Cyclic Activation Research Articles

Potential Skin Health Benefits of Abalone By-Products Suggested by Their Effects on MAPKS and PI3K/AKT/NF-kB Signaling Pathways in HDF and HaCaT Cells.

Abalone, a marine edible gastropod with nutritional value, is a popular seafood delicacy worldwide, especially in Asia; however, viscera by-products are generally discarded during processing. Therefore, we investigated the skin health benefits of abalone viscera ultrasonic extract (AVU) in human dermal fibroblasts (HDFs) and human keratinocyte (HaCaT) cells. AVU showed valuable protein contents, indicating that it is a worthy and safe material for industrial application. AVU increased collagen synthesis production and messenger RNA (mRNA) expression of Collagen Type I Alpha 1, 2, and 3 chains through the transforming growth factor beta/suppressor of mother against the decapentaplegic pathway in HDF cells. AVU also increased hyaluronic acid production, upregulated Hyaluronan Synthases 1, 2, and 3, filaggrin and aquaporin3 mRNA levels, and downregulated hyaluronidase mRNA levels in HaCaT cells. Furthermore, mechanistic studies showed that AVU increased the phosphorylation of extracellular signal-regulated kinase, p38, and cyclic AMP response-binding protein activation. AVU activated the transcription factors, phosphoinositide 3-kinase, protein kinase B, and nuclear factor kappa B cell p65 and downregulated the degranulation of inhibitory kappa B in HaCaT cells. Studies of hyaluronic acid production in AVU by inhibiting EKR, p38 and NF-κB have shown that p38 MAPK and NF-κB signaling are pivotal mechanisms, particularly in the AVU. These results demonstrated that AVU produced from by-products may improve skin health and may thus be used as a functional food and cosmetics ingredient.

Gas Sensing with Nanoporous In2O3 under Cyclic Optical Activation: Machine Learning-Aided Classification of H2 and H2O

Clean hydrogen is a key aspect of carbon neutrality, necessitating robust methods for monitoring hydrogen concentration in critical infrastructures like pipelines or power plants. While semiconducting metal oxides such as In2O3 can monitor gas concentrations down to the ppm range, they often exhibit cross-sensitivity to other gases like H2O. In this study, we investigated whether cyclic optical illumination of a gas-sensitive In2O3 layer creates identifiable changes in a gas sensor’s electronic resistance that can be linked to H2 and H2O concentrations via machine learning. We exposed nanostructured In2O3 with a large surface area of 95 m2 g−1 to H2 concentrations (0–800 ppm) and relative humidity (0–70%) under cyclic activation utilizing blue light. The sensors were tested for 20 classes of gas combinations. A support vector machine achieved classification rates up to 92.0%, with reliable reproducibility (88.2 ± 2.7%) across five individual sensors using 10-fold cross-validation. Our findings suggest that cyclic optical activation can be used as a tool to classify H2 and H2O concentrations.

Enhancing Benzylamine Electro-oxidation and Hydrogen Evolution through in-situ Electrochemical Activation of CoC2O4 Nanoarray.

The sluggish anodic oxygen evolution reaction (OER) seriously restricts the overall efficiency of water splitting. Here, we present an environmentally friendly and efficient aniline oxidation (BOR) to replace the sluggish OER, accomplishing the co-production of H2 and high value-added benzonitrile (BN) at low voltages. Cobalt oxalates grown on cobalt foam (CoC2O4·2H2O/CF) are adopted as the pre-catalysts, which further evolve into working electrocatalysts active for BOR and HER after appropriate electrochemical activation. Thereinto, cyclic voltammetry activation at positive potentials is performed to reconstruct cobalt oxalate via extensive oxidation, resulting in enriched Co(III) species and nanoporous structures beneficial for BOR, while chronoamperometry at negative potentials is introduced for the cathodic activation toward efficient HER with obvious improvement. The two activated electrodes can be combined into a two-electrode system, which achieves a high current density of 75 mA cm-2 at the voltage of 1.95 V, with the high Faraday efficiencies of both BOR (90.0%) and HER (90.0%) and the satisfactory yield of BN (76.8%).

Substrate stress relaxation regulates neural stem cell fate commitment

Adult neural stem cells (NSCs) reside in the dentate gyrus of the hippocampus, and their capacity to generate neurons and glia plays a role in learning and memory. In addition, neurodegenerative diseases are known to be caused by a loss of neurons and glial cells, resulting in a need to better understand stem cell fate commitment processes. We previously showed that NSC fate commitment toward a neuronal or glial lineage is strongly influenced by extracellular matrix stiffness, a property of elastic materials. However, tissues in vivo are not purely elastic and have varying degrees of viscous character. Relatively little is known about how the viscoelastic properties of the substrate impact NSC fate commitment. Here, we introduce a polyacrylamide-based cell culture platform that incorporates mismatched DNA oligonucleotide-based cross-links as well as covalent cross-links. This platform allows for tunable viscous stress relaxation properties via variation in the number of mismatched base pairs. We find that NSCs exhibit increased astrocytic differentiation as the degree of stress relaxation is increased. Furthermore, culturing NSCs on increasingly stress-relaxing substrates impacts cytoskeletal dynamics by decreasing intracellular actin flow rates and stimulating cyclic activation of the mechanosensitive protein RhoA. Additionally, inhibition of motor-clutch model components such as myosin II and focal adhesion kinase partially or completely reverts cells to lineage distributions observed on elastic substrates. Collectively, our results introduce a unique system for controlling matrix stress relaxation properties and offer insight into how NSCs integrate viscoelastic cues to direct fate commitment.

Phase engineering and surface reconstruction of FeNiMo alloys as high efficient electrode for oxygen evolution reaction

In the field of electrocatalysis, most of the electrodes have the problem of poor mechanical properties, which leads to the electrode can not be used on a large scale. At present, most bulk electrodes are used to study their mechanical properties due to their unique phase composition distribution and facile fabricate methods. But their novel properties in the field of electrocatalysts have not been fully developed. Multi-element bulk electrodes not only diversified the electronic states, but also build complex surface morphology by different dissolution rate between multi-phase distribution. In this paper, we synthesized the FeNiMo bulk electrode for oxygen evolution reaction (OER) with two-phase coexistence of Mo-doped face center cubic phase (FCC) and Mo-rich intermetallic compound (IMC) phase. During cyclic voltammetry activation, the surface reconstruction of Mo-rich IMC phases generated by ion leaching leaves Fe–Ni pore structures with more active area, which enhances OER performance. Meanwhile, the electron states get more diverse on the surface of remaining FCC phases due to Mo doping, which provides more suitable sites for four-step OER process. The FeNiMo electrode shows an ultra-low overpotential of 212 mV and 293.4 mV at a current density of 10 mA cm−2 and 100 mA cm−2, respectively. Moreover, it can maintain stability at 100 mA cm−2 for up to 72 h. This work provides a strategy for studying the relationship between phase composition and electrochemical performance of alloy bulk electrodes.

A new gene signature for endothelial senescence identifies self-RNA sensing by retinoic acid-inducible gene I as a molecular facilitator of vascular aging.

The number of senescent vascular endothelial cells increases during aging and their dysfunctional phenotype contributes to age-related cardiovascular disease. Identification of senescent cells is challenging as molecular changes are often tissue specific and occur amongst clusters of normal cells. Here, we established, benchmarked, and validated a new gene signature called EndoSEN that pinpoints senescent endothelial cells. The EndoSEN signature was enriched for interferon-stimulated genes (ISG) and correlated with the senescence-associated secretory phenotype (SASP). SASP establishment is classically attributed to DNA damage and cyclic GMP-AMP synthase activation, but our results revealed a pivotal role for RNA accumulation and sensing in senescent endothelial cells. Mechanistically, we showed that endothelial cell senescence hallmarks include self-RNA accumulation, RNA sensor RIG-I upregulation, and an ISG signature. Moreover, a virtual model of RIG-I knockout in endothelial cells underscored senescence as a key pathway regulated by this sensor. We tested and confirmed that RIG-I knockdown was sufficient to extend the lifespan and decrease the SASP in endothelial cells. Taken together, our evidence suggests that targeting RNA sensing is a potential strategy to delay vascular aging.

MoS2 Field-Effect Transistor Performance Enhancement by Contact Doping and Defect Passivation via Fluorine Ions and Its Cyclic Field-Assisted Activation.

MoS2-based field-effect transistors (FETs) and, in general, transition metal dichalcogenide channels are fundamentally limited by high contact resistance (RC) and intrinsic defects, which results in low drive current and lower carrier mobilities, respectively. This work addresses these issues using a technique based on CF4 plasma treatment in the contacts and further cyclic field-assisted drift and activation of the fluorine ions (F-), which get introduced into the contact region during the CF4 plasma treatment. The F- ions are activated using cyclic pulses applied across the source-drain (S/D) contacts, which leads to their migration to the contact edges via the channel. Further, using ab initio molecular dynamics and density functional theory simulations, these F- ions are found to bond at sulfur (S) vacancies, resulting in their passivation and n-type doping in the channel and near the S/D contacts. An increase in doping results in the narrowing of the Schottky barrier width and a reduction in RC by ∼90%. Additionally, the passivation of S vacancies in the channel enhances the mobility of the FET by ∼150%. The CF4 plasma treatment in contacts and further cyclic field-assisted activation of F- ions resulted in an ON-current (ION) improvement by ∼90% and ∼480% for exfoliated and CVD-grown MoS2, respectively. Moreover, this improvement in ION has been achieved without any deterioration in the ION/IOFF, which was found to be >7-8 orders.

Multi-effects of Mo on enhancement of wear and corrosion resistances of FeCoNiCrMox high entropy alloys coatings prepared by laser powder directed energy deposition

Currently, it is significant to investigate the effects of Mo on the wear and corrosion resistance of laser powder directed energy deposition (LP-DED) high entropy alloys (HEAs) coatings. In this work, FeCoCrNiMox (x = 0.1, 0.3, 0.5, at.%) HEAs coatings were prepared by LP-DED. New face-centered cubic (FCC2) phase separation occurred in Mo0.3 and Mo0.5 coatings due to the supersaturation of Mo and the repeated annealing effects. The cyclic thermal activation effect of LP-DED resulted in the formation of a large number of small sub-grains. The solute micro-segregation effect of dislocation walls promoted the formation of σ phases at sub-grain boundaries. The microhardness increased with increasing Mo content owing to the precipitation of hard σ phase. The hardness of Mo0.5 coating was comparable to that of the as-cast HEAs mainly being composed of body-centered cubic (BCC) phase. The increase of phase led to abrasive wear and oxidation wear instead of common adhesive wear mechanism. Corrosion resistances of the LP-DED HEAs coatings were superior to that of LP-DED SS316L. The corrosion resistance by electrochemical tests showed Mo0.3 > Mo0.5 > Mo0.1. The corrosion competing effects between sub-grains led to a layer-by-layer uniform corrosion due to the unique microstructure, which prevented the occurrence of large-sized and deep localized pitting corrosion. σ phase can act as a stabilizer to improve significantly the inter-subgranular corrosion resistance at trans-passivated state. This study provides an insight on the multi-effects of Mo in HEAs for fine tuning of sub-granular micro-structures and enhancement of wear and corrosion resistances.

Cyclic voltammetry activation of magnetron sputtered copper–zinc bilayer catalysts for electrochemical CO2 reduction

We present a novel method to prepare bimetallic Cu–Zn catalysts for electrochemical CO2 reduction using sputtering and subsequent electrochemical cyclic voltammetry treatment.

The role of cerebral activation in the sleep-wake cycle

The development of views on cerebral activation in the wakefulness-sleep cycle, starting with the work of Constantin von Economo, is considered. The emphasis is on the cyclic activation of high-amplitude discharges in sleep, which, with known assumptions, can include K-complexes, as well as patterns of delta-like waves. Considering the participation of the peripheral nervous system in this, the integrative role of cyclic activation of high-amplitude discharges in the organization of the sleep-wake cycle is discussed.

Application of the acoustic emission method for ranking by fatigue damage of the material of trunnions of drying cylinders of cardboard and paper-making machines

Using the example of assessing the technical condition of the trunnions of drying cylinders of cardboard-making machines (CDM), the question of the possibility of ranking cyclically loaded elements of dynamic equipment according to the degree of damage to their material by fatigue cracks using acoustic emission (AE) measurements is discussed. As a result of special laboratory studies with varying loads in the cycle of loading and lubrication of the crack banks, the features of AE from the friction of the crack banks and plastic deformation at the crack tip during its growth in a viscous material have been established. It is shown that during cyclic loading of the material, AE signals from the friction of its shores are detected more steadily than AE signals from a crack jump with an increase in its length, and that tracking the former ensures the detection of fatigue damage of the material even under loading conditions insufficient for crack growth. Based on the data obtained, three AE signs of the presence of fatigue damage of the material of the elements of dynamic equipment were developed under the condition of cyclic activation of the movement of the crack banks. As a result of industrial testing of the developed AE features, their operability was confirmed and their boundary values on the operating trunnions of CDM drying cylinders were clarified, and a method for ranking trunnions by the level of damage by fatigue cracks was proposed. By comparing the results of AE measurements with ultrasound control, the reliability of the proposed approach was evaluated, which showed the probability of detecting a fatigue crack in the trunnions of CDM drying cylinders at the level of 71 %, with the probability of their skipping and false rejection of the product 12 and 17 %, respectively. The developed technique is also transferable to other massive dynamic equipment after clarifying the boundary values of AE signs of fatigue damage of the material on this type of object.

A Numerical Study of the Behavior of Micropile Foundations under Cyclic Thermal Loading

Micropiles are small-diameter foundation elements that are widely used in building refurbishment to reinforce existing foundations or provide new foundations where access for construction is difficult. Thermally-activated (TA) micropiles could be useful as an efficient means of providing cost-effective ground-coupling when shallow geothermal energy systems are considered in building rehabilitation. It is well-established that thermal activation of pile foundations results in thermo-mechanical interactions between the pile and the surrounding soil. These thermally-induced effects need to be examined to ensure that they do not adversely impact the load transfer function of the micropile. Numerical analysis is able to produce reliable predictions of thermo-mechanical behavior of TA piles, and this study applied this technique to examine the cyclic thermal behavior of micropiles, isolated and in groups. For the situations considered in this study, it is shown that during cyclic thermal activation, irrecoverable movements are unlikely to be significant in design terms, if the initial mobilization of the shaft resistance is low. Though stable, cyclic thermal movement amplitudes are large enough that they should be considered in design. The study highlights that large changes in thermal stress can develop and be locked-in to the response of long flexible piles, and that these should be verified in design. Further, as pile spacing reduces, thermal interference results in a loss of heat exchange capacity per pile, which has to be considered in the design of large groups of TA micropiles. Therefore, TA micropiles can offer an efficient and secure means of providing ground coupling in shallow geothermal energy systems.

Small cytosolic double-stranded DNA represses cyclic GMP-AMP synthase activation and induces autophagy

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a major mediator of inflammation following stimulation with >45bp double-stranded DNA (dsDNA). Herein, we identify a class of ∼20-40bp small cytosolic dsDNA (scDNA) molecules that compete with long dsDNA (200-1,500bp herring testis [HT]-DNA) for binding to cGAS, thus repressing HT-DNA-induced cGAS activation. The scDNA promotes cGAS and Beclin-1 interaction, releasing Rubicon, a negative regulator of phosphatidylinositol 3-kinase class III (PI3KC3), from the Beclin-1-PI3KC3 complex. This leads to PI3KC3 activation and induces autophagy, causing degradation of STING and long cytosolic dsDNA. Moreover, DNA damage decreases, and autophagy inducers increase scDNA levels. scDNA transfection and treatment with autophagy inducers attenuate DNA damage-induced cGAS activation. Thus, scDNA molecules serve as effective brakes for cGAS activation, preventing excessive inflammatory cytokine production following DNA damage. Our findings may have therapeutic implications for cytosolic DNA-associated inflammatory diseases.

A Direct Comparison of Targeted Muscle Reinnervation and Regenerative Peripheral Nerve Interfaces to Prevent Neuroma Pain.

Targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) surgeries manage neuroma pain; however, there remains considerable discord regarding the best treatment strategy. We provide a direct comparison of TMR and RPNI surgery using a rodent model for the treatment of neuroma pain. The tibial nerve of 36 Fischer rats was transected and secured to the dermis to promote neuroma formation. Pain was assessed using mechanical stimulation at the neuroma site (direct pain) and von Frey analysis at the footpad (to assess tactile allodynia from collateral innervation). Once painful neuromas were detected 6 weeks later, animals were randomized to experimental groups: (a) TMR to the motor branch to biceps femoris, (b) RPNI with an extensor digitorum longus graft, (c) neuroma excision, and (d) neuroma in situ. The TMR/RPNIs were harvested to confirm muscle reinnervation, and the sensory ganglia and nerves were harvested to assess markers of regeneration, pain, and inflammation. Ten weeks post-TMR/RPNI surgery, animals had decreased pain scores compared with controls ( P < .001) and they both demonstrated neuromuscular junction reinnervation. Compared with neuroma controls, immunohistochemistry showed that sensory neuronal cell bodies of TMR and RPNI showed a decrease in regeneration markers phosphorylated cyclic AMP receptor binding protein and activation transcription factor 3 and pain markers transient receptor potential vanilloid 1 and neuropeptide Y ( P < .05). The nerve and dorsal root ganglion maintained elevated Iba-1 expression in all cohorts. RPNI and TMR improved pain scores after neuroma resection suggesting both may be clinically feasible techniques for improving outcomes for patients with nerve injuries or those undergoing amputation.

Mechanosensitive stem cell fate choice is instructed by dynamic fluctuations in activation of Rho GTPases

During the intricate process by which cells give rise to tissues, embryonic and adult stem cells are exposed to diverse mechanical signals from the extracellular matrix (ECM) that influence their fate. Cells can sense these cues in part through dynamic generation of protrusions, modulated and controlled by cyclic activation of Rho GTPases. However, it remains unclear how extracellular mechanical signals regulate Rho GTPase activation dynamics and how such rapid, transient activation dynamics are integrated to yield long-term, irreversible cell fate decisions. Here, we report that ECM stiffness cues alter not only the magnitude but also the temporal frequency of RhoA and Cdc42 activation in adult neural stem cells (NSCs). Using optogenetics to control the frequency of RhoA and Cdc42 activation, we further demonstrate that these dynamics are functionally significant, where high- vs. low-frequency activation of RhoA and Cdc42 drives astrocytic vs. neuronal differentiation, respectively. In addition, high-frequency Rho GTPase activation induces sustained phosphorylation of the TGFβ pathway effector SMAD1, which in turn drives the astrocytic differentiation. By contrast, under low-frequency Rho GTPase stimulation, cells fail to accumulate SMAD1 phosphorylation and instead undergo neurogenesis. Our findings reveal the temporal patterning of Rho GTPase signaling and the resulting accumulation of an SMAD1 signal as a critical mechanism through which ECM stiffness cues regulate NSC fate.

Fission product yields from the U238(n,f) reaction at En=4.6 MeV

We present cumulative fission product yields from the $^{238}\mathrm{U}(n,f)$ reaction at an incident energy of 4.6 MeV for fission products with half-lives from less than one second to several hours. We employed direct $\ensuremath{\gamma}$-ray spectroscopy to measure unseparated fission products with a conventional neutron activation analysis and a cyclic activation technique using the RApid Belt-driven Irradiated Target Transfer System (RABITTS). Yields were determined for 78 isotopes and isomers, covering the mass range $84\ensuremath{\le}A\ensuremath{\le}148$ and the charge range from $33\text{(As)}\ensuremath{\le}Z\ensuremath{\le}58\text{(Ce)}$. Our experimental cumulative yields are compared to the literature and evaluated data at ${E}_{n}\ensuremath{\approx}0.5$ MeV from ENDF/B-VIII.0 and JEFF-3.3 libraries and with theoretical models using the gef and freya codes at ${E}_{n}=4.6$ MeV.

Biglycan Involvement in Heart Fibrosis: Modulation of Adenosine 2A Receptor Improves Damage in Immortalized Cardiac Fibroblasts.

Cardiac fibrosis is a common pathological feature of different cardiovascular diseases, characterized by the aberrant deposition of extracellular matrix (ECM) proteins in the cardiac interstitium, myofibroblast differentiation and increased fibrillar collagen deposition stimulated by transforming growth factor (TGF)-β activation. Biglycan (BGN), a small leucine-rich proteoglycan (SLRPG) integrated within the ECM, plays a key role in matrix assembly and the phenotypic control of cardiac fibroblasts. Moreover, BGN is critically involved in pathological cardiac remodeling through TGF-β binding, thus causing myofibroblast differentiation and proliferation. Adenosine receptors (ARs), and in particular A2AR, may play a key role in stimulating fibrotic damage through collagen production/deposition, as a consequence of cyclic AMP (cAMP) and AKT activation. For this reason, A2AR modulation could be a useful tool to manage cardiac fibrosis in order to reduce fibrotic scar deposition in heart tissue. Therefore, the aim of the present study was to investigate the possible crosstalk between A2AR and BGN modulation in an in vitro model of TGF-β-induced fibrosis. Immortalized human cardiac fibroblasts (IM-HCF) were stimulated with TGF-β at the concentration of 10 ng/mL for 24 h to induce a fibrotic phenotype. After applying the TGF-β stimulus, cells were treated with two different A2AR antagonists, Istradefylline and ZM241385, for an additional 24 h, at the concentration of 10 µM and 1 µM, respectively. Both A2AR antagonists were able to regulate the oxidative stress induced by TGF-β through intracellular reactive oxygen species (ROS) reduction in IM-HCFs. Moreover, collagen1a1, MMPs 3/9, BGN, caspase-1 and IL-1β gene expression was markedly decreased following A2AR antagonist treatment in TGF-β-challenged human fibroblasts. The results obtained for collagen1a1, SMAD3, α-SMA and BGN were also confirmed when protein expression was evaluated; phospho-Akt protein levels were also reduced following Istradefylline and ZM241385 use, thus suggesting that collagen production involves AKT recruited by the A2AR. These results suggest that A2AR modulation might be an effective therapeutic option to reduce the fibrotic processes involved in heart pathological remodeling.

Neuroprotective Effects of Carbonic Anhydrase Inhibition and Cyclic Adenosine Monophosphate Activation in Mouse Model of Transient Global Cerebral Ischemia and Reperfusion.

Cerebral ischemia is the primary basis of stroke, both sharing common pathogenic origins leading to irreversible brain damage if blood supply is not restored promptly. Existing evidence indicates that carbonic anhydrase (CA) inhibitors (CAIs) may impart therapeutic benefits against ischemia-reperfusion (I/R) pathology via the adenylyl cyclase-cyclic adenosine monophosphate (cAMP) pathway. We hypothesize that CAI and cAMP activation may enhance the therapeutic outcome against I/R conditions. In this investigation, the potential of dichlorphenamide (CAI) and the role of cAMP against ischemia-reperfusion injury were evaluated using a transient global cerebral I/R (tGCI/R) model. Swiss albino mice were subjected to bilateral common carotid artery occlusion (BCCAo) for 20min and reperfusion (R) or sham surgery on day 1. Dichlorphenamide (DCPA, 20mg/kg) and/or forskolin (cAMP agonist, 3mg/kg) was administered intraperitoneally (i.p.) after BCCAo/R for 14days. Results showed that tGCI/R impaired neurocognitive functions and lowered brain levels of cAMP and protein kinase A (PKA) that were ameliorated by DCPA and/or forskolin (FSK). DCPA and/or FSK attenuated tGCI/R-induced brain edema, blood-brain barrier dysfunction, oxidative-nitrosative stress, pro-inflammatory cytokines, acetylcholinesterase activity, cell death, and neurotransmitter imbalance (e.g., glutamate, γ-aminobutyric acid). The study showed that DCPA improved neurological and biochemical parameters against tGCI/R injury via cAMP-PKA-mediated activation of protective mechanisms. However, DCPA and FSK in combination showed much enhanced therapeutic outcomes against tGCI/R. Therefore, CA and cAMP present novel targets that may retard the progress of a transient ischemic attack to a full-blown stroke.

Genetic Ablation of the DNA Damage Response Pathway Attenuates Lamin-Associated Dilated Cardiomyopathy in Mice

Hereditary dilated cardiomyopathy (DCM) is a primary disease of cardiac myocytes caused by mutations in genes encoding proteins with a diverse array of functions. Mutations in the LMNA gene, encoding the nuclear envelope protein lamin A/C, are the second most common causes of DCM. The phenotype is characterized by progressive cardiac dysfunction, leading to refractory heart failure, myocardial fibrosis, cardiac arrhythmias, and sudden cardiac death. The molecular pathogenesis of DCM caused by the LMNA mutations is not well known. The LMNA protein is involved in nuclear membrane stability. It is also a guardian of the genome involved in the processing of the topoisomerases at the transcriptionally active domain and the repair of double-stranded DNA breaks (DSBs). Deletion of the mouse Lmna gene in cardiac myocytes leads to premature death, DCM, myocardial fibrosis, and apoptosis. The phenotype is associated with increased expression of the cytosolic DNA sensor cyclic GMP-AMP synthase (CGAS) and activation of the DNA damage response (DDR) pathway. Genetic blockade of the DDR pathway, upon knockout of the Mb21d1 gene encoding CGAS, prolonged survival, improved cardiac function, partially restored levels of molecular markers of heart failure, and attenuated myocardial apoptosis and fibrosis in the LMNA-deficient mice. The findings indicate that targeting the CGAS/DDR pathway might be beneficial in the treatment of DCM caused by mutations in the LMNA gene.

Effect of caffeine on mitochondrial biogenesis in the skeletal muscle - A narrative review.

Caffeine is one of the most widely used substances as recreational drug for performance-enhancement in sport, underpinned by a strong evidence base. Although the effects of caffeine are widely investigated within the scope of performance physiology, the molecular effects of caffeine within skeletal muscle remain unclear. Evidence from invitro and invivo models suggest that caffeine regulates the glucose metabolism in the skeletal muscle. Moreover, caffeine seems to stimulate CaMKII, PPARδ/β, AMPK and PGC1α, classical markers of exercise-adaptations, including mitochondrial biogenesis and mitochondrial content. This review summarizes evidence to suggest caffeine-effects within skeletal muscle fibers, focusing on the putative role of caffeine on mitochondrial biogenesis to explore whether caffeine supplementation might be a strategy to enhance mitochondrial biogenesis.