TGF-β3 (250 ng/mL) group after seven days (P < 0.05 vs. control); the calcium content in each group increased significantly after 21 and 28 days (P < 0.001 vs. control). The best result was achieved in the TGF-β3 (500 ng/mL) group. All results showed that TGF-β3/CS can promote osteogenic differentiation of hPDLSC and may be involved in the p38 MAPK signaling pathway. TGF-β3/CS has the potential for application in the repair of incomplete alveolar bone defects.

The devastating growth in the worldwide frequency of neurocognitive disorders and its allied difficulties such as decline in memory, spatial competency, and ability to focus poses a significant psychological public health problem. Inhibitor of Differentiation (ID) proteins are members of a family of helix-loop-helix (HLH) transcription factors. ID proteins have been demonstrated to be involved in neurodevelopmental & depressive diseases and thus may influence neurocognitive deficiencies due to environmental exposure. Previously, it has been demonstrated that environmental factors such as estrogenic endocrine disruptors (EEDs) have played an essential role in the influence of various neurocognitive disorders such as Alzheimer’s, Dementia, and Parkinson’s disease. Based on this increasing number of reports, we consider the impact of these environmental pollutants on ID proteins. Better understanding of how these ID proteins by which EED exposure can affect neurocognitive disorders in populations will prospectively deliver valuable information in the impediment and regulation of these diseases linked with environmental factor exposure.

Patients with chronic obstructive pulmonary disease (COPD) may require frequent hospitalization due to worsening symptoms. Preventing prolonged hospital stay and readmission becomes a challenge for healthcare professionals treating patients with COPD. Although the integration of health and social care supports greater collaboration and enhanced patient care, organisational structure and poor leadership may hinder the implementation of patient-oriented goals. This paper presents a case of a 64-years-old chronic smoker with severe COPD who was to be discharged on long-term oxygen therapy (LTOT). It further highlights the healthcare decisions made to ensure the patient’s safety at home, and further provide a long-lasting solution to the existing medical and social needs. The goal was accomplished through a discharge plan that reflects multidisciplinary working, efficient leadership and change management using Havelock’s theory. While COPD is characterized by frequent exacerbation and hospital readmission, it was emphasized that most failed discharge could be attributed to bureaucratic organizational workflow which might not be in the patient’s best interest. It was further demonstrated that healthcare professionals are likely to miss the window of opportunity to apply innovative and long-lasting solutions to the patient’s health condition in an attempt to remedy the immediate symptoms of COPD.

Purpose - The purpose of the study is to investigate the missing link between leadership style and job satisfaction among Mongolian public sector employees. This study reiterates the mediating role of organizational climate (OC) and work style (WS) in a new proposed model. Methodology - The questionnaire is designed by a synthesis of existing constructs in the current relevant literature. The research sample consisted of 143 officers who work in the primary and middle units of territory and administration of Mongolia. Factor analysis, reliability test, collinearity test, and correlation analyses confirm validity and reliability of the model. Multiple regression analysis, using Structural Equation Modeling (SEM), tests the hypotheses of the study. Practical implications - This study has several important implications for studies related to organizational behavior and job satisfaction. Furthermore, the implications of findings are beneficial to organizations aiming at improving policies and practices related to organizational behavior and human resource management. Regulators and supervisors of private or public organizations aiming to increase the level of their employees’ job satisfaction will also benefit from the findings. Therefore, this study’s new proposed model can be the basis of fundamental research to build a better human resource policy. Although leadership style is an influential factor for job satisfaction, this study identifies the mediating missing links between leadership style and employees’ job satisfaction. Findings: The findings of this research indicate that organizational climate and work style complement and fully mediate the relationship between leadership style and job satisfaction. Appropriate leadership style is most effective when it matches organizational climate as well as employees’ work style. Furthermore, suitable organizational climate will increases the level of job satisfaction. If work style of employees is respected and taken into consideration, leadership style can find its way into job satisfaction. Originality/value - This study is the first to understand the motivators of job satisfaction in government sector of Mongolia. This study suggests valuable findings for executive officers, junior and primary unit’s officers of register sector of government in Mongolia. The findings of this study help managers and executives in their effort to develop and implement successful human resource strategies.

Familial Mediterranean fever (FMF) is a systemic autoinflammatory disorder caused by inherited mutations in the MEFV (Mediterranean FeVer) gene located on chromosome 16 (16p13.3) and coding pyrin protein. Despite the existing data on MEFV mutations, the exact mechanism of their effect on the development of pathological processes leading to autoinflammation observed in FMF, remains unclear. Induced pluripotent stem cells (iPSCs) are considered an important tool for studying the molecular genetic mechanisms of various diseases due to their ability to differentiate into any cell type, including macrophages, which contribute to the development of FMF. In this study, we developed iPSCs of an Armenian patient with FMF having M694V, p.(Met694Val) (c.2080A&gt;G, rs61752717) pathogenic mutation in exon 10 of the MEFV gene. As a result of direct differentiation, macrophages expressing CD14 and CD45 surface markers were obtained. In addition, we found that the morphology of patient macrophages derived from iPSCs with MEFV mutation was significantly different from that of differentiated from iPSCs of a healthy donor carrying wild-type MEFV gene.

Neurogenesis in the adult brain plays a major role in the cognitive ability of animals including learning and memory. Poria cocos (Schw.) Wolf (P. cocos) has been known as a traditional Chinese edible medicinal herb with the potential effect to improve learning and memory. However, the effect mechanisms are still elusive. In this study, significant neuronal differentiation-promoting activities of the ethanol extracts of P. cocos (EEPC) were tested in Neuro-2a cells and mouse cortical neural stem/progenitor cells (NSPCs). Subsequently, 97 compounds of EEPC were identified using UHPLC-Q-Exactive-MS/MS. After investigation of neuronal differentiation-promoting activities of 4 major compounds (Ethyl palmitoleate, L-(-)-Arabitol, Choline and Adenosine), only Choline has significant neuronal differentiation-promoting activity. In summary, we investigated the neuronal differentiation-promoting activity and chemical compositions of EEPC, the study of the neuronal differentiation-promoting effect of ether extract of P. cocos indicated P. cocos’s positive effect on learning and memory functions. This is the first investigation of the neuronal differentiation-promoting effect of ether extract of P. cocos based on similar research references.

In recent years, bone tissue engineering (BTE) has made significant progress in promoting the direct and functional connection between bone and graft, including osseointegration and osteoconduction, to facilitate the healing of damaged bone tissues. Herein, we introduce a new, environmentally friendly, and cost-effective method for synthesizing reduced graphene oxide (rGO) and hydroxyapatite (HAp). The method uses epigallocatechin-3-O-gallate (EGCG) as a reducing agent to synthesize rGO (E-rGO), and HAp powder is obtained from Atlantic bluefin tuna (Thunnus thynnus). The physicochemical analysis indicated that the E-rGO/HAp composites had exceptional properties for use as BTE scaffolds, as well as high purity. Moreover, we discovered that E-rGO/HAp composites facilitated not only proliferation, but also early and late osteogenic differentiation of human mesenchymal stem cells (hMSCs). Our work suggests that E-rGO/HAp composites may play a significant role in promoting the spontaneous osteogenic differentiation of hMSCs, and we envision that the E-rGO/HAp composites could serve as promising candidates for BTE scaffolds, stem cell differentiation stimulators, and implantable device components due to their biocompatible and bioactive properties. Overall, we suggest a new approach for developing cost-effective and environmentally friendly E-rGO/HAp composite materials for BTE application.

Multi- and hyper-spectral, multi-angular top-of-canopy reflectance data call for an efficient retrieval system which can improve the retrieval of standard canopy parameters (as albedo, LAI, fAPAR), and exploit the information to retrieve additional parameters (e.g. leaf pigments). Furthermore consistency between the retrieved parameters and quantification of uncertainties are required for many applications. % (2) methods We present a retrieval system for canopy and sub-canopy parameters (OptiSAIL), which is based on a model comprising SAIL, PROSPECT-D (leaf properties), TARTES (snow properties), a soil model (BRDF, moisture), and a cloud contamination model. The inversion is gradient based and uses codes % created by Automatic Differentiation. The full per pixel covariance-matrix of the retrieved parameters is computed. For this demonstration, single observation data from the Sentinel-3 SY_2_SYN (synergy) product is used. The results are compared with the MODIS 4-day LAI/fPAR product and PhenoCam site photography. OptiSAIL produces generally consistent and credible results, at least matching the quality of the technically quite different MODIS product. For most of the sites, the PhenoCam images support the OptiSAIL retrievals. The system is computationally efficient with a rate of 150 pixel per second (7 millisecond per pixel) for a single thread on a current desktop CPU using observations on 26 bands. Not all of the model parameters are well determined in all situations. Significant correlations between the parameters are found, which can change sign and magnitude over time. OptiSAIL appears to meet the design goals, puts real-time processing with this kind of system into reach, seamlessly extends to hyper-spectral and multi-sensor retrievals, and promises to be a good platform for sensitivity studies. The incorporated cloud and snow detection adds to the robustness of the system.

The bark of Rhus verniciflua Stokes (RVS) is used as a food additive and herbal medicine for various inflammatory disorders and cancer in Eastern Asia. RVS exerted anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, but whether this effect occurs in macrophages after oral administration has not been determined. We used a thioglycollate-induced peritonitis model to obtain macrophages from mice given RVS. We examined the systemic inflammatory response to intraperitoneal LPS. RVS-treated mice had an increased population of peritoneal exudate cells expressing CD11b and SRA. Increased uptake of Alexa Fluor 488-labeled acetylated lipoprotein was observed in monocyte-derived macrophages from RVS-treated mice. When these cells from the RVS group were stimulated with LPS, the levels of tumor necrosis factor (TNF)- and interleukin (IL)-6 in the supernatant decreased, but the level of IL-12 increased. The surface expression of CD86 was reduced, but surface expression of class II MHC molecules was increased. RVS suppressed the serum levels of LPS-induced TNF- and IL-6. RVS enhanced monocyte differentiation in thioglycollate-induced peritonitis by increasing scavenger receptor expression and activity. Macrophages isolated from mice given RVS responded differently to LPS. These findings demonstrate that RVS confers selective anti-inflammatory activity without causing the overall inhibitory effects on immune cells.

The present study was conducted to investigate the effects of rhizome extract of Dioscorea batatas (Dioscoreae Rhizoma, Chinese Yam) and its bioactive compound, allantoin, on myoblast differentiation and mitochondrial biogenesis in skeletal muscle cells. Yams were extracted in water and the extract was analyzed by HPLC. The expression of C2C12 myotubes differentiation and mitochondrial biogenesis regulators were determined by reverse transcriptase (RT)-PCR or Western blot. The glucose levels and total ATP contents were determined by glucose consumption, glucose uptake and ATP assays, respectively. Treatment with yam extract (1 mg/mL) and allantoin (0.2 and 0.5 mM) significantly increased of MyHC expression compared with non-treated myotubes. Yam extract and allantoin significantly increased the expression of mitochondrial biogenesis regulating proteins, PGC1?, Sirt-1, NRF-1, and TFAM, as well as the phosphorylation of AMPK and ACC in C2C12 myotubes. Furthermore, yam extract and allantoin significantly increased the glucose uptake levels and the ATP contents. Finally, HPLC analysis revealed that the yam extract contained 1.53% of allantoin. Yam extract and allantoin, stimulated myoblast differentiation into myotubes and increased energy production through upregulation of mitochondrial biogenesis regulators. These findings indicate that yam extract and allantoin can help to prevent the skeletal muscle dysfunction through stimulation of energy metabolism.

Background: Proteins targeted by the Ubiquitin Proteasome System (UPS) are identified for degradation by the proteasome, which has been implicated in the development of neuro-degenerative diseases. Major histocompatibility complex (MHC) molecules present peptides broken down by the proteasome and are involved in neuronal plasticity, regulating synapse number and axon regeneration in the central or peripheral nervous system during develop-ment and in brain diseases. The mechanisms governing these effects are mostly unknown, but evidence from different compartments of the cerebral cortex indicates the presence of im-mune-like MHC receptors in the central nervous system. Methods: We have used human induced pluripotent stem cells (iPSC) differentiated to neural stem cells and then to motor neurons as a developmental model to better understand the structure of the proteasome in developing motor neurons. We perform a proteomic analysis of starting human skin fibroblasts, their matching iPSC, differentiated neural stem cells and motor neurons that highlighted significant differences in the constitutive proteasome and immunoproteasome subunits during development towards motor neurons from iPSC. Results: Proteomic analysis showed that the catalytic proteasome subunits expressed in fi-broblasts differ to those in neural stem cells and motor neurons. Western blot analysis con-firmed the proteomic data, particularly the decreased expression of Beta5i (PSMB8) subunit immunoproteasome. Conclusion: The constitutive proteasome subunits are upregulated in iPSC from HFF and the immunoproteasome subunit beta 5i expression is higher in MN than NSC suggesting a im-munoproteasome phenotype in MN. The immunoproteasome may have implications on motor neuron development and neurodevelopmental diseases that warrants further investi-gation.

Periodontal ligament fibroblasts (PdLFs) exert important functions in oral tissue and bone remodeling following mechanical forces, which are specifically applied during orthodontic tooth movement (OTM). Located between the teeth and the alveolar bone, mechanical stress activates the mechanomodulatory functions of PdLFs including the regulation of local inflammation and activation of further bone-remodeling cells. Previous studies suggested the growth differentiation factor 15 (GDF15) as important pro-inflammatory regulator during the PdLFs mechanoresponse. However, the precise mechanism remains to be clarified, as GDF15 may act both intracrine and by receptor binding, potentially also in an autocrine manner. The extent to which PdLFs are susceptible to extracellular GDF15 has not yet been investigated. Thus, our study aims to examine the influence of GDF15 exposure on cellular properties of PdLFs and their mechanoresponse, which seems particularly relevant regarding disease- and aging-associated elevated GDF15 serum levels. Therefore, in addition to investigating potential GDF15 receptors, we analyzed its impact on proliferation, survival, senescence, and differentiation of human PdLFs, demonstrating a pro-osteogenic effect upon long-term stimulation. Furthermore, we detected an altered force-related inflammation and impaired osteoclast differentiation. Overall, our data suggest a major impact of extracellular GDF15 on PdLFs differentiation and their mechanoresponse.

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment perform glycolysis to produce energy, i.e., ATP. Since the origin of CAFs is unidentified, it is not determined whether the intracellular metabolism transitions from oxidative phosphorylation (OXPHOS) to glycolysis when normal tissue fibroblasts differentiate into CAFs. In this study, we established an experimental system and induced the in vitro differentiation of mesenchymal stem cells (MSCs) to CAFs. Additionally, we performed metabolomic and RNA-sequencing analyses before and after differentiation to investigate changes in the intracellular metabolism. Consequently, we discovered that OXPHOS, which was the primary intracellular metabolism in MSCs, was reprogrammed to glycolysis. In addition, we identified CAF-specific metabolites that were expressed during this reprogramming and determined their presence in the pancreatic tumor tissues of mouse models. Thus, we conclude that normal tissue fibroblasts that differentiate into CAFs undergo a metabolic reprogramming from OXPHOS to glycolysis. Moreover, we identified the CAF-specific metabolites expressed during metabolic reprogramming as potential future biomarkers for pancreatic cancer.

Background/methods: For mechanistic studies, in vitro human B cell differentiation and generation of plasma cells are invaluable techniques. However, the heterogeneity of both T cell-dependent (TD) and T cell-independent (TI) stimuli and the disparity of culture conditions used in existing protocols makes interpretation of results challenging. The aim of the present study was to achieve the most optimal B cell differentiation conditions using isolated CD19⁺ B cells and PBMC cultures. We addressed multiple seeding densities, different durations of culturing and various combinations of TD stimuli and TI stimuli including B cell receptor (BCR) triggering. B cell expansion, proliferation and differentiation was analyzed after 6 and 9 days by measuring B cell proliferation and expansion, plasmablast and plasma cell formation and immunoglobulin (Ig) secretion. In addition, these conditions were extrapolated using cryopreserved cells and differentiation potential was compared. Results: This study demonstrates improved differentiation efficiency after 9 days of culturing for both B cell and PBMC cultures using CD40L and IL-21 as TD stimuli and 6 days for CpG and IL-2 as TI stimuli. We arrived at optimized protocols requiring 2500 and 25.000 B cells per culture well for TD and TI assays, respectively. The results of the PBMC cultures were highly comparable to the B cell cultures, which allows dismissal of additional B cell isolation steps prior to culturing. In these optimized TD conditions, the addition of anti-BCR showed little effect on phenotypic B cell differentiation, however it interferes with Ig secretion measurements. Addition of IL-4 to the TD stimuli showed significantly lower Ig secretion. The addition of BAFF to optimized TI conditions showed enhanced B cell differentiation and Ig secretion in B cell but not in PBMC cultures. With this approach, efficient B cell differentiation and Ig secretion was accomplished when starting from fresh or cryopreserved samples. Conclusion: Our methodology demonstrates optimized TD and TI stimulation protocols for more indepth analysis of B cell differentiation in primary human B cell and PBMC cultures while requiring low amounts of B cells, making them ideally suited for future clinical and research studies on B cell differentiation of patient samples from different cohorts of B cell-mediated diseases.

The study of neurodegenerative diseases using pluripotent stem cells requires new methods to assess neurodevelopment and neurodegeneration of specific neuronal subtypes. The cholinergic system, characterized by its use of the neurotransmitter acetylcholine, is one of the first to degenerate in Alzheimer’s disease and is also affected in frontotemporal dementia. We developed a differentiation protocol to generate basal forebrain cholinergic neurons (BFCNs) from induced pluripotent stem cells (iPSCs) aided by the use of small molecule inhibitors and growth factors. Ten iPSC lines were successfully differentiated into BFCNs using this protocol. The neuronal cultures were characterised through RNA and protein expression, and functional analysis of neurons was confirmed by whole-cell patch clamp. We have developed a reliable protocol using only small molecule inhibitors and growth factors, while avoiding transfection or cell sorting methods, to achieve a BFCN culture that expresses the characteristic markers of cholinergic neurons.

Irish beef farms have experienced poor viability longitudinally, with officially acknowledged ‘crisis’ levels in 2013. In response, beef Producer Organisation (PO) legislation was introduced. Through the lens of international evidence in the literature about how POs function, this paper presents an analysis of Irish stakeholders’ views in the context of a public consultation process. While stakeholders indicate the need for individual POs to collaborate, little emphasis is placed on other factors necessary for success: collaboration with other chain actors; and market differentiation of products. Stakeholders identified primary threats as poor engagement on the part of both farmers and processors/purchasers.

The study aimed to know the direct effect of strategic leadership on the quality of service represented by wireless communications services, in addition to knowing the indirect effect of strategic leadership on the quality of service when using performance as an intermediary variable. This research was conducted in government institutions in the Republic of Yemen. Represented by the offices of the Ministry of Communications and Information Technology in five Yemeni cities, it targeted senior management employees, boards of directors, and middle management concerned with strategic planning and strategic leadership. To measure and evaluate the factors of strategic leadership and service quality in Offices of the Yemeni Ministry of Communications Ministry of Communications and Information Technology of the Republic of Yemen. Moreover, performance. A questionnaire was formulated and distributed to the study sample, and data was collected through questionnaires for 150 individuals in some offices of the Yemeni Ministry of Communications. This study uses structural equation model analysis from the Partial Least Squares program through the Smart Plus 4 programs. The study reached a set of results, including that all models show a direct, positive and significant effect of strategic leadership on the quality of service represented by the quality of services in the offices of the Ministry of Communications. As well as the positive relationship between them, as well as the direct and positive impact of performance on the quality of service, as well as the positive and significant relationship between them. While the results indicated a positive and significant indirect effect of strategic leadership on service quality, there is also a positive and significant indirect relationship between strategic leadership on service quality when using performance as an intermediary variable.

To meet the calls of the International Labor Organization and National Institutes of Occupational Safety and Health, this paper discusses how to build Occupational, Health, Safety (OSH), and Well-Being competence by expanding education to non-traditional undergraduate disciplines. The authors provide (1) theoretical background on why this would benefit society as a whole, (2) learning theory strategies for teaching OHS and Well-being outside of traditional majors, (3) case studies of how this can occur in undergraduate classes and (4) opportunities and challenges for the future.

This study delves into the dynamics of relational energy (RE) within organizational context, examining some of its antecedents and decedents. Specifically, it investigates the influence of psychological capital (PsyCap) and humor on RE, and subsequently, the latter’s impact on job performance (JB) mediated by job engagement (JE). A research model based on structural equation modelling carried out with 481 employees in private service industries demonstrates several key relationships. It reveals that both PsyCap and affiliative humor positively affect RE, while aggressive humor exerts a negative influence. Furthermore, RE shows positive association with JE and JP, with JE serving as a mediator. To the authors’ knowledge, this is the first study to present an integrated model encompassing this exact combination of influencers and consequences of RE as well as to be investigated within Western Balkans cultural context. Therefore, it represents a novel approach. Additionally, the research addresses crucial questions regarding the existence and strategic significance of RE within organizational interactions. The findings offer valuable insights for organizations seeking to enhance employee engagement, performance, and wellbeing – even during health crises such as COVID-19 – by fostering RE. The study advances the understanding of RE in organizational settings and provides a foundation for future research in this domain.

This article explores the concept of sustainable leadership in the digital era and the role of technology in promoting environmental sustainability. As the world becomes increasingly interconnected through digital advancements, leaders are facing new challenges and opportunities to address environmental concerns. This article examines the key characteristics of sustainable leadership and discusses how technology can be utilized to promote environmental sustainability. It highlights various technological innovations and strategies that leaders can employ to foster a sustainable organizational culture. Moreover, the article discusses potential barriers and limitations of technology in achieving sustainability goals. Overall, it emphasizes the significance of sustainable leadership and technology integration in addressing environmental challenges in the digital era.

Business school curriculums are designed to improve business skills and a student’s eventual workplace performance. In addition to these business skill sets the emerging business environment demands softer skills associated with ethical decision-making and sustainable business practices. Understanding the key influencers of ethical orientation and attitudes towards the environment is the first critical step for curriculum planning designed to develop both ethical decision-making and environmental sensibilities of students in business schools. Using a bivariate regression analysis (OLS) that compared the established New Ecological Paradigm (NEP) scale and the newly introduced Ethical Orientation Scale (EOS), this study assesses environmental eco-consciousness and ethical orientation over time and across varying socio-demographic variables. The study shows first, that in addition to socio-cultural variables, situational factors influence ethical decision-making. Secondly, it illuminates that ethical orientations as measured by the EOS predicts beliefs about the environment as measured by the NEP scale. It further provides evidence of the ethical underpinnings of the New Ecological Paradigm as well as provides initial validation for the new EOS. These outcomes provide additional levers to assist business educators in the creation of high impact teaching strategies to measure and encourage ethical decision-making and sustainable business practices that protect the environment.

The Rev. Martin Luther King Jr. and Nelson Mandela were two of the world's most iconic civil (political) (human) rights advocates and leaders of all time. Both advocated for, and to varying degrees, applied elements of peaceful protests to the achievement of their goals. Both spent time in jail, often concurrently, but eventually forced their respective countries to extend the same rights that white populations had denied Africans and African Americans. For the US, civil rights, voting rights, right to education, housing and housing loans suggested that equality had been achieved, capped in South Africa by the election of Nelson Mandela as the first majority-rule president, and in the US, by Barack Obama’s election to the presidency. Yet the historical over-policing, police mistreatment and more generally, the judicial system’s inordinate ‘targeting’ of African Americans, with egregious cases running from Emmett Till to Rodney King to Walter Scott to Breonna Taylor to George Floyd to Rayshard Brooks and thousands of others shows the danger of such magical thinking. The now-persistent global wave pursuing human rights, civil rights and the right to be treated equally, primarily driven by the loosely-organized Black Lives Matter (BLM) movement, has become the leading voice in pursuit of equality. Riots such as those in LA, protests in Ferguson and everywhere in summer 2020 has ushered new civil rights campaign. In the US and elsewhere, it has morphed to include historical issues such as monuments to colonialism, the US civil war, slavery and slave owners and traders, institutions, companies and people whose wealth and existence has links to slavery. Instructively, the protests persisted even as COVID-19, the hundred-year plague, continues to ravage the world. Lost in the moment is the absence of central leadership and leaders such as MLK or Mandela. Their charisma and effectiveness has been lacking for 50 years. This paper evaluates whether this has led to inconsistent civil and human rights pursuit for equality, or whether perchance, Mandela and MLK were extraordinary, once-in-a-lifetime transformative leaders uniquely selected by history for their time.

Exploring the spatio-temporal differentiation characteristics and coupling coordination relationship of the composite ecosystem of urban agglomerations is of great significance for promoting the synergistic development and integration construction of urban agglomerations. This paper is based on LUCC data, DEM, temperature, precipitation and other multi-source data, taking the central Yunnan urban agglomeration as an example. The entropy weight method is first used to determine the comprehensive weights to evaluate the regional economic and social development level. Then, the InVEST (Integrated Valuation of Ecosystem Services and Trade-offs)model was used to quantitatively calculate and analyze the spatial and temporal evolution characteristics of the four ecosystem services, including water conservation, soil conservation, carbon sequestration services, and habitat quality. The coupling coordination model was used to quantitatively analyze the evolution of the coupling coordination of the composite ecosystems in the central Yunnan urban agglomeration during the period of 2010-2020, and to reveal its development law. The results show the following: ①During the study period, the socio-economic subsystems in central Yunnan urban agglomeration demonstrated an outward radiative growth from Kunming City, marked by underdeveloped sub-centers and prevalent low-level areas. ②Trends in ecosystem services varied, with water and soil conservation showing fluctuating increases, carbon sequestration remaining stable, and habitat quality declining. The integrated ecosystem services critically important zone is mainly located in the northeastern region and southwestern edge of the study area. ③Economic, social and ecological subsystems are highly coupled, with consistent overall development trends and strong interactions. ④The increase in the degree of harmonization amounted to 7.82%, with lagging subsystems varying in different degree of harmonization subregions. The study can provide a scientific basis for urban agglomerations to formulate scientific and reasonable development policies, promoting regional sustainable development and optimizing the spatial pattern of the national territory.

The paper proposes a game theory model of price oligopoly with a heterogeneous product, where total demand depends linearly on the minimum market price. This model develops the Bertrand oligopoly for the case of imperfect price elasticity of demand. The most interesting result is an asymmetric Nash equilibrium with different prices and sales in the situation of symmetric oligopolists. The asymmetry is explained by the fact that a decrease in the minimum market price leads not only to a reallocation of consumers among firms, but also to an increase in total demand. Modifications of a two-stage game with a leader and followers and the price discrimination model are also considered. Microeconomic substantiation of the model is given on the basis of the spatial differentiation approach.

The time interval description is a natural way to introduce finite intervals, like finite time intervals. This approach depends on results for radiation propagation from star sources, where properties relate to a propagation surface, which is finite for every realistic event and measurement. In contrast the usual vector approach like for Newton’s laws depends on introducing an infinite coordinate system. A time interval only approach necessarily has to start from scratch. Properties for time intervals have to be defined with time intervals. Where the first parts of this paper are devoted to time interval set properties, in the discussion part these are applied to quantities and measurements within astronomy. The introduction provides a survey of results.

Naive CD4+ T cells engage cognate peptide MHC-II complexes (pMHC-IIs) to differentiate and acquire one of several T helper (Th) fates whose specific trajectories are guided by a dynamic cytokine milieu that develops in response to antigenic entity. This physiological process is often erroneously conflated with a pathological one termed Th polarization. Using the SPIRAL model, we argue here that unlike Th fate choice, innate signaling alone is insufficient to initiate Th polarization in naive CD4+ T cells, that it instead develops from pre-existing memory CD4+ T cells that express cross-reactive TCRs, and that it inevitably leads to immunopathology.

Spiritual intelligence had an impact on different biblical leaders, and in this text, we see some cases to serve as a sample (Joseph, Bezalel, and Daniel). In the Bible, this impact is demonstrated in innovations introduced by Joseph in Egypt, Bezalel the manager of the macro project of building in crisis time, Daniel the politician. It is the supreme intelligence and leaders are invited to make a shift from rationality to spirituality. The more leaders of organizations will use spiritual intelligence, the more leaders and followers will experience satisfaction, joy, accomplishment.

Adult mesenchymal stem cells (MSCs) are a promising cell source for tissue regeneration. However, ex vivo expansion results in cell senescence; cells lose their proliferation and differentiation capacity. Fetal MSCs can be an alternative due to their robust proliferation and differentiation capacities as well as immune privilege properties. Given the rejuvenation effect of decellularized extracellular matrix (dECM) on adult MSCs, it remains unknown whether dECM influences the regenerative potential of fetal stem cells. In this study, passage five fetal nucleus pulposus cells (fNPCs) and fetal synovium-derived stem cells (fSDSCs) were expanded on dECMs deposited by fNPCs (NECM) and fSDSCs (SECM) for one passage with expansion on tissue culture plastic (Plastic) as a control. We found that dECM expanded fNPCs and fSDSCs exhibited both similarities and differences in expression of stemness genes and surface markers. Expanded fNPCs yielded more differentiated pellets after chondrogenic induction but no adipogenic differentiation following adipogenic induction in both Plastic and dECM groups than the corresponding fSDSC group. Despite a significant increase in fNPCs, dECM expanded fSDSCs exhibited no increase in chondrogenic potential; however, compared to the Plastic group, dECM expanded fSDSCs exhibited a small increase in osteogenic potential and a great increase in adipogenic potential. These results suggest that fNPCs are more sensitive to NECM rejuvenation for cartilage tissue engineering and regeneration; in contrast, dECMs exhibited limited effects on fSDSC rejuvenation in chondrogenic capacity except for enhanced adipogenic capacity following expansion on SECM.

Hyperplastic dental follicles (HDFs) represent odontogenic hamartomatous lesions originating from pericoronal tissues and are often associated with impacted or embedded teeth. These lesions may occasionally feature unique calcifying bodies, known as calcifying whorled nodules (CWN), characterized by stromal cells arranged in a whorled or spiral fashion. CWNs are typically observed in multiple calcifying hyperplastic dental follicles or regional odontodysplasia. In our study, we examined 40 cases of HDFs, including nine instances with characteristics of CWNs, which were infrequently accompanied by odontodysplasia. Histological examination was conducted on all 40 cases, with immunohistochemical analysis performed on 21 of them. Among the cases with CWN, nine affected a single embedded tooth, with one exception. CWNs exhibited diverse calcifications featuring sparse or entirely deposited psammoma bodies, and some displayed dentinoid formation. Immunohistochemically, stromal cells of HDFs were frequently positive for CD56 and nestin. In contrast, CWNs were negative for CD56 but positive for nestin and HES1, with a few DSP-positive calcified bodies. Our results revealed that hamartomatous calcifying HFDs can impact multiple and single-embedded teeth. CWNs composed of nestin and HES1-positive ectomesenchymal cells demonstrated the potential to differentiate into odontoblasts and contribute to dentin matrix formation under the influence of HES1. This study is the first report documenting odontoblastic differentiation in HDFs.

The evolutionary transition from single-celled to multicellular individuality requires organismal fitness to shift from the cell-level to the cell group. This reorganization of fitness occurs by allocating the two components of fitness, survival and reproduction, between two specialized cell types in the multicellular group – soma and germ, respectively. How does the genetic basis for such fitness reorganization evolve? One possible mechanism is the co-option of life-history genes present in the unicellular ancestors of a multicellular lineage. Single-celled organisms must regulate their investment in survival and reproduction in response to environmental changes, particularly decreasing reproduction to ensure survival when stressed. Such stress response life-history genes can provide the foundation for the genetic basis for cellular differentiation in multicellular lineages. The regA gene family in volvocine green algae provides a model system to study how this co-option occurs. We discuss the origin and evolution of the volvocine regA gene family, including regA – the gene that controls somatic cell development in the model organism Volvox carteri. We hypothesize that the co-option of life history trade-off genes is a general mechanism involved in the transition to multicellular individuality, making volvocine algae and the regA family a useful template for similar investigations in other lineages.

(1) Background: Many malignancies are driven by mutations which affect the gene for fibroblast growth factor receptor (FGFR) 1. Previously we have documented that signal transduction from FOP2–FGFR1 fusion protein in KG1 cells downregulated the expression of vitamin D receptor (VDR) gene. In this paper we investigated if also other FGFRs were responsible for the regulation of the VDR expression. (2) Methods: We used human myeloid leukemia cells U937, and bone cancer cell line U2OS, and cell transfection methods in order to address the above questions. (3) Results: In myeloid leukemia cells overexpression of FGFR 1-4 caused shift to granulocytic differentiation, upregulated expression of VDR, and sensitized these cells to 1,25-dihydroxyvitamin D (1,25D)-induced monocytic differentiation, while in bone cells, signal transduction activated by FGF1 was not responsible for regulation of VDR expression and activity. (4) Conclusions: Since the overexpression of FGFRs occurs in many neoplasms, it may be reasonable to use 1,25D analogs in these cancers, in which overexpression of FGFRs leads to VDR upregulation.

The effective implementation of a sustainable supply chain leadership (SSCL) strategy at each organization’s level, positively impacts on corporation’s competitive advantage and sustainable development. While fears have been acknowledged in previous literature, the benefit of designing Sustainable supply chain models for operational excellence and sustainable development is a noteworthy exploration. The study collected statistical data using an online Survey- monkey questionnaire from 46 of the top 100 JSE-listed companies with the intention to elucidate the large firms’ transition from longstanding linear approaches to sustainable production and consumption to a more circular approach. A bivariate data analysis was used to generate the results in SPSS. The results indicate a positive contribution of SSCL strategy to operational excellence and sustainable development of large corporations if only the entire supply chain system is well-coordinated and implemented. This study makes a vital contribution by proposing a new SSCL model for fast-tracking corporate sustainability and enhancing corporate contributions to sustainable growth.

Retinoids are vitamin A derivatives and include trans-retinoic acid, isotretinoin, tamibarotene, and bexarotene, all of which are currently available for clinical use. The clinical development of retinoid therapy for neuroblastoma has a history spanning more than four decades. The most promising agent is isotretinoin, which can contribute to improving event-free survival in patients with high-risk neuroblastoma by approximately 10 % when administered over six months as maintenance therapy. Although isotretinoin is regarded as an essential component in the standard clinical management of high-risk neuroblastoma, its use for this purpose in the US and EU is off-label. To promote isotretinoin use in Japan as a treatment for neuroblastoma, our clinical research team is planning to launch an investigator-initiated, registration-directed clinical trial. The present review article discusses the basic science behind retinoid therapy, pre-clinical / clinical evidence on neuroblastoma, the concept of the proposed clinical trial, and prospects for this therapy.

In the recent years, tissue engineering researchers have exploited a variety of biomaterials that can potentially mimic extracellular matrix (ECM) for tissue regeneration. Natural cellulose, mainly obtained from bacterial (BC) and plant-based (PC) sources, can serve as a high potential scaffold material for different regenerative purposes. Natural cellulose has drawn the attention of researchers due to its advantage over synthetic cellulose in terms of availability, cost-effectiveness, perfusablility, biocompatibility, negligible toxicity, mild immune response and due to imitating native tissues. In this article, we will review the recent in vivo and in vitro studies aimed to assess the potentials of natural cellulose for the purpose of soft (skin, heart, veins, nerve, among others) and hard (bone and tooth) tissue engineering.

The identification and molecular characterization of cellular hierarchies in complex tissues is key to understanding both normal cellular homeostasis and tumorigenesis. The mammary epithelium is a heterogeneous tissue consisting of two main cellular compartments, an outer basal layer containing myoepithelial cells and an inner luminal layer consisting of estrogen receptor-negative (ER⁻) ductal cells and secretory alveolar cells (in the fully functional differentiated tissue) and hormone-responsive estrogen receptor-positive (ER⁺) cells. Recent publications have used single-cell RNA-sequencing (scRNA-seq) analysis to decipher epithelial cell differentiation hierarchies in human and murine mammary glands, and reported the identification of new cell types and states based on the expression of the luminal progenitor cell marker KIT (c-Kit). These studies allow for comprehensive and unbiased analysis of the different cell types that constitute a heterogeneous tissue. Here we discuss scRNA-seq studies in the context of previous research in which mammary epithelial cell populations were molecularly and functionally characterized, and identified c-Kit⁺ progenitors and cell states analogous to those reported in the recent scRNA-seq studies.

The molecular study of fat cell development in the human body is essential for our understanding of obesity and related diseases. Mesenchymal stem/stromal cells (MSC) are the ideal source to study fat formation as they are the progenitors of adipocytes. In this work, we used human MSCs, received from surgery waste, and differentiate them into fat adipocytes. The combination of several layers of information coming from lipidomics, metabolomics and proteomics enabled comprehensive analysis of the biochemical pathways in adipogenesis. Simultaneous analysis of metabolites, lipids and proteins in cell culture is challenging due to the compound’s chemical difference so that most studies involve separate analysis with unimolecular strategies. In this study, we employed a multimolecular approach using a two–phase extraction to monitor the crosstalk between lipid metabolism and protein-based signaling in a single sample (~105 cells). We developed an innovative analytical workflow including standardization with in-house produced 13C-isotopically labeled compounds, hyphenated high-end mass spectrometry (high-resolution Orbitrap MS) and chromatography (HILIC, RP) for simultaneous untargeted screening and targeted quantification. Metabolite and lipid concentrations ranged over 3-4 orders of magnitude and were detected down to the low fmol (absolute on column) level. Biological validation and data interpretation of the multiomics workflow was performed based on proteomics network reconstruction, metabolic modelling (MetaboAnalyst 4.0) and pathway analysis (OmicsNet). Comparing MSCs and adipocytes, we observed significant regulation of different metabolites and lipids such as triglycerides, gangliosides and carnitine with 113 fully reprogrammed pathways. The observed changes are in accordance with literature findings dealing with adipogenic differentiation of MSC. These results are a proof of principle for the power of multimolecular extraction combined with orthogonal LC-MS assays and network construction. Considering the analytical and biological validation performed in this study, we conclude that the proposed multiomics workflow is ideally suited for comprehensive follow-up studies on adipogenesis and is fit for purpose for different applications.

Proactivity is a particularly important attribute of knowledge-intensive organizations, where the work required to increase the potential of knowledge-intensive employees is crucial. A priority challenge for these firms is also to understand the increasing importance of the functioning of cognitive mechanisms leading to increased knowledge workers' well-being following the implementation of the psychological contract. The aim of this article is to identify the relationship between inclusive leadership, the fulfillment of the psychological contract, two dimensions of well-being: workplace and life well-being and knowledge workers' proactivity. Based on survey data collected through the CAWI method from 1.000 knowledge workers employed in Polish companies in the business services sector, the research hypotheses were tested using a stepwise equation modelling (SEM) technique, leading to a model containing all the main constructs. The results obtained indicate that inclusive leadership positively impacts the fulfillment of the psychological contract. Furthermore, the fulfillment of the psychological contract positively affects proactive working behavior with and the wellbeing of knowledge workers. Along with proactive work behavior, two dimensions of well-being, were examined as outcome variables. The analysis also shows that knowledge-intensive organizations, intending to build the proactivity of their employees and nurture a high level of well-being in their lives and in the workplace, should take care to fulfil the expectations and obligations of the psychological contract. However, one way to achieve this is for managers to use an inclusive management style, which supports an atmosphere of a safe working environment in a diverse setting and leads to employees feeling comfortable sharing their opinions and ideas. The study of inclusive leadership in the context of knowledge-intensive organizations provides human resource professionals and employee man-agers with important insights into how inclusive leadership can effectively contribute to the psychological contract, which will consequently lead to proactive work behavior and also improve employees' workplace and life well-being.

Functional articular cartilage regeneration remains an unmet medical challenge, increasing the interest for innovative biomaterial-based tissue engineering (TE) strategies. Hydrogels, 3D macromolecular networks with hydrophilic groups, present articular cartilage-like features such as high water content and load-bearing capacity. In this study, 3D porous polyethylene glycol diacrylate (PEGDA) hydrogels were fabricated combining the gas foaming technique and an UV-based crosslinking strategy. The 3D porous PEGDA hydrogels were characterized in terms of their physical, structural and mechanical properties. Our results showed that the size of the hydrogels pores can be modulated by varying the initiator concentration. In vitro cytotoxicity tests showed that 3D porous PEGDA hydrogels presented high biocompatibility both with human chondrocytes and osteoblast-like cells. Importantly, the 3D porous PEGDA hydrogels supported the viability and chondrogenic differentiation of human bone marrow-derived mesenchymal stem/stromal cells (hBM-MSCs)-based spheroids as demonstrated by the positive staining of typical cartilage extracellular matrix (ECM) (glycosaminoglycans (GAGs)) and upregulation of chondrogenesis marker genes. Overall, the produced 3D porous PEGDA hydrogels presented cartilage-like mechanical properties and supported MSC-spheroid chondrogenesis, highlighting their potential as suitable scaffolds for cartilage TE or disease modelling strategies.

Teeth include mesenchymal stem cells (MSCs), which are multipotent cells that promote tooth growth and repair. Dental tissues, specifically the dental pulp and the dental bud, constitute a relevant source of multipotent stem cells, known as dental-derived stem cells (d-DSCs): dental pulp stem cells (DPSCs) and dental bud stem cells (DBSCs). Cell treatment with bone-associated factors and stimulation with small molecule compounds are, among the available methods, the ones who show excellent advantages promoting stem cell differentiation and osteogenesis. Recently, attention has been paid to studies on natural and non-natural compounds. Many fruits, vegetables and some drugs contain molecules that can enhance MSC osteogenic differentiation and therefore bone formation. The purpose of this review is to examine research work over the past 7 years that has investigated two different types of MSCs from dental tissues that are attractive targets for bone tissue engineering: DPSCs and DBSCs. We focused on articles hypothesizing the identification and study of compounds that induce proliferation and osteogenic differentiation of the two d-DSC populations, representing an interesting issue for regenerative medicine. The reconstruction of bone defects in fact is still a challenge for personalized medicine.

The aim of this study was to investigate the role of DNA methylation in the regulation of in vitro and in vivo cartilage formation. Based on the data of an RNA chip-assay performed on chondrifying BMP2-overexpressing C3H10T1/2 cells, the relative expression of Tet1 (tet methylcytosine dioxygenase 1), Dnmt3a (DNA methyltransferase 3) and Ogt (O-linked N-acetylglucosamine transferase) genes was examined with RT-qPCR in mouse cell-line based and primary micromass cultures. RNA probes for in situ hybridization were used on frozen sections of 15-day-old mouse embryos. DNA methylation was inhibited with 5-azacytidine during culturing. We found very strong but gradually decreasing expression of Tet1 throughout the entire course of in vitro cartilage differentiation along with strong signals in the cartilaginous embryonic skeleton. Dnmt3a and Ogt expressions did not show significant changes with RT-qPCR and gave weak in situ hybridization signals. Inhibition of DNA methylation applied during early stages of differentiation reduced cartilage-specific gene expression and cartilage formation. In contrast, it had stimulatory effect when added to differentiated chondrocytes. Our results indicate that the DNA demethylation-inducing Tet1 is a significant epigenetic factor of chondrogenesis, and inhibition of DNA methylation exerts distinct effects in different phases of in vitro cartilage formation.

FoxP3 is a transcription factor essential for the differentiation and function of T regulatory cells (Tregs). There are two major subsets of Tregs: natural Tregs (nTregs) generated in thymus and inducible Tregs (iTregs) produced in peripheral immune system. It has been documented that iTreg development is dependent on soluble mediators including interleukin 2 (IL2), transforming growth factor β (TGFβ) and all-trans-retinoic acid (ATRA). In our experiments we performed a gene expression array, followed by Real-time PCR experiments, to study the expression of genes regulated by 1,25-dihydroxyvitamin D (1,25D) or ATRA in cells of myeloid origin. Our experiments revealed that ATRA alone, but also a cocktail of mediators consisting of IL2, TGFβ and ATRA, upregulate the expression of FOXP3 gene in lymphoid cells, but also in normal and leukemic myeloid cells. The FoxP3 expression is followed by a phenotypic changes in cells of myeloid origin. Our results indicate that signaling pathways which are used in the late stages of T cell differentiation, are also active in the cells of myeloid lineage