Search

Complexities in treating breast cancer with bone metastasis are enhanced by a vicious protumorigenic pathology, involving a shift in skeletal homeostasis toward aggressive osteoclast activity and polarization of immune cells supporting tumor growth and immunosuppression. Recent studies signify the role of receptor activator of NF-κB ligand (RANKL) beyond skeletal pathology in breast cancer, including tumor growth and immunosuppression. By using an osteoprotegerin (OPG) variant, which we developed recently through protein engineering to uncouple TNF-related apoptosis-inducing ligand (TRAIL) binding, this study established the potential of a cell-based OPGY49R therapy for both bone damage and immunosuppression in an immunocompetent mouse model of orthotopic and metastatic breast cancers. In combination with agonistic death receptor (DR5) activation, the OPGY49R therapy significantly increased both bone remolding and long-term antitumor immunity, protecting mice from breast cancer relapse and osteolytic pathology. With limitations, cost, and toxicity issues associated with the use of denosumab, bisphosphonates, and chemotherapy for bone metastatic disease, use of OPGY49R combination could offer a viable alternate therapeutic approach.

Supplementary Figures S1-S6

Supplementary Table

Supplementary Methods

The natural abundance of magnesium together with its high volumetric energy capacity and less-dendritic anodes makes Mg-ion batteries an appealing alternative to the widely used Li-ion batteries. However, Mg cathode materials under current investigation suffer from various shortcomings such as low operation voltage and high energy barrier for ion migration, resulting in poor battery performance. Here, we propose a garnet-type intercalation cathode active material, Mg3Si3(MoO6)2, for high-performance Mg-ion batteries. Through first-principles density functional theory calculations, it is demonstrated that Mg3Si3(MoO6)2 possesses a high average discharge voltage (2.35 V vs Mg/Mg2+), a low ion migration barrier (∼0.2 eV), and a minimal volume change (∼4%) concurrently, which comprises excellent intercalation cathode chemistry. The small energy barrier for ion migration is shown to arise from the favorable change in the Mg coordination along the migration route within the garnet host. These findings present an additional direction to develop competent Mg-ion batteries for future energy storage applications.

Large-scale graphene samples are mostly grown through chemical processes, which unavoidably introduce structural defects such as vacancies and adatoms that impede thermal transport. Recently, atomic layer deposition (ALD) utilizing metallic elements has proven healing capability of both structural defects and thermal transport in graphene, but the details of recovery mechanism have been elusive. In this study, we carry out molecular dynamics simulations to investigate the Pt-ALD-assisted healing reaction in graphene. Considering single (SV), double vacancies (DV) and C adatoms (Cad) as representative imperfections, it is revealed that SVs and DVs are healed through direct Pt-filling and C adatoms are removed from graphene surface predominantly via dissociating O2 molecules due to the catalytic effect of Pt. Moreover, examining thermal conductivity (κ) shows that removal of Cad plays a key role in recovering κ whereas the improvement due to vacancy filling is insignificant. The spectral analysis of the lattice vibrations further demonstrates that the enhanced κ originates from the enhanced mean free path of the flexural phonon modes in a low frequency range (

The article suggests the implementation of certain legal devices to enable developing countries to achieve policy flexibility to take advantage of the opportunities presented by the expansion of digital trade while balancing some of the risks which this may present to consumers in the sphere of privacy as well as threats to governments in the form of national security. These include a ‘renegotiation clause’ as well as the familiar classification of ‘special and differential treatment’ for developing or least-developed countries. Digital Trade, Non-discrimination, Renegotiation clause, Special and Differential Treatment, Developing or least developed countries, Korea, China and Japan, Post-Covid-19

The influence of N-substituent and pKa of azole rings has been investigated for the performance of high-temperature polymer electrolyte membrane fuel cells (HT-PEMFCs). Imidazole, benzimidazole, and triazole groups were functionalized on the side chains of poly(phenylene oxide), respectively. Each azole group is categorized by their N-substituent into two types: unsubstituted and methyl-substituted azoles. The membranes with methyl-substituted azoles showed higher phosphoric acid (PA) doping levels with an average increase of 20% compared to those with unsubstituted azoles in the full-doped states. However, unsubstituted azoles more effectively improved the proton conductivity and the membrane with unsubstituted imidazole (IMPPO-H) showed a high anhydrous proton conductivity of 153 mS/cm at 150 °C. In contrast, the membranes with methyl-substituted azoles showed a higher PA retention with an average increase of 81% compared to those with unsubstituted azoles. The higher PA retention of methyl-substituted azoles also led to the higher fuel cell performance with the maximum increase of 95% in the power density. It was also revealed that higher pKa of azoles enhanced the PA retention and the fuel cell performance. Based on the experimental results of PA retention and density functional theory calculations, the PA loss mechanism was also proposed.

Complexities in treating breast cancer with bone metastasis are enhanced by a vicious protumorigenic pathology, involving a shift in skeletal homeostasis toward aggressive osteoclast activity and polarization of immune cells supporting tumor growth and immunosuppression. Recent studies signify the role of receptor activator of NF-κB ligand (RANKL) beyond skeletal pathology in breast cancer, including tumor growth and immunosuppression. By using an osteoprotegerin (OPG) variant, which we developed recently through protein engineering to uncouple TNF-related apoptosis-inducing ligand (TRAIL) binding, this study established the potential of a cell-based OPGY49R therapy for both bone damage and immunosuppression in an immunocompetent mouse model of orthotopic and metastatic breast cancers. In combination with agonistic death receptor (DR5) activation, the OPGY49R therapy significantly increased both bone remolding and long-term antitumor immunity, protecting mice from breast cancer relapse and osteolytic pathology. With limitations, cost, and toxicity issues associated with the use of denosumab, bisphosphonates, and chemotherapy for bone metastatic disease, use of OPGY49R combination could offer a viable alternate therapeutic approach.

Our previous work showed that there is a limitation in the use of dihydrofolate reductase (dhfr)/methotrexate (MTX)-mediated gene amplification systems in dhfr-non-deficient HEK293 cells, as endogenous dhfr may interfere with the amplification process. In the present study, we successfully generated Epstein-Barr virus nuclear antigen-1 (EBNA-1)-amplified HEK293 cells in a dhfr-non-deficient HEK293 cell background using a single-plasmid vector-based gene amplification system with shRNA targeting the 3'-UTR of endogenous dhfr. The introduction of this shRNA efficiently downregulated the expression of endogenous dhfr in the HEK293 cells without affecting exogenous dhfr expression. The downregulation of endogenous dhfr improved the efficiency of EBNA-1 amplification, as evidenced by a comparison with the amplification extent in cells lacking shRNA expression at the same MTX concentration. The EBNA-1 expression levels from the EBNA-1-amplified clones selected in this study were higher than those obtained from EBNA-1-amplified clones that were generated using the conventional amplification in our previous study. Consistent with previous studies, EBNA-1 amplification improved the production of the Fc-fusion protein through a specific protein productivity (qp)-enhancing effect, rather than by improving cell growth or transfection efficiency. In addition, the N-glycan profiles in the Fc-fusion protein produced using this transient gene expression (TGE) system were not affected by EBNA-1 amplification. These results indicate the potential utility of EBNA-1-amplified mammalian cells, developed using a single-plasmid vector-based gene amplification system, for efficient protein production. KEY POINTS: • EBNA-1-amplified HEK293 cells were established using gene amplification system. • EBNA-1 amplification in TGE system can increase the Fc-fusion protein productivity. • EBNA-1 amplification does not affect the N-glycan profile in the Fc-fusion protein.

Therapeutic interventions to harness the immune system against tumor cells have provided mixed results in the past for several solid tumors and hematologic malignancies. However, immunotherapy has advanced considerably over the last decade and is becoming an integral combination for treating patients with advanced solid tumors. In particular, prostate cancer immunotherapy has shown modest efficacy for patients in the past. With several key discoveries on immune mechanisms and advanced molecular diagnostic platforms recently, immunotherapy is re-emerging as a viable option for prostate cancer, especially castration-resistant prostate cancer (CRPC), to stimulate antitumor immunity. Combination of patient-tailored immunotherapy and immune checkpoint blockers with conventional cytotoxic agents and androgen receptor–targeted therapies should move the field forward. With a recent adaptation that the application of immune checkpoint inhibitors has been successful in the treatment of more than a dozen solid tumors, including melanoma, lymphoma, liver, cervical, gastrointestinal, and breast cancers, it is a timely endeavor to harness immunotherapy for prostate cancer. Here, we provide an account on the progression of immunotherapy with new discoveries and precision approaches for tumors, in particular CRPC, from mechanistic standpoint to emerging limitations and future directions.

Understanding the mechanism of thermal energy transport in a single nanotube (NT) is essential for successfully engineering nanostructured conducting polymers to apply to thermoelectrics or flexible electronic devices. We report the characterization of the in-plane thermal energy transport in a single poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) NT via direct measurement of the in-plane thermal conductivity (κ). We also demonstrate that the in-plane κ of PEDOT:PSS NT can be tuned within the range of 0.19 to 1.92 W·m-1·K-1 merely by changing the solvent used to treat the NTs in the post-fabrication stage. The in-plane thermal energy transport in a pristine NT, with its low in-plane κ, is primarily due to phonons; in a sulfuric acid-treated NT however, significant electronic contributions lead to a high in-plane κ. The present study will contribute to understanding the mechanism of thermal energy transport in highly disordered structures, such as conducting polymers, and to designing highly efficient polymer-based devices in which in-plane κ plays a pivotal role in determining the energy conversion efficiency.

Low- or self-powered infrared sensors can be used in a broad range of applications, including networking mobile edge devices and image recognition for autonomous driving technology. Here, we show state-of-the-art self-powered near-infrared (NIR) sensors using graphene/In/InSe/Au as a photoactive region. The self-powered NIR sensors show outstanding performance, achieving a photoresponsivity of ∼8.5 A W

The photon upconversion (UC) is the process that has been known for a long time. Especially, lanthanide-based UC materials recently have attracted huge interest of scientific community due to their narrow visible emission bands upon near-infrared (NIR) excitation. However, the excitation in the high excitation power of NIR can cause highly bright and broad emission (B-UC). Such explosive B-UC was distinct at high excitation condition with UC wavelength encompassing the entire visible range. Previously, the proposed model of B-UC origination includes heat, multi-photon absorption, and accumulated thermal energy transfer. In this article, we will show various experimental and theoretical evidence supporting the idea that B-UC arises from photophysical pathways. Here, the key experimental evidence for photophysical pathways model of B-UC is to measure B-UC in the low-temperature environment (22 K). In addition, the density functional theory was used to regenerate energy levels which would be compared to the absorption spectral bands in Er2O3. As a result, we are confident of an electron tunneling model from 2P3/2 of Er3+ to oxygen vacancy level (VO) of Er2O3. Then, VO electrons are sequentially excited to the conduction band of Er2O3 by energy transfer from 4F9/2 of Er3+. Finally, the electrons return to the VO of Er2O3 with concomitant B-UC.

The natural abundance of magnesium together with its high volumetric energy capacity and less-dendritic anodes makes Mg-ion batteries an appealing alternative to the widely used Li-ion batteries. However, Mg cathode materials under current investigation suffer from various shortcomings such as low operation voltage and high energy barrier for ion migration, resulting in poor battery performance. Here, we propose a garnet-type intercalation cathode active material, Mg

The short half-life and use of recombinant bone morphogentic protein (BMP)-2 in large doses poses major limitations in the clinic. Events regulating post-translational processing and degradation of BMP2 in situ, linked to its secretion, have not been understood. Towards identifying mechanisms regulating intracellular BMP2 stability, we first discovered that inhibiting proteasomal degradation enhances both intracellular BMP2 level and its extracellular secretion. Next, we identified BMP2 degradation occurs through an ubiquitin-mediated mechanism. Since ubiquitination precedes proteasomal turnover and mainly occurs on lysine residues of nascent proteins, we systematically mutated individual lysine residues within BMP2 and tested them for enhanced stability. Results revealed that substitutions on four lysine residues within the pro-BMP2 region and three in the mature region increased both BMP2 turnover and extracellular secretion. Structural modeling revealed key lysine residues involved in proteasomal degradation occupy a lysine cluster near proprotein convertase cleavage site. Interestingly, mutations within these residues did not affect biological activity of BMP2. These data suggest preventing intracellular proteasomal loss of BMP2 through genetic modifications can overcome limitations related to its short half-life.

The influence of N-substituent and p

Here, we propose a new modulation method using chirp spread spectrum (CSS) modulation to indicate the result of long-range acoustic communication (LRAC). CSS modulation had outstanding matched filter characteristics even though the channel was complex. The performance of the matched filter depends on the time&ndash, bandwidth product. We studied the method of using the same modulation method while increasing the amount of the time&ndash, bandwidth product. When differential encoding is applied, the de-modulation is made using the difference between the current symbol and the previous symbol. If the matched filter is applied using both the current and the previous symbol, such as the use of two symbols, the amount of the time&ndash, bandwidth product can be doubled, and this method can make the output of the matched filter larger. The proposed method was verified in lake and sea experiments, in which the experimental environment was analyzed and compared with the result using the channel impulse response (CIR) of the lake and sea. The lake experiment was conducted over a distance of about 100&ndash, 300 m between the transmitter and receiver and at a depth of ~40 m. As a result of the communication, the conventional method&rsquo, s bit error rate (BER) was , but the proposed method&rsquo, s BER was . The sea experiment was conducted over a distance of ~90 km and at a depth of ~1 km, and the conventional method BER in this experiment was , while the proposed method&rsquo, s BER was 0.

The adhesion strength of lateral heterostructures composed of transition metal dichalcogenides ($\mathrm{Mo}{\mathrm{S}}_{2}, \mathrm{Mo}{\mathrm{Se}}_{2}, {\mathrm{WS}}_{2}$, and $\mathrm{W}{\mathrm{Se}}_{2}$) monolayers is investigated with first-principles electronic structure calculations. Our density functional theory calculations demonstrate that the adhesion strength, which is gauged by the ideal work of separation (${W}_{\mathrm{sep}}$), strongly depends on the local atomic configuration, and that ${W}_{\mathrm{sep}}$ becomes enhanced (diminished) at the interface where a chalcogen atom forms bonds with one (two) W and two (one) Mo atoms compared to those of the homogeneous cases. It is further shown that the increase (decrease) in ${W}_{\mathrm{sep}}$ from the homogeneous value is caused by the charge redistribution among the interfacial bonds, which is determined by the differences in the electronegativity of the transition metal species at the interface. Such geometrically controlled interfacial strength presents a route to control the materials' mechanical characteristics through structural engineering.

Aims: We investigated whether miRNA (miR) 146a-5p-loaded nanoparticles (NPs) can attenuate neuropathic pain behaviors in the rat spinal nerve ligation-induced neuropathic pain model by inhibiting activation of the NF-κB and p38 MAPK pathways in spinal microglia. Materials & methods: After NP preparation, miR NPs were assessed for their physical characteristics and then injected intrathecally into the spinal cords of rat spinal nerve ligation rats to test their analgesic effects. Results: miR NPs reduced pain behaviors for 11 days by negatively regulating the inflammatory response in spinal microglia. Conclusion: The anti-inflammatory effects of miR 146a-5p along with nanoparticle-based materials make miR NPs promising tools for treating neuropathic pain.

While controlling the cation contents in perovskite rare-earth nickelate thin films, a metal-to-insulator phase transition is reported. Systematic control of cation stoichiometry has been achieved by manipulating the irradiation of excimer laser in pulsed laser deposition. Two rare-earth nickelate bilayer thin-film heterostructures with the controlled cation stoichiometry (i.e. stoichiometric and Ni-excessive) have been fabricated. It is found that the Ni-excessive nickelate film is structurally less dense than the stoichiometric film, albeit both of them are epitaxial and coherent with respect to the underlying substrate. More interestingly, as a temperature decreases, a metal-to-insulator transition is only observed in the Ni-excessive nickelate films, which can be associated with the enhanced disproportionation of the Ni charge valence. Based on our theoretical results, possible origins (e.g. anti-site defects) of the low-temperature insulating state are discussed with the need of future work for deeper understanding. Our work can be utilized to realize unusual physical phenomena (e.g. metal-to-insulator phase transitions) in complex oxide films by manipulating the chemical stoichiometry in pulsed laser deposition.

Various atomistic defects ever-present in graphene have triggered unwanted phonon scattering, thereby significantly deteriorating the heat transport property of the graphene. Consequently, continuous endeavors have been made to minimize these atomistic defects. Here, we first experimentally show that defect healing based on atomic layer deposition (ALD) can significantly mitigate the degradation in the thermal conductivity of the graphene. After defect healing with Pt and Al2O3 ALD, the thermal conductivities of graphene synthesized by conventional chemical vapor deposition were improved by ∼83% and ∼64%, respectively. It is speculated that the healing atoms facilitate heat transfer across the defects, by eliminating the influence of vacancy in the graphene layer, which likely increases the phonon lifetime (leading to a noticeable improvement in thermal conductivity). This study provides an understanding of how defect engineering could affect phonon transport in 2D materials and sheds light on affordable graphene with excellent thermal conductivity.

Sodium butyrate (NaBu) is an efficient supplement for increasing recombinant protein production in Chinese hamster ovary (CHO) cell culture. To elucidate the effects of NaBu on miRNA expression profile in recombinant CHO (rCHO) cells, differentially expressed miRNAs in NaBu-treated rCHO cells were assessed by NanoString nCounter analysis. This result showed that eight mature mouse miRNAs (let-7b, let-7d, miR-15b, miR-25, miR-27a, miR-99a, miR-125a-5p, and miR-125b-5p) were differentially expressed. Furthermore, quantitative real-time RT-PCR analysis of eight mature CHO miRNAs, annotated using a miRBase database, confirmed the transcriptomic findings. Among the potential corresponding target mRNAs for the selected mature miRNAs, seven cell growth-related target genes (e2f2, akt2, mtor, bcl-2, bim, p38α, and bmf) and five N-glycosylation-related target genes (neu1, b4galt3, gale, man1b1 and mgat4a) were selected by considering the effectiveness of NaBu on rCHO cell culture. The altered expression patterns of the 12 target mRNAs were inversely correlated with those of the selected mature miRNAs. Altogether, NanoString nCounter analysis may be useful for identifying differentially expressed miRNAs in rCHO cells.

In this study, we investigate the Poisson's ratio of transition-metal dichalcogenides (TMDCs) with a chemical formula of MX2, where M = Mo, W and X = S, Se, respectively, from first-principles. Through density functional theory calculations, it is demonstrated that the Poisson's ratio of MX2 exhibits not only a substantial difference between the planar and vertical values but also a systematic dependence on the chalcogen species. Among the TMDCs, MoS2 displays the strongest anisotropy, which entails a distinctive contracting response under a planar strain. We find that such pronounced anisotropy in the Poisson's ratio of the TMDCs originates from the different filling of the in- (px, py, dxy, and d x 2 − y 2 ) and out-of-plane (pz, dyz, dzx, and d z 2 ) electronic orbitals depending on the transition-metal elements. These findings shed a new light on the elastic properties of TMDCs which continue to be interesting and show intriguing phenomena.

Despite the relatively low transfection efficiency and low specific foreign protein productivity (qp) of Chinese hamster ovary (CHO) cell-based transient gene expression (TGE) systems, TGE-based recombinant protein production technology predominantly employs CHO cells for pre-clinical research and development purposes. To improve TGE in CHO cells, Epstein-Barr virus nuclear antigen-1 (EBNA-1)/polyoma virus large T antigen (PyLT)-co-amplified recombinant CHO (rCHO) cells stably expressing EBNA-1 and PyLT were established using dihydrofolate reductase/methotrexate-mediated gene amplification. The level of transiently expressed Fc-fusion protein was significantly higher in the EBNA-1/PyLT-co-amplified pools compared to control cultures. Increased Fc-fusion protein production by EBNA-1/PyLT-co-amplification resulted from a higher qp attributable to EBNA-1 but not PyLT expression. The qp for TGE-based production with EBNA-1/PyLT-co-amplified rCHO cells (EP-amp-20) was approximately 22.9-fold that of the control culture with CHO-DG44 cells. Rather than improved transfection efficiency, this cell line demonstrated increased levels of mRNA expression and replicated DNA, contributing to an increased qp. Furthermore, there was no significant difference in N-glycan profiles in Fc-fusion proteins produced in the TGE system. Taken together, these results showed that the use of rCHO cells with co-amplified expression of the viral elements EBNA-1 and PyLT improves TGE-based therapeutic protein production dramatically. Therefore, EBNA-1/PyLT-co-amplified rCHO cells will likely be useful as host cells in CHO cell-based TGE systems.