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In today’s world of ‘Asianisation’ whereby the countries of Asia are reinventing their historical linkages and asserting their combined power on the world stage, an understanding of the cultures of neighbours and how reciprocal cultural linkages can contribute to enhance cooperation among the countries assumes importance. India shares a long history of cultural and commercial contacts with the region of Southeast Asia including Thailand date back to the very early centuries of the Common Era, perhaps even earlier. India’s interaction with this region in terms of history, culture and religion has been unique, deep, rich and apparently visible even today. Since time immemorial, the Bay of Bengal has been a highway of communication between the two regions bringing closer the cultures, economies and the people of both sides. Culture, along with commerce, contributed to exchange of ideas and knowledge between the two regions. The people of this land became so responsive to the Indian cultural elements that they imbibed and well adapted these to the native environmental conditions. Through contact and interaction, Indian cultural influence slowly and gradually penetrated into the local pattern of life in Southeast Asia. This peaceful penetration of Indian culture was carried out by traders, Brahmin priests, Buddhist monks, scholars and adventurers all along the maritime trade routes. The notable feature of this early interaction is that, the native people of Southeast Asia did not follow Indian cultural traits blindly. They absorbed only those Indian cultural elements into their indigenous cultural patterns which were either consisted with or could be shaped to their own beliefs and necessities. The process of Indian cultural influence never eradicated indigenous foundation of their society and culture. Moreover, it has been a mutual learning process in which both sides learned many things from each other. In order to understand and comprehend the processes responsible for such deep cultural interactions, Thailand has been chosen as a case study, owing to its geographical and historical proximity. India and Thailand located in each other’s extended neighbourhood and share a unique cultural linkage with the great Indian Emperor Ashoka, sending Buddhist missionaries to Thailand and thus making it one of the major religions in Thailand and the rest of Southeast Asia. A notable feature of this time-honoured cultural interaction is that it has been entirely peaceful and having no political ambitions. In modern times, the civilisational linkages constitute a special asset for the further development of multifaceted relationship between the two countries. The shared cultural heritage helps both the countries to understand and confront contemporary challenges. This article attempts to study the cultural dimensions of India’s multifaceted interaction with Thailand in the historical context. It argues that history and culture are central to any understanding of prospective Indo-Thai relations, and therefore, should be harnessed and promoted as a foreign policy tool to take the bilateral relations to the next level.

Human multipotent mesenchymal stromal cells (hMSCs) are currently developed as cell therapeutics for different applications, including regenerative medicine, immune modulation, and cancer treatment. The biological properties of hMSCs can be further modulated by genetic engineering. Viral vectors based on human adenovirus type 5 (HAdV-5) belong to the most frequently used vector types for genetic modification of human cells in vitro and in vivo. However, due to a lack of the primary attachment receptor coxsackievirus and adenovirus receptor (CAR) in hMSCs, HAdV-5 vectors are currently not suitable for transduction of this cell type without capsid modification. Here we present several transduction enhancers that strongly enhance HAdV-5-mediated gene transfer into both bone marrow- and adipose tissue-derived hMSCs. Polybrene, poly-l-lysine, human lactoferrin, human blood coagulation factor X, spermine, and spermidine enabled high eGFP expression levels in hMSCs. Importantly, hMSCs treated with enhancers were not affected in their migration behavior, which is a key requisite for many therapeutic applications. Exemplary, strongly increased expression of tumor necrosis factor (TNF)-stimulated gene 6 (TSG-6) (a secreted model therapeutic protein) was achieved by enhancer-facilitated HAdV-5 transduction. Thus, enhancer-mediated HAdV-5 vector transduction is a valuable method for the engineering of hMSCs, which can be further exploited for the development of innovative hMSC therapeutics., publishedVersion

Fibroblasts residing in the connective tissues constitute the stem cell niche, particularly in organs such as skin. Although the effect of fibroblasts on stem cell niches and organ aging is an emerging concept, the underlying mechanisms are largely unresolved. We report a mechanism of redox-dependent activation of transcription factor JunB, which, through concomitant upregulation of p16INK4A and repression of insulin growth factor-1 (IGF-1), initiates the installment of fibroblast senescence. Fibroblast senescence profoundly disrupts the metabolic and structural niche, and its essential interactions with different stem cells thus enforces depletion of stem cells pools and skin tissue decline. In fact, silencing of JunB in a fibroblast-niche-specific manner-by reinstatement of IGF-1 and p16 levels-restores skin stem cell pools and overall skin tissue integrity. Here, we report a role of JunB in the control of connective tissue niche and identified targets to combat skin aging and associated pathologies.

Severe angiopathy is a major driver for diabetes associated secondary complications. Knowledge on underlying mechanisms essential for advanced therapies to attenuate these pathologies is limited. Injection of ABCB5+ stromal precursors (SPs) at the edge of non-healing diabetic wounds in a murine db/db model, closely mirroring human type II diabetes, profoundly accelerates wound closure. Strikingly, enhanced angiogenesis was substantially enforced by the release of the ribonuclease angiogenin from ABCB5+ SPs. This compensates for the profoundly reduced angiogenin expression in non-treated murine chronic diabetic wounds. Silencing of angiogenin in ABCB5+ SPs prior to injection significantly reduced angiogenesis and delayed wound closure in diabetic db/db mice implying an unprecedented key role for angiogenin in tissue regeneration in diabetes. These data hold significant promise for further refining SPs-based therapies of non-healing diabetic foot ulcers and other pathologies with impaired angiogenesis.

Mutations in the CD18 gene encoding the common β‐chain of β2 integrins result in impaired wound healing in humans and mice suffering from leukocyte adhesion deficiency syndrome type 1 (LAD1). Transplantation of adipose tissue‐derived mesenchymal stem cells (MSCs) restores normal healing of CD18−/− wounds by restoring the decreased TGF‐β1 concentrations. TGF‐β1 released from MSCs leads to enhanced myofibroblast differentiation, wound contraction, and vessel formation. We uncover that MSCs are equipped with a sensing mechanism for TGF‐β1 concentrations at wound sites. Low TGF‐β1 concentrations as occurring in CD18−/− wounds induce TGF‐β1 release from MSCs, whereas high TGF‐β1 concentrations suppress TGF‐β1 production. This regulation depends on TGF‐β receptor sensing and is relayed to microRNA‐21 (miR‐21), which subsequently suppresses the translation of Smad7, the negative regulator of TGF‐β1 signaling. Inactivation of TGF‐β receptor, or overexpression or silencing of miR‐21 or Smad7, abrogates TGF‐β1 sensing, and thus prevents the adaptive MSC responses required for tissue repair., Mesenchymal stem cells accelerate wound healing in CD18−/− mice by releasing TGF‐β1 in an environmental‐adaptive manner. The sensing of environmental TGF‐β1 level is mediated by TGF‐β receptor/microRNA‐21/Smad7 signaling.

Increased concentrations of reactive oxygen species (ROS) originating from dysfunctional mitochondria contribute to diverse aging-related degenerative disorders. But so far little is known about the impact of distinct ROS on metabolism and fate of stromal precursor cells. Here, we demonstrate that an increase in superoxide anion radicals due to superoxide dismutase 2 (Sod2) deficiency in stromal precursor cells suppress osteogenic and adipogenic differentiation through fundamental changes in the global metabolite landscape. Our data identify impairment of the pyruvate and l-glutamine metabolism causing toxic accumulation of alpha-ketoglutarate in the Sod2-deficient and intrinsically aged stromal precursor cells as a major cause for their reduced lineage differentiation. Alpha-ketoglutarate accumulation led to enhanced nucleocytoplasmic vacuolation and chromatin condensation-mediated cell death in Sod2-deficient stromal precursor cells as a consequence of DNA damage, Hif-1α instability, and reduced histone H3 (Lys27) acetylation. These findings hold promise for prevention and treatment of mitochondrial disorders commonly associated with aged individuals.

We here address the question whether the unique capacity of mesenchymal stem cells to re‐establish tissue homeostasis depends on their potential to sense pathogen‐associated molecular pattern and, in consequence, mount an adaptive response in the interest of tissue repair. After injection of MSCs primed with the bacterial wall component LPS into murine wounds, an unexpected acceleration of healing occurs, clearly exceeding that of non‐primed MSCs. This correlates with a fundamental reprogramming of the transcriptome in LPS‐treated MSCs as deduced from RNAseq analysis and its validation. A network of genes mediating the adaptive response through the Toll‐like receptor 4 (TLR4) pathway responsible for neutrophil and macrophage recruitment and their activation profoundly contributes to enhanced wound healing. In fact, injection of LPS‐primed MSCs silenced for TLR4 fails to accelerate wound healing. These unprecedented findings hold substantial promise to refine current MSC‐based therapies for difficult‐to‐treat wounds., Mesenchymal stem cells sense and shape their neighbourhood, accelerating tissue repair when injected into wounds. Exposure to LPS results in a profound transcriptomic shift in MSCs towards a multifaceted anti‐microbial defence and rapid wound closure.

Background The occurrence of chronic wounds, account for significant suffering of diabetic people, together with increasing healthcare burden. The chronic wounds associated with diabetes do not undergo the normal healing process rather stagnate into chronic proinflammatory phase as well as declined fibroblast function and impaired cell migration. Hypothesis SIRT1, which is the most studied isoform of the sirtuin family in mammals, has now emerged as a crucial target for improving diabetic wound healing. It is an NAD+ dependent deacetylase, originally characterized to deacetylate histone proteins leading to heterochromatin formation and gene silencing. It is now known to regulate a number of cellular processes like cell proliferation, division, senescence, apoptosis, DNA repair, and metabolism. Methodology The retrieval of potentially relevant studies was done by systematically searching of three databases (Google Scholar, Web of science and PubMed) in December 2019. The keywords used as search terms were related to SIRT1 and wound healing. The systematic search retrieved 649 papers that were potentially relevant and after selection procedure, 73 studies were included this review and discussed below. Results Many SIRT1 activating compounds (SACs) were found protective and improve diabetic wound healing through regulation of inflammation, cell migration, oxidative stress response and formation of granulation tissue at the wound site. Conclusions However, contradictory reports describe the opposing role of SACs on the regulation of cell migration and cancer incidence. SACs are therefore subjected to intense research for understanding the mechanisms responsible for controlling cell migration and therefore possess prospective to enter the clinical arena in the foreseeable future.

In this study, we report the beneficial effects of a newly identified dermal cell subpopulation expressing the ATP-binding cassette subfamily B member 5 (ABCB5) for the therapy of nonhealing wounds. Local administration of dermal ABCB5+-derived mesenchymal stem cells (MSCs) attenuated macrophage-dominated inflammation and thereby accelerated healing of full-thickness excisional wounds in the iron-overload mouse model mimicking the nonhealing state of human venous leg ulcers. The observed beneficial effects were due to interleukin-1 receptor antagonist (IL-1RA) secreted by ABCB5+-derived MSCs, which dampened inflammation and shifted the prevalence of unrestrained proinflammatory M1 macrophages toward repair promoting anti-inflammatory M2 macrophages at the wound site. The beneficial anti-inflammatory effect of IL-1RA released from ABCB5+-derived MSCs on human wound macrophages was conserved in humanized NOD-scid IL2rγnull mice. In conclusion, human dermal ABCB5+ cells represent a novel, easily accessible, and marker-enriched source of MSCs, which holds substantial promise to successfully treat chronic nonhealing wounds in humans. Stem Cells 2019;37:1057–1074

We here investigated whether the unique capacity of mesenchymal stem cells (MSCs) to re-establish tissue homeostasis depends on their potential to sense danger associated molecular pattern (DAMP) and to mount an adaptive response in the interest of tissue repair. Unexpectedly, after injection of MSCs which had been pretreated with the calcium-binding DAMP protein S100A8/A9 into murine full-thickness wounds, we observed a significant acceleration of healing even exceeding that of non-treated MSCs. This correlates with a fundamental reprogramming of the transcriptome in S100A8/A9 treated MSCs as deduced from RNA-seq analysis and its validation. A network of genes involved in proteolysis, macrophage phagocytosis, and inflammation control profoundly contribute to the clean-up of the wound site. In parallel, miR582-5p and genes boosting energy and encoding specific extracellular matrix proteins are reminiscent of scar-reduced tissue repair. This unprecedented finding holds substantial promise to refine current MSC-based therapies for difficult-to-treat wounds and fibrotic conditions.

Chronic wounds pose a stern challenge to health care systems with growing incidence especially in the aged population. In the presence of increased iron concentrations, recruitment of monocytes from the circulation and activation towards ROS and RNS releasing M1 macrophages together with the persistence of senescent fibroblasts at the wound site are significantly enhanced. This unrestrained activation of pro-inflammatory macrophages and senescent fibroblasts has increasingly been acknowledged as main driver causing non-healing wounds. In a metaphor, macrophages act like stage directors of wound healing, resident fibroblasts constitute main actors and increased iron concentrations are decisive parts of the libretto, and ��� if dysregulated ��� are responsible for the development of non-healing wounds. This review will focus on recent cellular and molecular findings from chronic venous leg ulcers and diabetic non-healing wounds both constituting the most common pathologies often resulting in limb amputations of patients. This not only causes tremendous suffering and loss of life quality, but is also associated with an increase in mortality and a major socio-economic burden. Despite recent advances, the underlying molecular mechanisms are not completely understood. Overwhelming evidence shows that reactive oxygen species and the transition metal and trace element iron at pathological concentrations are crucially involved in a complex interplay between cells of different histogenetic origin and their extracellular niche environment. This interplay depends on a variety of cellular, non-cellular biochemical and cell biological mechanisms. Here, we will highlight recent progress in the field of iron-dependent regulation of macrophages and fibroblasts and related pathologies linked to non-healing chronic wounds., publishedVersion

This work develops a methodology for human error identification and prioritization.HTA and SHERPA have been used for human error analysis.Experts' linguistic input w.r.t risk parameters is modeled using fuzzy logic.Fuzzy VIKOR method has been used for risk prioritisation purpose.This work will help in safety critical resource allocation strategy development. Human error identification and subsequent prioritization are the foremost tasks involved in HRA. In this study a methodology is developed for performing these tasks with an application to overhead crane operations. The application of the present methodology will help to understand how the risk associated with the human errors propagates through different hierarchy levels. The methodology provides a framework for quantifying the risk of different human errors using the experts' subjective opinions only. The incorporation of fuzzy VIKOR technique enables us develop a ranking mechanism for the failure modes where the individual constituent components are non-commensurable in nature. The developed ranking mechanism helps the decision makers in optimal allocation of safety critical resources, used for risk mitigation purposes.

Being a powerful tool in modelling industrial and service operations, Petri net (PN) has been extremely used in different domains, but its application in safety study is limited. In this study, we model the gantry crane operations used for industrial activities using generalized stochastic PNs. The complete cycle of operations of the gantry crane is split into three parts namely inspection and loading, movement of load, and unloading of load. PN models are developed for all three parts and the whole system as well. The developed PN models have captured the safety issues through reachability tree. The hazardous states are identified and how they ultimately lead to some unwanted accidents is demonstrated. The possibility of falling of load and failure of hook, sling, attachment and hoist rope are identified. Possible suggestions based on the study are presented for redesign of the system. For example, mechanical stoppage of operations in case of loosely connected load, and warning system for use of wrong buttons is tested using modified models.

Cells and tissues are exposed to stress from numerous sources. Senescence is a protective mechanism that prevents malignant tissue changes and constitutes a fundamental mechanism of aging. It can be accompanied by a senescence associated secretory phenotype (SASP) that causes chronic inflammation. We present a Boolean network model-based gene regulatory network of the SASP, incorporating published gene interaction data. The simulation results describe current biological knowledge. The model predicts different in-silico knockouts that prevent key SASP-mediators, IL-6 and IL-8, from getting activated upon DNA damage. The NF-κB Essential Modulator (NEMO) was the most promising in-silico knockout candidate and we were able to show its importance in the inhibition of IL-6 and IL-8 following DNA-damage in murine dermal fibroblasts in-vitro. We strengthen the speculated regulator function of the NF-κB signaling pathway in the onset and maintenance of the SASP using in-silico and in-vitro approaches. We were able to mechanistically show, that DNA damage mediated SASP triggering of IL-6 and IL-8 is mainly relayed through NF-κB, giving access to possible therapy targets for SASP-accompanied diseases., Author summary The senescence associated secretory phenotype is developed by cells undergoing permanent cell cycle arrest. This phenotype is characterized by the secretion of a variety of factors that facilitate tissue breakdown and inflammation and is therefore theorized to, in part, be causal for aging and age-related diseases. In recent years the SASP has been implicated in a variety of chronic inflammatory diseases. Due to these advances, it is imperative to better understand the dynamics of this cellular phenotype and to find ways to disrupt it. We have developed a Boolean network incorporating the major signaling pathways of the SASP that allows us to specifically investigate interactions of the pathways and genes involved. We validated our model by reliably reproducing published data on the SASP. We utilized our model to uncover components that directly control the detrimental effects of the senescence associated secretory phenotype that are largely caused by IL-6 and IL-8, two major factors of the SASP in establishing and spreading senescence as well as causing local inflammation. In subsequent in-vitro experiments, we were able to verify our computational results and could suggest NEMO as one potential target for therapy of SASP-related diseases.

PGC-1α is a versatile inducer of mitochondrial biogenesis and responsive to the changing energy demands of the cell. As mitochondrial ATP production requires proteins that derive from translation products of cytosolic ribosomes, we asked whether PGC-1α directly takes part in ribosomal biogenesis. Here, we show that a fraction of cellular PGC-1α localizes to the nucleolus, the site of ribosomal transcription by RNA polymerase I. Upon activation PGC-1α associates with the ribosomal DNA and boosts recruitment of RNA polymerase I and UBF to the rDNA promoter. This induces RNA polymerase I transcription under different stress conditions in cell culture and mouse models as well as in healthy humans and is impaired already in early stages of human Huntington’s disease. This novel molecular link between ribosomal and mitochondrial biogenesis helps to explain sarcopenia and cachexia in diseases of neurodegenerative origin.

The evolutionarily conserved IGF-1 signalling pathway is associated with longevity, metabolism, tissue homeostasis, and cancer progression. Its regulation relies on the delicate balance between activating kinases and suppressing phosphatases and is still not very well understood. We report here that IGF-1 signalling in vitro and in a murine ageing model in vivo is suppressed in response to accumulation of superoxide anions (O2∙-) in mitochondria, either by chemical inhibition of complex I or by genetic silencing of O2∙--dismutating mitochondrial Sod2. The O2∙--dependent suppression of IGF-1 signalling resulted in decreased proliferation of murine dermal fibroblasts, affected translation initiation factors and suppressed the expression of α1(I), α1(III), and α2(I) collagen, the hallmarks of skin ageing. Enhanced O2∙- led to activation of the phosphatases PTP1B and PTEN, which via dephosphorylation of the IGF-1 receptor and phosphatidylinositol 3,4,5-triphosphate dampened IGF-1 signalling. Genetic and pharmacologic inhibition of PTP1B and PTEN abrogated O2∙--induced IGF-1 resistance and rescued the ageing skin phenotype. We thus identify previously unreported signature events with O2∙-, PTP1B, and PTEN as promising targets for drug development to prevent IGF-1 resistance-related pathologies.

Summary The free radical theory of aging postulates that the production of mitochondrial reactive oxygen species is the major determinant of aging and lifespan. Its role in aging of the connective tissue has not yet been established, even though the incidence of aging-related disorders in connective tissue-rich organs is high, causing major disability in the elderly. We have now addressed this question experimentally by creating mice with conditional deficiency of the mitochondrial manganese superoxide dismutase in fibroblasts and other mesenchyme-derived cells of connective tissues in all organs. Here, we have shown for the first time that the connective tissue-specific lack of superoxide anion detoxification in the mitochondria results in reduced lifespan and premature onset of aging-related phenotypes such as weight loss, skin atrophy, kyphosis (curvature of the spine), osteoporosis and muscle degeneration in mutant mice. Increase in p16INK4a, a robust in vivo marker for fibroblast aging, may contribute to the observed phenotype. This novel model is particularly suited to decipher the underlying mechanisms and to develop hopefully novel connective tissue-specific anti-aging strategies.

Resveratrol has been reported to have a wide variety of biological effects. However, little is known regarding its role on phosphorylation of histone H3, MAP kinase p38, SIR2 and p53 in type I diabetic nephropathy (DN). Hence, the present study was undertaken to examine changes in the above said parameters by resveratrol treatment. Male Sprague-Dawley rats were rendered diabetic using a single dose of streptozotocin (55 mg/kg, i.p.). DN was assessed by measurements of blood urea nitrogen and creatinine levels. Phosphorylation of histone H3, SIR2, p53 and MAP kinase p38 expression were examined by western blotting. This study reports that treatment of resveratrol prevents the decrease in the expression of SIR2 in diabetic kidney. It also prevents increase in p38, p53 expression and dephosphorylation of histone H3 in diabetic kidney. This is the first report which suggests that protection against development of diabetic nephropathy by resveratrol treatment involves change in phosphorylation of histone H3, expression of Sir-2, p53 and p38 in diabetic kidney.

The free radical theory of aging postulates that the production of mitochondrial reactive oxygen species is the major determinant of aging and lifespan. The skin represents an excellent and accessible model organ to study aging that is characterized by atrophy, wrinkle formation, reduced tensile strength and impaired wound healing. Oxidative stress as a consequence of an imbalance in prooxidants and antioxidants with increased ROS concentrations has been demonstrated in the aged skin in vitro and in vivo, suggesting the important role of the antioxidant balance. Here we will summarize recent data on the role of the mitochondrial superoxide dismutase 2 in skin aging.

Background/aims PGC-1α is a versatile inducer of mitochondrial biogenesis and responsive to the changing energy demands of the cell. As mitochondrial ATP production requires proteins that derive from translation products of cytosolic ribosomes, we asked whether PGC-1α directly takes part in ribosomal biogenesis. Methods/techniques In a first step, we performed in vitro assays using confocal microscopy and Chromatin-immunoprecipitation in HEK and N2A cells. The results were confirmed in co-immunoprecipitation assays. Secondly, different tissues of WT and PGC-1α KO mice were investigated. To translate the in vitro data into in vivo, we cultivated primary cells of brown adipose tissue of WT and PGC-1α KO mice to reproduce the in vitro results. For translation into the human system, we investigated muscle biopsies of 21 healthy humans as well as 6 patients with Huntington’s disease. Results/outcome We show that a fraction of cellular PGC-1α localises to the nucleolus, the site of ribosomal biogenesis. Upon activation it strongly binds the ribosomal DNA and boosts recruitment of RNA polymerase I and UBF to the rDNA promoter. This induces RNA polymerase I transcription under different stress conditions in cell culture and mouse models as well as in healthy humans and is impaired already in early stages of human Huntington’s disease. Conclusions These results extend the hypothesis, that PGC-1α regulates rDNA transcription under different stress conditions to the observation that even basal levels of ribosomal biogenesis are affected by dysregulation of PGC-1α in Huntington’s disease. This novel molecular link between ribosomal and mitochondrial biogenesis helps to explain sarcopenia and cachexia in diseases of neurodegenerative origin.

The free radical theory of aging postulates that the production of mitochondrial reactive oxygen species is the major determinant of aging and lifespan. Its role in aging of the connective tissue has not yet been established, even though the incidence of aging-related disorders in connective tissue-rich organs is high, causing major disability in the elderly. We have now addressed this question experimentally by creating mice with conditional deficiency of the mitochondrial manganese superoxide dismutase in fibroblasts and other mesenchyme-derived cells of connective tissues in all organs. Here, we have shown for the first time that the connective tissue-specific lack of superoxide anion detoxification in the mitochondria results in reduced lifespan and premature onset of aging-related phenotypes such as weight loss, skin atrophy, kyphosis (curvature of the spine), osteoporosis and muscle degeneration in mutant mice. Increase in p16(INK4a) , a robust in vivo marker for fibroblast aging, may contribute to the observed phenotype. This novel model is particularly suited to decipher the underlying mechanisms and to develop hopefully novel connective tissue-specific anti-aging strategies.