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The cluster of differentiation 47 (CD47) protein is abundantly expressed on various malignant cells and suppresses the phagocytic function of macrophages and dendritic cells. High CD47 expression levels are correlated with poor cancer survival. Antagonizing CD47 antibodies with potent antitumor effects have been developed in clinical trials, but have critical side effects, inducing anemia and thrombocytopenia. To develop a safe and potent CD47 blockade, we designed extracellular vesicles (EVs) harboring signal regulatory protein alpha (SIPRα)-EV-SIRPα (EVs that express SIPRα). EV-SIRPα showed minimal toxic effects on hematologic parameters and utilized RBCs as delivery vehicles to tumors rather than inducing anemia. EV-SIRPα inhibited ligation of residual CD47 molecules, which attribute to the EV-endocytosis-mediated CD47 depletion and steric hindrance of EV. In an immunologically cold tumor model, EV-SIRPα induced tumor-specific T-cell-mediated antitumor effects. When directly administered to the accessible lesions, EV-SIRPα monotherapy elicited an abscopal effect in the B16F10 tumor model by increasing immune cell infiltration and CD8sup+/sup-mediated immunity against non-treated tumors. The combinational approach by loading doxorubicin into the EV-SIRPα dramatically reduced the tumor burden and led to 80% complete remission rate. Thus, a potent EV-based CD47 blockade that is hematologically safe, has efficient signaling blocking efficacy, and has systemic antitumor immunity against cancer is recommended.

Context Conservative treatment is effective for treating and managing herniated lumbar disc with radiating leg pain. Objectives To investigate the effects of motion style acupuncture treatment (MSAT) on the pelvic joint for this condition. Design This prospective observational study was a pilot study for a future randomized, controlled trial (RCT). Setting [masked for review]. Patients/Interventions We enroled 40 patients and allocated them to two groups (both n = 20). Groups 1 and 2 received integrative Korean medicine treatment (KMT) and integrative KMT with MSAT for pelvic joint, respectively. Primary outcome was the Numeric Rating Scale (NRS) score for low back pain. Secondary outcomes were the Oswestry Disability Index (ODI), Visual analogue Scale (VAS), and EuroQol 5-Dimension-5-level (EQ-5D-5 L) scores. Efficacy was assessed by comparing the baseline and Day 4 results. Safety was assessed based on the frequency and severity of all adverse events. Results On Day 14, except for ODI in Group 1, the NRS, VAS, and EQ-5D-5 L scores showed significant improvements in both groups. On Day 90, both groups showed significant improvements in the NRS, ODI, and EQ-5D-5 L scores. There was a significant between-group difference in the NRS score on Day 7. On Day 14, Group 2 had a significantly lower VAS score for radiating leg pain than Group 1. Twelve patients reported adverse events associated with integrative KMT; however, there was no association with pelvic joint MSAT. Conclusion Adding MSAT for pelvic joint to conventional integrative KMT may ameliorate radiating leg pain and improve the quality of life.

The purpose of this study was to determine whether statins can enhance anticancer effects in head and neck squamous cell carcinoma (HNSCC) when used with cisplatin and act as immunogenic cell death (ICD) inducers that can be used in cancer immunotherapy. Statins alone showed both in vitro and in vivo inhibitory effects against HNSCC, and synergistic antitumor effects were observed when combined with cisplatin in a syngeneic murine HNSCC model. Statins increased calreticulin exposure and endoplasmic reticulum stress-related signals in HNSCC cells. In addition, it was confirmed that statins could activate antigen-presenting cells and tumor-specific CD8+ T cells with an increase in their numbers in the tumor tissues and draining lymph nodes, with this effect showing significant improvement following the combination therapy with cisplatin. Moreover, in triple combination with both cisplatin and anti-programmed cell death 1 receptor (anti-PD-1) antibody, statins dramatically induced further tumor eradication and improved the survival of tumor-bearing mice. Taken together, these results demonstrate that statins, administered in combination with anti-PD-1 antibody, could enhance the anticancer effect of cisplatin and potentiate the efficacy of immunotherapy for HNSCC and present a rationale for repurposing statins as an adjuvant immunotherapeutic option for HNSCC.

Cancer immunotherapy (CI) represented by immune checkpoint inhibitors (ICIs) presents a new paradigm for cancer treatment. However, the types of cancer that attain a therapeutic benefit from ICIs are limited, and the efficacy of these treatments does not meet expectations. To date, research on ICIs has mainly focused on identifying biomarkers and patient characteristics that can enhance the therapeutic effect on tumors. However, studies on combinational strategies for CI are being actively conducted to overcome the resistance to ICI treatment. Moreover, it has been confirmed that dramatic anticancer effects are achieved through "neoadjuvant" immunotherapy with ICIs in treatment-naïve cancer patients; consequently, it has become necessary to consider how to best apply cancer immunotherapies for patients, even with respect to their tumor stages. In this review, we sought to discuss the right timing of ICI treatment in consideration of the progression of cancer with a changing tumor-immune microenvironment. Furthermore, we investigated which types of combinational treatments and their corresponding sequences of administration could optimize the therapeutic effect of ICIs to expand the applicable target of ICIs and increase their therapeutic efficacy. Finally, we discussed several delivery pathways and methods that can maximize the effect of ICIs.

Non-invasive tracking of T-cells may help to predict the patient responsiveness and therapeutic outcome. Herein, we developed bioorthogonal T-cell labeling and tracking strategy using bioorthogonal click chemistry. First, ovalbumin (OVA) antigen-specific cytotoxic T-cells (CTLs) were incubated with N-azidoacetyl-D-mannosamine-tetraacylated (Ac4ManNAz) for incorporating azide ( N3) groups on the surface of CTLs via metabolic glycoengineering. Subsequently, azide groups on the CTLs were chemically labeled with near infrared fluorescence (NIRF) dye, Cy5.5, conjugated dibenzylcyclooctyne (DBCO-Cy5.5) via bioorthogonal click chemistry, resulting in Cy5.5-labeled CTLs (Cy5.5-CTLs). The labeling efficiency of Cy5.5-CTLs could be readily controlled by changing concentrations of Ac4ManNAz and DBCO-Cy5.5 in cultured cells. Importantly, Cy5.5-CTLs presented the strong NIRF signals in vitro and they showed no significant changes in the functional properties, such as cell viability, proliferation, and antigen-specific cytolytic activity. In ovalbumin (OVA)-expressing E.G-7 tumor-bearing immune-deficient mice, intravenously injected Cy5.5-CTLs were clearly observed at targeted solid tumors via non-invasive NIRF imaging. Moreover, tumor growth inhibition of E.G-7 tumors was closely correlated with the intensity of NIRF signals from Cy5.5-CTLs at tumors after 2–3 days post-injection. The Cy5.5-CTLs showed different therapeutic responses in E.G-7 tumor-bearing immune-competent mice, in which they were divided by their tumor growth efficacy as ‘high therapeutic response (TR (+))’ and ‘low therapeutic response (TR (-))’. These different therapeutic responses of Cy5.5-CTLs were highly correlated with the NIRF signals of Cy5.5-CTLs at targeted tumor tissues in the early stage. Therefore, non-invasive tracking of T-cells can be able to predict and elicit therapeutic responses in the adoptive T-cell therapy.

Signal-regulatory protein alpha (SIRPα) engaged by CD47, that is overexpressed in a wide range of human solid tumors, serves as a 'Don't eat me' signal for phagocytic cells such as macrophages and dendritic cells. The SIRPα-CD47 interactions have recently attracted increasing attention in both cancer diagnosis and cancer immunotherapy. Herein, we designed and suggested a lysosomal enzyme-activatable vSIRPα-probe (vSIRPα-probe) capable of facilitating CD47-targeted cancer imaging and eliciting anti-cancer immune responses depending on phagocytosis as a versatile platform for potential cancer theranostic applications. For more efficient and precise cancer targeting, a recombinant SIRPα variant (vSIRPα) having a 50,000-fold higher binding affinity to CD47 than wild-type SIRPα was used to fabricate the vSIRPα-probe by conjugating to a dark-quenched fluorogenic peptide that is a substrate of lysosomal endopeptidases. The vSIRPα-probe could specifically bind to CD47 in different types of cancer cells and be activated by dequenching after cellular internalization. By interrupting the SIRPα-CD47 interaction between macrophages and cancer cells, the vSIRPα-probe promoted the destruction of cancer cells by macrophage-mediated phagocytosis, which was highly comparable to the un-modified vSIRPα recombinant protein. In the mouse tumor-xenografts treated with intravenous injection of the vSIRPα-probe, its enhanced in vivo tumor-targeting and imaging abilities drastically diminished after blocking the SIRPα-CD47 interaction via intratumoral administration of anti-CD47 antibodies. This study demonstrates that our vSIRPα-probe provides a promising tumor-targeted immunotheranostic probe for a novel cancer diagnostic and therapeutic strategy.

Cancer immunotherapy is a powerful approach for cancer treatment, but its clinical effects rely on the tumor's immune conditions. In particular, low response rates to PD-1 blockades are highly correlated with impaired T cell priming. Here, we demonstrate that E. coli-derived monophosphoryl lipid A (EcML) activates dendritic cells in a toll-like receptor-4 (TLR-4)-dependent manner and increases the sensitivity of cancer cells to anti-PD-1 immunotherapy. EcML is a mixture of 4'-monophosphoryl lipids A (MPLAs) produced directly by an engineered Escherichia coli strain; it has a unique congener composition that differentiates it from the well-established MPLA adjuvants, 3-O-desacyl-4'-monophosphoryl lipid A and glucopyranosyl lipid A. Given that active dendritic cells initiate adaptive immune responses, we investigated the anti-tumor activity of an aqueous formulation of EcML. Upon sensing EcML via TLR-4, dendritic cells matured into powerful antigen-presenting cells that could stimulate naïve T cells. EcML reduced tumor growth in the B16F10 mouse model via dendritic cell activation and potentiated PD-1 blockade therapy in the B16F10-OVA melanoma model. These data identify EcML as a promising TLR-4 agonist that can induce anti-tumor immune responses and potentiate PD-1 blockade therapy against tumors.

Alternatively activated or M2 macrophages, as opposed to the well characterized pro-inflammatory or M1 macrophages, vitally regulate anti-inflammation, wound healing, and tissue repair to maintain tissue homeostasis. Although ubiquitous presence of macrophages in diverse tissues, exposed to different physical environments, infers distinct immune responses of M2 macrophages with high phenotypic heterogeneity, the underlying mechanism of how the varying extracellular mechanical conditions alter their immunological activation remains unclear. Here, we demonstrate that M2 activation requires a threshold mechanical cue from the extracellular microenvironment, and matrix rigidity-dependent macrophage spreading is mediated by the F-actin formation that is essential to regulate mechanosensitive M2 activation of macrophages. We identified a new mechanosensing function of STAT6 (signal transducer and activator of transcription 6), a key transcription factor for M2 activation, whose intranuclear transportation is promoted by the rigid matrix that facilitates the F-actin formation. Our findings further highlight the critical role of mechanosensitive M2 activation of macrophages in long-term adaptation to the extracellular microenvironment by bridging nuclear mechanosensation and immune responses.

The rapid and precise clearance of apoptotic cells (efferocytosis) involves a series of phagocytic processes through which apoptotic cells are recognized, engulfed, and degraded within phagocytes. The Rho-family GTPases critically rearrange the cytoskeleton for these phagocytic processes, but we know little about the mechanisms by which regulatory proteins control the spatiotemporal activities of the Rho-family GTPases. Here, we identify ArhGAP12 as a functional GTPase-activating protein (GAP) of Rac1 during Stabilin-2 mediated efferocytosis. ArhGAP12 constitutively forms a complex with the phosphatidylserine receptor, Stabilin-2, via direct interaction with the downstream protein, GULP, but is released from the complex when Stabilin-2 interacts with apoptotic cells. When the phagocytic cup is closed and the apoptotic cell is surrounded by the phagosomal membrane, ArhGAP12 localizes to the phagocytic cup via a specific interaction with phosphatidylinositol-4,5-bisphosphate, which is transiently biosynthesized in the phagocytic cup. Down-regulation of ArhGAP12 results in sustained Rac1 activity, arrangement of F-actin, and delayed phagosome-lysosome fusion. Our results collectively suggest that ArhGAP12 carries dual roles in Stabilin-2 mediated efferocytosis: it binds to GULP/Stabilin-2 and switches off Rac1 basal activity and switches on the Rac1 by releasing itself from the complex. In addition, the spatiotemporal membrane targeting of ArhGAP12 inactivates Rac1 in a time-specific and spatially coordinated manner to orchestrate phagosome maturation. This may shed light on how other RhoGAPs spatiotemporally inactivate Rac or Cdc42 during phagocytosis by various cells, in different circumstances.

Myeloid lineage immune cells, such as macrophages and dendritic cells, play important roles in the induction of antitumor immunity during the initial stage of the cancer-immunity cycle, eliciting antitumor adaptive immunity by phagocytosing cancer cells and processing cancer-specific antigens, and then presenting these antigens to T cells. During this process, cancer cell phagocytosis can be prevented by inhibitory signals, and the signaling cascades that elicit immune responses against cancer antigens can be inhibited by immunosuppressive myeloid cells in the tumor microenvironment. A number of therapeutic strategies for enhancing cancer cell phagocytosis and promoting antitumor immunity by targeting myeloid lineage cells have recently been developed. Here, we discuss recent advances in cancer immunotherapy that involve the targeting of myeloid lineage immune cells to induce effective antitumor immunity.

Herein, we propose new 8-node hexahedral, 6-node prismatic, and 5-node pyramidal 3D solid finite elements enriched by cover functions. To resolve the linear dependence problem, piecewise linear shape functions are adopted as the partition of unity functions. Various mesh patterns are considered for investigation of the linear dependence problem, and no rank deficiency is observed. We demonstrate convergence behavior and effectiveness of the new enriched elements, and adaptive use of cover functions through six problems: an ad hoc problem, a tool jig problem, a slender beam problem, a gear problem, and a connecting rod problem.

Ultrafast Electron Diffraction (UED) system, using an electron bunch of the duration with less than 100 fs and of the energy with 3 MeV, has been developed as a tool probing the ultrafast dynamics in pump–probe experiments. To keep the temporal and transverse characteristics of the electron bunch for the time-resolved electron diffraction, the bunch charge is limited to be the pico-Coulomb or less. S-band transverse deflecting cavity working on T M 120 mode is designed, fabricated, and installed in the UED system to measure directly the fs-scaled pulse duration of low-energy and low-charge electron bunches. We describe the design and the expected performance of a single-cell RF deflector. For the electron beam of 3 MeV in energy and 1.88 pC in charge, we could measure the bunch duration of 69 fs and the timing jitter of 62 fs, both in rms.

A novel adhesion process called “plasma press” has been investigated for achieving stronger bonding between two different materials. It was first developed to be applied in multilayer flexible printed circuit boards for next generation flexible mobile electronics. The plasma process is a hot pressing method employing plasma between the two materials in order to activate the material surfaces. Compared to the conventional hot-pressed sample, the plasma-pressed sample exhibited up to 130% higher adhesion strength. The stronger bond strength achieved in the plasma-pressed sample is attributed to the formation of active carboxyl functional groups and dangling bonds on the material surfaces by the presence of the plasma during the hot pressing process for bonding.

Radicals generated during reactive ion etching (RIE) cannot be electrically controlled, causing isotropic etching and chemical damage to the sidewall of the etched feature during the etching process. In this study, using a reactive ion beam etcher (RIBE) installed with a dual exhaust system, where an additional exhaust valve was introduced to pump out radicals from the inductively coupled plasma (ICP) source chamber in addition to the conventional main gate valve in the process chamber, the radical flux relative to ion flux during the RIE process has been controlled and the effect of additional exhausting through the ICP source chamber for the control of radical flux relative to ion flux on the properties of etching has been investigated using CF4 gas. The results showed that the additional exhausting of the radicals through the ICP source chamber not only decreased the ICP source chamber pressure but also decreased the ratio of radical flux to ion flux to the substrate. The lower ICP source chamber pressure could be also obtained without additional exhausting through the ICP source chamber by decreasing the CF4 gas flow rate to the ICP source chamber, however, the lower ratio of radical flux to ion flux was observed for the dual exhaust system. It is believed that, for the next generation RIBE, multiple exhausting is beneficial for anisotropic etching of nanoscale features by controlling the radical flux to the sidewall and ion flux to the bottom of a nanoscale feature during the etching.

This paper reports on the development of a new type of heat exchanger with bimetal fins for controlling the calorific value of water through phase change material (PCM) heat storage. It presents detailed numerical and experimental data on the velocity and temperature of water flow in a channel equipped with bimetal fins on the wall. Computational fluid dynamics and particle image velocimetry are used to analyze the flow behavior around the bimetal fins. The bimetal fins increase the insulation performance at the wall, such that the heat loss rate is decreases by a maximum of 56%. Furthermore, the flow rate and calorific value can be controlled at 10 L/min and 50 kJ, respectively. Consequently, the discharging-time during which hot water can be generated increases by a maximum of 70 min.

Presentation of an endogenous bioactive ligand in its native form is a key factor in controlling and determining its bioactivity, stability, and therapeutic efficacy. In this study, we developed a novel strategy for presenting trimeric ligands on nanocages by designing, optimizing and testing based on the rational design, high-resolution structural analysis and agonistic activity assays in vitro and in vivo. We successfully designed a nanocage that presents the TNF superfamily member, TRAIL (TNF-related apoptosis-inducing ligand) in its native-like trimeric structure. The native structure of TRAIL complexes was mimicked on the resulting trimeric TRAIL-presenting nanocages (TTPNs) by inserting sufficient spacing, determined from three-dimensional structural models, to provide optimal access to the corresponding receptors. The efficacy of TTPNs as an anti-tumor agent was confirmed in preclinical studies, which revealed up to 330-fold increased affinity, 62.5-fold enhanced apoptotic activity, and improved pharmacokinetic characteristics and stability compared with the monomeric form of TRAIL (mTRAIL). In this latter context, TTPNs exhibited greater than 90% stability over 1 mo, whereas ∼50% of mTRAIL aggregated within 2 d. Consistent with their enhanced stability and ultra-high affinity for the TRAIL receptor, TTPNs effectively induced apoptosis of tumor cells in vivo, leading to effective inhibition of tumor growth. Although TRAIL was used here as a proof-of-concept, all members of the TNF superfamily share the TNF homology domain (THD) and have similar distances between ecto-domain C-termini. Thus, other TNF superfamily ligands could be genetically substituted for the TRAIL ligand on the surface of this biomimetic delivery platform.

In this paper, we propose a new 4-node 2D solid finite element enriched by interpolation cover functions. Instead of using the bilinear shape functions of the standard 4-node finite elements, piecewise linear shape functions are adopted as the partition of unity functions to resolve the linear dependence problem; thus, rank deficiency of the stiffness matrix is not observed. Higher order cover functions can be arbitrarily employed to increase solution accuracy without mesh refinements or introduction of additional nodes. The new enriched 4-node element also shows good convergence behavior, even when distorted meshes are used. Herein, we investigate the linear dependence problem of the new enriched element. Its convergence, effectiveness, and usefulness are demonstrated through the solution of four plane stress problems: an ad hoc problem, a tool jig problem, a slender beam problem, and an automotive wheel problem.

This study proposes a pile-guided floater, a new mooring concept, for large offshore floating structures such as an offshore liquefied natural gas (LNG) bunkering terminal. The economic feasibility of the new mooring system was demonstrated through a cost–benefit analysis. The environmental loads acting on the floaters were computed using wave data at the target location. The mooring system was designed using finite element analysis to estimate the additional investment. An LNG ship-to-ship bunkering operation that included an LNG bunkering terminal, LNG carrier, LNG bunkering shuttle, and LNG receiving ship was adopted. To estimate the technical feasibility and economic benefit of the proposed mooring system, the availabilities of two types of LNG bunkering terminals were compared considering the acceptance criteria for LNG ship-to-ship transfers. One LNG bunkering terminal was a typical barge-type floater and the other was the pile-guided floater. The relative motion of the terminal with the LNG carrier and the LNG bunkering shuttle was analyzed. The limiting wave height was determined from the maximum relative vertical motion between the floaters at the position of the LNG loading arms. The availability of the pile-guided LNG bunkering terminal was significantly improved owing to the reduced vertical motion. Finally, a cost–benefit analysis verified that the new mooring concept for an offshore LNG bunkering terminal was economically feasible.

Self-selective coating is a new coating process that utilizes surface energy differences for metal ink coating. Hydrophobic and hydrophilic areas are defined on carbon black coated Polyimide (PI) substrate surface using atmospheric plasmas. At this state, when Ag ink is sprayed on PI, metal line is self-formed on hydrophilic surface due to its surface energy differences. As a result, an Ag ink line width of less than 6 μm could be formed on the PI surface after removing the carbon black. Due to the formation of the Ag line on the hydrophilic PI surface, the adhesion force of the Ag ink formed on the PI surface was ~ 64% higher than that of the Ag ink formed on the hydrophobic PI surface.

Atherosclerosis plaque is a major cause of cardiovascular diseases across the globe and a silent killer. There are no physical symptoms of the disease in its early stage and current diagnostic techniques cannot detect the small plaques effectively or safely. Plaques formed in blood vessels can cause serious clinical problems such as impaired blood flow or sudden death, regardless of their size. Thus, detecting early stage of plaques is especially more important to effectively reduce the risk of atherosclerosis. Nanoparticle based delivery systems are recognized as a promising option to fight against this disease, and various targeting ligands are typically used to improve their efficiency. So, the choice of appropriate targeting ligand is a crucial factor for optimal targeting efficiency. cRGD peptide and collagen IV targeting peptide, which binds with the αvβ3 integrin overexpressed in the neovasculature of the plaque and collagen type IV present in the plaque, respectively, are frequently used for the targeting of nanoparticles. However, at present no study has directly compared these two peptides. Therefore, in this study, we have prepared cRGD or collagen IV targeting (Col IV-tg-) peptide conjugated and iron oxide nanoparticle (IONP) loaded Pluronic based nano-carriers for systemic comparison of their targeting ability towards in vivo atherosclerotic plaque in Apolipoprotein E deficient (Apo E-/-) mouse model. Nano-carriers with similar size, surface charge, and IONP loading content but with different targeting ligands were analyzed through in vitro and in vivo experiments. Near infrared fluorescence imaging and magnetic resonance imaging techniques as well as Prussian blue staining were used to compare the accumulation of different ligand conjugated nano-caariers in the aorta of atherosclerotic mice. Our results indicate that cRGD based targeting is more efficient than Col IV-tg-peptide in the early stage of atherosclerosis.

In this paper, we present the multi-physics design and high-power tests of a fundamental power coupler for superconducting cavities. The fabricated power coupler was a coaxial capacitive-type coupler based on a conventional 3 1 8 -inch Electronic Industries Alliance 50- Ω coaxial transmission line with a titanium nitride (TiN)-coated single ceramic window. The coupler had three diagnostic ports for vacuum, arc, and electron pick-ups to monitor radio frequency (RF) breakdowns. To reduce the thermal load required to reach the cryogenic temperature , the thermal intercepts were located at 4.5 K and 40 K for liquid helium use and at 4.5 K and 77 K for liquid helium and nitrogen use. A transition box for adjusting the antenna penetration depth and matching impedance was designed. A high-power test was performed with a 20 kW and 325 MHz solid-state power amplifier. The power coupler was connected to a rectangular test cavity with high vacuum and various measuring equipment, such as an arc detector, a power meter, and an electron pick-up probe. The interlock system under vacuum and arc instrumentations prevented the RF window from breaking the power coupler window during the high-power test. We conducted high-power tests for more than 12 h at 12 kW in a 325 MHz continuous wave mode to verify the performance of the designed power coupler.

In this study, a time-of-flight mass spectrometer is developed to analyze the mass-to-charge ratio of ion beams generated from an electron beam ion source (EBIS) at the RAON heavy ion accelerator facility. The time-of-flight mass spectrometer comprises a Bradbury–Nielson gate, steerer, mirror electrode, and microchannel plate detector. The Bradbury–Nielson gate is applied to generate a bunch beam with a 5-ns pulse width at the front end of the time-of-flight system. A double-stage reflector is employed to obtain a beam chromatic correction from the energy spread of the ion beam generated from the EBIS. The design is created through optics simulation using the SIMION code, with 133Cs as the reference ion. Consequently, the charge state of 27+ separated from neighboring states at a maximum voltage of 20 kV is obtained. By utilizing ion sources of Cs1+ (m/z 133) and Rb1+ (m/z 85 and m/z 87) to perform the performance test on the designed TOFMS system, the spectral peak of the ion sources and a relatively high mass resolution are obtained. This paper introduces the development process and test results of the time-of-flight mass spectrometer in detail.

Ferritin nanocages are of particular interest as a novel platform for drug and vaccine delivery, diagnosis, biomineralization scaffold and more, due to their perfect and complex symmetry, ideal physical properties, high biocompatibility, low toxicity profiles as well as easy manipulation by genetic or chemical strategies. However, a short half-life is still a hurdle for the translation of ferritin-based nanomedicines into the clinic. Here, we developed a series of rationally designed long circulating ferritin nanocages (LCFNs) with 'Intrinsically Disordered Proteins (IDP)' as a stealth layer for extending the half-life of ferritin nanocages. Through predictions with 3D modelling, the LCFNs were designed, generated and their pharmacokinetic parameters including half-life, clearance rate, mean residence time, and more, were evaluated by qualitative and quantitative analysis. LCFNs have a tenfold increased half-life and overall improved pharmacokinetic parameters compared to wild-type ferritin nanocages (wtFN), corresponding to the low binding against bone marrow-derived macrophages (BMDMs) and endothelial cells. Subsequently, a tumor targeting moiety, epidermal growth factor receptor (EGFR)-targeting affibody peptide, was fused to LCFNs for evaluating their potential as a theragnostic platform. The tumor targeting-LCFNs successfully accumulated to the tumor tissue, by efficient targeting via active and passive properties, and also the shielding effect of IDP in vivo. This strategy can be applied to other protein-based nanocages for further progressing their use in the field of nanomedicine.

The Korea Heavy Ion Medical Accelerator (KHIMA) project has been developed for cancer therapy. The injector system consists of a low energy beam transport (LEBT) line, a radio-frequency quadrupole, a drift tube linac with two tanks, and a medium energy beam transport (MEBT) line with a charge stripper section. The injector system transports and accelerates the 12 C 4 + beam that is produced from electron cyclotron resonance ion source up to 7 MeV/u, respectively. The 12 C 6 + beam, which is transformed by a charge stripper from the 12 C 4 + beam, is injected into a synchrotron and accelerated up to 430 MeV/u. The lattice for the injector system was designed to optimize the beam parameters and to meet beam requirements for the synchrotron. We performed start-to-end simulations from the LEBT line to the MEBT line to confirm that the required design goals of the beam and injector system were met. Our simulation results indicate that our design achieves the required performance and a good transmission efficiency of 90%. We present the lattice design and beam dynamics for the injector system in the KHIMA project.

Photo-induced apoptosis-targeted chemotherapy (PIATC) was designed and characterized to propose a new protocol for improved chemotherapy. Intratumoral injection was selected as the mode of administration of the anticancer drug, doxorubicin (DOX). To extend the retention time of DOX at the tumor parenchyma, in-situ gel formation was induced through the sol-gel transition of the Pluronic NPs containing a prodrug of DOX or a photosensitizer. The prodrug (DEVD-S-DOX) was designed to be inactive with a peptide moiety (Aspartic acid-Glutamic acid-Valine-Aspartic acid: DEVD) linked to DOX and to be cleaved into free DOX by caspase-3 expressed with apoptosis. For reactive oxygen species (ROS)-mediated apoptosis, photo-irradiation with methylene blue (MB, photosensitizer) was utilized. The sol-gel transition of the Pluronic NPs containing reactive species, DEVD-S-DOX or MB, was examined by measuring the cloud point and the gel strength in response to temperature change. ROS-mediated apoptosis was observed by measuring the ROS and membrane integrity with induced apoptosis. The in vivo antitumor efficacy of PIATC was measured with a cardiotoxicity assay in tumor-bearing mice.

A loss-of-coolant accident (LOCA) has always been significantly considered one of the most important initiating events. However, most probabilistic safety assessment models, up to now, have undoubtedly adopted the three groups of LOCA, and even an exact break size boundary that used in WASH-1400 reports was published in 1975. With an awareness of the importance of a realistic PSA for a risk-informed application, several studies have tried to find the realistic thermal-hydraulic behavior of a LOCA, and improve the PSA model. The purpose of this research is to obtain realistic results of the LOCA core damage frequency based on a success criteria analysis using the best-estimate thermal-hydraulics code. To do so, the Korea Standard Nuclear Power Plant (KSNP) was selected for this study. The MARS code was used for a thermal hydraulics analysis and the AIMS code was used for the core damage quantification. One of the major findings in the thermal hydraulics analysis was that the decay power is well removed by only a normal secondary cooling in LOCAs of below 1.4 in and by only a high pressure safety injection in LOCAs of 0.8–9.4 in. Based on the thermal hydraulics results regarding new break size boundaries and new success criteria, five new event trees (ETs) were developed. The core damage frequency of new LOCA ETs is 5.80E−07 (/y), which is 12% less than the conventional PSA ETs. In this research, we obtained not only thermal-hydraulics characteristics for the entire break size of a LOCA in view of the deterministic safety assessment, but also a more realistic core damage frequency of the LOCAs using updated information. The difference between the results of the present study and the conventional knowledge can be used to modify the current emergency operator procedures and to design another nuclear power plant type.

Korea repeatedly experiences flash floods and droughts that cause traumatic environmental conditions with huge economic impact. Recently due to climate change, the frequency and magnitude of natural disasters associated with extreme hydrologic events increased rapidly in Korea. Floods caused the greatest damage among all natural disasters. To prevent this damage it is important to inform people about ongoing and upcoming flash flood events to avoid the loss of life and property. In this study hardware and software based smart technology is used to develop an early flood warning system for Mushim stream watershed to send to end users early flood warning messages about potentially impacted areas. Hydrologic Engineering Center's Hydrologic Modeling System (HEC-HMS) is the core of flood alert application provides the forecast with sufficient lead time and decides the threshold conditions of runoff/stage. Short range weather forecasts from Korea Meteorological Administration (KMA) at every three hours interval, are stored in hydro-meteorological database and fed in HEC-HMS for identification of flood risks. Server-Client based program used to visualize the real time flood condition and to deliver the early warning message. The findings of this study are expected to be used as basic data required for designing of flood mitigation measures at Mushim stream watershed to cope with the flash flood events in future. The flood hazard maps thus developed will be useful to policy-makers and responsible authorities, as well as to local residents in finding suitable measures for reducing flood risk in the study area.

The effective chemotherapeutic drug, doxorubicin (DOX), elicits immunogenic cell death (ICD) and additional anticancer immune responses during chemotherapy. However, it also induces severe side effects and systemic immunosuppression, hampering its wide clinical application. Herein, we constructed cancer-activated DOX prodrug by conjugating the cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly, FRRG) to a doxorubicin (DOX), resulting in FRRG-DOX that self-assembled into cancer-activated DOX prodrug nanoparticles (CAP-NPs). The resulting CAP-NPs were further stabilized with the FDA-approved compound, Pluronic F68. CAP-NPs formed stable prodrug nanoparticles and they were specifically cleaved to cytotoxic DOX molecules only in cathepsin B-overexpressing cancer cells, inducing a cancer cell-specific cytotoxicity. In particular, the CAP-NPs induced ICD through cathepsin B-cleavage mechanism only in targeted cancer cells in vitro. In colon tumor-bearing mice, selectively accumulated CAP-NPs at tumors enhanced antitumor immunity without DOX-related severe toxicity, inflammatory response and systemic immunosuppression. Moreover, cytotoxicity against immune cells infiltrated into tumor microenvironment was significantly reduced compared to free DOX, leading to increased response to checkpoint inhibitor immunotherapy. The combinatorial treatment of CAP-NPs with anti-PD-L1 exhibited high rate of complete tumor regression (50%) compared to free DOX with anti-PD-L1. Concurrently, DOX-related side effects were greatly reduced during chemoimmunotherapy. Collectively, our results suggest that cancer-activated DOX prodrug nanoparticles provide a promising approach to increase clinical benefit by inducing an immune response preferentially only to targeted cancer cells, not to normal cells and immune cells, and potentiates checkpoint inhibitor immunotherapy.

The objectives of this experiment were to investigate if the domestic Italian Ryegrass (IRG) haylage is a suitable feed for maintenance horses. Thoroughbred horses (n = 10) were confined to a stall and provided the fixed amount of hay and haylage 3 times daily for 2 experimental periods. The first experiment was conducted for 11 d to observe horses’ preferences such as the first choice and the residuals of forages. The fixed amount of 1,500g of timothy hay and 1,500g of domestic IRG haylage was given 3 times at 08:30, 12:00, 16:30 to each horse at the same time and was assessed for first choice and the feed residuals. The 7 d were for the study to begin to adapt to the experimental conditions and the experiments were conducted from the 8th to 11th of the experimental day. The second experiment was to observe horses’ performance comparing the domestic IRG haylage and timothy hay affecting changes in the BCS and weight for horses and the eating time. Horses were offered the fixed amount of 3,000g of timothy hay and 3,000g of domestic IRG haylage was given 3 times at 08:30, 12:00, 16:30 to each horse at the same time. The results were recorded at 12:00 on d 0 and d 30. The chemical components of IRG haylage were greater in crude protein (16.26 vs 9.35%), ether extract (3.98 vs 3.15%), and ash (10.37 vs 6.97%). Timothy hay was higher in dry matter (91.4 vs 97.5%), crude fiber (24.9 vs 22.6%), and NFE (47 vs 34.3%). No mycotoxins were found in forages such as Aflatoxin B1, B2, G1, G2, A, and Ochratoxin A. The chi-squared test was used to compare the scores for preferences among horses. The weight and the body condition score (BCS) were compared using the student t-test. The mixed model with an ANOVA was used for the feed residuals and the eating duration. The level of significance was set at P

Duck meat consumption in South Korea has increased in recent years, but no standard about duck farm-specific biosecurity and hygiene guidelines have yet been established. We here investigated Salmonella contamination levels in duck farms to evaluate biosecurity and hygiene practices. We collected 1,116 environmental samples from 31 duck farms in Jeonnam Province, South Korea. The Salmonella-positive farm rate dramatically increased, from 22.6 to 71.0%, on introduction of ducklings. As the ducklings aged 4–6 wk, the positive rate slightly decreased to 64.5%. The Salmonella detection rate on each sampled surface, such as the feed pan (34.4%), wall (33.9%), litter (32.3%), and nipples (24.2%), was highest at 3 wk of age. The most frequently detected Salmonella serovars were Salmonella London (22.2%), Salmonella Albany (21.6%), Salmonella Bareilly (17.0%), and Salmonella Indiana (16.5%). Implementation of cleaning and disinfection procedures, rodent control, and metal house walls significantly lowered the prevalence of Salmonella (P

In the 1970s, Gian-Carlo Rota laid a rigorous foundation for umbral calculus which is based on the modern concepts like a linear functional, a differential operator and an adjoint. The motivation for this paper starts from the question that what if the usual exponential function in the generating function of a Sheffer sequence is replaced by degenerate exponential functions. The sequences thus defined are called λ-Sheffer sequences. It may be said that this question is very natural in view of the regained recent interests in degenerate special numbers and polynomials. It turns out that these correspond to replacing the linear functional and the differential operator respectively by λ-linear functionals and λ-differential operators. In this article, we give an account of λ-Sheffer sequences and degenerate Sheffer sequences, and illustrate them with many examples.

Large-format lithium-ion battery (LIB) cells have limitations such as reduced safety and life due to the large temperature difference in the cells. Thus, in this study, the tab type, tab attachment positions, and cell aspect ratio, which determine the shape of the LIB cell, were optimized to minimize the temperature difference in a 45-Ah lithium iron phosphate(LFP)/graphite large-format cell. As a constraint, the area of the LIB cell was kept constant to maintain a constant capacity of the LIB cell. A 3D electrochemical–thermal model was used to calculate the temperature distribution in the LIB cell. By optimizing the cell aspect ratio, tab type, and tab attachment positions, the temperature difference was minimized because of the decreased internal resistance, and the cell life increased owing to the reduced temperature difference. Moreover, the optimized cell design showed a 7.3% lower discharge capacity reduction than that of the initial design at 1000 cycles. Results show that optimization is an effective method to minimize the temperature difference in large-format LIBs and enhance their life.

For the GBAR (Gravitational Behaviour of Antihydrogen at Rest) experiment at CERN's Antiproton Decelerator (AD) facility we have constructed a source of slow positrons, which uses a low-energy electron linear accelerator (linac). The driver linac produces electrons of 9 MeV kinetic energy that create positrons from bremsstrahlung-induced pair production. Staying below 10 MeV ensures no persistent radioactive activation in the target zone and that the radiation level outside the biological shield is safe for public access. An annealed tungsten-mesh assembly placed directly behind the target acts as a positron moderator. The system produces $5\times10^7$ slow positrons per second, a performance demonstrating that a low-energy electron linac is a superior choice over positron-emitting radioactive sources for high positron flux., published in NIM A. 33 pages 9 figures

Recently, the strain-smoothed element (SSE) method has been developed for 3-node triangular and 4-node tetrahedral solid elements. The method was also applied for enhancing the membrane performance of a 3-node triangular shell element (MITC3+ element). Using the SSE method, convergence behaviors of the finite elements were significantly improved without additional degrees of freedom. However, the application of the SSE method is limited to constant strain finite elements such as 3-node triangular and 4-node tetrahedral elements. In this paper, the SSE method is applied to a 4-node quadrilateral finite element. Doing so, the piecewise linear shape functions are employed instead of standard bilinear shape functions. The proposed strain-smoothed 4-node quadrilateral element passes all the basic tests, and shows a significantly improved accuracy in various numerical examples.

Extraction mirrors installed at the most upstream position of interferometry beam size monitor are frequently used for measuring the beam size in storage rings. These mirrors receive the high power synchrotron radiation and are distorted owing to the heat distribution that depends on the position on the mirror surface. The distortion of the mirror changes the effective separation of the slit in the interferometry beam size monitor. Estimation of the effects of the front-end mirror distortion is important for measuring the beam size accurately. In this paper, we present the result of the numerical simulation of the temperature distribution and thermal expansion of the front-end mirror using ANSYS code, the theoretical basis of the effects of mirror distortion and compare with experimental results from Pohang Light Source II (PLS-II) at the Pohang Accelerator Laboratory (PAL). The equipment in the beam diagnosis line in PLS-II and experimental set-up for measuring the distortion of the front-end mirror using a multi-hole square array Hartmann screen are described.

Existence of the genomically and epigenomically diverse subclones in a tumor severely limits the therapeutic efficacy of targeted agents. To overcome such a limitation, we prepared a novel targeted prodrug, EMC-DEVD-S-DOX, which comprises two important features: radiation-induced apoptosis targeting and albumin-binding properties. In particular, the prodrug binds circulating albumin after intravenous administration and then activated by caspase-3, which is upregulated from apoptotic cells that responded to radiotherapy. The prodrug was designed to bind circulating albumin to extend half-life and facilitate tumor accumulation in order to increase the possibility of contacting caspase-3, which is only transiently upregulated during apoptosis. Our results showed that EMC-DEVD-S-DOX had a prolonged half-life with enhanced tumor accumulation, which clearly benefited the therapeutic effect of the prodrug. Also, agreeing with the in vitro studies that showed ignorable cytotoxic effect in the absence of caspase-3, the prodrug was effective only when combined with radiotherapy without any noticeable systemic toxicity in vivo. Due to the highly selective action of EMC-DEVD-S-DOX independent to the complex genomic profiles of tumor, the prodrug would overcome the limitation of current targeted therapy and potentiate radiotherapy in the clinical oncology.

A combination therapy consisting of radiotherapy and chemotherapy is performed using the core/shell nanoparticles (NPs) containing gold NPs and doxorubicin (DOX). Gold NPs in the core/shell NPs were utilized as a radiosensitizer. To examine the morphology and size distribution of the core/shell NPs, transmittance electron microscopy and dynamic light scattering were used. The in vitro release behavior, cellular uptake and toxicity were also observed to verify the functionality of the core/shell NPs as a nanocarrier. To demonstrate the advantage of the core/shell NPs over traditional gold NPs reported in the combination therapy, we evaluated the accumulation behavior of the core/shell NPs at the tumor site using the biodistribution. Antitumor efficacy was observed with and without radiation to evaluate the role of gold NPs as a radiosensitizer.

We present several explicit formulas and recurrence relations for the degenerate Mittag-Leffler polynomials. We also give several connections between Mittag-Leffler polynomials and other known families of polynomials.

Cancer cell-derived extracellular vesicles have been linked to the pathogenesis of various cancers; however, the role of extracellular vesicles in tumorigenesis remains unclear. To identify extracellular vesicle proteins involved in cancer metastasis, quantitative proteomic analyses were performed on extracellular vesicles derived from two representative breast cancer cell lines: the less invasive MCF-7 and the invasive MDA-MB-231. Proteomic analysis allowed for the identification of 270 proteins in the extracellular vesicles. Here we report a new function of EDIL3 on extracellular vesicles, which are sufficient for enhancement of cell invasion and for acceleration of lung metastasis in vivo. This invasion is most likely mediated via the integrin-FAK signaling cascade in breast cancer cells. However, these effects are suppressed when EDIL3 is inactivated, providing evidence for a critical role of EDIL3 in development of cancer. Consistently, in human patients with metastatic breast cancer, the levels of EDIL3 on circulating extracellular vesicles are significantly elevated. This information is a remarkable breakthrough in understanding of the molecular mechanism underlying metastasis of breast cancer as well as in the research for cancer biomarkers using circulating extracellular vesicles. Furthermore, targeting EDIL3 on extracellular vesicles may lead to a new therapeutic option for treatment of breast cancer.

Since the introduction about twenty years ago by Behera and Panda, the balancing numbers have been studied intensively and many interesting properties of them have been discovered. The balancing polynomials are natural generalizations of the balancing numbers. In this paper, we study sums of finite products of balancing polynomials and represent them in terms of nine orthogonal polynomials. In particular, we obtain an expression of such sums of finite products in terms of balancing polynomials which is much neater than some previously found one. Our proof is based on a simple relation between balancing polynomials and Chebyshev polynomials of the second kind observed by Frontczak.

Sepsis is a potentially fatal complication of infections and there are currently no effective therapeutic options for severe sepsis. In this study, we revealed the secretion mechanism of transforming growth factor β-induced protein (TGFBIp) that was recently identified as a therapeutic target for sepsis, and designed TGFBIp acetylation inhibitory peptide (TAIP) that suppresses acetylation of lysine 676 in TGFBIp. To improve bioavailability and biodegradation of the peptide, TAIP was conjugated to polyamidoamine (PAMAM) dendrimers. Additionally, the cell-penetrating peptide (CPP) was conjugated to the TAIP-modified PAMAM dendrimers for the intracellular delivery of TGFBIp. The resulting nanostructures, decorated with TAIP and CPP via poly(ethylene glycol) linkage, improved the mortality and organ damage in the septic mouse model and suppressed lipopolysaccharide-activated severe vascular inflammatory responses in endothelial cells. Thus, the dendrimer-based nanostructures for delivery of TAIP using CPP show great promise in practical applications in sepsis therapy.

I recent years, studying degenerate versions of some special polynomials, which was initiated by Carlitz in an investigation of the degenerate Bernoulli and Euler polynomials, regained lively interest of mant mathematicains. In this paper, as a degenerate version of polyexponential functions introduced by Hardy, we study degenerate polyexponential functions and derive various properties of them. Also, we introduce new type degenerate Bell polynomials, which are different from the previous studied partially degenerate Bell polynomials and arise naturally in the recent study of degenerate zero-truncated Poissonrandom variables, and deduce some of their properties. Furthermore, we derive some identities connecting the polyexponential functions and the new type degenerate Bell polynomials., Comment: 13 pages

The present study was conducted to evaluate the bonding performance of reinforced concrete beams with electric arc furnace oxidizing slag aggregates. The specimens were tested by varying the aggregates, and the top and bottom longitudinal reinforcement position, depending on concrete placement. The specimens containing electric arc furnace oxidizing slag aggregates showed bond performance that was on average of about 8% to 20% higher than that of the specimens using natural aggregates. The bond strength was higher at the corner longitudinal reinforcement than at the inner longitudinal reinforcement and higher at the bottom reinforcement than at the top reinforcement, regardless of the aggregate type. The experimental results were consistent with results from previous studies with concrete containing natural aggregates. Comparison with previous studies confirmed the excellent bond performance of the concrete with electric arc furnace oxidizing slag aggregates, and demonstrated the use of concrete containing electric arc furnace oxidizing slag aggregates for structural members.