Cycle Progression Research Articles

Interleukin-22 promotes endometrial carcinoma cell proliferation and cycle progression via ERK1/2 and p38 activation.

Endometrial carcinoma (EC) is one of the most common gynecological malignant tumors, but its underlying pathogenic mechanisms are largely obscure. Interleukin-22 (IL-22), one cytokine in the tumor immune microenvironment, was reported to be associated with carcinoma progression. Here, we aimed to investigate the regulation of IL-22 in endometrial carcinoma. Enzyme-linked immunosorbent assay (ELISA) analysis of IL-22 was done in 27 controls and 51 patients with EC. We examined the proliferative potential, cycle progression, and signaling pathways modulated by IL-22 in EC cells. Western blot analysis was performed to investigate the expression of proliferative and cycle-related proteins in EC cells. The effect of IL-22 mediated by interleukin-22 receptor alpha 1 (IL-22RA1) was examined using cell transfection with small interfering RNA (siRNA). In addition, a xenograft tumor model was performed to assess the effect of IL-22 in vivo. We demonstrated significant up-regulation of serum IL-22 concentrations in EC patients (42.59 ± 23.72pg/mL) compared to the control group (27.47 ± 8.29pg/mL). High levels of IL-22 concentrations appear to correlate with malignant clinicopathological features of EC. Treatment with IL-22 promoted cell proliferation and G1/S phase progression in Ishikawa and HEC-1B cells. Western blot analysis revealed that c-Myc, cyclin E1, cyclin-dependent kinase (CDK)2, cyclin D1, CDK4, CDK6, p-extracellular signal-regulated kinase1/2 (p-ERK1/2), and p-p38 were highly expressed in EC cells exposed to IL-22. Moreover, in the EC mice model, we found that giving exogenous IL-22 increased tumor volume and weight. Immunohistochemistry showed that intra-tumor Ki-67 expression was up-regulated upon IL-22 treatment. The IL-22-mediated changes in cell proliferation, cycle progression, and protein expression can be effectively inhibited by the ERK1/2 inhibitor U0126 and the p38 inhibitor SB202190. In addition, the role of IL-22 in EC is receptor-dependent. Our findings suggest that IL-22 promotes endometrial carcinoma cell proliferation and G1/S phase progression by activating ERK1/2 and p38 signaling. Therefore, IL-22 may represent a potential therapeutic target for the treatment of endometrial carcinoma.

Hepatitis B Virus-Induced Resistance to Sorafenib and Lenvatinib in Hepatocellular Carcinoma Cells: Implications for Cell Viability and Signaling Pathways.

Background/Objectives: Sorafenib and lenvatinib are tyrosine kinase inhibitors used in hepatocellular carcinoma (HCC) treatment. This study investigates how hepatitis B virus (HBV) infection affects their efficacy in HepG2 hepatoma cells. Methods: HepG2 and HBV-infected HepG2/2215 cells were treated with varying concentrations of both drugs. The cell viability, cell cycle gene expression, cycle progression, and phosphorylation levels of ERK and AKT were analyzed. Results: The HBV-infected cells showed significant alterations in their cell cycle gene expressions, with an 80-fold increase in CCND2 expression and a higher proportion of cells in the G2/M phase, indicating enhanced proliferation. While both drugs decreased HepG2 cell viability in a concentration-dependent manner, HBV infection conferred resistance, as evidenced by the increased viable cells in the HepG2/2215 cultures. Sorafenib and lenvatinib decreased key cyclin and cyclin-dependent kinase expressions in uninfected cells, with less effect on the HBV-infected cells. Both drugs lowered the pERK and pAKT levels in the HepG2 cells. In the HBV-infected cells, sorafenib reduced the pERK and pAKT levels to a lesser extent. However, treatment with lenvatinib elevated the levels of pERK and pAKT. Conclusions: In conclusion, HBV infection increases resistance to both sorafenib and lenvatinib in hepatoma cells by influencing the cell cycle regulatory genes and critical signaling pathways. However, the resistance mechanisms likely differ between the two medications.

TARDBP drives T-cell acute lymphoblastic leukemia progression by binding MDM2 mRNA, involving β-catenin pathway.

T-cell acute lymphoblastic leukemia (T-ALL) is a dangerous hematological malignancy. The trans-activation response DNA binding protein (TARDBP), an RNA/DNA binding protein, is involved in the growth and metastasis of multiple cancers. However, TARDBP has not been reported in T-ALL. It was found that TARDBP was highly expressed in pediatric T-ALL samples by microarray GSE26713 (log2 fold change >1, p < .05). Herein, TARDBP was silenced and overexpressed by lentivirus transduction in T-ALL cell lines, including Jurkat and Molt4 cells. Invitro, silencing TARDBP inhibited T-ALL cell proliferation and cycle progression and accelerated cell apoptosis, while overexpressing TARDBP induced the opposite effects. In addition, we investigated whether the β-catenin pathway could be activated by TARDBP in T-ALL cells. Moreover, XAV-939, a β-catenin inhibitor, was capable of suppressing the malignant phenotypes in TARDBP-overexpressed T-ALL cells. Invivo, TARDBP-silenced or TARDBP-overexpressed T-ALL cells were injected into mice. We found that TARDBP promoted T-ALL cell growth in the spleens and bone marrows of mice. On the basis of GSE26713, there was a significant correlation between TARDBP and mouse double minute 2 (MDM2). The RIP-PCR assay demonstrated that TARDBP bound MDM2 mRNA in T-ALL cells. The rescue experiments further revealed the roles of the TARDBP/MDM2 axis in T-ALL cell phenotypes, which was also reflected by mRNA-seq. In aggregate, we explored a promising biomarker, TARDBP, for T-ALL treatment. The underlying mechanisms might involve the interaction with MDM2 mRNA and the regulation of the β-catenin pathway.

The development of grain resolved stress fields around notch tips in soft-textured zirconium polycrystals: A three-dimensional synchrotron X-ray diffraction study

Texture, microstructure, and local grain neighbourhood contribute to the development of localized stresses in polycrystals. For hexagonal close-packed materials, crystal's elastic and plastic anisotropy can also be a major contributing factor, yet there is a paucity of experimental studies focusing on the extent of contribution of such parameters on the magnitude of localized stresses at microscales. This study focuses on addressing this knowledge gap by deforming double-edge-notched soft-textured α-zirconium specimens in-situ, while measuring grain scale tensorial stresses using high energy synchrotron X-ray diffraction. The specimens were subjected to cyclic loads to study the evolution of stresses in the vicinity of both shallow and deep notches. The soft-texture of the specimens is such that there are no c-axes of grains aligned along the macroscopic loading direction thereby inhibiting deformation twinning. The “as-measured” microstructures and notch geometries were imported into a crystal plasticity finite element model for further analysis. Results show that despite the absence of c-axes of grains aligned along loading direction, the developed stresses were substantially influenced by crystallographic orientations. Stress drop was observed near the onset of plasticity with further loading and the orientation and position effects were highlighted. A plastic deformation mechanism was revealed where, upon specimen loading, the mechanical constraints enforced during grain-grain interactions led to hardening. Accordingly, a parameter was devised to quantify the grain level hardening arising from this mechanism. It was shown that grain-scale stress concentration factors vary significantly before the onset of plasticity, but they settle in the plastic zone and with the progression of cycles.

The Role of the PI3K/Akt/mTOR Axis in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies globally, representing a significant public health problem with a poor prognosis. The development of efficient therapeutic strategies for HNSCC prevention and treatment is urgently needed. The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved transduction network in eukaryotic cells that promotes cell survival, growth, and cycle progression. Dysfunction in components of this pathway, such as hyperactivity of PI3K, loss of PTEN function, and gain-of-function mutations in AKT, are well-known drivers of treatment resistance and disease progression in cancer. In this review, we discuss the major mutations and dysregulations in the PAM signaling pathway in HNSCC. We highlight the results of clinical trials involving inhibitors targeting the PAM signaling pathway as a strategy for treating HNSCC. Additionally, we examine the primary mechanisms of resistance to drugs targeting the PAM pathway and potential therapeutic strategies.

Coordinated Control Method for Unequal-Cycle Adjacent Intersections Using Vehicle–Road Collaboration

In areas with significant changes in traffic demand and high vehicle dispersion at adjacent intersections, such as the surrounding roads of large shopping malls and schools, traffic problems are prone to occur. This is due to the unequal signal cycle lengths used at upstream and downstream intersections, which lead to periodic phase offsets as the cycles progress. To address this, we propose a multi-strategy integrated vehicle–road coordinated control method to tackle traffic flow operational issues caused by the offset characteristics of unequal-cycle adjacent intersections. A multi-strategy combined algorithm and control logic is established, which includes downstream intersection coordinated phase green extension, dynamic offset adjustment, and transitional queue speed guidance. The proposed method can substantially minimize the offset from falling into an incompatible threshold, effectively reducing queuing and early arrival of vehicles in the straight-through direction. It enables arriving vehicles to pass through the intersection without or with minimal stopping. Finally, the effectiveness of the method is validated using simulation experiments. A vehicle–road coordinated simulation verification platform was established, and comparative experiments were designed. The results indicate that the multi-strategy combined vehicle–road coordinated control method proposed in this paper, while ensuring the original through capacity for straight movements, can effectively reduce queue lengths, the number of stops, average vehicle delay, and travel time for single-direction straight lanes. This improvement enhances the efficiency of coordinated movements in the unequal–cycle adjacent intersections.

METTL14 contributes to the progression of nasopharyngeal carcinoma through regulating the stability of AOC1 mRNA

BackgroundNasopharyngeal carcinoma (NPC) is a malignant epithelial tumor of the nasopharyngeal mucosa with a high incidence rate all over the world. Methyltransferase-like 14 (METTL14) is a major RNA N6-adenosine methyltransferase implicated in tumor progression by regulating RNA function. This study is designed to explore the biological function and mechanism of METTL14 in NPC.MethodsMETTL14 and Amine oxidase copper containing 1 (AOC1) expression were detected by real-time quantitative polymerase chain reaction (RT-qPCR). The protein levels of METTL14, AOC1, Cyclin D1, B-cell lymphoma-2 (Bcl-2), and N-cadherin were measured using western blot. Cell proliferation, cycle progression, apoptosis, migration, and invasion were assessed using 5-ethynyl-2’-deoxyuridine (EdU), Colony formation, flow cytometry, wound scratch, and transwell assays. The interaction between METTL14 and AOC1 was verified using RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), and dual-luciferase reporter assays. The biological role of METTL14 on NPC tumor growth was examined by the xenograft tumor model in vivo.ResultsMETTL14 and AOC1 were highly expressed in NPC tissues and cells. Moreover, METTL14 knockdown might block NPC cell proliferation, migration, invasion, and induce cell apoptosis in vitro. In mechanism, METTL14 might enhance the stability of AOC1 mRNA via m6A methylation. METTL14 silencing might repress NPC tumor growth in vivo.ConclusionMETTL14 might boosted the development of NPC cells partly by regulating the stability of AOC1 mRNA, which provided a promising therapeutic target for NPC treatment.

Inhibition of Melanoma Cell Growth by Salvianolic Acid A through CHK2-CDC25A Pathway Modulation.

This study investigated the impact of salvianolic acids, derived from Danshen, on melanoma cell growth. Specifically, we assessed the ability of salvianolic acid A (Sal A) to modulate melanoma cell proliferation. We used human melanoma A2058 and A375 cell lines to investigate the effects of Sal A on cell proliferation and death by measuring bromodeoxyuridine incorporation and lactate dehydrogenase release. We assessed cell viability and cycle progression using water soluble tetrazolium salt-1 (WST-1) mitochondrial staining and propidium iodide. Additionally, we used a phospho-kinase array to investigate intracellular kinase phosphorylation, specifically measuring the influence of Sal A on checkpoint kinase-2 (Chk-2) via western blot analysis. Sal A inhibited the growth of A2058 and A375 cells dose-responsively and induced cell cycle arrest at the G2/M phase. Notably, Sal A selectively induces Chk-2 phosphorylation without affecting Chk-1, thereby degrading Chk-2-regulated genes Cdc25A and Cdc2. However, Sal A does not affect the Chk1-Cdc25C pathway. Salvianolic acids, especially Sal A, effectively hinder melanoma cell growth by inducing Chk-2 phosphorylation and disrupting G2/M checkpoint regulation.

Abstract 3043: MYC activation and PTEN loss synergistically activate proliferation in a mouse model of lethal prostate cancer

Abstract Prostate cancer kills 30,000 men per year in the U.S. Yet, of all primary prostate cancers, only a relatively small percentage are aggressive and have the potential to become life threatening. In terms of genomic copy number alterations, concurrent amplification of MYC and loss of tumor suppressor PTEN is the strongest predictor of prostate cancer specific mortality. We have previously shown, in a novel mouse model, that combined MYC overexpression and Pten loss results in the development of precursor lesions (PIN) that lead to aggressive metastatic prostatic adenocarcinoma, yet overexpression of MYC alone or Pten loss alone result only in precursor lesion development. Here, we performed genome wide transcriptome analysis using bulk RNA seq to obtain clues regarding the synergy between MYC overexpression and Pten loss. Prostates harboring PIN lesion were dissected from mice engineered to have MYC activation alone, Pten loss alone, and the combination thereof (BMPC mice), as well as invasive primary adenocarcinomas and metastatic lesions from BMPC mice. Principal Components Analysis (PCA) analysis separated the lesions into highly distinct groups. Genes contributing the most to the first principal component were related to inflammation and cell proliferation/cell cycle progression by functional annotation. The proliferation-related genes were increased somewhat by MYC overexpression alone, were not increased Pten loss, and were more consistently increased by combined MYC overexpression and Pten loss in BMPC. Strikingly, mice with combined MYC overexpression and Pten loss showed approximately 2-4 fold higher Ki67 proliferation index than mice with MYC activation alone. PIN lesions driven by MYC overexpression or PTEN loss alone were characterized by Gene Set Enrichment Analysis (GSEA). Among the pathways with the highest negative enrichment scores in PIN samples with PTEN loss were those that generally describe ribosome biogenesis and translation. PIN lesions with Pten loss showed lower hybridization signals for the 45S rRNA, which was increased by MYC alone and somewhat more in BMPC PIN lesions. Our results demonstrate that combined activation of MYC and Pten loss drive increased cell proliferation beyond that seen with either gene alteration alone. These findings suggest that a key part of the molecular mechanisms by which MYC and PTEN alterations may synergize to drive aggressive prostate cancer is related to increased tumor cell proliferation. Surprisingly, we uncovered the novel finding that Pten loss, in the absence of MYC overexpression, is associated with decreased expression of genes coding for proteins that mediate translation, as well as decreased 45S pre-rRNA. Since ribosome biogenesis is a key driver of cell proliferation, it is likely that loss of both copies of PTEN alone, in the absence of MYC overexpression, would be selected against in early lesions in prostate cancer. Citation Format: Michael Rubenstein, Tracy Jones, Jessica Hicks, Apurv Rege, Qizhi Zheng, Carolina Gomes-Alexandre, Gretchen Hubbard, Srinivasan Yegnasubramanian, Charles Bieberich, Angelo DeMarzo. MYC activation and PTEN loss synergistically activate proliferation in a mouse model of lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3043.

Bisphenol A promotes cell death in healthy respiratory system cells through inhibition of cell proliferation and induction of G2/M cell cycle arrest.

Bisphenol A (BPA) is a substance that can harm the environment and human health by interfering with the normal functioning of the body's hormonal system. It is commonly found in various plastic-based products such as cosmetics, canned foods, beverage containers, and medical equipment and as well as it can also be absorbed by inhalation. There have been limited studies on the effects of BPA on lung fibroblasts, and it is still unclear how high levels of BPA can impact respiratory system cells, particularly the lungs and trachea. In this research, we aimed to investigate the cell cycle disruption potential of BPA on respiratory system cells by examining healthy trachea and lung cells together for the first time. The findings indicated that BPA exposure can alter the healthy cells' morphology, leading to reduced cellular viability that has been assessed by MTT and SRB assays. BPA treatment was able to activate caspase3 as expected, which could cause apoptosis in treated cells. Although the highest dose of BPA did not increase the apoptotic rate of rat trachea cells, it remarkably caused them to become necrotic (52.12%). In addition to quantifying the induction of apoptosis and necrosis by BPA, cell cycle profiles were also determined using flow cytometry. Thereby, BPA treatment unexpectedly inhibited the cell cycle's progression by causing G2/M cell cycle arrest in both lung and tracheal cells, which hindered cell proliferation. The findings of the study suggested that exposure to BPA could lead to serious respiratory problems, even respiratory tract cancers via alterations in the cell cycle.

MTCH2 stimulates cellular proliferation and cycles via PI3K/Akt pathway in breast cancer

The MTCH2 protein is located on the mitochondrial outer membrane and regulates mitochondria-related cell death. This study set out to investigate the role of MTCH2 in the underlying pathophysiological mechanisms of breast cancer (BC). MTCH2 expression levels in BC were analyzed using bioinformatics prior to verification by cell lines in vitro. Experiments of over-expression and siRNA-mediated knockdown of MTCH2 were conducted to assess its biological functions, including its effects on cellular proliferation and cycle progression. Xenografts were utilised for in vivo study and signaling pathway alterations were examined to identify the mechanisms driven by MTCH2 in BC proliferation and cell-cycle regulation. MTCH2 was up-regulated in BC and correlated with patients’ overall survival. Over-expression of MTCH2 promoted cellular proliferation and cycle progression, while silencing MTCH2 had the opposite effect. Xenograft experiments were utilised to confirm the in vitro cellular findings and it was identified that the PI3K/Akt signaling pathway was activated by MTCH2 over-expression and suppressed by its silencing. Moreover, the activation of IGF-1R rescued cellular growth and cycle arrest induced by MTCH2-silencing. Overall, this study reveals that expression of MTCH2 in BC is upregulated and potentiates cellular proliferation and cycle progression via the PI3K/Akt pathway.

Crack-induced abrupt capacity degradation in commercial LiNi0.8Co0.1Mn0.1O2 (NCM811)/SiO x -graphite pouch batteries.

Reasons for abrupt capacity fading in commercial LiNi0.8Co0.1Mn0.1O2 (NCM811)/SiO x -graphite pouch batteries were evaluated using electrochemical methods. These approaches consist of charge and discharge curves, differential curves and electrochemical impedance spectroscopy (EIS), and some advanced verification techniques constituting scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD). The predominance testament concerning capacity attenuation through experimental verification after the battery is disassembled proves that the silicon-based anode material deteriorates further, bringing about a significant number of cracks with the progression of cycles. In addition, electrolyte enters into the cracks, generating the excessive growth of the solid electrolyte interface (SEI) and the expansion of impedance, which eventually causes the failure of conductive networks, dilemma of ion transmission and increment in polarization, ultimately contributing to lithium dendrites.

Response and Failure of Circumferential Sharp-Notched C2700 Brass Tubes under Cyclic Bending

This paper investigates the response and failure of circumferential sharp-notched C2700 brass tubes with four different notch depths of 0.2, 0.4, 0.6, 0.8, and 1.0 mm subjected to cyclic bending. The wall thickness is 1.5 mm for all tested tubes, and cyclic bending loads are applied until buckling failure occurs. The experimental moment-curvature relationships exhibit a stable loop from the first bending cycles. An increase in the notch depth results in the decrease of the peak bending moment. The experimental relationships between ovalization and curvature demonstrate symmetry, serrations, and a growth pattern as cycles progress, regardless of the notch depth. Regarding the curvature-number of cycles required to initiate buckling relationships, it can be observed that five notch depths correspond to five parallel straight lines when plotted on double logarithmic coordinates. Finally, this study employs the theoretical formulation proposed by Lee in 2010 to describe the aforementioned relationships. The theoretical analysis is compared with experimental data, revealing a close alignment between the two approaches.

Small Molecule Inhibitors Targeting the "Undruggable" Survivin: The Past, Present, and Future from a Medicinal Chemist's Perspective.

Survivin, a homodimeric protein and a member of the IAP family, plays a vital function in cell survival and cycle progression by interacting with various proteins and complexes. Its expression is upregulated in cancers but not detectable in normal tissues. Thus, it has been regarded and validated as an ideal cancer target. However, survivin is "undruggable" due to its lack of enzymatic activities or active sites for small molecules to bind/inhibit. Academic and industrial laboratories have explored different strategies to overcome this hurdle over the past two decades, with some compounds advanced into clinical testing. These strategies include inhibiting survivin expression, its interaction with binding partners and homodimerization. Here, we provide comprehensive analyses of these strategies and perspective on different small molecule survivin inhibitors to help drug discovery targeting "undruggable" proteins in general and survivin specifically with a true survivin inhibitor that will prevail in the foreseeable future.

Deubiquitinating enzyme PSMD7 promotes bladder cancer development: Involvement of RAB1A stabilization

BackgroundProteasome 26S subunit, non-ATPase 7 (PSMD7) is a deubiquitinating enzyme that is involved in the stability of ubiquitinated proteins and participates in the development of multiple types of cancer. The roles of PSMD7 and its potential mechanisms in bladder cancer (BC) remain elusive. MethodsIn this study, we identified that PSMD7 was overexpressed in BC tissues based on gene expression omnibus (GEO) database and TNMplot web. To investigate the functional role of PSMD7, two BC cell lines, T24 and 5637, were selected. The cells were transfected with vectors containing short hairpin RNAs against PSMD7 or plasmids containing full-length PSMD7 to knockdown or overexpress PSMD7. ResultsOur results revealed that silencing PSMD7 inhibited cell proliferation, cycle progression, migration, invasion, and promoted cell apoptosis, whereas PSMD7 overexpression led to the opposite effects in the BC cells. Mechanically, PSMD7 influenced the protein expression but not the mRNA expression of the Ras-related protein Rab-1 A (RAB1A). PSMD7 combined with RAB1A and negatively regulated its ubiquitination, indicating that PSMD7 enhanced the stability of RAB1A through post-transcriptional modification. Moreover, the rescue experiment demonstrated that RAB1A was an important downstream effector molecule of PSMD7. Besides, the negative regulation of silencing PSMD7 on tumor growth was confirmed in mice. ConclusionsOur study substantiated a novel mechanism by which PSMD7 stabilized RAB1A to accelerate the progression of BC.

Solar Cycle Observations

We describe the defining observations of the solar cycle that provide constraints for the dynamo processes operating within the Sun. Specifically, we report on the following topics: historical sunspot numbers and revisions; active region (AR) flux ranges and lifetimes; bipolar magnetic region tilt angles; Hale and Joy’s law; the impact of rogue ARs on cycle progression and the amplitude of the following cycle; the spatio-temporal emergence of ARs that creates the butterfly diagram; polar fields; large-scale flows including zonal, meridional, and AR in-flows; short-term cycle variability; and helioseismic results including mode parameter changes.

Sequence self-selection by cyclic phase separation.

The emergence of functional oligonucleotides on early Earth required a molecular selection mechanism to screen for specific sequences with prebiotic functions. Cyclic processes such as daily temperature oscillations were ubiquitous in this environment and could trigger oligonucleotide phase separation. Here, we propose sequence selection based on phase separation cycles realized through sedimentation in a system subjected to the feeding of oligonucleotides. Using theory and experiments with DNA, we show sequence-specific enrichment in the sedimented dense phase, in particular of short 22-mer DNA sequences. The underlying mechanism selects for complementarity, as it enriches sequences that tightly interact in the dense phase through base-pairing. Our mechanism also enables initially weakly biased pools to enhance their sequence bias or to replace the previously most abundant sequences as the cycles progress. Our findings provide an example of a selection mechanism that may have eased screening for auto-catalytic self-replicating oligonucleotides.

Chemical conversion of parasitic residual lithium compounds into beneficial artificial interface for cycle life improvement of LiNi0.8Mn0.1Co0.1O2 cathodes

LiNi0.8Mn0.1Co0.1O2 (NMC811) is the suitable cathode material for 300 Wh kg−1 lithium-ion battery packs due to their high specific capacity and operating potential of ∼3.7 V. The major bottleneck in the commercialization of NMC811 arises from the formation of residual lithium compounds (RLCs) on the surface during synthesis, its accumulation during storage, and the bulk/interfacial degradation when cycled using conventional electrolytes. Removing RLCs and ceasing their reformation complicate the material production line. Herein, we propose a single-step solution of converting parasitic RLCs into beneficial artificial interfaces by reacting RLCs with LiPF6 and Lithium Bis(oxalate)borate salts in tandem. It results in a bilayer arrangement of multiple components having LiF and Li3PO4 in the inner layer and LixBOyFz in the outer layer. The interface-modified material retains 90 % of initial capacity over 200 cycles, whereas the pristine NMC811 loses ∼50% capacity. The surface modification improves coulombic efficiency, reduces voltage polarization, lowers the growth of resistances with the progression of cycling, regulates the composition of cathode-electrolyte interphase, restricts cationic disorder, and provides interfacial stability during long-term cycling. In short, the applied methodology not only mitigates the issue of detrimental RLCs but also boosts the electrochemical performances of Ni-rich cathodes significantly.

Experimental study on the freezing-thawing behavior of compacted earth

Most of compacted earthen constructions are located at temporary and seasonal frozen areas, consequently exposed to repeated freezing-thawing (F-T) environment induced by significant temperature fluctuations. The F-T cycles can cause severe damage to the compacted earthen materials and reduce the structure’s durability. In this paper, a series F-T tests were performed in order to study the damage mechanism of the compacted earthen materials subjected to F-T cycles. The experiments were carried out under two confining pressures (σc= 0 kPa and 50 kPa) and three freezing temperatures (TF=−5℃, −8℃ and −13℃), with a thawing temperature of TT= 9℃. Evolution of elastic moduli and accumulation of irreversible strain at the end of each F-T processes were analyzed through cyclic loading–unloading tests under undrained condition. Results indicate that each F-T cycle could be characterized by main six stages, whose physical meaning has been explained through a thermodynamic approach. With increasing number of F-T cycles, a growth of the Young’s modulus was observed when the material was in a frozen state, and the opposite was found for the thawed state. This may be explained by an increase in macro-porosity as F-T cycles progress, which would be in line with the accumulation of residual deformation and the increase of freezing and thawing temperatures. The applied confining pressure was eventually found to provide a positive resistance against permanent deformation. This discovery can provide experimental support to the safety design of earthen wall situated in cold regions.

Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells

PurposeWe and others have demonstrated that MYC-amplified medulloblastoma (MB) cells are susceptible to class I histone deacetylase inhibitor (HDACi) treatment. However, single drug treatment with HDACi has shown limited clinical efficacy. We hypothesized that addition of a second compound acting synergistically with HDACi may enhance efficacy.MethodsWe used a gene expression dataset to identify PLK1 as a second target in MB cells and validated the relevance of PLK1 in MB. We measured cell metabolic activity, viability, and cycle progression in MB cells after treatment with PLK1-specific inhibitors (PLK1i). Chou–Talalay synergy calculations were used to determine the nature of class I HDACi entinostat and PLK1i interaction which was validated. Finally, the clinical potential of the combination was assessed in the in vivo experiment.ResultsMYC-amplified tumor cells are highly sensitive towards treatment with ATP-competitive PLK1i as a monotherapy. Entinostat and PLK1i in combination act synergistically in MYC-driven MB cells, exerting cytotoxic effects at clinically relevant concentrations. The downstream effect is exerted via MYC-related pathways, pointing out the potential of MYC amplification as a clinically feasible predictive biomarker for patient selection. While entinostat significantly extended survival of mice implanted with orthotopic MYC-amplified MB PDX, there was no evidence of the improvement of survival when treating the animals with the combination.ConclusionThe combination of entinostat and PLK1i showed synergistic interaction in vitro, but not in vivo. Therefore, further screening of blood–brain barrier penetrating PLK1i is warranted to determine the true potential of the combination as no on-target activity was observed after PLK1i volasertib treatment in vivo.