pADP-ribosylation regulates the cytoplasmic localization, cleavage, and pro-apoptotic function of HuR.

HuR (ElavL1) is one of the main post-transcriptional regulators that determines cell fate. Although the role of HuR in apoptosis is well established, the post-translational modifications that govern this function remain elusive. In this study, we show that PARP1/2-mediated poly(ADP)-ribosylation (PARylation) is instrumental in the pro-apoptotic function of HuR. During apoptosis, a substantial reduction in HuR PARylation is observed. This results in the cytoplasmic accumulation and the cleavage of HuR, both of which are essential events for apoptosis. These effects are mediated by a pADP-ribose-binding motif within the HuR-HNS region (HuR PAR-binding site). Under normal conditions, the association of the HuR PAR-binding site with pADP-ribose is responsible for the nuclear retention of HuR. Mutations within this motif prevent the binding of HuR to its import factor TRN2, leading to its cytoplasmic accumulation and cleavage. Collectively, our findings underscore the role of PARylation in controlling the pro-apoptotic function of HuR, offering insight into the mechanism by which PARP1/2 enzymes regulate cell fate and adaptation to various assaults.

Tankyrase-1 regulates RBP-mediated mRNA turnover to promote muscle fiber formation.

Poly(ADP-ribosylation) (PARylation) is a post-translational modification mediated by a subset of ADP-ribosyl transferases (ARTs). Although PARylation-inhibition based therapies are considered as an avenue to combat debilitating diseases such as cancer and myopathies, the role of this modification in physiological processes such as cell differentiation remains unclear. Here, we show that Tankyrase1 (TNKS1), a PARylating ART, plays a major role in myogenesis, a vital process known to drive muscle fiber formation and regeneration. Although all bona fide PARPs are expressed in muscle cells, experiments using siRNA-mediated knockdown or pharmacological inhibition show that TNKS1 is the enzyme responsible of catalyzing PARylation during myogenesis. Via this activity, TNKS1 controls the turnover of mRNAs encoding myogenic regulatory factors such as nucleophosmin (NPM) and myogenin. TNKS1 mediates these effects by targeting RNA-binding proteins such as Human Antigen R (HuR). HuR harbors a conserved TNKS-binding motif (TBM), the mutation of which not only prevents the association of HuR with TNKS1 and its PARylation, but also precludes HuR from regulating the turnover of NPM and myogenin mRNAs as well as from promoting myogenesis. Therefore, our data uncover a new role for TNKS1 as a key modulator of RBP-mediated post-transcriptional events required for vital processes such as myogenesis.

Thin-Film Composite Membranes for Hydrogen Evolution with a Saline Catholyte Water Feed.

Hydrogen gas evolution using an impure or saline water feed is a promising strategy to reduce overall energy consumption and investment costs for on-site, large-scale production using renewable energy sources. The chlorine evolution reaction is one of the biggest concerns in hydrogen evolution with impure water feeds. The "alkaline design criterion" in impure water electrolysis was examined here because water oxidation catalysts can exhibit a larger kinetic overpotential without interfering chlorine chemistry under alkaline conditions. Here, we demonstrated that relatively inexpensive thin-film composite (TFC) membranes, currently used for high-pressure reverse osmosis (RO) desalination applications, can have much higher rejection of Cl- (total crossover of 2.9 ± 0.9 mmol) than an anion-exchange membrane (AEM) (51.8 ± 2.3 mmol) with electrolytes of 0.5 M KOH for the anolyte and 0.5 M NaCl for the catholyte with a constant current (100 mA/cm2 for 20 h). The membrane resistances, which were similar for the TFC membrane and the AEM based on electrochemical impedance spectroscopy (EIS) and Ohm's law methods, could be further reduced by increasing the electrolyte concentration or removal of the structural polyester supporting layer (TFC-no PET). TFC membranes could enable pressurized gas production, as this membrane was demonstrated to be mechanically stable with no change in permeate flux at 35 bar. These results show that TFC membranes provide a novel pathway for producing green hydrogen with a saline water feed at elevated pressures compared to systems using AEMs or porous diaphragms.

A Review of Potential Electrochemical Applications in Buildings for Energy Capture and Storage.

The integration of distributed renewable energy technologies (such as building-integrated photovoltaics (BIPV)) into buildings, especially in space-constrained urban areas, offers sustainable energy and helps offset fossil-fuel-related carbon emissions. However, the intermittent nature of these distributed renewable energy sources can negatively impact the larger power grids. Efficient onsite energy storage solutions capable of providing energy continuously can address this challenge. Traditional large-scale energy storage methods like pumped hydro and compressed air energy have limitations due to geography and the need for significant space to be economically viable. In contrast, electrochemical storage methods like batteries offer more space-efficient options, making them well suited for urban contexts. This literature review aims to explore potential substitutes for batteries in the context of solar energy. This review article presents insights and case studies on the integration of electrochemical energy harvesting and storage into buildings. The seamless integration can provide a space-efficient source of renewable energy for new buildings or existing structures that often have limited physical space for retrofitting. This work offers a comprehensive examination of existing research by reviewing the strengths and drawbacks of various technologies for electrochemical energy harvesting and storage, identifying those with the potential to integrate into building skins, and highlighting areas for future research and development.

Computational Quantum Chemistry Insights into the Mechanism of VO2 + Reduction on Graphene-Based Electrodes.

The identity of active sites for redox reactions within vanadium redox flow batteries (VRFBs) isstill controversial despite decades of research into the matter. Here, we use density functional theory to examine the premise of selected surface functional groups as active sites and provide mechanistic insights into the reaction pathway for the positive electrode reaction. The adsorption of electroactive species on phenol and carbene-like edge carbon sites was compared using model aromatic clusters. Phenol groups were not favorable sites for the chemisorption of VO2 + in either V-down or O-down approach In contrast, carbene-like edge carbon sites readily adsorbed VO2 + via an oxygen-down approach, mimicking gas-phase CO2 adsorption mechanisms. Subsequent steps to complete the reaction pathway are a series of proton adsorptions and reaction products desorption. The rate-determining step for a reaction pathway using an edge site is VO2+ desorption step with a Gibbs energy of activation of +84 kcal mol-1 .

GLI3 regulates muscle stem cell entry into GAlert and self-renewal.

Satellite cells are required for the growth, maintenance, and regeneration of skeletal muscle. Quiescent satellite cells possess a primary cilium, a structure that regulates the processing of the GLI family of transcription factors. Here we find that GLI3 processing by the primary cilium plays a critical role for satellite cell function. GLI3 is required to maintain satellite cells in a G0 dormant state. Strikingly, satellite cells lacking GLI3 enter the GAlert state in the absence of injury. Furthermore, GLI3 depletion stimulates expansion of the stem cell pool. As a result, satellite cells lacking GLI3 display rapid cell-cycle entry, increased proliferation and augmented self-renewal, and markedly enhanced regenerative capacity. At the molecular level, we establish that the loss of GLI3 induces mTORC1 signaling activation. Therefore, our results provide a mechanism by which GLI3 controls mTORC1 signaling, consequently regulating muscle stem cell activation and fate.

Thermodynamic and Kinetic Analyses of Ion Intercalation/Deintercalation Using Different Temperatures on NiHCF Electrodes for Battery Electrode Deionization.

Prussian blue analogues are used in electrochemical deionization due to their cation sorption capabilities and ion selectivity properties. Elucidating the fundamental mechanisms underlying intercalation/deintercalation is important for the development of ion-selective electrodes. We examined the thermodynamic and kinetic properties of nickel hexacyanoferrate electrodes by studying different temperatures effects on intercalation/deintercalation with monovalent ions (Li+, Na+, K+, and NH4+) relevant to battery electrode deionization applications. Higher temperatures reduced the interfacial charge transfer resistance and increased the diffusion coefficient of cations in the solid material. Ion transport in the solid material, rather than interfacial charge transfer, was found to be the rate-controlling step, as shown by higher activation energies for ion transport (e.g., 31 ± 3 kJ/mol for K+) than for interfacial charge transfer (5 ± 1 kJ/mol for K+). The largest increase in cation adsorption capacity with temperature was observed for NH4+ (28.1% from 15 to 75 °C) due to its smallest activation energy. These results indicate that ion hydration energy determines the intercalation potential and activation energies of ion transport in solid material control intercalation/deintercalation rate. Together with the endothermic behavior of deintercalation and exothermic behavior of intercalation, the higher operating temperature results in improvement of ion adsorption capacity depending on specific cations.

Influence of Hydrotropes on the Solubilities and Diffusivities of Redox-Active Organic Compounds for Aqueous Flow Batteries.

In this study, we explored the extent to which hydrotropes can be used to increase the aqueous solubilities of redox-active compounds previously used in flow batteries. We measured how five hydrotropes influenced the solubilities of five redox-active compounds already soluble in aqueous electrolytes (≥0.5 M). The solubilities of the compounds varied as a function of hydrotrope type and concentration, with larger solubility changes observed at higher hydrotrope concentrations. 4-OH-TEMPO underwent the largest solubility increase (1.18 ± 0.04 to 1.99 ± 0.12 M) in 20 weight percent sodium xylene sulfonate. The presence of a hydrotrope in solution decreased the diffusion coefficients of 4-OH-TEMPO and 4,5-dihydroxy-1,3-benzenedisulfonate, which was likely due to the increased solution viscosity as opposed to a specific hydrotrope-solute interaction because the hydrotropes did not alter their molecules' hydraulic radii. The standard rate constants and formal potentials of both 4-OH-TEMPO and 4,5-dihydroxy-1,3-benzenedisulfonate remained largely unchanged in the presence of a hydrotrope. The results suggest that using hydrotropes may be a feasible strategy for increasing the solubilities of redox-active compounds in aqueous flow batteries without substantially altering their electrochemical properties.

Pharmacological or genetic inhibition of iNOS prevents cachexia-mediated muscle wasting and its associated metabolism defects.

Cachexia syndrome develops in patients with diseases such as cancer and sepsis and is characterized by progressive muscle wasting. While iNOS is one of the main effectors of cachexia, its mechanism of action and whether it could be targeted for therapy remains unexplored. Here, we show that iNOS knockout mice and mice treated with the clinically tested iNOS inhibitor GW274150 are protected against muscle wasting in models of both septic and cancer cachexia. We demonstrate that iNOS triggers muscle wasting by disrupting mitochondrial content, morphology, and energy production processes such as the TCA cycle and acylcarnitine transport. Notably, iNOS inhibits oxidative phosphorylation through impairment of complexes II and IV of the electron transport chain and reduces ATP production, leading to energetic stress, activation of AMPK, suppression of mTOR, and, ultimately, muscle atrophy. Importantly, all these effects were reversed by GW274150. Therefore, our data establish how iNOS induces muscle wasting under cachectic conditions and provide a proof of principle for the repurposing of iNOS inhibitors, such as GW274150 for the treatment of cachexia.

Depletion of HuR in murine skeletal muscle enhances exercise endurance and prevents cancer-induced muscle atrophy.

The master posttranscriptional regulator HuR promotes muscle fiber formation in cultured muscle cells. However, its impact on muscle physiology and function in vivo is still unclear. Here, we show that muscle-specific HuR knockout (muHuR-KO) mice have high exercise endurance that is associated with enhanced oxygen consumption and carbon dioxide production. muHuR-KO mice exhibit a significant increase in the proportion of oxidative type I fibers in several skeletal muscles. HuR mediates these effects by collaborating with the mRNA decay factor KSRP to destabilize the PGC-1α mRNA. The type I fiber-enriched phenotype of muHuR-KO mice protects against cancer cachexia-induced muscle loss. Therefore, our study uncovers that under normal conditions HuR modulates muscle fiber type specification by promoting the formation of glycolytic type II fibers. We also provide a proof-of-principle that HuR expression can be targeted therapeutically in skeletal muscles to combat cancer-induced muscle wasting.

Alternative polyadenylation and the stress response.

The cellular stress response is a universal mechanism necessary for the survival of all organisms. This multifaceted process is primarily driven by regulation of gene expression to produce an intracellular environment suitable for promoting cell survival and recovery. Posttranscriptional regulatory events are considered as critical mechanisms that modulate core characteristics of mRNA transcripts to promote cell adaptation to various assaults. While the impact of processes such as mRNA splicing, turnover, localization, and translation on the cellular stress response has been extensively studied, recent observations highlight the role of alternative polyadenylation (APA) in response to challenges such as oxidative stress, heat shock, and starvation. The role of APA is comprehensive with far reaching effects on mRNA stability, mRNA localization, and protein coding sequences. Nonetheless, APA remains a relatively unappreciated mode of gene regulation despite its role in regulating key mediators of the stress response. The goal of this review is to provide an overview of the recent advances in our understanding of the various ways by which APA affects cell adaptation to its environment and discuss how a defect in APA could have deleterious consequences on cell survival. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA Processing > 3' End Processing.

Electrochemical impedance spectroscopy and finite element analysis modeling of a 4-electrode humidity sensor for natural gas transportation pipelines.

Reliable corrosion monitoring of natural gas transmission lines is a major tool providing a foundation for safe management of natural gas infrastructures. Through the development of membrane-based electrochemical sensors which are able to function in low-conductivity gas environments, corrosion monitoring practices can be further strengthened by real-time monitoring of key risk factors such as relative humidity and corrosion rates of corrodible structures. In this work, we demonstrate and validate how a 4-electrode conductivity sensor can provide a means to monitor relative humidity in gases via electrochemical impedance spectroscopy through finite element analysis (FEA). For a relative humidity range of 5%-55%, the impedance response varied from 1 kΩ to 66 kΩ, showing a high sensitivity for gas humidity. To confirm that the measured impedance values reliably interpreted relative humidity, it was found that precise estimation of the sensor's cell constant was needed. FEA was used to assess how the cell constant depended on the electrode geometry, membrane geometry, and electrode placement within the sensor. Through this approach, assumptions about the characteristic area and length were validated using electrolyte equipotential and current density vector mapping. This reduced possible cell constant uncertainties by 70%. With a cell constant of 14.84 cm-1, obtained via FEA, membrane conductivity values were in good agreement with published data.

The AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation-associated cachectic muscle wasting.

Activation of AMPK has been associated with pro-atrophic signaling in muscle. However, AMPK also has anti-inflammatory effects, suggesting that in cachexia, a syndrome of inflammatory-driven muscle wasting, AMPK activation could be beneficial. Here we show that the AMPK agonist AICAR suppresses IFNγ/TNFα-induced atrophy, while the mitochondrial inhibitor metformin does not. IFNγ/TNFα impair mitochondrial oxidative respiration in myotubes and promote a metabolic shift to aerobic glycolysis, similarly to metformin. In contrast, AICAR partially restored metabolic function. The effects of AICAR were prevented by the AMPK inhibitor Compound C and were reproduced with A-769662, a specific AMPK activator. AICAR and A-769662 co-treatment was found to be synergistic, suggesting that the anti-cachectic effects of these drugs are mediated through AMPK activation. AICAR spared muscle mass in mouse models of cancer and LPS induced atrophy. Together, our findings suggest a dual function for AMPK during inflammation-driven atrophy, wherein it can play a protective role when activated exogenously early in disease progression, but may contribute to anabolic suppression and atrophy when activated later through mitochondrial dysfunction and subsequent metabolic stress.

STAT3 promotes IFNγ/TNFα-induced muscle wasting in an NF-κB-dependent and IL-6-independent manner.

Cachexia is a debilitating syndrome characterized by involuntary muscle wasting that is triggered at the late stage of many cancers. While the multifactorial nature of this syndrome and the implication of cytokines such as IL-6, IFNγ, and TNFα is well established, we still do not know how various effector pathways collaborate together to trigger muscle atrophy. Here, we show that IFNγ/TNFα promotes the phosphorylation of STAT3 on Y705 residue in the cytoplasm of muscle fibers by activating JAK kinases. Unexpectedly, this effect occurs both in vitro and in vivo independently of IL-6, which is considered as one of the main triggers of STAT3-mediated muscle wasting. pY-STAT3 forms a complex with NF-κB that is rapidly imported to the nucleus where it is recruited to the promoter of the iNos gene to activate the iNOS/NO pathway, a well-known downstream effector of IFNγ/TNFα-induced muscle loss. Together, these findings show that STAT3 and NF-κB respond to the same upstream signal and cooperate to promote the expression of pro-cachectic genes, the identification of which could provide effective targets to combat this deadly syndrome.

Radionuclides in bats using a contaminated pond on the Nevada National Security Site, USA.

Perched groundwater percolating through radionuclide contamination in the E Tunnel Complex on the Nevada National Security Site, formerly the Nevada Test Site, emerges and is stored in a series of ponds making it available to wildlife, including bats. Since many bat species using the ponds are considered sensitive or protected/regulated and little information is available on dose to bats from radioactive water sources, bats were sampled to determine if the dose they were receiving exceeded the United States Department of Energy dose limit of 1.0E-3 Gy/day. Radionuclide concentrations in water, sediment, and flying insects were also measured as input parameters to the dose rate model and to examine trophic level relationships. The RESRAD-Biota model was used to calculate dose rates to bats using different screening levels. Efficacy of RESRAD-Biota and suggested improvements are discussed. Dose to bats foraging and drinking at these ponds is well below the dose limit set to protect terrestrial biota populations.

The translation inhibitor pateamine A prevents cachexia-induced muscle wasting in mice.

Cachexia, or muscle-wasting syndrome, is one of the major causes of death in patients affected by diseases such as cancer, AIDS and sepsis. However, no effective anti-cachectic treatment is currently available. Here we show that a low dose of pateamine A, an inhibitor of translation initiation, prevents muscle wasting caused by the cytokines interferon γ and tumour necrosis factor α or by C26-adenocarcinoma tumours. Surprisingly, although high doses of pateamine A abrogate general translation, low doses selectively inhibit the expression of pro-cachectic factors such as inducible nitric oxide synthase. This selectivity depends on the 5'UTR of inducible nitric oxide synthase messenger RNA (mRNA) that, unlike the 5'UTR of MyoD mRNA, promotes the recruitment of inducible nitric oxide synthase mRNA to stress granules, where its translation is repressed. Collectively, our data provide a proof of principle that nontoxic doses of compounds such as pateamine A could be used as novel drugs to combat cachexia-induced muscle wasting.

The impact of mRNA turnover and translation on age-related muscle loss.

The deterioration of skeletal muscle that develops slowly with age, termed sarcopenia, often leads to disability and mortality in the elderly population. As the proportion of elderly citizens continues to increase due to the dramatic rise in life expectancy, there are rising concerns about the healthcare cost and social burden of caring for geriatric patients. Thus, there is a growing need to understand the underlying mechanisms of sarcopenic muscle loss so that more efficacious therapies may be developed. Building evidence suggests that the onset of age-related muscle loss is linked to the age-related changes in gene expression that occur during sarcopenia. In recent work, the posttranscriptional regulation of gene expression by RNA-binding proteins (RBPs) and microRNA (miRNA) involved in the turnover and translation of mRNA were shown as key players believed to be involved in the induction of muscle wasting. Furthermore, posttranscriptional regulation may also be linked to the reduced ability of muscle satellite cells to contribute to muscle mass during ageing, a key contributing factor to sarcopenic progression. Here we highlight how the activation of pathways such as the p38 MAPK and the phosphoinositide 3-kinase (PI3K) pathways alter the ability of RBPs to regulate the expression of their target mRNAs encoding proteins involved in cell cycle (p21 and p16), as well as myogenesis (Pax7, myogenin and MyoD). Further investigation into the role of RBPs and miRNA during sarcopenia may provide new insights into the development and progression of this disorder, which may lead to the development of new treatment options for elderly patients suffering from sarcopenia.

Prosthodontic maintenance requirements of implant-retained overdentures using the locator attachment system.

The aim of this study was to investigate the prosthodontic maintenance requirements of patients rehabilitated with maxillary and mandibular implant-retained overdentures using the Locator Attachment System by retrospectively reviewing case records. Fifty patients made 112 unplanned return visits over a 3-year period. The most common reasons for returning were denture adjustments (n = 45), inadequate retention (n = 39), and loosening of the implant abutments (n = 14). Implant-retained overdentures using the Locator Attachment System have comparable prosthodontic maintenance requirements to other attachment systems. Problems associated with these prostheses are usually simple to resolve chairside.

Inducible nitric oxide synthase (iNOS) in muscle wasting syndrome, sarcopenia, and cachexia.

Muscle atrophy-also known as muscle wasting-is a debilitating syndrome that slowly develops with age (sarcopenia) or rapidly appears at the late stages of deadly diseases such as cancer, AIDS, and sepsis (cachexia). Despite the prevalence and the drastic detrimental effects of these two syndromes, there are currently no widely used, effective treatment options for those suffering from muscle wasting. In an attempt to identify potential therapeutic targets, the molecular mechanisms of sarcopenia and cachexia have begun to be elucidated. Growing evidence suggests that inflammatory cytokines may play an important role in the pathology of both syndromes. As one of the key cytokines involved in both sarcopenic and cachectic muscle wasting, tumor necrosis factor α (TNFα) and its downstream effectors provide an enticing target for pharmacological intervention. However, to date, no drugs targeting the TNFα signaling pathway have been successful as a remedial option for the treatment of muscle wasting. Thus, there is a need to identify new effectors in this important pathway that might prove to be more efficacious targets. Inducible nitric oxide synthase (iNOS) has recently been shown to be an important mediator of TNFα-induced cachectic muscle loss, and studies suggest that it may also play a role in sarcopenia. In addition, investigations into the mechanism of iNOS-mediated muscle loss have begun to reveal potential therapeutic strategies. In this review, we will highlight the potential for targeting the iNOS/NO pathway in the treatment of muscle loss and discuss its functional relevance in sarcopenia and cachexia.

Premixed antibiotic bone cement: an in vitro comparison of antimicrobial efficacy.

After Food and Drug Administration (FDA) approval of premixed antibiotic bone cements (polymethylmethacrylate [PMMA]), these products are being used with increasing frequency during revision and primary hip and knee arthroplasties. To date, no studies have compared the antimicrobial efficacy of more than 2 products directly. Using a 7-day modified Kirby-Bauer assay, we assessed the in vitro antibacterial properties of 5 FDA-approved, commercially available antibiotic PMMAs. Significant differences in antimicrobial activity were noted among the antibiotic PMMA products included in this investigation. Antibacterial activity of all products tested was greatest on day 1 and rapidly diminished thereafter. Results of this investigation suggest that the antibacterial efficacies of premixed antibiotic PMMA products are not equivalent.