Modification of Transition-Metal Redox by Interstitial Water in Hexacyanometalate Electrodes for Sodium-Ion Batteries.

A sodium-ion battery (SIB) solution is attractive for grid-scale electrical energy storage. Low-cost hexacyanometalate is a promising electrode material for SIBs because of its easy synthesis and open framework. Most hexacyanometalate-based SIBs work with aqueous electrolyte, and interstitial water in the material has been found to strongly affect the electrochemical profile, but the mechanism remains elusive. Here we provide a comparative study of the transition-metal redox in hexacyanometalate electrodes with and without interstitial water based on soft X-ray absorption spectroscopy and theoretical calculations. We found distinct transition-metal redox sequences in hydrated and anhydrated NaxMnFe(CN)6·zH2O. The Fe and Mn redox in hydrated electrodes are separated and are at different potentials, leading to two voltage plateaus. On the contrary, mixed Fe and Mn redox in the same potential range is found in the anhydrated system. This work reveals for the first time how transition-metal redox in batteries is strongly affected by interstitial molecules that are seemingly spectators. The results suggest a fundamental mechanism based on three competing factors that determine the transition-metal redox potentials. Because most hexacyanometalate electrodes contain water, this work directly reveals the mechanism of how interstitial molecules could define the electrochemical profile, especially for electrodes based on transition-metal redox with well-defined spin states

Integrin α6β4 Upregulates Amphiregulin and Epiregulin Through Base Excision Repair-Mediated DNA Demethylation and Promotes Genome-Wide DNA Hypomethylation

Aberrant DNA methylation patterns are a common theme across all cancer types. Specific DNA demethylation of regulatory sequences can result in upregulation of genes that are critical for tumor development and progression. Integrin α6β4 is highly expressed in pancreatic carcinoma and contributes to cancer progression, in part, through the specific DNA demethylation and upregulation of epidermal growth factor receptor (EGFR) ligands amphiregulin (AREG) and epiregulin (EREG). Whole genome bisulfite sequencing (WGBS) revealed that integrin α6β4 signaling promotes an overall hypomethylated state and site specific DNA demethylation of enhancer elements within the proximal promoters of AREG and EREG. Additionally, we find that the base excision repair (BER) pathway is required to maintain expression of AREG and EREG, as blocking DNA repair molecules, TET1 GADD45A, TDG, or PARP-1 decreased gene expression. Likewise, we provide the novel finding that integrin α6β4 confers an enhanced ability on cells to repair DNA lesions and survive insult. Therefore, while many known signaling functions mediated by integrin α6β4 that promote invasive properties have been established, this study demonstrates that integrin α6β4 can dramatically impact the epigenome of cancer cells, direct global DNA methylation levels toward a hypomethylated state, and impact DNA repair and subsequent cell survival

Preclinical Evaluation of Novel Fatty Acid Synthase Inhibitors in Primary Colorectal Cancer Cells and a Patient-Derived Xenograft Model of Colorectal Cancer

Fatty Acid Synthase (FASN), a key enzyme of de novo lipogenesis, is upregulated in many cancers including colorectal cancer (CRC); increased FASN expression is associated with poor prognosis. Potent FASN inhibitors (TVBs) developed by 3-V Biosciences demonstrate anti-tumor activity in vitro and in vivo and a favorable tolerability profile in a Phase I clinical trial. However, CRC characteristics associated with responsiveness to FASN inhibition are not fully understood. We evaluated the effect of TVB-3664 on tumor growth in nine CRC patient-derived xenografts (PDXs) and investigated molecular and metabolic changes associated with CRC responsiveness to FASN inhibition. CRC cells and PDXs showed a wide range of sensitivity to FASN inhibition. TVB-3664 treatment showed significant response (reduced tumor volume) in 30% of cases. Anti-tumor effect of TVB-3664 was associated with a significant decrease in a pool of adenine nucleotides and alterations in lipid composition including a significant reduction in fatty acids and phospholipids and an increase in lactosylceramide and sphingomyelin in PDXs sensitive to FASN inhibition. Moreover, Akt, Erk1/2 and AMPK were major oncogenic pathways altered by TVBs. In summary, we demonstrated that novel TVB inhibitors show anti-tumor activity in CRC and this activity is associated with a decrease in activation of Akt and Erk1/2 oncogenic pathways and significant alteration of lipid composition of tumors. Further understanding of genetic and metabolic characteristics of tumors susceptible to FASN inhibition may enable patient selection and personalized medicine approaches in CRC

Kinetic Theory Approach to Modeling of Cellular Repair Mechanisms under Genome Stress

Under acute perturbations from outer environment, a normal cell can trigger cellular self-defense mechanism in response to genome stress. To investigate the kinetics of cellular self-repair process at single cell level further, a model of DNA damage generating and repair is proposed under acute Ion Radiation (IR) by using mathematical framework of kinetic theory of active particles (KTAP). Firstly, we focus on illustrating the profile of Cellular Repair System (CRS) instituted by two sub-populations, each of which is made up of the active particles with different discrete states. Then, we implement the mathematical framework of cellular self-repair mechanism, and illustrate the dynamic processes of Double Strand Breaks (DSBs) and Repair Protein (RP) generating, DSB-protein complexes (DSBCs) synthesizing, and toxins accumulating. Finally, we roughly analyze the capability of cellular self-repair mechanism, cellular activity of transferring DNA damage, and genome stability, especially the different fates of a certain cell before and after the time thresholds of IR perturbations that a cell can tolerate maximally under different IR perturbation circumstances

Immunogenicity of a silica nanoparticle-based SARS-CoV-2 vaccine in mice

Safe and effective vaccines have been regarded early on as critical in combating the COVID-19 pandemic. Among the deployed vaccine platforms, subunit vaccines have a particularly good safety profile but may suffer from a lower immunogenicity compared to mRNA based or viral vector vaccines. In fact, this phenomenon has also been observed for SARS-CoV-2 subunit vaccines comprising the receptor-binding domain (RBD) of the spike (S) protein. Therefore, RBD-based vaccines have to rely on additional measures to enhance the immune response. It is well accepted that displaying antigens on nanoparticles can improve the quantity and quality of vaccine-mediated both humoral and cell-mediated immune responses. Based on this, we hypothesized that SARS-CoV-2 RBD as immunogen would benefit from being presented to the immune system via silica nanoparticles (SiNPs). Herein we describe the preparation, in vitro characterization, antigenicity and in vivo immunogenicity of SiNPs decorated with properly oriented RBD in mice. We found our RBD-SiNP conjugates show narrow, homogeneous particle distribution with optimal size of about 100 nm for efficient transport to and into the lymph node. The colloidal stability and binding of the antigen was stable for at least 4 months at storage- and in vivo-temperatures. The antigenicity of the RBD was maintained upon binding to the SiNP surface, and the receptor-binding motif was readily accessible due to the spatial orientation of the RBD. The particles were efficiently taken up in vitro by antigen-presenting cells. In a mouse immunization study using an mRNA vaccine and spike protein as benchmarks, we found that the SiNP formulation was able to elicit a stronger RBD-specific humoral response compared to the soluble protein. For the adjuvanted RBD-SiNP we found strong S-specific multifunctional CD4+ T cell responses, a balanced T helper response, improved auto- and heterologous virus neutralization capacity, and increased serum avidity, suggesting increased affinity maturation. In summary, our results provide further evidence for the possibility of optimizing the cellular and humoral immune response through antigen presentation on SiNP

Impact of snowpack emissions on deduced levels of OH and peroxy radicals at Summit, Greenland

Levels of OH and peroxy radicals in the atmospheric boundary layer at Summit, Greenland, a locationsurrounded by snow from which HOx radical precursors are known to be emitted, were deduced usingsteady-state analyses applied to (OH + HO2 + CH3O2), (OH + HO2), and OHHO2 cycling. The resultsindicate that HOx levels at Summit are significantly increased over those that would result from O3photolysis alone, as a result of elevated concentrations of HONO, HCHO, H2O2, and other compounds.Estimated midday levels of (HO2 + CH3O2) reached 3040 pptv during two summer seasons. Calculated OHconcentrations averaged between 05:00 and 20:00 (or 21:00) exceeded 4 * 10^6 molecules cm^3,comparable to (or higher than) levels expected in the tropical marine boundary layer. These findingsimply rapid photochemical cycling within the boundary layer at Summit, as well as in the upper pore spacesof the surface snowpack. The photolysis rate constants and OH levels calculated here imply that gas-phasephotochemistry plays a significant role in the budgets of NOx, HCHO, H2O2, HONO, and O3, compounds thatare also directly affected by processes within the snowpack

S-club: An overlay based efficient service discovery mechanism in CROWN grid

Information service plays a key role in Grid system, handles resource discovery and management process. Employing existing information service architectures suffers from poor scalability, long search response time, and large traffic overhead. In this paper, we propose a service club mechanism, called S-Club, for efficient service discovery. In S-Club, an overlay based on existing GIS mesh network of CROWN is built, so that GISs are organized as service clubs. Each club serves for a certain type of service while each GIS may join one or more clubs. S-Club is adopted in RLDS as the information service in CROWN Grid and the performance of S-Club is evaluated by comprehensive simulations. The results show that S-Club scheme significantly improves search performance and outperforms existing approaches. © 2005 IEEE