Mesenchymal stem cells as promoters, enhancers, and playmakers of the translational regenerative medicine

Since their first isolation and characterization by Friedenstein et al. in 1974, mesenchymal stem cells (MSCs) were proven essential for tissue regeneration and homeostasis. Over the years, thanks to a better understanding of the molecular mechanisms underlying the therapeutic effects of MSCs, several approaches with MSC-based therapies have been proposed, in order to treat different human diseases. In this light, MSCs are currently being tested in preclinical in vivo settings as well as in early-stage clinical trials for their ability to modulate immune responses, fostering wound healing and tissue regeneration of various tissue types and organs, including the skin, bone, cartilage, brain, muscle, and tendons

Targeting RAGE prevents muscle wasting and prolongs survival in cancer cachexia

Background: Cachexia, a multifactorial syndrome affecting more than 50% of patients with advanced cancer and responsible for ~20% of cancer-associated deaths, is still a poorly understood process without a standard cure available. Skeletal muscle atrophy caused by systemic inflammation is a major clinical feature of cachexia, leading to weight loss, dampening patients' quality of life, and reducing patients' response to anticancer therapy. RAGE (receptor for advanced glycation end-products) is a multiligand receptor of the immunoglobulin superfamily and a mediator of muscle regeneration, inflammation, and cancer. Methods: By using murine models consisting in the injection of colon 26 murine adenocarcinoma (C26-ADK) or Lewis lung carcinoma (LLC) cells in BALB/c and C57BL/6 or Ager−/− (RAGE-null) mice, respectively, we investigated the involvement of RAGE signalling in the main features of cancer cachexia, including the inflammatory state. In vitro experiments were performed using myotubes derived from C2C12 myoblasts or primary myoblasts isolated from C57BL/6 wild type and Ager−/− mice treated with the RAGE ligand, S100B (S100 calcium-binding protein B), TNF (tumor necrosis factor)α±IFN (interferon) γ, and tumour cell- or masses-conditioned media to analyse hallmarks of muscle atrophy. Finally, muscles of wild type and Ager−/− mice were injected with TNFα/IFNγ or S100B in a tumour-free environment. Results: We demonstrate that RAGE is determinant to activate signalling pathways leading to muscle protein degradation in the presence of proinflammatory cytokines and/or tumour-derived cachexia-inducing factors. We identify the RAGE ligand, S100B, as a novel factor able to induce muscle atrophy per se via a p38 MAPK (p38 mitogen-activated protein kinase)/myogenin axis and STAT3 (signal transducer and activator of transcription 3)-dependent MyoD (myoblast determination protein 1) degradation. Lastly, we found that in cancer conditions, an increase in serum levels of tumour-derived S100B and HMGB1 (high mobility group box 1) occurs leading to chronic activation/overexpression of RAGE, which induces hallmarks of cancer cachexia (i.e. muscle wasting, systemic inflammation, and release of tumour-derived pro-cachectic factors). Absence of RAGE in mice translates into reduced serum levels of cachexia-inducing factors, delayed loss of muscle mass and strength, reduced tumour progression, and increased survival. Conclusions: RAGE is a molecular determinant in inducing the hallmarks of cancer cachexia, and molecular targeting of RAGE might represent a therapeutic strategy to prevent or counteract the cachectic syndrome

Human cachexia induces changes in mitochondria, autophagy and apoptosis in the skeletal muscle

Cachexia is a wasting syndrome characterized by the continuous loss of skeletal muscle mass due to imbalance between protein synthesis and degradation, which is related with poor prognosis and compromised quality of life. Dysfunctional mitochondria are associated with lower muscle strength and muscle atrophy in cancer patients, yet poorly described in human cachexia. We herein investigated mitochondrial morphology, autophagy and apoptosis in the skeletal muscle of patients with gastrointestinal cancer-associated cachexia (CC), as compared with a weight-stable cancer group (WSC). CC showed prominent weight loss and increased circulating levels of serum C-reactive protein, lower body mass index and decreased circulating hemoglobin, when compared to WSC. Electron microscopy analysis revealed an increase in intermyofibrillar mitochondrial area in CC, as compared to WSC. Relative gene expression of Fission 1, a protein related to mitochondrial fission, was increased in CC, as compared to WSC. LC3 II, autophagy-related (ATG) 5 and 7 essential proteins for autophagosome formation, presented higher content in the cachectic group. Protein levels of phosphorylated p53 (Ser46), activated caspase 8 (Asp384) and 9 (Asp315) were also increased in the skeletal muscle of CC. Overall, our results demonstrate that human cancer-associated cachexia leads to exacerbated muscle-stress response that may culminate in muscle loss, which is in part due to disruption of mitochondrial morphology, dysfunctional autophagy and increased apoptosis. To the best of our knowledge, this is the first report showing quantitative morphological alterations in skeletal muscle mitochondria in cachectic patients

Synthesis of Large-Scale Monolayer 1T′-MoTe2and Its Stabilization via Scalable hBN Encapsulation

Out of the different structural phases of molybdenum ditelluride (MoTe2), the distorted octahedral 1T′ possesses great interest for fundamental physics and is a promising candidate for the implementation of innovative devices such as topological transistors. Indeed, 1T′-MoTe2 is a semimetal with superconductivity, which has been predicted to be a Weyl semimetal and a quantum spin Hall insulator in bulk and monolayer form, respectively. Large instability of monolayer 1T′-MoTe2 in environmental conditions, however, has made its investigation extremely challenging so far. In this work, we demonstrate homogeneous growth of large single-crystal (up to 500 μm) monolayer 1T′-MoTe2 via chemical vapor deposition (CVD) and its stabilization in air with a scalable encapsulation approach. The encapsulant is obtained by electrochemically delaminating CVD hexagonal boron nitride (hBN) from copper foil, and it is applied on the freshly grown 1T′-MoTe2 via a top-down dry lamination step. The structural and electrical properties of encapsulated 1T′-MoTe2 have been monitored over several months to assess the degree of degradation of the material. We find that when encapsulated with hBN, the lifetime of monolayer 1T′-MoTe2 successfully increases from a few minutes to more than a month. Furthermore, the encapsulated monolayer can be subjected to transfer, device processing, and heating and cooling cycles without degradation of its properties. The potential of this scalable heterostack is confirmed by the observation of signatures of low-temperature phase transition in monolayer 1T′-MoTe2 by both Raman spectroscopy and electrical measurements. The growth and encapsulation methods reported in this work can be employed for further fundamental studies of this enticing material as well as facilitate the technological development of monolayer 1T′-MoTe2

Stress-strain in electron-beam activated polymeric micro-actuators

Actuation of thin polymeric films via electron irradiation is a promising avenue to realize devices based on strain engineered two-dimensional materials. Complex strain profiles demand a deep understanding of the mechanics of the polymeric layer under electron irradiation; in this article, we report a detailed investigation on electron-induced stress on a poly-methyl-methacrylate (PMMA) thin film material. After an assessment of stress values using a method based on dielectric cantilevers, we directly investigate the lateral shrinkage of PMMA patterns on epitaxial graphene, which reveals a universal behavior, independent of the electron acceleration energy. By knowing the stress-strain curve, we finally estimate an effective Young's modulus of PMMA on top of graphene, which is a relevant parameter for PMMA-based electron-beam lithography and strain engineering applications

Terahertz detection by epitaxial-graphene field-effect-transistors on silicon carbide

We report on room temperature detection of terahertz radiation by means of antenna-coupled field effect transistors (FETs) fabricated using epitaxial graphene grown on silicon carbide. The achieved photoresponsivity (similar to 0.25 V/W) and noise equivalent power (similar to 80 nW/root Hz) result from the combined effect of two independent detection mechanisms: over-damped plasma wave rectification and thermoelectric effects, the latter ascribed to the presence of carrier density junctions along the FET channel. The calculated plasmonic and thermoelectric response reproduces qualitatively well the measured photovoltages; the experimentally observed sign-switch demonstrates the stronger contribution of plasmonic detection compared to the thermoelectric one. These results unveil the potential of plasmonic detectors exploiting epitaxial graphene on silicon carbide for fast large area imaging of macroscopic samples

SRF role as a mechano-transductor in response to exercise in cancer cachexia

Introduction: Recent studies showed that physical activity increased survival in cancer patient and animal models of cancer cachexia. The underlying mechanisms, however, are still largely unknown. Methods: To identify signalling pathways involved in exercise-dependent maintenance of muscle mass and function in cachexia, we investigated the role of serum response factor (SRF)—a transcription factor playing a pivotal a role in muscular growth, differentiation and regeneration—in C26-bearing mice in the absence or presence of voluntary exercise (wheel running). Results: SRF levels are decreased at protein level in cachexia. Consistently, a decrease in the expression of SRF target genes such as MyoD and SK-actin occurs in C26-bearing mice, suggesting a decrease of SRF transcriptional activity. These tumour effects were counteracted by wheel running and associated to the rescue of muscle mass and function. However, a minimum amount of exercise (2 km/day) is necessary to keep SRF levels elevated in cachexia over a threshold which is necessary to exert beneficial effects. SRF levels inversely correlate with wasting in mice, suggesting that SRF play a role in maintaining body mass (mostly accounted for by muscle mass). We also observe the recruitment of nuclei within the muscle fibres in response to exercise, which could contribute to muscle homeostasis and is consistent with the previously observed opposite effects of tumour and exercise on MyoD and Pax7 expression. Conclusions: Our results suggest that physical activity rescues SRF expression as well as its transcriptional activity, highlighting the importance of genetic activation induced by skeletal muscle activity for muscle rescue and homeostasis. These effects could be extended to the fibre microenvironment, including myogenic stem cell activity

Increasing the active surface of titanium islands on graphene by nitrogen sputtering

Titanium-island formation on graphene as a function of defect density is investigated. When depositing titanium on pristine graphene, titanium atoms cluster and form islands with an average diameter of about 10nm and an average height of a few atomic layers. We show that if defects are introduced in the graphene by ion bombardment, the mobility of the deposited titanium atoms is reduced and the average diameter of the islands decreases to 5nm with monoatomic height. This results in an optimized coverage for hydrogen storage applications since the actual titanium surface available per unit graphene area is significantly increased

Myomegalin is a novel protein of the golgi/centrosome that interacts with a cyclic nucleotide phosphodiesterase

Subcellular targeting of the components of the cAMP-dependent pathway is thought to be essential for intracellular signaling. Here we have identified a novel protein, named myomegalin, that interacts with the cyclic nucleotide phosphodiesterase PDE4D, thereby targeting it to particulate structures. Myomegalin is a large 2,324-amino acid protein mostly composed of α-helical and coiled-coil structures, with domains shared with microtubule-associated proteins, and a leucine zipper identical to that found in the Drosophila centrosomin. Transcripts of 7.5-8 kilobases were present in most tissues, whereas a short mRNA of 2.4 kilobases was detected only in rat testis. A third splicing variant was expressed predominantly in rat heart. Antibodies against the deduced sequence recognized particulate myomegalin proteins of 62 kDa in testis and 230-250 kDa in heart and skeletal muscle. Immunocytochemistry and transfection studies demonstrate colocalization of PDE4D and myomegalin in the Golgi/centrosomal area of cultured cells, and in sarcomeric structures of skeletal muscle. Myomegalin expressed in COS-7 cells coimmunoprecipitated with PDE4D3 and sequestered it to particulate structures. These findings indicate that myomegalin is a novel protein that functions as an anchor to localize components of the cAMP-dependent pathway to the Golgi/centrosomal region of the cell