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Abstract Background Postoperative cognitive dysfunction (POCD) is one of the major complications after surgery, with devastating clinical outcomes. Although POCD is a condition with a multifactorial pathophysiology, blood-brain barrier (BBB) dysfunction and neuronal injury have been shown to play a critical role, especially in the elderly. Previous studies have demonstrated that the choice of anesthetics affect BBB permeability and neuroinflammation. However, most studies are carried out on animals, with limited research undertaken on humans. Therefore, we will compare the effect of intravenous anesthetics and inhaled anesthetics on BBB dysfunction and the change of inflammatory markers after surgery. Methods One hundred and fifty-four patients who are 60 years of age or older undergoing major surgery for more than 2 h will be randomly allocated to two anesthetics groups (intravenous, inhaled) in a 1:1 ratio. In the intravenous anesthetics group (group P), propofol will be infused with a target-controlled infusion (TCI) system throughout the entire surgery. In the inhaled anesthetics group (group G), bolus injection of propofol will be administered for loss of consciousness, and simultaneously sevoflurane will be initiated for the maintenance of anesthesia. The primary outcome is the change in serum S100 calcium binding protein β (S100β) at four time points: before induction of anesthesia, at the end of surgery, 4 h after surgery, postoperative day 1. Secondary outcomes include changes in the inflammatory markers, serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, and C-reactive protein; the incidence of delirium; and the change in the cognitive function between groups. In patients pre-scheduled for postoperative intensive care unit admission, the cerebrospinal fluid/serum albumin quotient (Qalb) between the two groups will be compared before and after surgery, and change in inflammatory markers in serum and CSF will be analyzed in relation to the Qalb. Discussion The current study will compare the effect of intravenous versus inhaled anesthetics on blood-brain barrier permeability and, as a result, the difference in neuroinflammation in elderly patients. Also, the study results will provide additional information to develop intraoperative anesthetic strategies to reduce POCD. Trial registration The trial was prospectively registered at Clinical Trials protocol registration with identifier 2310-117-126 on April 9, 2024.

Abstract Affective disorders are frequently associated with disrupted circadian rhythms. The existence of rhythmic secretion of central serotonin (5-hydroxytryptamine, 5-HT) pattern has been reported; however, the functional mechanism underlying the circadian control of 5-HTergic mood regulation remains largely unknown. Here, we investigate the role of the circadian nuclear receptor REV-ERBα in regulating tryptophan hydroxylase 2 (Tph2), the rate-limiting enzyme of 5-HT synthesis. We demonstrate that the REV-ERBα expressed in dorsal raphe (DR) 5-HTergic neurons functionally competes with PET-1—a nuclear activator crucial for 5-HTergic neuron development. In mice, genetic ablation of DR 5-HTergic REV-ERBα increases Tph2 expression, leading to elevated DR 5-HT levels and reduced depression-like behaviors at dusk. Further, pharmacological manipulation of the mice DR REV-ERBα activity increases DR 5-HT levels and affects despair-related behaviors. Our findings provide valuable insights into the molecular and cellular link between the circadian rhythm and the mood-controlling DR 5-HTergic systems.

Abstract In Asian patients with atrial fibrillation (AF) and end-stage renal disease (ESRD) undergoing dialysis, the use of direct oral anticoagulants (DOACs) remains debatable. From the national health insurance claims data in South Korea, we included 425 new users of OAC among patients with non-valvular AF and ESRD undergoing dialysis between 2013 and 2020. Patients were categorized into DOAC (n = 106) and warfarin group (n = 319). Clinical outcomes, including ischemic stroke, myocardial infarction (MI), intracranial hemorrhage (ICH), and gastrointestinal (GI) bleeding, were compared between the two groups using inverse probability of treatment weighting (IPTW) analysis. During the median follow-up of 3.2 years, the incidence of ischemic stroke was significantly reduced in the DOAC compared to the warfarin group [Hazard ratio (HR) 0.07; P = 0.001]. However, the incidence of MI (HR 1.32; P = 0.41) and GI bleeding (HR 1.78; P = 0.06) were not significantly different between the two groups. No ICH events occurred in the DOAC group, although the incidence rate did not differ significantly between the two groups (P = 0.17). In Asian patients with AF and ESRD undergoing dialysis, DOACs may be associated with a reduced risk of ischemic stroke compared with warfarin. The MI, ICH, and GI bleeding rates may be comparable between DOACs and warfarin.

Ralstonia pseudosolanacearum, a notorious phytopathogen, is responsible for causing bacterial wilt, leading to significant economic losses globally in many crops within the Solanaceae family. Despite various cultural and chemical control strategies, managing bacterial wilt remains a substantial challenge. This study demonstrates, for the first time, the effective use of plant-induced bacterial gene silencing against R. pseudosolanacearum, facilitated by Tobacco rattle virus-mediated gene silencing, to control bacterial wilt symptoms in Nicotiana benthamiana. The methodology described in this study could be utilized to identify novel phytobacterial virulence factors through both forward and reverse genetic approaches. To validate plant-induced gene silencing, small RNA fractions extracted from plant exudates were employed to silence bacterial gene expression, as indicated by the reduction in the expression of GFP and virulence genes in R. pseudosolanacearum. Furthermore, treatment of human and plant pathogenic Gram-negative and Gram-positive bacteria with plant-generated small RNAs resulted in the silencing of target genes within 48 hours. Taken together, the results suggest that this technology could be applied under field conditions, offering precise, gene-based control of target bacterial pathogens while preserving the indigenous microbiota.

IntroductionMalignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with unacceptably low cure rates occurring often in patients with neurofibromatosis 1 defects. To investigate oncolytic Herpes Simplex Virus (oHSV) as an immunotherapeutic approach, we compared viral replication, functional activity, and immune response between unarmed and interleukin 12 (IL-12)-armed oncolytic viruses in virus-permissive (B109) and -resistant (67C-4) murine MPNSTs.MethodsThis study compared two attenuated IL-12-oHSVs with γ134.5 gene deletions (Δγ134.5) and the same transgene expression cassette. The primary difference in the IL-12-oHSVs was in their ability to counter the translational arrest response in infected cells. Unlike M002 (Δγ134.5, mIL-12), C002 (Δγ134.5, mIL-12, IRS1) expresses an HCMV IRS1 gene and evades dsRNA activated translational arrest in infected cells.Results and discussionOur results show that oHSV replication and gene expression results in vitro were not predictive of oHSV direct oncolytic activity in vivo. Tumors that supported viral replication in cell culture studies resisted viral replication by both oHSVs and restricted M002 transgene expression in vivo. Furthermore, two IL-12-oHSVs with equivalent transcriptional activity differed in IL-12 protein production in vivo, and the differences in IL-12 protein levels were reflected in immune infiltrate activity changes as well as tumor growth suppression differences between the IL-12-oHSVs. C002-treated tumors exhibited sustained IL-12 production with improved dendritic cells, monocyte-macrophage activity (MHCII, CD80/CD86 upregulation) and a polyfunctional Th1-cell response in the tumor infiltrates.ConclusionThese results suggest that transgene protein production differences between oHSVs in vivo, in addition to replication differences, can impact OV-therapeutic activity.

Summary: Chronic pain is associated with alterations in fundamental cellular processes. Here, we investigate whether Beclin 1, a protein essential for initiating the cellular process of autophagy, is involved in pain processing and is targetable for pain relief. We find that monoallelic deletion of Becn1 increases inflammation-induced mechanical hypersensitivity in male mice. However, in females, loss of Becn1 does not affect inflammation-induced mechanical hypersensitivity. In males, intrathecal delivery of a Beclin 1 activator, tat-beclin 1, reverses inflammation- and nerve injury-induced mechanical hypersensitivity and prevents mechanical hypersensitivity induced by brain-derived neurotrophic factor (BDNF), a mediator of inflammatory and neuropathic pain. Pain signaling pathways converge on the enhancement of N-methyl-D-aspartate receptors (NMDARs) in spinal dorsal horn neurons. The loss of Becn1 upregulates synaptic NMDAR-mediated currents in dorsal horn neurons from males but not females. We conclude that inhibition of Beclin 1 in the dorsal horn is critical in mediating inflammatory and neuropathic pain signaling pathways in males.

Background Although programmed intermittent epidural bolus (PIEB) is effective for labor analgesia, an appropriate flow rate has not been established. Therefore, we investigated the analgesic effect based on different epidural injection flow rates. Methods Nulliparous women scheduled for spontaneous labor were enrolled in this randomized trial. After injection of intrathecal 0.2% ropivacaine 3 mg with fentanyl 20 μg, participants were randomized to three study groups. Epidural analgesics, 10 ml during one hour, were administered with patient controlled epidural analgesia as follows (0.2% ropivacaine 60 ml, fentanyl 180 μg, and 0.9% saline 40 ml): continuous (n = 28, 10 ml/h for continuous infusion), PIEB (n = 29, 240 ml/h for bolus infusion of 10 ml), or manual (n = 28, 1200 ml/h for bolus injection of 10 ml). The primary outcome was hourly consumption of the epidural solution. The time interval between labor analgesia and the first breakthrough pain was investigated. Results The median (Q1, Q3) hourly consumption of epidural anesthetics was significantly different among the groups (continuous: 14.3 [8.7, 16.9] ml, PIEB: 9.4 [6.2, 9.8] ml, manual: 8.6 [7.6, 9.9] ml; P < 0.001). The time to breakthrough pain for the PIEB group was longer than that for the other groups (continuous: 78.5 [35.8, 185.0] min, PIEB: 200.0 [88.5, 441.5] min, manual: 60.5 [37.3, 162.0] min, P = 0.027). Conclusions PIEB, with a low-flow rate, provided more adequate labor analgesia than a continuous epidural infusion or manual injection with a high-flow rate.

Acute liver failure caused by alcoholic hepatitis (AH) is only effectively treated with liver transplantation. Livers of patients with AH show a unique molecular signature characterized by defective hepatocellular redox metabolism, concurrent to hepatic infiltration of neutrophils that express myeloperoxidase (MPO) and form neutrophil extracellular traps (NETs). Exacerbated NET formation and MPO activity contribute to liver damage in mice with AH and predicts poor prognosis in AH patients. The identification of pathways that maladaptively exacerbate neutrophilic activity in liver could inform of novel therapeutic approaches to treat AH. Whether the redox defects of hepatocytes in AH directly exacerbate neutrophilic inflammation and NET formation is unclear. Here we identify that the protein content of the mitochondrial biliverdin exporter ABCB10, which increases hepatocyte-autonomous synthesis of the ROS-scavenger bilirubin, is decreased in livers from humans and mice with AH. Increasing ABCB10 expression selectively in hepatocytes of mice with AH is sufficient to decrease MPO gene expression and histone H3 citrullination, a specific marker of NET formation. These anti-inflammatory effects can be explained by ABCB10 function reducing ROS-mediated actions in liver. Accordingly, ABCB10 gain-of-function selectively increased the mitochondrial GSH/GSSG ratio and decreased hepatic 4-HNE protein adducts, without elevating mitochondrial fat expenditure capacity, nor mitigating steatosis and hepatocyte death. Thus, our study supports that ABCB10 function regulating ROS-mediated actions within surviving hepatocytes mitigates the maladaptive activation of infiltrated neutrophils in AH. Consequently, ABCB10 gain-of-function in human hepatocytes could potentially decrease acute liver failure by decreasing the inflammatory flare caused by excessive neutrophil activity.

Oncolytic viruses, modified for tumor-restricted infection, are a promising cancer immunotherapeutic, yet much remains to be understood about factors driving their activity and outcome in the tumor microenvironment. Here, we report that oncolytic herpes simplex virus C134, previously found to exert T cell-dependent efficacy in mouse models of glioblastoma, exerts T cell-independent efficacy in mouse models of medulloblastoma, indicating this oncolytic virus uses different mechanisms in different tumors. We investigated C134’s behavior in mouse medulloblastomas, using single cell RNA sequencing to map C134-induced gene expression changes across cell types, timepoints, and medulloblastoma subgroup models at whole-transcriptome resolution. Our work details substantial oncolytic virus-induced transcriptional remodeling of medulloblastoma-infiltrating immune cells, 10 subpopulations of monocytes and macrophages collectively demonstrating M1-like responses to C134, and suggests C134 be investigated as a potential new therapy for medulloblastoma.

This study aims to evaluate and determine the correlation between in vitro release and in vivo pharmacokinetics of two extended-release dosage forms of Cilostazol. In vitro release profiles for two dosage forms, tablet and capsule, were analyzed under physiologically mimicked medium conditions using the paddle and basket USP release apparatus. A single-dose, two-period crossover study design in beagle dogs was applied for the pharmacokinetic study. The fed and fast effects were considered for evaluation. Pseudo gastric release medium transfer setup study from pH 1.2 to pH 6.8 (+0.5% SLS) and pH 1.2 to pH 6.8 (+1.0% SLS) demonstrated that Pletaal® SR 200 mg capsules have higher drug release rates than Cilostan® CR 200 mg tablets. Similarly, in vivo study showed Cilostazol concentration in plasma and AUC was lower under the fast state than the fed state. The ratio of least squared geometric mean values, Cmax, AUC0-t, and AUC0-inf of Cilostazol were 2.53-fold, 2.89-fold, and 2.87-fold higher for Pletaal® SR 200 mg capsules compared with Cilostan® CR 200 mg tablets, respectively. Correlation of in vitro/in vivo data indicated that Pletal® SR 200 mg capsules have better release and pharmacodynamic effect than Cilostan® CR 200 mg tablets.

Abstract Background Toll-like receptor 7 (TLR7) is an endosomal TLR activated by single-stranded RNA, including endogenous microRNAs. Although TLR7 is known to promote inflammatory responses in pathophysiological conditions, its role in renal fibrosis has not been investigated. Here, we aim to investigate the inflammatory roles of TLR7 in kidney inflammation and fibrosis. Methods TLR7 knockout mice (Tlr7 −/−) subjected to AD-induced kidney injury were utilized to examine the role of TLR7 in kidney fibrosis. To elucidate the role of TLR7 in renal epithelial cells, NRK52E rat renal tubule epithelial cells were employed. Results Under fibrotic conditions induced by an adenine diet (AD), TLR7 was significantly increased in damaged tubule epithelial cells, where macrophages were highly infiltrated. TLR7 deficiency protected against AD-induced tubular damage, inflammation, and renal fibrosis. Under in vitro conditions, TLR7 activation increased NF-κB activity and induced chemokine expression, whereas TLR7 inhibition effectively blocked NF-κB activation. Furthermore, among the known TLR7 endogenous ligands, miR-21 was significantly upregulated in the tubular epithelial regions. In NRK52E cells, miR-21 treatment induced pro-inflammatory responses, which could be blocked by a TLR7 inhibitor. When the TLR7 inhibitor, M5049, was administered to the AD-induced renal fibrosis model, TLR7 inhibition significantly attenuated AD-induced renal inflammation and fibrosis. Conclusions Overall, activation of TLR7 by endogenous miR-21 in renal epithelial cells contributes to inflammatory responses in a renal fibrosis model, suggesting a possible therapeutic target for the treatment of renal fibrosis. Video Abstract

Abstract We measure group velocity dispersion of surface waves generated by two meteoroid impacts on Mars close to the lander of the InSight mission. This allows us to probe the crustal structure in the first few kilometers beneath the InSight lander. In combination with body wave arrival times from five impact events, we obtain direct seismic constraints on the seismic velocity of the crust in the vicinity of the InSight landing site. We confirm the existence of a uppermost low‐velocity layer with a mean thickness of ∼1.2 km, interpreted as layered volcanic materials, possibly interstratified with sedimentary and altered materials. Our joint inversion of surface and body waves shows a four‐layer model for the Martian crust, compatible with high‐ and low‐frequency P‐to‐S receiver functions estimated in previous studies.

Abstract Background Dexmedetomidine, one of the sedatives, has an analgesic effect. We aimed to investigate postoperative analgesia with dexmedetomidine as adjuvants for procedural sedation using perfusion index (PI). Methods In this prospective, randomized, case-control, observational study, 72 adult patients, 19–70 years, who were scheduled for chemoport insertion under monitored anesthesia care were performed. According to the group assignment, remifentanil or dexmedetomidine was simultaneously infused with propofol. The primary outcome was PI 30 min after admission to the post anesthesia care unit (PACU). And, pain severity using numerical rating scale (NRS) score and the relationship between NRS score and PI were investigated. Results During PACU staying, PI values were significantly different between the two groups PI values at 30 min after admission to the PACU were 1.3 (0.9–2.0) in the remifentanil group and 4.5 (2.9–6.8) in the dexmedetomidine group (median difference, 3; 95% CI, 2.1 to 4.2; P

Abstract Few studies have investigated the changes in patient state index (PSI) and bispectral index (BIS) in response to abrupt increase in electromyographic (EMG) activity. These were performed using intravenous anesthetics or reversal agents for neuromuscular blockade (NMB) other than sugammadex. We compared the changes in BIS and PSI values caused by the sugammadex reversal of NMB during steady-state sevoflurane anesthesia. We enrolled 50 patients with American Society of Anesthesiologists physical status 1 and 2. At the end of the surgery, we administered 2 mg kg−1 sugammadex while maintaining sevoflurane for a 10-min study period. The changes in BIS and PSI from baseline (T0) to train of four ratio of 90% were not significantly different (median difference 0; 95% CI − 3 to 2; P = 0.83), neither were the changes in BIS and PSI values from T0 to their maximum values (median difference 1; 95% CI − 1 to 4; P = 0.53). Maximum BIS and PSI were significantly higher than their baseline values (median difference 6; 95% CI 4–9; P

Nanosized drug delivery systems typically enter the cell via endocytosis. However, a significant amount of the endocytosed cargo cannot effectively escape from the endosome, resulting in drug degradation. Therefore, there are several ongoing efforts to develop transmembrane delivery systems that could circumvent endocytosis. In this study, phospholipid nanotube nanodrills (LDs) were formed onto the surface of a human serum albumin nanoparticle via self-assembling phospholipids. The nanodrill technology enhanced the intracellular uptake efficiency of nanoparticles via energy-independent direct cell membrane permeation. The length of the nanodrills according to the DSPE-PEG to DSPC ratio was investigated both experimentally and theoretically. Our findings demonstrated that longer nanodrills were formed on the surface of the nanoparticles as the ratio of DSPC (i.e., a strongly hydrophobic lipid) in the two phospholipids increases. Moreover, the intracellular uptake efficiency increased as the length of phospholipid nanodrills increased. In addition to enhancing intracellular delivery, the phospholipid nanodrills could penetrate the extracellular matrix and enable the introduction of nanoparticles, thus highlighting the promising tissue penetration capacity of phospholipid nanodrill technology. The improved cell permeability of LD technology was demonstrated by effectively inhibiting specific genes via siRNA-based therapeutic delivery. Moreover, this approach enhanced the efficacy of chemotherapeutics against chemo-resistant cancer cells. Therefore, LD technology could be used to deliver genetic materials and chemical-based therapeutics both in vitro and in vivo.

Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation, aberrant differentiation of keratinocytes, and dysregulated immune responses. WW domain-containing oxidoreductase (WWOX) is a non-classical tumor suppressor gene that regulates multiple cellular processes, including proliferation, apoptosis, and migration. This study aimed to explore the possible role of WWOX in the pathogenesis of psoriasis. Immunohistochemical analysis showed that the expression of WWOX was increased in epidermal keratinocytes of both human psoriatic lesions and imiquimod-induced mice psoriatic model. Immortalized human epidermal keratinocytes were transduced with a recombinant adenovirus expressing microRNA specific for WWOX to downregulate its expression. Inflammatory responses were detected using Western blotting, real-time quantitative reverse transcription polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay. In human epidermal keratinocytes, WWOX knockdown reduced nuclear factor-kappa B signaling and levels of proinflammatory cytokines induced by polyinosinic: polycytidylic acid [(poly(I:C)] in vitro. Furthermore, calcium chelator and protein kinase C (PKC) inhibitors significantly reduced poly(I:C)-induced inflammatory reactions. WWOX plays a role in the inflammatory reaction of epidermal keratinocytes by regulating calcium and PKC signaling. Targeting WWOX could be a novel therapeutic approach for psoriasis in the future.

Abstract The Hadley cell response to globally increasing CO2 concentrations is spatially complex, with an intensified rising branch and weakened descending branch. To better understand these changes, we examine the sensitivity of the Hadley cell to idealized radiative forcing in different latitude bands. The Hadley cell response is, to first order, governed by the latitudinal structure of the forcing. The strengthening of the upward branch is attributed to tropical forcing, whereas the weakening of the descending branch is attributed to extratropical forcing. These direct radiatively-forced Hadley cell responses are amplified by changes in atmospheric eddy heat transport while being partially offset by changes in gross moist stability and ocean heat uptake. The radiative feedbacks further modulate the Hadley cell response by altering the meridional atmospheric energy gradient. The Hadley cell projections under global warming are thus a result of opposing – and thus compensating – effects from tropical and extratropical radiative forcings.

Abstract NASA's InSight has detected a large magnitude seismic event, labeled S1222a. The event has a moment magnitude of MWMa4.7, with five times more seismic moment compared to the second largest event. The event is so large that features are clearly observed that were not seen in any previously detected events. In addition to body phases and Rayleigh waves, we also see Love waves, minor arc surface wave overtones, and multi‐orbit surface waves. At long periods, the coda event exceeds 10 hr. The event locates close to the North‐South dichotomy and outside the tectonically active Cerberus Fossae region. S1222a does not show any evident geological or tectonic features. The event is extremely rich in frequency content, extending from below 1/30 Hz up to 35 Hz. The event was classified as a broadband type event; we also observe coda decay and polarization similar to that of very high frequency type events.

Abstract The shallowest intracrustal layer (extending to 8 ± 2 km depth) beneath the Mars InSight Lander site exhibits low seismic wave velocity, which is likely related to a combination of high porosity and other lithological factors. The SsPp phase, an SV‐ to P‐wave reflection on the receiver side, is naturally suited for constraining the seismic structure of this top crustal layer since its prominent signal makes it observable with a single station without the need for stacking. We have analyzed six broadband and low‐frequency seismic events recorded on Mars and made the first coherent detection of the SsPp phase on the red planet. The timing and amplitude of SsPp confirm the existence of the ∼8 km interface in the crust and the large wave speed (or impedance) contrast across it. With our new constraints from the SsPp phase, we determined that the average P‐wave speed in the top crustal layer is between 2.5 and 3.2 km/s, which is a more precise and robust estimate than the previous range of 2.0–3.5 km/s obtained by receiver function analysis. The low velocity of Layer 1 likely results from the presence of relatively low‐density lithified sedimentary rocks and/or aqueously altered igneous rocks that also have a significant amount of porosity, possibly as much as 22%–30% by volume (assuming an aspect ratio of 0.1 for the pore space). These porosities and average P‐wave speeds are compatible with our current understanding of the upper crustal stratigraphy beneath the InSight Lander site.

For over three Earth years the Marsquake Service has been analyzing the data sent back from the Seismic Experiment for Interior Structure—the seismometer placed on the surface of Mars by NASA’s InSight lander. Although by October 2021, the Mars seismic catalog included 951 events, until recently all these events have been assessed as lying within a radius of 100° of InSight. Here we report two distant events that occurred within days of each other, located on the far side of Mars, giving us our first glimpse into Mars’ core shadow zone. The first event, recorded on 25 August 2021 (InSight sol 976), shows clear polarized arrivals that we interpret to be PP and SS phases at low frequencies and locates to Valles Marineris, 146° ± 7° from InSight. The second event, occurring on 18 September 2021 (sol 1000), has significantly more broadband energy with emergent PP and SS arrivals, and a weak phase arriving before PP that we interpret as Pdiff. Considering uncertain pick times and poorly constrained travel times for Pdiff, we estimate this event is at a distance between 107° and 147° from InSight. With magnitudes of MwMa 4.2 and 4.1, respectively, these are the largest seismic events recorded so far on Mars.

Orbital hematic cyst is characterized by cystic accumulation of hematogenous debris surrounded by a wall of fibrous tissue without an epithelial lining. It is a relatively uncommon benign cyst and occurs secondary to blunt trauma in most cases. We experienced a case of 53-year-old male who presented with proptosis of the left eye. A cystic lesion was found at the superolateral orbital rim of the patient. We report a case of orbital hematic cyst that was resected completely through the sub-brow approach.

Chronic kidney disease (CKD) is a kidney structure and function abnormality. CKD development and progression are strongly influenced by oxidative stress and inflammatory responses, which can lead to tubulointerstitial fibrosis. Unfortunately, there are no effective or specific treatments for CKD. We investigated the potential of the thiobarbiturate-derived compound MHY1025 to alleviate CKD by reducing oxidative stress and inflammatory responses. In vitro experiments using NRK52E renal tubular epithelial cells revealed that MHY1025 significantly reduced LPS-induced oxidative stress and inhibited the activation of the NF-κB pathway, which is involved in inflammatory responses. Furthermore, treatment with MHY1025 significantly suppressed the expression of fibrosis-related genes and proteins induced by TGFβ in NRK49F fibroblasts. Furthermore, we analyzed the MHY1025 effects in vivo. To induce kidney fibrosis, mice were administered 250 mg/kg folic acid (FA) and orally treated with MHY1025 (0.5 mg/kg/day) for one week. MHY1025 effectively decreased the FA-induced inflammatory response in the kidneys. The group treated with MHY1025 exhibited a significant reduction in cytokine and chemokine expression and decreased immune cell marker expression. Decreased inflammatory response was associated with decreased tubulointerstitial fibrosis. Overall, MHY1025 alleviated renal fibrosis by directly modulating renal epithelial inflammation and fibroblast activation, suggesting that MHY1025 has the potential to be a therapeutic agent for CKD.

The typical filters that protect us from harmful components, such as toxic gases and particulate matter (PM), are made from petroleum-based materials, which need to be replaced with other environmentally friendly materials. Herein, we demonstrate a route to fabricate biodegradable and dual-functional filtration membranes that effectively remove PM and toxic gases. The membrane was integrated using two layers: (i) cellulose-based nanofibers for PM filtration and (ii) metal–organic framework (MOF)-coated cotton fabric for removal of toxic gases. Zeolitic imidazolate framework (ZIF-8) was grown from the surface of the cotton fabric by the treatment of cotton fabric with an organic precursor solution and subsequent immersion in an inorganic precursor solution. Cellulose acetate nanofibers (NFs) were deposited on the MOF-coated cotton fabric via electrospinning. At the optimal thickness of the NF layer, the quality factor of 18.8 × 10−2 Pa−1 was achieved with a filtration efficiency of 93.1%, air permeability of 19.0 cm3/cm2/s, and pressure drop of 14.2 Pa. The membrane exhibits outstanding gas adsorption efficiencies (>99%) for H2S, formaldehyde, and NH3. The resulting membrane was highly biodegradable, with a weight loss of 62.5% after 45 days under standard test conditions. The proposed strategy should provide highly sustainable material platforms for practical multifunctional membranes in personal protective equipment.

How can we interpret predictions of a workload classification model? A workload is a sequence of operations executed in DRAM, where each operation contains a command and an address. Classifying a given sequence into a correct workload type is important for verifying the quality of DRAM. Although a previous model achieves a reasonable accuracy on workload classification, it is challenging to interpret the prediction results since it is a black box model. A promising direction is to exploit interpretation models which compute the amount of attribution each feature gives to the prediction. However, none of the existing interpretable models are tailored for workload classification. The main challenges to be addressed are to 1) provide interpretable features for further improving interpretability, 2) measure the similarity of features for constructing the interpretable super features, and 3) provide consistent interpretations over all instances. In this paper, we propose INFO (INterpretable model For wOrkload classification), a model-agnostic interpretable model which analyzes workload classification results. INFO provides interpretable results while producing accurate predictions. We design super features to enhance interpretability by hierarchically clustering original features used for the classifier. To generate the super features, we define and measure the interpretability-friendly similarity, a variant of Jaccard similarity between original features. Then, INFO globally explains the workload classification model by generalizing super features over all instances. Experiments show that INFO provides intuitive interpretations which are faithful to the original non-interpretable model. INFO also shows up to 2.0× faster running time than the competitor while having comparable accuracies for real-world workload datasets.

How can we interpret predictions of a workload classification model? A workload is a sequence of operations executed in DRAM, where each operation contains a command and an address. Classifying a given sequence into a correct workload type is important for verifying the quality of DRAM. Although a previous model achieves a reasonable accuracy on workload classification, it is challenging to interpret the prediction results since it is a black box model. A promising direction is to exploit interpretation models which compute the amount of attribution each feature gives to the prediction. However, none of the existing interpretable models are tailored for workload classification. The main challenges to be addressed are to 1) provide interpretable features for further improving interpretability, 2) measure the similarity of features for constructing the interpretable super features, and 3) provide consistent interpretations over all instances. In this paper, we propose INFO (INterpretable model For wOrkload classification), a model-agnostic interpretable model which analyzes workload classification results. INFO provides interpretable results while producing accurate predictions. We design super features to enhance interpretability by hierarchically clustering original features used for the classifier. To generate the super features, we define and measure the interpretability-friendly similarity, a variant of Jaccard similarity between original features. Then, INFO globally explains the workload classification model by generalizing super features over all instances. Experiments show that INFO provides intuitive interpretations which are faithful to the original non-interpretable model. INFO also shows up to 2.0× faster running time than the competitor while having comparable accuracies for real-world workload datasets.

Abstract Sargassum serratifolium (C. Agardh) C.Agardh, a marine brown alga, has been consumed as a food and traditional medicine in Asia. A previous study showed that the meroterpenoid-rich fraction of an ethanolic extract of S. serratifolium (MES) induced adipose tissue browning and suppressed diet-induced obesity and metabolic syndrome when orally supplemented. Sargahydroquinoic acid (SHQA) is a major component of MES. However, it is unclear whether SHQA regulates energy homeostasis through the central nervous system. To examine this, SHQA was administrated through the third ventricle in the hypothalamus in high-fat diet-fed C57BL/6 mice and investigated its effects on energy homeostasis. Chronic administration of SHQA into the brain reduced body weight without a change in food intake and improved metabolic syndrome-related phenotypes. Cold experiments and biochemical analyses indicated that SHQA elevated thermogenic signaling pathways, as evidenced by an increase in body temperature and UCP1 signaling in white and brown adipose tissues. Peripheral denervation experiments using 6-OHDA indicated that the SHQA-induced anti-obesity effect is mediated by the activation of the sympathetic nervous system, possibly by regulating genes associated with sympathetic outflow and GABA signaling pathways. In conclusion, hypothalamic injection of SHQA elevates peripheral thermogenic signaling and ameliorates diet-induced obesity.

This study established a dynamic Z-scheme driven heterostructure of ZnO-ZnS (ZnOS) nanoparticles (NPs) by sulfidation of ZnO NPs. The ZnOS composites with different atomic ratios of S/O were analyzed with multiple characterization techniques. The composite materials with a S/O atomic ratio of 1:1 yielded the best photocatalytic results for toxic Cr(VI) removal from water and H2 production from water under UV light. This study examined a dynamic Z-scheme energy transfer behavior at the junction of ZnOS composites for the first time via atomic and electronic structure modeling using density functional theory (DFT) simulations. ZnOS NPs were further immobilized on polyvinylidene fluoride (PVDF) via a non-solvent-induced phase separation method for functional recovery after photocatalysis.

Plants and animals serve as hosts for microbes. To protect themselves from microbe-induced damage, plants and animals need to differentiate self-molecules/signals from non-self, microbe-derived molecules. Damage-associated molecular patterns (DAMPs) are danger signals released from the damaged host tissue or present on the surface of stressed cells. Although a self-extracellular DNA has previously been shown to act as a DAMP in different plant species, the existence of a self-extracellular RNA (eRNA) as a danger signal in plants remains unknown. Here, we firstly evaluated the ability of a pepper self-eRNA to activate immunity against viral and bacterial pathogens under field conditions. Pepper leaves pre-infiltrated with self-eRNA exhibited reduced titer of the naturally occurring Tomato spotted wilt virus and diminished symptoms of Xanthomonas axonopodis pv. vesicatoria infection through eliciting defense priming of abscisic acid signaling. At the end of the growing season at 90 days after transplanting, pepper plants treated with self- and non-self-eRNAs showed no difference in fruit yield. Taken together, our discovery demonstrated that self-eRNA can successfully activate plant systemic immunity without any growth penalty, indicating its potential as a novel disease management agent against a broad range of pathogenic microbes.

Bacterial cellulose (BC) is a biodegradable, non-toxic, natural substance that can be obtained by culturing bacteria. It can be approached in various ways from physical, chemical, and biological points. BC nanoparticles have been applied as lubricating additives to improve the load capacity, anti-wear, and friction. The microcellular foaming process was created using a technology based on the saturation of the polymer by supercritical CO2 and rapid decompression. An increase in saturation pressure leads to an increase in the molecular potential energy of CO2, which can be more easily compressed into the cellulose matrix. Moreover, the high crystallinity and water content combination contribute to thermal stability. Specimen membranes produced by Komagataeibacter xylinus prepared with a thickness of 2 mm were saturated in supercritical condition, 10 MPa of CO2 for 4 h, and foamed at a temperature of 120 °C in a hot press. After the foaming process, we used dry ice to cool the BC. Before foaming, the friction coefficient continuously increased with the increase in cycles, and after foaming, a stable friction coefficient of 0.3 or less was secured despite the increase in the cycle. The microcellular foaming process significantly reduced and made BC’s coefficient of friction stable.

Extracellular vesicles (EVs) composed of a lipid bilayer are released from various cell types, including animals, plants, and microorganisms, and serve as important mediators of cell-to-cell communication. EVs can perform a variety of biological functions through the delivery of bioactive molecules, such as nucleic acids, lipids, and proteins, and can also be utilized as carriers for drug delivery. However, the low productivity and high cost of mammalian-derived EVs (MDEVs) are major barriers to their practical clinical application where large-scale production is essential. Recently, there has been growing interest in plant-derived EVs (PDEVs) that can produce large amounts of electricity at a low cost. In particular, PDEVs contain plant-derived bioactive molecules such as antioxidants, which are used as therapeutic agents to treat various diseases. In this review, we discuss the composition and characteristics of PDEVs and the appropriate methods for their isolation. We also discuss the potential use of PDEVs containing various plant-derived antioxidants as replacements for conventional antioxidants.

Here, Kim et al. apply various sequencing techniques (RPF-seq, QTI-seq, mRNA-seq, sRNA-seq) to unravel the high-resolution, longitudinal translatome and transcriptome of SARS-CoV-2. They identify a translation initiation site in the leader sequence of all genomic and subgenomic RNAs and show its relevance for the SARS-CoV-2 translatome.

miRNAs are loaded into Argonaute protein and repress complementary mRNA targets. Here the authors show the unappreciated role of RNA binding proteins for efficient miRNA targeting and expand the current understanding of miRNA targeting.

Abstract There were insufficient researches of the comparison between Bispectral Index (BIS) and Patient State Index (PSI) values during the recovery of moderate NMB. We investigated the response of these indices during neuromuscular blockade (NMB) reversal by sugammadex under steady-state total intravenous anesthesia (TIVA) using propofol/remifentanil. In this prospective, observational study, patients undergoing laparoscopic cholecystectomy were enrolled. At the end of surgery, after confirming that train-of-four (TOF) count as 1 or 2, we maintained a steady state (BIS value of 40–50). After administration of 2 mg kg−1 sugammadex, BIS, PSI, and electromyography (EMG) signal values were recorded at one-minute intervals for 10 min. The primary outcome was the difference between the changes in BIS and PSI from baseline to a TOF ratio (TOFR) of 90 after sugammadex administration in steady-state TIVA. A total of 48 patients completed this trial. There was no significant difference between the changes in BIS and PSI values from baseline to TOFR 90 (− 0.333 ± 4.955 vs. − 0.188 ± 4.616; 95% confidence interval [CI] − 2.095 to 1.803; p = 0.882). Both BIS-EMG and PSI-EMG values at baseline and TOFR 90 were not statistically different (95% CI − 0.550 to 1.092; p = 0.510, 95% CI − 1.569 to 0.527; p = 0.322, respectively). No patient experienced any complications. Changes in BIS and PSI values after NMB reversal during steady-state TIVA were not significantly different. Both BIS and PSI provide trustworthy values for monitoring anesthetic depth during NMB reversal under TIVA. Trial Registration: This study was registered in the Clinical Trial Registry of Korea ( https://cris.nih.go.kr : KCT 0003805).

The peroxisome proliferator-activated receptor (PPAR) nuclear receptor has been an interesting target for the treatment of chronic diseases. Although the efficacy of PPAR pan agonists in several metabolic diseases has been well studied, the effect of PPAR pan agonists on kidney fibrosis development has not been demonstrated. To evaluate the effect of the PPAR pan agonist MHY2013, a folic acid (FA)-induced in vivo kidney fibrosis model was used. MHY2013 treatment significantly controlled decline in kidney function, tubule dilation, and FA-induced kidney damage. The extent of fibrosis determined using biochemical and histological methods showed that MHY2013 effectively blocked the development of fibrosis. Pro-inflammatory responses, including cytokine and chemokine expression, inflammatory cell infiltration, and NF-κB activation, were all reduced with MHY2013 treatment. To demonstrate the anti-fibrotic and anti-inflammatory mechanisms of MHY2013, in vitro studies were conducted using NRK49F kidney fibroblasts and NRK52E kidney epithelial cells. In the NRK49F kidney fibroblasts, MHY2013 treatment significantly reduced TGF-β-induced fibroblast activation. The gene and protein expressions of collagen I and α-smooth muscle actin were significantly reduced with MHY2013 treatment. Using PPAR transfection, we found that PPARγ played a major role in blocking fibroblast activation. In addition, MHY2013 significantly reduced LPS-induced NF-κB activation and chemokine expression mainly through PPARβ activation. Taken together, our results suggest that administration of the PPAR pan agonist effectively prevented renal fibrosis in both in vitro and in vivo models of kidney fibrosis, implicating the therapeutic potential of PPAR agonists against chronic kidney diseases.

Loop-mediated isothermal amplification (LAMP) is one of the most widely used isothermal amplification technologies in molecular diagnostics. However, LAMP operates at a high temperature of 65 °C; thus, operating LAMP at a lower temperature is desirable to maximize its usefulness for on-site diagnosis. In this study, we propose a new version of LAMP, termed low-temperature LAMP, which operates at the physiological temperature of 37 °C. Low-temperature LAMP differs from conventional LAMP operating at 65 °C in terms of the concentrations of MgSO4 and deoxyribonucleoside triphosphates (dNTPs), as well as the lengths of DNA probes, which are crucial for the execution of low-temperature LAMP. Under the optimal conditions, the amplification efficiency of low-temperature LAMP is comparable to that of conventional LAMP. In addition, the ligation reaction at 37 °C, which is necessary to detect actual target nucleic acids, is combined without altering the temperature, enabling the identification of miR-21, a cancer-promoting oncogenic miRNA, with high sensitivity and selectivity. The method described in this paper does not require expensive DNA modifications or special additives and would facilitate the widespread application of LAMP in facility-limited or point-of-care settings, paving the way to improvements in other isothermal-amplification-based techniques.

Abstract The second-generation laryngeal mask airway (LMA) provides a higher sealing pressure than classical LMA and can insert the gastric drainage tube. We investigated the difference in respiratory variables according to the use of second-generation LMA and endotracheal tube (ETT) in laparoscopic living liver donor hepatectomy (LLDH). In this single-blind randomized controlled trial, intraoperative arterial carbon dioxide partial pressure at 2 h after the airway devices insertion (PaCO2_2h) was compared as a primary outcome. Participants were randomly assigned to the following groups: Group LMA (n = 45, used Protector LMA), or Group ETT (n = 43, used cuffed ETT). Intraoperative hemodynamic and respiratory variables including mean blood pressure (MBP), heart rate (HR), and peak inspiratory pressure (PIP) were compared. Postoperative sore throat, hoarseness, postoperative nausea and vomiting (PONV), and pulmonary aspiration were recorded. The PaCO2_2h were equally effective between two groups (mean difference: 0.99 mmHg, P = 0.003; 90% confidence limits: − 0.22, 2.19). The intraoperative change in MBP, HR, and PIP were differed over time between two groups (P 0.99, PONV: P > 0.99, and P = 0.65, respectively). No case showed pulmonary aspiration in both groups. Compared with endotracheal tube, second-generation LMA is equally efficient during LLDH. The second-generation LMA can be considered as the effective airway devices for securing airway in patients undergoing prolonged laparoscopic surgery. Trial Registration This study was registered at the Clinical Trial Registry of Korea ( https://cris.nih.go.kr . CRiS No. KCT0003711).

Circadian rhythm: microRNAs keep the clock in order A newly identified microRNA plays a key role in fine-tuning the genetic interactions governing the circadian rhythms in mammals, according to researchers in South Korea. Numerous studies have suggested that the Period genes, which negatively regulate the CLOCK and BMAL1 genes to produce a 24-hour feedback loop, may be further modified by microRNAs after they are transcribed. Kyungjin Kim at Daegu Gyeongbuk Institute of Science and Technology, South Korea, and co-workers confirmed that a novel microRNA, miR-25-3p, reduces the expression of a Period gene, Per2, in mice. When miR-25-3p is over-expressed, it dampens and shortens the oscillations of Per2 levels. Interestingly, the researchers showed that natural miR-25-3p expression levels varied across different parts of the brain, supporting the theory that different tissues of the body maintain their own unique circadian cycles.

Abstract One of the major obstacles to successful chemotherapy is multi-drug resistance (MDR). A multi-drug resistant cancerous cell abnormally overexpresses membrane transporters that pump anticancer drugs out of the cell, resulting in low anticancer drug delivery efficiency. To overcome the limitation, many attempts have been performed to inhibit the abilities of efflux receptors chemically or genetically or to increase the delivery efficiency of anticancer drugs. However, the results have not yet been satisfactory. In this study, we developed nanoparticle-microbubble complexes (DOX-NPs/Ce6-MBs) by conjugating doxorubicin loaded human serum albumin nanoparticles (DOX-NPs) onto the surface of Chlorin e6 encapsulated microbubbles (Ce6-MBs) in order to maximize anticancer efficiency by overcoming MDR. Under the ultrasound irradiation, DOX-NPs and Ce6 encapsulating self-assembled liposomes or micelles were effectively delivered into the cells due to the sonoporation effect caused by the microbubble cavitation. At the same time, reactive oxygen (ROS) generated from intracellularly delivered Ce6 by laser irradiation arrested the activity of ABCG2 efflux receptor overexpressed in doxorubicin-resistant breast cancer cells (MCF-7/ADR), resulting in increased the chemotherapy efficacy. In addition, the total number of side population cells that exhibit the properties of cancer stem-like cells were also reduced by the combination of photodynamic therapy and chemotherapy. In conclusion, DOX-NPs/Ce6-MBs will provide a platform for simultaneously overcoming MDR and increasing drug delivery and therefore, treatment efficiency, under ultrasound irradiation.

Sinus disease: nasal bacteria linked to manifestations of chronic disease Microbes living in the sinonasal cavity seem to affect the immune responses and clinical outcomes of patients with an inflammatory disease that can cause lasting pain, pressure, and swelling in the sinuses. Ji Heui Kim from the Asan Medical Center in Seoul, South Korea, and colleagues collected nasal swabs and blood from 31 people suffering from chronic rhinosinusitis with nasal polyps and from six healthy control individuals. They identified several specific bacterial groups whose presence or absence was associated with the abundance of certain white blood cell populations, a sign of inflammation. Some of these groups were linked to patient outcomes after nasal surgery but additional groups were also observed. The findings could help lead to new treatment strategies or diagnostic biomarkers for patients with this sinus disorder.

Abstract Background In the elderly, nutritional status and quality of life (QOL) could potentially affect food purchasing behaviors. We examined the association between combinations of nutritional status and QOL and food purchasing motives among the elderly. Methods A total of 143 community-dwelling elderly were recruited in Seoul, South Korea. Nutritional status and QOL were assessed and participants were divided into four groups according to those combinations. Binary logistic regression analysis was used to examine the odds of food purchasing motives according to combinations of nutritional status and QOL. Results As a result of comparing the scores (mean ± SD) of the overall important factors for food purchasing, health related factors such as Nutrition quality and Preventive of treatment effect were the highest score (4.4 ± 0.8), followed by Price (4.1 ± 0.9), Ease of purchase (3.8 ± 0.9), Ease of chewing (3.7 ± 0.9), and Taste (3.6 ± 0.9). Participants with a low nutritional status and low QOL had more eating-related problems (77.8%) including chewing difficulty (48.9%) and constipation (17.8%) than those with a high nutritional status and high QOL (P

Humans strongly rely on visual cues to understand scenes such as segmenting, detecting objects, or measuring the distance from nearby objects. Recent studies suggest that deep neural networks can take advantage of contextual representation for the estimation of a depth map for a given image. Therefore, focusing on the scene context can be beneficial for successful depth estimation. In this study, a novel network architecture is proposed to improve the performance by leveraging the contextual information for monocular depth estimation. We introduce a depth prediction network with the proposed attentive skip connection and a global context module, to obtain meaningful semantic features and enhance the performance of the model. Furthermore, our model is validated through several experiments on the KITTI and NYU Depth V2 datasets. The experimental results demonstrate the effectiveness of the proposed network, which achieves a state-of-the-art monocular depth estimation performance while maintaining a high running speed.

It is challenging to apply depth maps generated from sparse laser scan data to computer vision tasks, such as robot vision and autonomous driving, because of the sparsity and noise in the data. To overcome this problem, depth completion tasks have been proposed to produce a dense depth map from sparse LiDAR data and a single RGB image. In this study, we developed a deep convolutional architecture with cross guidance for multi-modal feature fusion to compensate for the lack of representation power of their modality. Two encoders, which are part of the proposed architecture, receive different modalities as inputs. They interact with each other by exchanging information in each stage through the attention mechanism during encoding. We also propose a residual atrous spatial pyramid block, comprising multiple dilated convolutions with different dilation rates, which are used to derive highly significant features. The experimental results of the KITTI depth completion benchmark dataset demonstrate that the proposed architecture shows higher performance than that of the other models trained in a two-dimensional space without pre-training or fine-tuning other datasets.

Advances in technology have led to the development of methods that can create desired visual multimedia. In particular, image generation using deep learning has been extensively studied across diverse fields. In comparison, video generation, especially on conditional inputs, remains a challenging and less explored area. To narrow this gap, we aim to train our model to produce a video corresponding to a given text description. We propose a novel training framework, Text-to-Image-to-Video Generative Adversarial Network (TiVGAN), which evolves frame-by-frame and finally produces a full-length video. In the first phase, we focus on creating a high-quality single video frame while learning the relationship between the text and an image. As the steps proceed, our model is trained gradually on more number of consecutive frames. This step-by-step learning process helps stabilize the training and enables the creation of high-resolution video based on conditional text descriptions. Qualitative and quantitative experimental results on various datasets demonstrate the effectiveness of the proposed method.

Background & aimsNonalcoholic fatty liver disease (NAFLD) is one of the most common health problems worldwide. Sleep apnea (SA) causes cardiovascular and metabolic problems, as well as a significant socioeconomic burden. Although several studies have found that SA causes NAFLD, there is no evidence that NAFLD causes SA. The goal of this study was to look at the relationship between NAFLD and SA in realworld data.MethodsWe evaluated 334,334 healthy individuals without comorbidities who underwent National Health checkups in the Republic of Korea from 2009 to 2014. NAFLD was defined by a surrogate marker, the fatty liver index (FLI). The association between FLI and SA was analyzed using multivariate Cox proportional hazards regression models.ResultsDuring a median followup of 5.3 years, 1,351 patients (0.4%) were newly diagnosed with SA. Subjects were categorized into quartile groups according to FLI (range: Q1, 0-4.9; Q2, 5.0-12.5; Q3, 12.6-31.0; Q4, >31.0). Subjects with higher FLIs had a significantly higher cumulative incidence of SA than those with lower FLIs (Q1, 119 [0.1%]; Q2, 210 [0.3%]; Q3, 339 [0.4%]; Q4, 683 [0.8%]; P < 0.001). Adjusted hazard ratios (HRs) revealed that a higher FLI was independently associated with an increased risk of SA (HR between Q4 and Q1, 4.03; 95% confidence interval, 3.22-5.05; P < 0.001). This association remained statistically significant after further adjustment for Body mass index (BMI) (HR between Q4 and Q1, 2.19; 95% confidence interval, 1.69-2.83; P < 0.001). FLI was significantly associated with an increased risk of new-onset SA regardless of baseline characteristics.ConclusionThis study demonstrated that NAFLD, assessed by FLI, was independently associated with increased risk for SA in the healthy Korean population.

Astaxanthin (AST) exhibits potent antioxidant and anti-inflammatory activities but poor stability and biological efficacy, which limit its application in the food and medical industries. In the present study, a new strategy was proposed to enhance the biological activities of AST using fetal bovine serum-derived extracellular vesicles (EVs). Saponin-assisted incubation was used to load AST owing to its high encapsulation efficiency and loading capacity. AST-incorporated EVs (EV-ASTs) maintained their original EV morphology and showed high stability at 4 °C, 25 °C, and 37 °C over a 28-day period, which was attributed to the protective environment provided by the phospholipid bilayer membrane of the EVs. Additionally, the EV-ASTs exhibited excellent antioxidant and anti-inflammatory activities in HaCaT keratinocytes and RAW 264.7 macrophage cells, respectively; these were significantly higher than those of free AST. Furthermore, the mechanism associated with the enhanced biological activities of EV-ASTs was evaluated by analyzing the expression of genes involved in antioxidation and anti-inflammation, in parallel with cellular in vitro assays. These results provide insights into methods for improving the performance of hydrophobic drugs using nature-derived EVs and will contribute to the development of novel drug-delivery systems.

Multidrug resistance (MDR) is one of the major barriers in chemotherapy. It is often related to the overexpression of efflux receptors such as P-glycoprotein (P-gp). Overexpressed efflux receptors inhibit chemotherapeutic efficacy by pumping out intracellularly delivered anticancer drugs. In P-gp-mediated MDR-related pathways, PI3K/Akt and NF-kB pathways are commonly activated signaling pathways, but these pathways are downregulated by melittin, a main component of bee venom. In this study, a polymersome based on a poly (lactic acid) (PLA)-hyaluronic acid (HA) (20k-10k) di-block copolymer and encapsulating melittin and doxorubicin was developed to overcome anticancer resistance and enhance chemotherapeutic efficacy. Through the simultaneous delivery of doxorubicin and melittin, PI3K/Akt and NF-κB pathways could be effectively inhibited, thereby downregulating P-gp and successfully enhancing chemotherapeutic efficacy. In conclusion, a polymersome carrying an anticancer drug and melittin could overcome MDR by regulating P-gp overexpression pathways.

In anticancer therapy, combination therapy has been suggested as an alternative to the insufficient therapeutic efficacy of single therapy. Among combination therapies, combination chemo- and photodynamic therapy are actively investigated. However, photodynamic therapy shows a limitation in the penetration depth of the laser. Therefore, sonodynamic therapy (SDT), using ultrasound instead of a laser as a trigger, is an upcoming strategy for deep tumors. Additionally, free drugs are easily degraded by enzymes, have difficulty in reaching the target site, and show side effects after systemic administration; therefore, the development of drug delivery systems is desirable for sufficient drug efficacy for combination therapy. However, nanocarriers, such as microbubbles, and albumin nanoparticles, are unstable in the body and show low drug-loading efficiency. Here, we propose polylactide (PLA)-poly (ethylene glycol) (PEG) polymersomes (PLs) with a high drug loading rate of doxorubicin (DOX) and verteporfin (VP) for effective combination therapy in both in vitro and in vivo experiments. The cellular uptake efficiency and cytotoxicity test results of VP-DOX-PLs were higher than that of single therapy. Moreover, in vivo biodistribution showed the accumulation of the VP-DOX-PLs in tumor regions. Therefore, VP-DOX-PLs showed more effective anticancer efficacy than either single therapy in vivo. These results suggest that the combination therapy of SDT and chemotherapy could show novel anticancer effects using VP-DOX-PLs.

Forest change detection is essential to prevent the secondary damage occurring by landslides causing profound results to the environment, ecosystem, and human society. The remote sensing technique is a solid candidate for identifying the spatial distribution of the forest. Even though the acquiring and processing of remote sensing images are costly and time- and labor-consuming, the development of open source data platforms relieved these burdens by providing free imagery. The open source images also accelerate the generation of algorithms with large datasets. Thus, this study evaluated the generalizability of forest change detection by using open source airborne images and the U-Net model. U-Net model is convolutional deep learning architecture to effectively extract the image features for semantic segmentation tasks. The airborne and tree annotation images of the capital area in South Korea were processed for building U-Net input, while the pre-trained U-Net structure was adopted and fine-tuned for model training. The U-Net model provided robust results of the segmentation that classified forest and non-forest regions, having pixel accuracies, F1 score, and intersection of union (IoU) of 0.99, 0.97, and 0.95, respectively. The optimal epoch and excluded ambiguous label contributed to maintaining virtuous segmentation of the forest region. In addition, this model could correct the false label images because of showing exact classification results when the training labels were incorrect. After that, by using the open map service, the well-trained U-Net model classified forest change regions of Chungcheong from 2009 to 2016, Gangwon from 2010 to 2019, Jeolla from 2008 to 2013, Gyeongsang from 2017 to 2019, and Jeju Island from 2008 to 2013. That is, the U-Net was capable of forest change detection in various regions of South Korea at different times, despite the training on the model with only the images of the capital area. Overall, this study demonstrated the generalizability of a deep learning model for accurate forest change detection.

Abstract Mars is the first extraterrestrial planet with seismometers (Seismic Experiment for Interior Structure, SEIS) deployed directly on its surface in the framework of the Interior Exploration using Seismic Investigations, Geodesy and Heat Transport (InSight) mission. The lack of strong Marsquakes, however, strengthens the need of seismic noise studies to additionally constrain the Martian structure. Seismic noise autocorrelations of single‐station recordings permit the determination of the zero‐offset reflection response underneath SEIS. We present a new autocorrelation study which employs state‐of‐the‐art approaches to determine a robust reflection response by avoiding bias from aseismic signals which are recorded together with seismic waves due to unfavorable deployment and environmental conditions. Data selection and segmentation is performed in a data‐adaptive manner which takes the data root‐mean‐square amplitude variability into account. We further use the amplitude‐unbiased phase cross‐correlation and work in the 1.2–8.9 Hz frequency band. The main target are crustal scale reflections, their robustness and convergence. The strongest signal appears at 10.6 s, and, if interpreted as a P‐wave reflection, would correspond to a discontinuity at about 21 km depth. This signal is a likely candidate for a reflection from the base of the Martian crust due to its strength, polarity, and stability. Additionally we identify, among the stable signals, a signal at about 6.15 s that can be interpreted as the P‐wave reflection from the mid‐crust at about 9.5 km depth.