Search Results (15)

Stem-cell behavior is governed not solely by intrinsic genetic programs but by highly specialized microenvironments—or niches—that integrate structural, biochemical, and mechanical cues to regulate quiescence, self-renewal, and differentiation. This review traces the evolution of stem-cell niche biology from foundational embryological discoveries to its current role as a central determinant in tissue regeneration and disease. We describe the cellular and extracellular matrix architectures that define adult stem-cell niches across diverse organs and dissect conserved signaling axes—including Wnt, BMP, and Notch—that orchestrate lineage commitment. Emphasis is placed on how aging, inflammation, fibrosis, and metabolic stress disrupt niche function, converting supportive environments into autonomous drivers of pathology. We then examine emerging therapeutic strategies that shift the regenerative paradigm from a stem-cell-centric to a niche-centric model. These include stromal targeting (e.g., FAP inhibition), which are engineered scaffolds that replicate native niche mechanics, extracellular vesicles that deliver paracrine cues, and composite constructs that preserve endogenous cell–matrix interactions. Particular attention is given to cardiac, hematopoietic, reproductive, and neurogenic niches, where clinical failures often reflect niche misalignment rather than intrinsic stem-cell deficits. We argue that successful regenerative interventions must treat stem cells and their microenvironment as an inseparable therapeutic unit. Future advances will depend on high-resolution niche mapping, mechanobiologically informed scaffold design, and niche-targeted clinical trials. Re-programming pathological niches may unlock regenerative outcomes that surpass classical cell therapies, marking a new era of microenvironmentally integrated medicine. Full article

(1) Background: The high recurrence rate and individual differences in stress susceptibility contribute to the diverse symptoms of depression, making full recovery and relapse prevention challenging. Emerging evidence suggests that fluctuations in microglial activity are closely linked to depression progression under chronic stress exposure. Changes in the brain microenvironment can elicit microglial priming, enhancing their sensitivity to external stimuli. However, few studies have longitudinally examined how microglial characteristics evolve throughout depression progression. (2) Methods: In this study, we investigated microglial morphological changes and their responses to acute stress at different stages of depression using the chronic unpredictable mild stress (CUMS) paradigm in mice. (3) Results: Our findings reveal that in the dentate gyrus, microglial activation indices, including cell number and morphology, exhibit distinct dynamic patterns depending on CUMS exposure duration. Notably, after 2 and 4 weeks of CUMS exposure followed by acute stress re-exposure, microglia display opposing response patterns. In contrast, after 6 weeks of CUMS exposure, primed microglia exhibit dysfunction, failing to respond to acute stress. Notably, depressive behaviors are not prominent after 2 weeks of CUMS exposure but become more pronounced after 4 and 6 weeks of exposure. Additionally, regardless of CUMS duration, body weight demonstrates an intrinsic capacity to normalize after stress cessation. (4) Conclusions: These findings suggest that microglial priming responses are state-dependent, either enhancing or suppressing secondary stimulus responses, or exceeding physiological limits, thereby preventing further activation. This study provides novel insights into the role of microglial priming in stress vulnerability and its contribution to depression progression. Full article

Post-Traumatic Stress Disorder (PTSD) is a multifaceted psychiatric disorder triggered by traumatic events, leading to prolonged psychological distress and varied symptoms. Rat models have been extensively used to explore the biological, behavioral, and neurochemical underpinnings of PTSD. This review critically examines the strengths and limitations of commonly used rat models, such as single prolonged stress (SPS), stress–re-stress (S-R), and predator-based paradigms, in replicating human PTSD pathology. While these models provide valuable insights into neuroendocrine responses, genetic predispositions, and potential therapeutic targets, they face challenges in capturing the full complexity of PTSD, particularly in terms of ethological relevance and translational validity. We assess the degree to which these models mimic the neurobiological and behavioral aspects of human PTSD, highlighting areas where they succeed and where they fall short. This review also discusses future directions in refining these models to improve their utility for translational research, aiming to bridge the gap between preclinical findings and clinical applications. Full article

Terms such as system crash, collapse of chaos and complexity can help one understand change, also in biological, socio-economic and technical systems. These terms need, however, explanation for fruitful dialogue on design of sustainable systems. We start this paper on Grass Based (GB) systems, therefore, dwelling on these terms and notions as review for the insiders and to help interested ‘outsiders’. We also stress the need to use additional and/or new paradigms for understanding of the nature of nature. However, we show that many such ‘new’ paradigms were known for long time around the globe among philosophers and common men, giving reason to include quotes and examples from other cultures and eras. In the past few centuries, those paradigms have become hidden, perhaps, under impressive but short-term successes of more linear paradigms. Therefore, we list hang-ups on paradigms of those past few centuries. We then outline what is meant by ‘GB systems’, which exist in multiple forms/‘scapes’. Coping with such variation is perhaps the most central aspect of complexity. To help cope with this variation, the different (GB) systems can be arranged on spatial, temporal, and other scales in such a way that the arrangements form logical sequences (evolutions) of stable states and transitions of Complex Adaptive Systems (CAS). Together with other ways to handle complexity, we give examples of such arrangements to illustrate how one can (re-)imagine, (re-)cognize and manage initial chaotic behaviors and eventual ‘collapse’ of chaos into design and/or emergence of new systems. Then, we list known system behaviors, such as predator–prey cycles, adaptive cycles, lock-in, specialization and even tendency to higher (or lower) entropy. All this is needed to understand changes in management of evolving GB into multi-scapes. Integration of disciplines and paradigms indicates that a win-win is likely to be exception rather than rule. With the rules given in this paper, one can reset teaching, research, rural development, and policy agendas in GB-systems and other areas of life. Full article

Nowadays, fossil fuels are used in a clearly unsustainable way that can bring potentially catastrophic consequences. Electricity is currently delivered to end users by generation and energy transmission companies. Previous research shows that the development of modern circular economy sets a need for the re-orientation of socio and economic development of decentralized systems, including energy basis. In addition to being ecological, the use of renewable energy sources also has economic significance by contributing to energy independence. Citizens, industries, local and national authorities become interconnected within emerging novel renewable energy sourcing communities, through which they establish trade of energy and, most importantly, models of investing and reshaping the distribution of renewable energy. The modern portfolio management of renewable energy networking is aiming toward decentralized systems of trade, where the consumer becomes a producer (prosumer) within the network, itself managed by users. Excess energy produced in the micro-grid nets within the over-arching national and transnational energy grid should be accounted for and managed with blockchain technology for financial and structural security. The decentralization of the energy market requires the establishment of strict norms that will regulate the market and taxation of profits arising. The extensive literature review on blockchain in the energy sector reflects a very pragmatic and narrow approach to the topic, although it is evident that the distribution of energy within the blockchain would enable economic development through reducing cost and ensuring more secure energy trade. Blockchain technology embeds the related digital codes, in which information will be visible to all, but also secured from hacking and duplicating. However, there are challenges to this paradigm, not least the energy consumption of the extensive nodal mesh required to perform the necessary protocols. This paper aims to provide an overview of the application of blockchain technology and the need for the development of the regulatory system and of potential solutions to the challenges posed. By undertaking an energy consumption analysis of blockchain implementation from first electronic principles, which has not been constructed before in the literature, this paper’s conclusion stresses the future demand for reducing energy consumption and considers the latest findings in the quantum coupling of light signals as a potential for solving the enormous ledger duplication structure problem. Full article

Poly(ADP-ribose) polymerase 1 (PARP1), as a potential target for the experimental therapy of acute lung injury (ALI), was identified over 20 years ago. However, clinical translation of this concept was not possible due to the lack of clinically useful PARP inhibitors. With the clinical introduction of several novel, ultrapotent PARP inhibitors, the concept of PARP inhibitor repurposing has re-emerged. Here, we evaluated the effect of 5 clinical-stage PARP inhibitors in oxidatively stressed cultured human epithelial cells and monocytes in vitro and demonstrated that all inhibitors (1–30 µM) provide a comparable degree of cytoprotection. Subsequent in vivo studies using a murine model of ALI compared the efficacy of olaparib and rucaparib. Both inhibitors (1–10 mg/kg) provided beneficial effects against lung extravasation and pro-inflammatory mediator production—both in pre- and post-treatment paradigms. The underlying mechanisms include protection against cell dysfunction/necrosis, inhibition of NF-kB and caspase 3 activation, suppression of the NLRP3 inflammasome, and the modulation of pro-inflammatory mediators. Importantly, the efficacy of PARP inhibitors was demonstrated without any potentiation of DNA damage, at least as assessed by the TUNEL method. These results support the concept that clinically approved PARP inhibitors may be repurposable for the experimental therapy of ALI. Full article

The oil and gas industry has shifted paradigms after seeing the drastic decrease in oil prices since 2015. Companies are now focused as much on cost reduction as much as production maximization to drive profitable operations. This aspect is more prevalent in unconventional plays with the need for long horizontal drilling and hydraulic fracturing (HF) operations to develop and produce from the tight reservoirs. There exists an optimum point between the costs of HF treatment and the expected production. Because of the paradigm shift, many operators are now focused on re-developing existing assets at much lower costs instead of developing newer, more costly assets. Re-fracturing existing wells provides an opportunity for companies to add economical wells to their portfolio. Re-fracturing consists of pumping HF treatments in wells that were previously drilled and completed. Although it may seem that the HF process on a well would be easier the second time around, this is not always the case. There are often numerous operational and engineering parameters that may cause screen outs due to excessively high surface treating pressure (STP) that can drastically affect the economics of a re-fractured well. Being able to isolate the effects of these parameters and estimate their marginal effect on treatment will help engineers design to better HF treatments and surface equipment to effectively implement treatments in the field. This novel study uses field treatment data from re-fractured wells to create dynamic multivariate regression models to characterize the effects of treatment parameters on the average STP. The model allows for engineers to isolate the effects of other treatment parameters and estimate their marginal effects on average STP by holding other variables of interest constant. The model also attempts to account for the temporal dependence of stress shadow effects from the previous zones by using the average STP as a good approximation. It was found that the distance between zones (perforation standoff) was statistically significant at the 90% level, average pump rate, acid volume displaced, and the presence of a 3.5” liner were all statistically significant predictors of average STP at the 95% level and average surface treating pressure from the previous stage at 99% significance. The model was used to predict the STP for another re-fractured well, which showed reasonable results. Full article

Helicobacter pylori (H. pylori) expresses the serine protease and chaperone High temperature requirement A (HtrA) that is involved in periplasmic unfolded protein stress response. Additionally, H. pylori-secreted HtrA directly cleaves the human cell adhesion molecule E-cadherin leading to a local disruption of intercellular adhesions during pathogenesis. HtrA-mediated E-cadherin cleavage has been observed in response to a broad range of pathogens, implying that it is a prevalent mechanism in humans. However, less is known whether E-cadherin orthologues serve as substrates for bacterial HtrA. Here, we compared HtrA-mediated cleavage of human E-cadherin with murine, canine, and simian E-cadherin in vitro and during bacterial infection. We found that HtrA targeted mouse and dog E-cadherin equally well, whereas macaque E-cadherin was less fragmented in vitro. We stably re-expressed orthologous E-cadherin (Cdh1) in a CRISPR/Cas9-mediated cdh1 knockout cell line to investigate E-cadherin shedding upon infection using H. pylori wildtype, an isogenic htrA deletion mutant, or complemented mutants as bacterial paradigms. In Western blot analyses and super-resolution microscopy, we demonstrated that H. pylori efficiently cleaved E-cadherin orthologues in an HtrA-dependent manner. These data extend previous knowledge to HtrA-mediated E-cadherin release in mammals, which may shed new light on bacterial infections in non-human organisms. Full article

The metabolic perturbations caused by competitive rugby are not well characterized. Our aim is to utilize untargeted metabolomics to develop appropriate interventions, based on the metabolic fluctuations that occur in response to this collision-based team sport. Seven members of an English Premiership rugby squad consented to provide blood, urine, and saliva samples daily, over a competitive week including gameday (GD), with physical demands and dietary intake also recorded. Sample collection, processing and statistical analysis were performed in accordance with best practice set out by the metabolomics standards initiative employing 700 MHz NMR spectroscopy. Univariate and multivariate statistical analysis were employed to reveal the acute energy needs of this high intensity sport are met via glycolysis, the TCA cycle and gluconeogenesis. The recovery period after cessation of match play and prior to training recommencing sees a re-entry to gluconeogenesis, coupled with markers of oxidative stress, structural protein degradation, and reduced fatty acid metabolism. This novel insight leads us to propose that effective recovery from muscle damaging collisions is dependent upon the availability of glucose. An adjustment in the periodisation of carbohydrate to increase GD+1 provision may prevent the oxidation of amino acids which may also be crucial to allay markers of structural tissue degradation. Should we expand the ‘Fuel for the work required’ paradigm in collision-based team sports to include ‘Fuel for the damage induced’? Full article

Current acceleration in digital practices, unexpected challenges in our social and spatial interactions, and sudden limitations in our physical spaces, mark unpredictable changes in our old normal. A different normal—as generated nowadays from the global pandemic 2020—is setting out, indeed, a mixed physical/virtual framework of the modification humanity is undertaking in being pushed into a new “digital age”; or better, as many scholars are saying, into the New Normal. A new normal in which the balance between physical and virtual interactions became in vantage of the second one in just one year, by increasing, at the same time, both the quantity and the quality of exchanging digital data. It is drafted a bi-dimensional enlarging that re-calls and stresses moreover the value of certain qualitative multi-data-based analyses aimed in reading the people’s common-sense to extrapolate wishes and needs within their daily lives; as the sentiment analysis applied to the urban planning processes wants to do. In synthesis, the bigger number of qualitative data coming from the web (from Socials mainly) became more affordable and more reliable (due to the new larger number of digital flows) in shaping new ways for a more effective public participation within the conventional planning process. In the pages of this article authors, through different but shared viewpoints, propose a possible answer to the topic of a new “Governance 3.0” addressing the attempt of a change of those consolidated paradigms within which the spatial dimension—in which we live and we act day by day—is shaped through planning processes consolidate over the years. Analyzing the relationship between Technocracy and Democracy, as defined by Khanna, it is argued that it is possible to realize new forecasts and to acquire a more democratic and participatory (inclusive) dimension of Governance, thanks to new digital technologies by exploring the general unconscious “feeling” of people, through anonymous data collection from Socials and similar platforms and without any direct or indirect interference with it. The Sentiment Analysis can “define automatic tools able to extract subjective information from texts in natural languages, such as opinions and sentiments, in order to create structured and actionable knowledge to be used by either a decision-support system or a decision-maker. Full article

The new paradigm of sustainable development highlights the importance of enforcing defined boundaries between economies, societies, and the environment within a system. Sustainability indicators are tools that have proven to be a successful aid in defining and creating system boundaries. This paper focuses on the development of sustainability indicators for Arctic tourism, with a special emphasis on the role of public participation in their determination. It presents a stakeholder-centric approach to indicator selection by developing a framework that effectively integrates public participation in the processes of indicators’ selection and designation, and highlights the importance of combining local and expert knowledge in these processes. The results reveal that the making of sustainability indicators is an ideal platform for local voices to be heard, and thus to have a significant stake in the overall process of tourism development. The most effective way to make their voices heard in the final decision-making process is via their evaluation of the adaptability and prioritization of these indicators. The results, furthermore, stress that sustainability indicators need to be constantly re-evaluated and updated, as tourism is part of a complex and dynamic system that is constantly changing. To provide a holistic vision of the impact of economic, environmental, and social factors, as well as the causality between them in the system, sustainability indicators must be integrated from many indicators. Since the monitoring of conventional indicators is often less complicated and more cost-effective than the monitoring of integrated indicators, a better result can however be reached by combining conventional indicators with sustainability indicators. Full article

This study was conducted to compare the effects of acute hyperthermia (45 °C for 4 h) on the viability, proliferation, and migratory activity through wound-healing assays of cow and sheep fibroblasts. The study examined the effects on primary cultures and first passage skin-derived fibroblasts. Relative quantification of HSP70, HSP90, P53, BAX, BCL2, and BECN1 was investigated after normalization to housekeeping genes GAPDH and beta-actin. The results revealed that cultured cow primary fibroblasts exhibited increased viability and reinitiated cell migration to close the cell monolayer scratch earlier than sheep cells. Similar patterns were observed in the first passage fibroblasts, with severe effects on sheep cells. Both cow and sheep cells exhibited decreased cell viability and failed to regain migratory activity after re-exposure of recovered heat-shocked cells. Effects of hyperthermia on sheep cells were potentiated by cell cryopreservation. The qPCR results showed that cow cells significantly increased HSP70 and HSP90 expression, which decreased the elevation of P53, and ameliorated the effects of the increased BAX/BCL2 ratio. The results provide a paradigm to compare thermotolerance among different animal species and revealed that trypsin could be an additional stress, which potentiates the effects of heat shock in in vitro experiments. Full article

This paper examines two sets of interrelated issues informing contemporary discussions on Islam and education that take place within both Muslim majority and minority contexts. The first set of issues concerns the academic conceptualisation of the study of education within diverse historical and contemporary Islamic cultural, intellectual, political, theological and spiritual traditions. After a critical examination of the current literature, the paper suggests that ‘Islamic Education Studies’ offers a distinctive academic framing that incorporates an interdisciplinary empirical and scholarly inquiry strategy capable of generating a body of knowledge and understanding guiding the professional practice and policy development in the field. Lack of conceptual clarity in various current depictions of the field, including ‘Muslim Education’, ‘Islamic Pedagogy’, ‘Islamic Nurture’ and ‘Islamic Religious Pedagogy’, is outlined and the frequent confusion of Islamic Education with Islamic Studies is critiqued. The field of Islamic Education Studies has theological and educational foundations and integrates interdisciplinary methodological designs in Social Sciences and Humanities. The second part of the inquiry draws attention to the lack of new theoretical insights and critical perspectives in Islamic Education. The pedagogic practice in diverse Muslim formal and informal educational settings does not show much variation and mostly is engaged with re-inscribing the existing power relations shaping the society. The juxtaposition of inherited Islamic and borrowed or enforced Western secular educational cultures appears to be largely forming mutually exclusive, antagonistic and often rigid ‘foreclosed’ minds within contemporary Muslim societies. The impact of the educational culture and educational institutions on the formation of resentful Islamic religiosities and the reproduction of authoritarian leadership within the wider mainstream Muslim communities have not been adequately explored. The study stresses the need to have a paradigm shift in addressing this widely acknowledged educational crisis. The formation of a transformative educational culture remains the key to being able to facilitate reflective and critical Muslim religiosities, and positive socio-economic and political change in Muslim majority and minority societies. This inquiry explores a significant aspect of this crisis by re-examining the degree to which Islamic and Western, liberal, secular conceptions and values of education remain irreconcilably divergent or open to a convergent dialogue of exchange, reciprocity and complementarity. The originality of the paper lies in offering a critical rethinking of Islamic Education through mapping the main relevant literature and identifying and engaging with the central theoretical issues while suggesting a new academic framing of the field and its interdisciplinary research agenda. Full article

Nutritional status provides metabolic substrates to activate AMP-Activated Protein Kinase (AMPK), the energy sensor that regulates metabolism. Recent evidence has demonstrated that AMPK has wider functions with respect to regulating immune cell metabolism and function. One such example is the regulatory role that AMPK has on NLRP3-inlflammasome and IL-1β biology. This in turn can result in subsequent negative downstream effects on glucose, lipid and insulin metabolism. Nutrient stress in the form of obesity can impact AMPK and whole-body metabolism, leading to complications such as type 2 diabetes and cancer risk. There is a lack of data regarding the nature and extent that nutrient status has on AMPK and metabolic-inflammation. However, emerging work elucidates to a direct role of individual nutrients on AMPK and metabolic-inflammation, as a possible means of modulating AMPK activity. The posit being to use such nutritional agents to re-configure metabolic-inflammation towards more oxidative phosphorylation and promote the resolution of inflammation. The complex paradigm will be discussed within the context of if/how dietary components, nutrients including fatty acids and non-nutrient food components, such as resveratrol, berberine, curcumin and the flavonoid genistein, modulate AMPK dependent processes relating to inflammation and metabolism. Full article

Sudden unexpected death in epilepsy (SUDEP) is the major cause of death in those patients suffering from refractory epilepsy (RE), with a 24-fold higher risk relative to the normal population. SUDEP risk increases with seizure frequency and/or seizure-duration as in RE and Status Epilepticus (SE). P-glycoprotein (P-gp), the product of the multidrug resistant ABCB1-MDR-1 gene, is a detoxifying pump that extrudes drugs out of the cells and can confer pharmacoresistance to the expressing cells. Neurons and cardiomyocytes normally do not express P-gp, however, it is overexpressed in the brain of patients or in experimental models of RE and SE. P-gp was also detected after brain or cardiac hypoxia. We have previously demonstrated that repetitive pentylenetetrazole (PTZ)-induced seizures increase P-gp expression in the brain, which is associated with membrane depolarization in the hippocampus, and in the heart, which is associated with fatal SE. SE can produce hypoxic-ischemic altered cardiac rhythm (HIACR) and severe arrhythmias, and both are related with SUDEP. Here, we investigate whether SE induces the expression of hypoxia-inducible transcription factor (HIF)-1α and P-gp in cardiomyocytes, which is associated with altered heart rhythm, and if these changes are related with the spontaneous death rate. SE was induced in Wistar rats once a week for 3 weeks, by lithium-pilocarpine-paradigm. Electrocardiograms, HIF-1α, and P-gp expression in cardiomyocytes, were evaluated in basal conditions and 72 h after SE. All spontaneous deaths occurred 48 h after each SE was registered. We observed that repeated SE induced HIF-1α and P-gp expression in cardiomyocytes, electrocardiographic (ECG) changes, and a high rate of spontaneous death. Our results suggest that the highly accumulated burden of convulsive stress results in a hypoxic heart insult, where P-gp expression may play a depolarizing role in cardiomyocyte membranes and in the development of the ECG changes, such as QT interval prolongation, that could be related with SUDEP. We postulate that this mechanism could explain, in part, the higher SUDEP risk in patients with RE or SE. Full article