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International audience; The FRiM fractal operator belongs to a family of operators, called ASAP, defined by an ordered selection of nearest neighbors. This generalization provides means to improve upon the good properties of FRiM. We propose a fast algorithm to build an ASAP operator mimicking the fractal structure of FRiM for pupils of any size and geometry and to learn the sparse coefficients from empirical data. We empirically show the good approximation by ASAP of correlated statistics and the benefits of ASAP for solving phase restoration problems.

Human bone marrow mesenchymal stem cell derived-extracellular vesicles (HBMSC-EV) are known for their regenerative and anti-inflammatory effects in animal models of myocardial ischemia. However, it is not known whether the efficacy of the EVs can be modulated by pre-conditioning of HBMSC by exposing them to either starvation or hypoxia prior to EV collection. HBMSC-EVs were isolated following normoxia starvation (NS), normoxia non-starvation (NNS), hypoxia starvation (HS), or hypoxia non-starvation (HNS) pre-conditioning. The HBMSC-EVs were characterized by nanoparticle tracking analysis, electron microscopy, Western blot, and proteomic analysis. Comparative proteomic profiling revealed that starvation pre-conditioning led to a smaller variety of proteins expressed, with the associated lesser effect of normoxia versus hypoxia pre-conditioning. In the absence of starvation, normoxia and hypoxia pre-conditioning led to disparate HBMSC-EV proteomic profiles. HNS HBMSC-EV was found to have the greatest variety of proteins overall, with 74 unique proteins, the greatest number of redox proteins, and pathway analysis suggestive of improved angiogenic properties. Future HBMSC-EV studies in the treatment of cardiovascular disease may achieve the most therapeutic benefits from hypoxia non-starved pre-conditioned HBMSC. This study was limited by the lack of functional and animal models of cardiovascular disease and transcriptomic studies.

Mesenchymal stromal cells (MSCs) represent a promising treatment for immune-related diseases due to their diverse immunomodulatory paracrine functions. However, progress of culture-expanded MSCs is hindered by inconsistent cell function, poor localization, and insufficient retention when administered as suspended cell injections, thus placing spatiotemporal dosing constraints on therapeutic functions. To address these limitations, we introduce the combination of in vitro interferon-gamma (IFN-γ) priming, a key stimulator of MSC immunosuppressive potency, and thermoresponsive cultureware to harvest cultured MSCs as directly transplantable scaffold-free immunosuppressive cell sheets. Here, we demonstrate that MSC sheets produced with IFN-γ priming upregulate expression of immunosuppressive factors indoleamine 2,3-dioxygenase (IDO-1), interleukin-10 (IL-10), programmed death ligand-1 (PD-L1), and prostaglandin E2 (PGE2) in both dose- and duration-dependent manners. In addition, IFN-γ primed MSC sheets showed increased ability to inhibit T-cell proliferation via indirect and direct contact, specifically related to increased IDO-1 and PGE2 concentrations. Furthermore, this study’s use of human clinical-grade single-cell-derived clonal bone marrow-derived MSCs, contributes to the future translatability and clinical relevancy of the produced sheets. Ultimately, these results present the combination of IFN-γ priming and MSC sheets as a new strategy to improve MSC-mediated treatment of localized inflammatory diseases.

Land salinization, resulting from the ongoing climate change phenomena, is having an increasing impact on coastal ecosystems like salt marshes. Although halophyte species can live and thrive in high salinities, they experience differences in their salt tolerance range, being this a determining factor in the plant distribution and frequency throughout marshes. Furthermore, intraspecific variation to NaCl response is observed in high-ranging halophyte species at a population level. The present study aims to determine if the environmental history, namely heavy metal pre-conditioning, can have a meaningful influence on salinity tolerance mechanisms of Spartina patens, a highly disperse grass invader in the Mediterranean marshes. For this purpose, individuals from pristine and heavy metal contaminated marsh populations were exposed to a high-ranging salinity gradient, and their intraspecific biophysical and biochemical feedbacks were analyzed. When comparing the tolerance mechanisms of both populations, S. patens from the contaminated marsh appeared to be more resilient and tolerant to salt stress, this was particularly present at the high salinities. Consequently, as the salinity increases in the environment, the heavy metal contaminated marsh may experience a more resilient and better adapted S. patens community. Therefore, the heavy metal pre-conditioning of salt mash populations appears to be able to create intraspecific physiological variations at the population level that can have a great influence on marsh plant distribution outcome.

Stiffness control is critical in human manipulation. The ability to transition between a low stiffness state, allowing for compliant interactions with the environment, through to rigid states, where it is possible to exert high forces, enables much functionality. Particle jamming provides an elegant method of modulating stiffness online. We develop an un-actuated anthropomorphic hand, with jamming particles enclosed in the joints surrounded by a moulded silicone skin. This approach to stiffness control also allows for control of posture, through 'pre-conditioning' by interacting with the environment in a soft state and then jamming the joints when in a new posture using a single vacuum source and control valve. To demonstrate the capabilities of this new design and fabrication approach, we introduce a 'pre-conditioning' algorithm for exploiting the soft/rigid state transition and environmental interactions to fix the hand in a given demand posture. This approach allows for accurate posture control, which translates to high grasping success rates. In conclusion, we demonstrate the advantages of the new design and fabrication approach, where jamming joints can be used to passively perform a variety of tasks through pre-conditioning of the hand posture. © 2021 IEEE.

Lipopolysacharide (LPS) pre-conditioning (PC), has been shown to exert protective effects against cytotoxic effects. Therefore, we hypothesized, the tolerance produced by LPS PC will be resulted by the alterations and modifications in gene and protein expression. With reference to the results of MTT assays, AO/PI staining, and Annexin V-FITC analyses of LPS concentration (0.7815–50 μg/mL) and time-dependent (12–72 h) experiments, the pre-exposure to 3 μg/mL LPS for 12 h protected the differentiated PC12 cells against 0.75 mg/mL LPS apoptotic concentration. LPS-treated cells secreted more inflammatory cytokines like IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-6, IL-17, IFN-γ, and TNF-α than LPS-PC cells. The production of inflammatory mediators ROS and NO was also higher in the LPS-induced cells compared to LPS-PC cells. Conversely, anti-inflammatory cytokines (like IL-10, IL-13, CNTF, and IL-1Ra) were upregulated in the LPS-PC cells but not in the LPS-induced cells. Meanwhile, the LPS initiated caspase-8 which in turn activates effector caspase 3/7. When the activities of caspases in the LPS-induced cells were inhibited using z-VADfmk and z-DEVDfmk, the expressions of c-MYC and Hsp70 were increased, but p53 was reduced. The potential molecules associated with protective and destructive effect was measured by RT2 Profiler PCR array to elucidate the signaling pathways and suggested inhibition NF-κB/caspase-3 signaling pathway regulates the cytoprotective genes and proto-oncogenes. In conclusion, this study provides a basis for future research to better understand the molecular mechanism underlying LPS pre-conditioning /TLR4 pre-activation and its functional role in offering cytoprotective response in neuronal environment.

Lipopolysacharide (LPS) pre-conditioning (PC), has been shown to exert protective effects against cytotoxic effects. Therefore, we hypothesized, the tolerance produced by LPS PC will be resulted by the alterations and modifications in gene and protein expression. With reference to the results of MTT assays, AO/PI staining, and Annexin V-FITC analyses of LPS concentration (0.7815–50 μg/mL) and time-dependent (12–72 h) experiments, the pre-exposure to 3 μg/mL LPS for 12 h protected the differentiated PC12 cells against 0.75 mg/mL LPS apoptotic concentration. LPS-treated cells secreted more inflammatory cytokines like IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-6, IL-17, IFN-γ, and TNF-α than LPS-PC cells. The production of inflammatory mediators ROS and NO was also higher in the LPS-induced cells compared to LPS-PC cells. Conversely, anti-inflammatory cytokines (like IL-10, IL-13, CNTF, and IL-1Ra) were upregulated in the LPS-PC cells but not in the LPS-induced cells. Meanwhile, the LPS initiated caspase-8 which in turn activates effector caspase 3/7. When the activities of caspases in the LPS-induced cells were inhibited using z-VADfmk and z-DEVDfmk, the expressions of c-MYC and Hsp70 were increased, but p53 was reduced. The potential molecules associated with protective and destructive effect was measured by RT2 Profiler PCR array to elucidate the signaling pathways and suggested inhibition NF-κB/caspase-3 signaling pathway regulates the cytoprotective genes and proto-oncogenes. In conclusion, this study provides a basis for future research to better understand the molecular mechanism underlying LPS pre-conditioning /TLR4 pre-activation and its functional role in offering cytoprotective response in neuronal environment.

An alternative control method to the use of chemical insecticides against soil dwelling insect pests is the application of entomopathogenic nematodes formulated in alginate beads for enhanced shelf life. The aim was to compare the benefit on nematode survival and infectivity of: (i) pre-conditioning of juveniles, and (ii) coating of alginate beads. The nematodes Steinernema glaseri, Steinernema carpocapsae, and Heterorhabditis bacteriophora were reproduced in last instar larvae of the wax moth Galleria mellonella and the infective juveniles emerged were subjected to two capture treatments: white traps and plaster of Paris, the latter was utilized as a pre-conditioning treatment. A total of 1,000 infective juveniles were formulated in each sodium alginate bead with or without an alginate coating. The beads were stored at 23 ± 3°C and a bidistilled water suspension of nematodes was set as a control. The survivorship of these formulates and their infectivity on Galleria mellonella larvae were evaluated every 7 d post-formulation (dpf). In beads without pre-conditioning juveniles nor coating, Steinernema carpocapsae had the higher survival rate (58.8%), the longest survival time (28 dpf) and the higher infectivity (100%) as well. Pre-conditioning improved the survival and infectivity of Steinernema glaseri by 22.5% at 21 dpf and 70.0% at 14 dpf, respectively. Alginate coating increased survival (21.7%) and infectivity (95%) of Heterorhabditis bacteriophora for up to 28 dpf. The combination of pre-conditioning and coating slightly favored the survival (10% for up to 14 dpf) of Steinernema glaseri and infectivity (100% for up to 35 dpf) of Steinernema carpocapsae. Non pre-conditioned Steinernema carpocapsae formulated in uncoated beads was the combination with better performance in survivorship (58.8%) and infectivity (100%) at 28 dpf. It was concluded that non pre-conditioned Steinernema carpocapsae formulated in uncoated beads was the combination with better survivorship and infectivity.

It has recently been revealed that during the aorta-clamped period, D-Ala2, D-Leu5-Enkephalin (DADLE) infusion can protect the spinal cord against ischemia and reperfusion (I/R) injury. However, the protective effects of DADLE administration prior to ischemia or at the time of early reperfusion have not yet been investigated. Drug pre- or post-conditioning can serve as a more valuable clinical strategy. Therefore, the present study was designed to investigate the neuroprotective effect of DADLE infusion at different time intervals in order to determine the optimum time point for ischemic spinal cord protection. A total of 40 New Zealand white rabbits were randomly divided into 5 groups: Sham-operated (Sham), normal saline pre-conditioning (NS), DADLE per-conditioning (Dper), DADLE pre-conditioning (Dpre) and DADLE post-conditioning (Dpost). All animals were subjected to spinal cord ischemia for 30 min followed by 48 h reperfusion. Hind limb motor functions were assessed according to the Tarlov criterion when the animals regained consciousness, 6, 24 and 48 h after reperfusion. Histological analysis and the number of viable α-motor neurons were also used to assess the extent of spinal cord injury. Compared with the NS group, the Tarlov scores and the number of normal neurons were significantly higher in the Dper group (P

Generalist herbivores can face many challenges when choosing their host plant. This can be particularly difficult if their choice and performance are affected by host experience. Greenhouse whitefly, Trialeurodes vaporariorum Westwood (Hemiptera: Aleyrodidae), is an invasive generalist herbivore, which has established in year-round greenhouses at northern latitudes where it cannot overwinter outdoors. It mainly uses crops such as cucumber (Cucumis sativus L.), tomato (Solanum lycopersicum L.), and ornamentals as host plants. However, every summer the insect escapes greenhouses and is exposed to natural vegetation. We evaluated the performance of T. vaporariorum on diverse vegetation outside greenhouses after prolonged experience of greenhouse crops. First, we surveyed the vegetation near infested greenhouses. Development success of the insect differed among wild hosts. We identified five new hosts among 12 plant species that bore pupae and were thus considered suitable as the insect's host plants. Members of the Urticaceae and Onagraceae were the most preferred and frequently inhabited by all insect life stages. The highest abundance of insects occurred in plots with low plant species richness, independent of plant family in these habitats. We then studied experimentally the impact of 1 year of preconditioning to one of three common greenhouse crops, cucumber, tomato, or poinsettia (Euphorbia pulcherrima Willd. ex Klotzsch), on the performance of the preconditioned adults and their progeny on four wild plants. Adults from tomato and poinsettia preferred the novel host species over the species to which they were preconditioned. The whitefly population preconditioned to cucumber was the most fecund on all offered hosts. We conclude that generalist herbivores can have large variation in performance, despite polyphagy, on novel hosts as shown by the variable abundance of T. vaporariorum pupae among outdoor hosts. Furthermore, performance of whiteflies on natural vegetation was affected by experience on greenhouse crops. Based on our observations, we provide insights and recommendations for pest management.

Background: To evaluate the effect of anaesthesia and ICU sedation with sevoflurane to protect the myocardium against ischemia-reperfusion injury associated to cardiac surgery assessed by troponin release. Methods: We performed a prospective, open-label, randomized study in cardiac surgery with cardiopulmonary bypass. Patients were randomized to an algorithm-based intervention group and a control group. The main outcome was the perioperative kinetic of cardiac troponin I (cTnI). The secondary outcomes included composite endpoint, GDF-15 (macrophage inhibitory cytokine-1) value, arterial lactate levels, and the length of stay (LOS) in the ICU. Results: Of 82 included patients, 81 were analyzed on an intention-to-treat basis (intervention group: n = 42; control group: n = 39). On inclusion, the intervention and control groups did not differ significantly in terms of demographic and surgical data. The postoperative kinetics of cTnI did not differ significantly between groups: the mean difference was 0.44 ± 1.09 μg/ml, P = .69. Incidence of composite endpoint and GDF-15 values were higher in the sevoflurane group than in propofol group. The intervention and control groups did not differ significantly in terms of ICU stay and hospital stay. Conclusion: The use of an anaesthesia and ICU sedation with sevoflurane was not associated with a lower incidence of myocardial injury assessed by cTnI. Sevoflurane administration was associated with higher prevalence of acute renal failure and higher GDF-15 values.

Mesenchymal stromal cells (MSCs) are self-renewing, culture-expandable adult stem cells that have been isolated from a variety of tissues, and possess multipotent differentiation capacity, immunomodulatory properties, and are relatively non-immunogenic. Due to this unique set of characteristics, these cells have attracted great interest in the field of regenerative medicine and have been shown to possess pronounced therapeutic potential in many different pathologies. MSCs' mode of action involves a strong paracrine component resulting from the high levels of bioactive molecules they secrete in response to the local microenvironment. For this reason, MSCs' secretome is currently being explored in several clinical contexts, either using MSC-conditioned media (CM) or purified MSC-derived extracellular vesicles (EVs) to modulate tissue response to a wide array of injuries. Rather than being a constant mixture of molecular factors, MSCs' secretome is known to be dependent on the diverse stimuli present in the microenvironment that MSCs encounter. As such, the composition of the MSCs' secretome can be modulated by preconditioning the MSCs during in vitro culture. This manuscript reviews the existent literature on how preconditioning of MSCs affects the therapeutic potential of their secretome, focusing on MSCs' immunomodulatory and regenerative features, thereby providing new insights for the therapeutic use of MSCs' secretome. We would like to acknowledge Norte Portugal Regional Operational Programme (NORTE 2020) in the framework of the project “Bioengineered Therapies for Infectious Diseases and Tissue Regeneration” (NORTE-01-0145-FEDER-000012). We also acknowledge Fundação para a Ciência e a Tecnologia (FCT) and Fundo Europeu de Desenvolvimento Regional (FEDER) funds through the COMPETE 2020-Operacional Programme for Competitiveness and Internationalization (POCI), Portugal 2020-in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). We also acknowledge EUROSPINE TRF for the funded project “Disc Regeneration, Immuno, and Neuro Modulation” , ref. 2017_05 . In addition, JF and RG also acknowledge FCT for funding the BiotechHealth Ph.D. fellowship (PD/BD/135486/2018) and the FCT Investigator Grant (IF/00638/2014), respectively.

The astonishing clinical success of CD19 chimeric antigen receptor (CAR) T-cell therapy has led to the approval of two second generationchimeric antigen receptors (CARs) for acute lymphoblastic leukemia (ALL) andnon-Hodgkin lymphoma (NHL). The focus of the field is nowon emulating these successes in other hematological malignancies where less impressive complete response rates are observed. Furtherengineering of CAR T cells or co-administration of other treatment modalities may successfully overcome obstacles to successful therapy inother cancer settings.We therefore present a model in which others can conduct pre-clinical testing of CD19 CAR T cells. Results in this well tested B-cell lymphomamodel are likely to be informative CAR T-cell therapy in general.This protocol allows the reproducible production of mouse CAR T cells through calcium phosphate transfection of Plat-E producer cells withMP71 retroviral constructs and pCL-Eco packaging plasmid followed by collection of secreted retroviral particles and transduction usingrecombinant human fibronectin fragment and centrifugation. Validation of retroviral transduction, and confirmation of the ability of CAR T cellsto kill target lymphoma cells ex vivo, through the use of flow cytometry, luminometry and enzyme-linked immunosorbent assay (ELISA), is alsodescribed.Protocols for testing CAR T cells in vivo in lymphoreplete and lymphodepleted syngeneic mice, bearing established, systemic lymphoma aredescribed. Anti-cancer activity is monitored by in vivo bioluminescence and disease progression. We show typical results of eradication ofestablished B-cell lymphoma when utilizing 1st or 2nd generation CARs in combination with lymphodepleting pre-conditioning and a minority ofmice achieving long term remissions when utilizing CAR T cells expressing IL-12 in lymphoreplete mice.These protocols can be used to evaluate CD19 CAR T cells with different additional modification, combinations of CAR T cells and othertherapeutic agents or adapted for the use of CAR T cells against different target antigens.

Irreversible myocardial damage happens in the presence of prolonged and severe ischemia. Several phenomena protect the heart against myocardial infarction and other adverse outcomes of ischemia and reperfusion (IR), namely: hibernation related to stunned myocardium, ischemic preconditioning (IPC), ischemic post-conditioning, and their pharmacological surrogates. Ischemic preconditioning consists in the induction of a brief IR to reduce damage of the tissue caused by prolonged and severe ischemia. Nitric oxide (NO) signaling plays an essential role in IPC. Nitric oxide-sensitive guanylate cyclase/cyclic guanosine-3′,5′-monophosphate (cGMP)-dependent protein kinase type I-signaling pathway protects against the IR injury during myocardial infarction. Mitochondrial ATP-sensitive and Ca2+-activated K+ channels are involved in NO-mediated signaling in IPC. Independently of the cGMP-mediated induction of NO production, S-nitrosation represents a regulatory molecular mechanism similar to phosphorylation and is essential for IPC. Unlike conditioning phenomena, the mechanistic basis of myocardial stunning and hibernation remains poorly understood. In this review article, we hypothesize that the disruption of electrical syncytium of the myocardium may underly myocardial stunning and hibernation. Considering that the connexins are the building blocks of gap junctions which represent primary structural basis of electrical syncytium, we discuss data on the involvement of connexins into myocardial conditioning, stunning, and hibernation. We also show how NO-mediated signaling is involved in myocardial stunning and hibernation. Connexins represent an essential element of adaptation phenomena of the heart at the level of both the cardio- myocytes and the mitochondria. Nitric oxide targets mitochondrial connexins which may affect electrical syncytium continuum in the heart. Mitochondrial connexins may play an essential role in NO-dependent mechanisms of myocardial adaptation to ischemia.

A new era of plant biochemistry at the systems level is emerging, providing detailed descriptions of biochemical phenomena at the cellular and organismal level. This new era is marked by the advent of metabolomics—the qualitative and quantitative investigation of the entire metabolome (in a dynamic equilibrium) of a biological system. This field has developed as an indispensable methodological approach to study cellular biochemistry at a global level. For protection and survival in a constantly-changing environment, plants rely on a complex and multi-layered innate immune system. This involves surveillance of ‘self’ and ‘non-self,’ molecule-based systemic signalling and metabolic adaptations involving primary and secondary metabolites as well as epigenetic modulation mechanisms. Establishment of a pre-conditioned or primed state can sensitise or enhance aspects of innate immunity for faster and stronger responses. Comprehensive elucidation of the molecular and biochemical processes associated with the phenotypic defence state is vital for a better understanding of the molecular mechanisms that define the metabolism of plant–pathogen interactions. Such insights are essential for translational research and applications. Thus, this review highlights the prospects of metabolomics and addresses current challenges that hinder the realisation of the full potential of the field. Such limitations include partial coverage of the metabolome and maximising the value of metabolomics data (extraction of information and interpretation). Furthermore, the review points out key features that characterise both the plant innate immune system and enhancement of the latter, thus underlining insights from metabolomic studies in plant priming. Future perspectives in this inspiring area are included, with the aim of stimulating further studies leading to a better understanding of plant immunity at the metabolome level.

Unexpected cardiac adverse effects are the leading causes of discontinuation of clinical trials and withdrawal of drugs from the market. Since the original observations in the mid-90s, it has been well established that cardiovascular risk factors and comorbidities (such as ageing, hyperlipidaemia, and diabetes) and their medications (e.g. nitrate tolerance, adenosine triphosphate-dependent potassium inhibitor antidiabetic drugs, statins, etc.) may interfere with cardiac ischaemic tolerance and endogenous cardioprotective signalling pathways. Indeed drugs may exert unwanted effects on the diseased and treated heart that is hidden in the healthy myocardium. Hidden cardiotoxic effects may be due to (i) drug-induced enhancement of deleterious signalling due to ischaemia/reperfusion injury and/or the presence of risk factors and/or (ii) inhibition of cardioprotective survival signalling pathways, both of which may lead to ischaemia-related cell death and/or pro-arrhythmic effects. This led to a novel concept of ‘hidden cardiotoxicity’, defined as cardiotoxity of a drug that manifests only in the diseased heart with e.g. ischaemia/reperfusion injury and/or in the presence of its major comorbidities. Little is known on the mechanism of hidden cardiotoxocity, moreover, hidden cardiotoxicity cannot be revealed by the routinely used non-clinical cardiac safety testing methods on healthy animals or tissues. Therefore, here, we emphasize the need for development of novel cardiac safety testing platform involving combined experimental models of cardiac diseases (especially myocardial ischaemia/reperfusion and ischaemic conditioning) in the presence and absence of major cardiovascular comorbidities and/or cotreatments.

We previously demonstrated that pre‐conditioning with CpG oligonucleotide (ODN) 1668 induces quick up‐regulation of gene expression 3 hours post‐murine myocardial ischaemia/reperfusion (I/R) injury, terminating inflammatory processes that sustain I/R injury. Now, performing comprehensive microarray and biocomputational analyses, we sought to further enlighten the “black box” beyond these first 3 hours. C57BL/6 mice were pretreated with either CpG 1668 or with control ODN 1612, respectively. Sixteen hours later, myocardial ischaemia was induced for 1 hour in a closed‐chest model, followed by reperfusion for 24 hours. RNA was extracted from hearts, and labelled cDNA was hybridized to gene microarrays. Data analysis was performed with BRB ArrayTools and Ingenuity Pathway Analysis. Functional groups mediating restoration of cellular integrity were among the top up‐regulated categories. Genes known to influence cardiomyocyte survival were strongly induced 24 hours post‐I/R. In contrast, proinflammatory pathways were down‐regulated. Interleukin‐10, an upstream regulator, suppressed specifically selected proinflammatory target genes at 24 hours compared to 3 hours post‐I/R. The IL1 complex is supposed to be one regulator of a network increasing cardiovascular angiogenesis. The up‐regulation of numerous protective pathways and the suppression of proinflammatory activity are supposed to be the genetic correlate of the cardioprotective effects of CpG 1668 pre‐conditioning.

Mesenchymal stem cells (MSCs) are on the cusp of regenerative medicine due to their differentiation capacity, favorable culture conditions, ability to be manipulated in vitro, and strong immunomodulatory activity. Recent studies indicate that the pleiotropic effects of MSCs, especially their immunomodulatory potential, can be largely attributed to paracrine factors. Exosomes, vesicles that are 30-150 nanometers in diameter that function in cell-cell communication, are one of the key paracrine effectors. MSC-derived exosomes are enriched with therapeutic miRNAs, mRNAs, cytokines, lipids, and growth factors. Emerging evidences support the compelling possibility of using MSC-derived exosomes as a new form of therapy for treating several different kinds of disease such as heart, kidney, immune diseases, neural injuries, and neurodegenerative disease. This review provides a summary of current knowledge and discusses engineering of MSC-derived exosomes for their use in translational medicine.

Team-sport athletes and coaches use varied strategies to enhance repeated-sprint ability (RSA). Aside from physical training, a well-conducted warm-up enhances RSA via increased oxidative metabolism. Strategies that impede blood flow could potentiate the effects of a warm-up due to their effects on the endothelial and metabolic functions. This study investigated whether performing a warm-up combined with blood-flow restriction (WFR) induces ergogenic changes in blood volume, muscle oxygenation, and RSA. In a pair-matched, single-blind, pre-post parallel group design, 15 American football players completed an RSA test (12 &times, 20 m, 20 s rest), preceded by WFR or a regular warm-up (SHAM). Pressure was applied on the athletes&rsquo, upper thighs for &asymp, 15 min using elastic bands. Both legs were wrapped at a perceived pressure of 7 and 3 out of 10 in WFR and SHAM, respectively. Changes in gastrocnemius muscle oxygen saturation (SmO2) and total hemoglobin concentration ([THb]) were monitored with near-infrared spectroscopy. Cohen&rsquo, s effect sizes (ES) were used to estimate the impact of WFR. WFR did not clearly alter best sprint time (ES &minus, 0.25), average speed (ES 0.25), total time (ES &minus, 0.12), and percent decrement score (ES 0.39). While WFR did not meaningfully alter average SmO2 and [THb], the intervention clearly increased the maximum [THb] and the minimum and maximum SmO2 during some of the 12 sprint/recovery periods (ES 0.34&ndash, 1.43). Results indicate that WFR positively alters skeletal muscle hemodynamics during an RSA test. These physiological changes did not improve short-term RSA, but could be beneficial to players during longer activities such as games.

© 2016, Springer Science+Business Media New York.Ischemic heart disease is a common cause of patients’ death worldwide. Recently, cardiac pre- and post-conditioning (IPC, IPoC) were indentified to reduce infarct size. Nevertheless, not only infarct size but also post-infarct remodelling is critical for the long-term enhancing effect. Calcium-sensing receptors (CaSRs) signalling was shown to be involved in IPC and IPoC in the heart. This study aims to clarify CaSRs expression after ischemia-reperfusion injury (I/R), IPC and IPoC. Experiments were performed on adult Wistar rats with left anterior descending coronary artery (LAD) occlusion. Troponin I (TnI) levels were measured in plasma of all animals to quantify the infarct size. Sham-operated animals, rats with I/R, IPC, and IPoC were compared. Left and right ventricular tissue samples from these groups were collected for qRT-PCR analysis. CaSR expression was enhanced in rats with I/R and IPC. Its increase after IPoC was not pronounced. In contrast, left ventricles (LV) showed decreased CaSR expression in rat hearts after I/R, IPC, and IPoC. Data suggest differences in CaSR regulation between LV and RV. Enhanced CaSR expression in RV was observed in tissue with small infarct size.

A conditioning process is usually needed for a newly fabricated proton exchange membrane (PEM) fuel cell to be activated. Depending on the membrane electrode assemblies, this process can take hours and even days to complete. To provide for accelerated conditioning techniques that can complete the process in a short time, this paper compares various reported methods to condition a PEM single cell. The major objectives are to identify accelerated conditioning approaches that can significantly reduce the conditioning duration for the existing conditioning regime in an operationally easy manner, and to understand the fundamental principles that govern accelerated conditioning. Various effects investigated include temperature, cycling steps, and cycling frequencies. Other techniques, such as short circuiting, hydrogen pumping, and hot water circulation, are also discussed. For each technique, measurements are taken using electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV), and linear sweep voltammetry (LSV).

This paper tells the story of how hormesis became recognized as a fundamental concept in biology, affecting toxicology, microbiology, medicine, public health, agriculture, and all areas related to enhancing biological performance. This paper assesses how hormesis enhances resilience to normal aging and protects against a broad spectrum of neurodegenerative, cardiovascular, and other diseases, as well as trauma and other threats to health and well-being. This paper also explains the application of hormesis to several neurodegenerative diseases such as Parkinson’s and Huntington’s disease, macrophage polarization and its systematic adaptive protections, and the role of hormesis in enhancing stem cell functioning and medical applications.

O teste de tetrazólio destaca-se entre os demais testes devido à possibilidade de avaliar simultaneamente a viabilidade e o vigor de sementes. A recomendação existente para condução deste teste com sementes de algodoeiro é morosa, além de apresentar dificuldades na forma de preparo e avaliação. Diante do fato, este trabalho teve por objetivo a redução do tempo de preparo das sementes de algodoeiro para a execução do teste. Inicialmente foram realizados três ensaios: 1- corte distal seguido de corte longitudinal: após o pré-umedecimento em papel e imersão em água por seis, oito e 16 horas, respectivamente; 2- corte distal nas sementes secas: seguido de imersão direta em água por quatro, seis e oito horas e, em papel, por 16 horas; 3- imersão - corte - imersão: após duas horas de imersão, foi feito o corte na extremidade oposta ao eixo embrionário seguido de imersão em água por quatro, seis e oito horas a 25°C. O tratamento corte distal do lado oposto do embrião após duas horas de imersão, seguida de mais seis horas de embebição, reduziu o tempo e facilitou o preparo das sementes para condução do teste. Em seguida, foram testadas as concentrações de tetrazólio 0,1% e 0,075% e as temperaturas 30, 35 e 40ºC. Posteriormente, foi realizada a validação da metodologia proposta, com cinco lotes de sementes, em que foram comparados os resultados com os da germinação e primeira contagem. Conclui-se que, para as sementes de algodoeiro, o teste de tetrazólio deve ser executado da seguinte forma: imersão em água por duas horas, seguido de corte na extremidade oposta ao eixo embrionário e posterior imersão por mais seis horas em água, seguida da remoção do tegumento e da membrana interna e, por fim, as sementes devem ser colocadas em solução de tetrazólio a 0,075% e mantidas em estufa a 40ºC por 150 minutos. The tetrazolium test stands out among other tests because it allows the simultaneous evaluation of seed viability and vigor. The existing recommendation for conducting the test with cotton seeds is rather slow and presents difficulties in the way of preparing and evaluating seeds. Considering this fact, this study aimed to reduce cotton seed preparation time in order to conduct the test. Three assays were conducted initially: 1- distal cut followed by a longitudinal cut, after pre-moistening the seeds in paper and immersing them in water for six, eight, and 16 hours, respectively; 2- distal cut on dry seeds, followed by direct immersion in water for four, six, and eight hours, and in paper for 16 hours; 3- immersion - cut - immersion: after immersion for two hours, the end opposite to the embryo axis was cut, and immersion in water followed for four, six, and eight hours at 25°C. The treatment involving a distal cut on the side opposite to the embryo after immersion for two hours, followed by imbibition for a further six hours reduced the time required and facilitated seed preparation for the test. Next, tetrazolium concentrations of 0.1% and 0.075% were tested at temperatures of 30, 35 and 40°C. Later, the proposed methodology was validated using five seed lots, by comparing the results obtained with germination and first count results. From the results obtained, it was concluded that, for cotton seeds, the tetrazolium test should be conducted in the following manner: immersion of seeds in water for two hours, followed by a cut on the end opposite to the embryo axis, and then immersion for another six hours in water, followed by removal of the integument plus the inner membrane and, finally, the seeds should be placed in tetrazolium solution at 0.075% and maintained in an incubator at 40°C for 150 minutes.

Acute myocardial infarction (MI) is one of the leading causes of mortality worldwide. MI is the heart muscle irreversible death secondary to prolonged ischemia. Over the last few decades, medical progress in how and when to restore blood flow to the ischemic area have markedly improved patient survival. Although early heart reperfusion is acknowledged to be the most effective way to limit infarct size, post-ischemic reperfusion is associated with detrimental effects, such as myocardial stunning, ventricular arrhythmias, microvascular dysfunction, and cell death. The molecular mechanisms of these reperfusion injuries remain to be elucidated and their management is very challenging. Among the various therapeutic molecular approaches proposed by experimental studies, nitric oxide (NO) role in protecting heart against MI and reperfusion injuries has been widely assessed and discussed (1–4). NO is a gasotransmitter that is abundantly produced in the cardiovascular system mainly by the NO synthase (NOS) enzymes system. Two isoforms, endothelial NOS (eNOS) and neuronal NOS (nNOS), are constitutively expressed in both myocardium and vessels, whereas inducible NOS (iNOS) is detected only in pathological conditions, such as inflammatory and/or oxidative stress. Both eNOS and nNOS are low-NO output Ca2+-dependent enzymes, while iNOS is a high-NO output Ca2+-independent enzyme. In physiological conditions, NOS form homodimers (“coupled” NOS) that catalyze NO production from l-arginine and O2 through electron transfer from NADPH on the reductase domain of one monomer to the oxidase domain of the second monomer. In pathological conditions, such as in the absence of the essential cofactor tetrahydrobiopterin (BH4), eNOS can be “uncoupled” to produce O2− instead of NO. In stress conditions, NO protects tissues through two distinct pathways. In the first one, NO activates the soluble guanylate cyclase (sGC) that initiates cyclic guanosine monophosphate (cGMP) production, leading to the activation of protein kinase G (PKG). As sGC is the major cell receptor for NO and the NO/sGC/cGMP/PKG pathway plays a critical role in both myocardium excitation–contraction coupling and cardiovascular function regulation (5–8), NO cardioprotective role was first attributed to PKG activation (9–11). However, a second pathway in which proteins are directly modified by NO addition to sulfhydryl residues, a process known as S-nitrosylation (SNO), has recently emerged in the scientific literature. Although PKG activation pathway has been largely involved in NO-mediated cardioprotection (11–13), SNO is now taking the front stage and is considered to be a key player in cardioprotection through (i) the transient modification of protein activity and/or (ii) their protection from irreversible oxidation (14–17). Indeed, Sun et al. (18) showed that reduced heart vulnerability to ischemia–reperfusion (IR) following acute ischemic preconditioning is mainly related to SNO signaling and not to PKG activation through the NO–SGC–cGMP pathway. Accordingly, we found that in exercise training-induced cardioprotection against IR injuries, protein SNO level, but not cGMP level, increased during early reperfusion (19). The same year, Methner et al. (20), using a Cre/loxP approach to selectively ablate type I PKG in cardiomyocytes, demonstrated that ischemic post-conditioning reduced infarct size in these mice like in wild type controls. Moreover, they showed that the cardioprotective effect against IR injury of mitochondria-targeted S-nitrosothiol (MitoSNO), which allows NO and S-nitrosothiol accumulation in mitochondria, was comparable in mice that specifically lack PKG in cardiomyocytes and in controls. This indicates that MitoSNO cardioprotective effect is independent of PKG. The current literature strongly supports NO implication in cardioprotection. However, the mechanism is still debated and whether increased NO availability during IR is cytoprotective remains to be demonstrated. Here, we discuss how NO might contribute to protect heart and particularly the importance of NO (i) localization, (ii) concentration, and (iii) time of availability during IR.

We propose an alternative parameterization of Logistic Regression (LR) for the categorical data, multi-class setting. LR optimizes the conditional log-likelihood over the training data and is based on an iterative optimization procedure to tune this objective function. The optimization procedure employed may be sensitive to scale and hence an effective pre-conditioning method is recommended. Many problems in machine learning involve arbitrary scales or categorical data (where simple standardization of features is not applicable). The problem can be alleviated by using optimization routines that are invariant to scale such as (second-order) Newton methods. However, computing and inverting the Hessian is a costly procedure and not feasible for big data. Thus one must often rely on first-order methods such as gradient descent (GD), stochastic gradient descent (SGD) or approximate second-order such as quasi-Newton (QN) routines, which are not invariant to scale. This paper proposes a simple yet effective pre-conditioner for speeding-up LR based on naive Bayes conditional probability estimates. The idea is to scale each attribute by the log of the conditional probability of that attribute given the class. This formulation substantially speeds-up LR's convergence. It also provides a weighted naive Bayes formulation which yields an effective framework for hybrid generative-discriminative classification. © 2014 IEEE., This research has been supported by the Australian Research Council (ARC) under grant DP140100087 and Asian Office of Aerospace Research and Development, Air Force Office of Scientific Research under contract FA23861214030.

The reduction or cessation of the blood supply to an organ results in tissue ischemia. Ischemia can cause significant tissue damage, and is observed as a result of a thrombosis, as part of a disease process, and during surgery. However, the restoration of the blood supply often causes more damage to the tissue than the ischemic episode itself. Research is therefore focused on identifying the cellular pathways involved in the protection of organs from the damage incurred by this process of ischemia reperfusion (I/R). The hypoxia-inducible factors (HIFs) are a family of heterodimeric transcription factors that are stabilized during ischemia. The genes that are expressed downstream of HIF activity enhance oxygen-independent ATP generation, cell survival, and angiogenesis, amongst other phenotypes. They are, therefore, important factors in the protection of tissues from I/R injury. Interestingly, a number of the mechanisms already known to induce organ protection against I/R injury, including preconditioning, postconditioning, and activation of signaling pathways such as adenosine receptor signaling, converge on the HIF system. This review describes the evidence for HIFs playing a role in I/R protection mediated by these factors, highlights areas that require further study, and discuss whether HIFs themselves are good therapeutic targets for protecting tissues from I/R injury.

Small-conductance Ca(2+)-activated K(+) channel activation is an emerging therapeutic approach for treatment of neurological diseases, including stroke, amyotrophic lateral sclerosis and schizophrenia. Our previous studies showed that activation of SK channels exerted neuroprotective effects through inhibition of NMDAR-mediated excitotoxicity. In this study, we tested the therapeutic potential of SK channel activation of NS309 (25 μM) in cultured human postmitotic dopaminergic neurons in vitro conditionally immortalized and differentiated from human fetal mesencephalic cells. Quantitative RT-PCR and western blotting analysis showed that differentiated dopaminergic neurons expressed low levels of SK2 channels and high levels of SK1 and SK3 channels. Further, protein analysis of subcellular fractions revealed expression of SK2 channel subtype in mitochondrial-enriched fraction. Mitochondrial complex I inhibitor rotenone (0.5 μM) disrupted the dendritic network of human dopaminergic neurons and induced neuronal death. SK channel activation reduced mitochondrial membrane potential, while it preserved the dendritic network, cell viability and ATP levels after rotenone challenge. Mitochondrial dysfunction and delayed dopaminergic cell death were prevented by increasing and/or stabilizing SK channel activity. Overall, our findings show that activation of SK channels provides protective effects in human dopaminergic neurons, likely via activation of both membrane and mitochondrial SK channels. Thus, SK channels are promising therapeutic targets for neurodegenerative disorders such as Parkinson's disease, where dopaminergic cell loss is associated with progression of the disease.

Despite current treatment options, cardiac failure is associated with significant morbidity and mortality highlighting a compelling clinical need for novel therapeutic approaches. Based on promising pre-clinical data, stem cell therapy has been suggested as a possible therapeutic strategy. Of the candidate cell types evaluated, mesenchymal stromal/stem cells (MSCs) have been widely evaluated due to their ease of isolation and ex vivo expansion, potential allogeneic utility and capacity to promote neo-angiogenesis and endogenous cardiac repair. However, the clinical application of MSCs for mainstream cardiovascular use is currently hindered by several important limitations, including suboptimal retention and engraftment and restricted capacity for bona fide cardiomyocyte regeneration. Consequently, this has prompted intense efforts to advance the therapeutic properties of MSCs for cardiovascular disease. In this review, we consider the scope of benefit from traditional plastic adherence-isolated MSCs and the lessons learned from their conventional use in preclinical and clinical studies. Focus is then given to the evolving strategies aimed at optimizing MSC therapy, including discussion of cell-targeted techniques that encompass the preparation, pre-conditioning and manipulation of these cells ex vivo, methods to improve their delivery to the heart and innovative substrate-directed strategies to support their interaction with the host myocardium. Refereed/Peer-reviewed

Mesenchymal stem cells (MSCs) are an attractive candidate for autologous cell therapy, but their ability to repair damaged myocardium is severely compromised with advanced age. Development of viable autologous cell therapy for treatment of heart failure in the elderly requires the need to address MSC ageing. In this study, MSCs from young (2 months) and aged (24 months) C57BL/6 mice were characterized for gene expression of IGF-1, FGF-2, VEGF, SIRT-1, AKT, p16(INK4a) , p21 and p53 along with measurements of population doubling (PD), superoxide dismutase (SOD) activity and apoptosis. Aged MSCs displayed senescent features compared with cells isolated from young animals and therefore were pre-conditioned with glucose depletion to enhance age affected function. Pre-conditioning of aged MSCs led to an increase in expression of IGF-1, AKT and SIRT-1 concomitant with enhanced viability, proliferation and delayed senescence. To determine the myocardial repair capability of pre-conditioned aged MSCs, myocardial infarction (MI) was induced in 24 months old C57BL/6 wild type mice and GFP expressing untreated and pre-conditioned aged MSCs were transplanted. Hearts transplanted with pre-conditioned aged MSCs showed increased expression of paracrine factors, such as IGF-1, FGF-2, VEGF and SDF-1α. This was associated with significantly improved cardiac performance as measured by dp/dt(max), dp/dt(min), LVEDP and LVDP, declined left ventricle (LV) fibrosis and apoptosis as measured by Masson's Trichrome and TUNEL assays, respectively, after 30 days of transplantation. In conclusion, pre-conditioning of aged MSCs with glucose depletion can enhance proliferation, delay senescence and restore the ability of aged cells to repair senescent infarcted myocardium.

Üç boyutlu elektromanyetik saçılım ve ışınım problemlerinin çalışılmasında yoğun doğrusal sistemlere yol açan ayrıklaştırılmış yüzey integral denklemlerini çözmek yaygın bir yöntemdir. Çözümün karmaşıklığının azalmasından dolayı, bu doğrusal denklemlerin Krylov altuzayı ve çok seviyeli hızlı çokkutup (ÇSHÇY) yöntemleri kullanılarak iteratif çözümü son derece çekici hale gelmiştir. Fakat bu yaklaşım sadece yakınsama için gereken iterasyon sayısı aşırı derecede yüksek olmadığı sürece işe yaramaktadır. Maalesef, pek çok pratik durumda bu geçerli olmamaktadır. Özellikle, açık yüzey ve karmaşık gerçek hayat problemleri kötü koşullu doğrusal sistemlere yol açmaktadır. Bu tarz problemlerin iteratif çözümleri, kabaca sistem matrislerine yaklaşan tersi alınabilir matrisler olarak tanımlanan öniyileştiriciler olmadan mümkün olmamaktadır.Bu doktora tezinde, büyük ölçekli yüzey integral denklemi problemleri için geliştirdiğimiz etkin öniyileştiricileri sunmaktayız. İlk olarak, en yaygın ve oturmuş bir öniyileştirme yöntemi olan eksik LU (ELU) öniyileştirmesini ele aldık. Bu öniyileştiricilerin nasıl bir kara kutu formunda ve güvenli olarak kullanılabileceklerini gösterdik. Önemli avantajlarına rağmen, ELU öniyileştiricileri temel olarak sıralı bir yapıda oldukları için, paralel çözümlerde kullanılmak üzere bir seyrek yaklaşık ters (SYT) öniyileştiricisi geliştirdik. Paralel ölçeklenebilirlik için önemli olan özgün bir yük dengeleme yöntemi geliştirdik. Daha sonra SYT öniyileştiricilerini, yoğun sistemi bir iç-dış çözümü şeklinde öniyileştiren yakın alan matris sisteminin iteratif çözümünde kullanarak geliştirdik. Mükemmel iletkenler için geliştirdiğimiz son öniyileştirici, benzer bir iç-dış çözümü kullanmakta, ama iç çözümler için ÇSHÇY'nin yaklaşık bir versiyonunu kullanmaktadır. Bu yolla, helikopterler ve metamalzemeler içeren çok sayıda karmaşık gerçek hayat problemini makul iterasyon sayılarında çözmeyi başardık.Son olarak, diyelektrik problemlerinin ayrıklaştırılmasından elde edilen doğrusal sistemlerin öniyileştirilmelerini hedefledik. Mükemmel iletkenlerden farklı olarak, bu sistemler bölünmüş yapıdadırlar.Schur tümleyenine indirgemeyle bu bölünmüş yapıyı öniyileştirme için kullandık. Bu yolla, diyelektrik fotonik kristaller gibi, çözümü zor gerçek hayat problemlerinin makul sürelerde çözümünü mümkün kılan etkin öniyileştiricilerin geliştirilmesi mümkün olmuştur. A popular method to study electromagnetic scattering and radiation of threedimensionalelectromagnetics problems is to solve discretized surface integralequations, which give rise to dense linear systems. Iterative solution of suchlinear systems using Krylov subspace iterative methods and the multilevel fastmultipole algorithm (MLFMA) has been a very attractive approach for largeproblems because of the reduced complexity of the solution. This scheme workswell, however, only if the number of iterations required for convergence of theiterative solver is not too high. Unfortunately, this is not the case for manypractical problems. In particular, discretizations of open-surface problems andcomplex real-life targets yield ill-conditioned linear systems. The iterative solutionsof such problems are not tractable without preconditioners, which can beroughly defined as easily invertible approximations of the system matrices.In this dissertation, we present our efforts to design effective preconditioners forlarge-scale surface-integral-equation problems. We first address incomplete LU(ILU) preconditioning, which is the most commonly used and well-establishedpreconditioning method. We show how to use these preconditioners in a blackboxform and safe manner. Despite their important advantages, ILU preconditionersare inherently sequential. Hence, for parallel solutions, a sparseapproximate-inverse (SAI) preconditioner has been developed. We propose anovel load-balancing scheme for SAI, which is crucial for parallel scalability.Then, we improve the performance of the SAI preconditioner by using it for theiterative solution of the near-field matrix system, which is used to preconditionthe dense linear system in an inner-outer solution scheme. The last preconditionerwe develop for perfectly-electric-conductor (PEC) problems uses the sameinner-outer solution scheme, but employs an approximate version of MLFMA forinner solutions. In this way, we succeed to solve many complex real-life problemsincluding helicopters and metamaterial structures with moderate iteration countsand short solution times. Finally, we consider preconditioning of linear systemsobtained from the discretization of dielectric problems. Unlike the PEC case,those linear systems are in a partitioned structure. We exploit the partitionedstructure for preconditioning by employing Schur complement reduction. In thisway, we develop effective preconditioners, which render the solution of difficultreal-life problems solvable, such as dielectric photonic crystals. 211

In recent years, hyperbaric oxygen (HBO) has been used in the treatment of a lot of diseases such as decompression sickness, arterial gas embolism, carbon dioxide poisoning, soft tissue infection, refractory osteomyelitis, and problematic wound, but little is known about its application in liver transplantation. Although several studies have been conducted to investigate the protective effects of HBO on liver transplantation and liver preservation, there are still some controversies on this issue, especially its immunomodulatory effect. In this short review, we briefly summarize the findings supporting the application of HBO during liver transplantation (including donors and recipients).

Phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha) on serine 51 is effected by specific stress-activated protein kinases. eIF2alpha phosphorylation inhibits translation initiation promoting a cytoprotective gene expression program known as the integrated stress response (ISR). Stress-induced activation of GADD34 feeds back negatively on this pathway by promoting eIF2alpha dephosphorylation, however, GADD34 mutant cells retain significant eIF2alpha-directed phosphatase activity. We used a somatic cell genetic approach to identify a gene encoding a novel regulatory subunit of a constitutively active holophosphatase complex that dephosphorylates eIF2alpha. RNAi of this gene, which we named constitutive repressor of eIF2alpha phosphorylation (CReP, or PPP1R15B), repressed the constitutive eIF2alpha-directed phosphatase activity and activated the ISR. CReP RNAi strongly protected mammalian cells against oxidative stress, peroxynitrite stress, and more modestly against accumulation of malfolded proteins in the endoplasmic reticulum. These findings suggest that therapeutic inhibition of eIF2alpha dephosphorylation by targeting the CReP-protein-phosphatase-1 complex may be used to access the salubrious qualities of the ISR.

The polymer/clay nanocomposite has unique morphologies which help to improve the properties of the nanocomposite material itself. The morphologies are the intercalation and also the exfoliation. Intercalation is happen when the clay layers is penetrated by epoxy resin and the epoxy resin continue to expand inside the clay layers and with several help from other process the clay layers being separated and disperse throughout the epoxy resin. The separation of the clay layers is called exfoliation. There is a lot method being studied by the researchers all over the world to control these morphologies. Some of them are shearing and pre-conditioning. The objective of this study is to check the relationship between the effects of the homopolymerize state of the sample after pre-conditioning for various times/temperatures and then the sample being sheared by using the roll mill machine to see the dispersion of the clay particle. Several nanocomposite samples are pre-conditioned at a certain temperature and time, and then the sample is being sheared using the 2-roll mill machine. In this report also studies the effect of using different epoxy resin on the homopolymerize state of the samples.

In this paper, we extend the work of Günther-Hanssen (2020) in applying the INTERNODES method to problems in contact mechanics. In an initial work on this topic, Günther-Hanssen showed that the INTERNODES method could be successfully applied but also revealed several challenges in efficiently solving iteratively the linear systems arising from the method. In this work, we investigate preconditioning techniques for such linear systems. The highly efficient Liu-Woodbury outer-inner preconditioners we propose achieve very fast convergence and to a great extent independent of the mesh size. Our paper is structured as follows: In Section 2 we recall the INTERNODES matrix derived by Günther-Hanssen in the specific context of contact mechanics. We discuss some of its properties and prove a few theoretical results. In Section 3, we begin by motivating the choice of solver for the linear system. We then discuss theoretical aspects relating to preconditioning techniques and later propose our first preconditioner. In the last part of this section we show how it leads to a new linear system for which we propose a second preconditioner. Finally, in Section 4, we conduct a few numerical experiments supporting the theoretical results.