Kaempferol, a flavonoid, found in traditional medicine, fruits, and vegetables, and an HDAC inhibitor, is a powerful anti-cancer reagent against various cancer cell lines. However, detailed ...mechanisms involved in the treatment of gastric cancer (GC) using kaempferol are not fully understood. In our study, we investigated the biological activity and molecular mechanism involved in kaempferol-mediated treatment of GC. Kaempferol promoted autophagy and cell death, and increased LC3-I to LC3-II conversion and the downregulation of p62 in GC. Furthermore, our results showed that kaempferol induces autophagic cell death via the activation of the IRE1-JNK-CHOP signaling, indicating ER stress response. Indeed, the inhibition of ER stress suppressed kaempferol-induced autophagy and conferred prolonged cell survival, indicating autophagic cell death. We further showed that kaempferol mediates epigenetic change via the inhibition of G9a (HDAC/G9a axis) and also activates autophagic cell death. Taken together, our findings indicate that kaempferol activates the IRE1-JNK-CHOP signaling from cytosol to nucleus, and G9a inhibition activates autophagic cell death in GC cells.
This study aimed to assess the performance of ChatGPT, specifically the GPT-3.5 and GPT-4 models, in understanding complex surgical clinical information and its potential implications for surgical ...education and training.
The dataset comprised 280 questions from the Korean general surgery board exams conducted between 2020 and 2022. Both GPT-3.5 and GPT-4 models were evaluated, and their performances were compared using McNemar test.
GPT-3.5 achieved an overall accuracy of 46.8%, while GPT-4 demonstrated a significant improvement with an overall accuracy of 76.4%, indicating a notable difference in performance between the models (P < 0.001). GPT-4 also exhibited consistent performance across all subspecialties, with accuracy rates ranging from 63.6% to 83.3%.
ChatGPT, particularly GPT-4, demonstrates a remarkable ability to understand complex surgical clinical information, achieving an accuracy rate of 76.4% on the Korean general surgery board exam. However, it is important to recognize the limitations of large language models and ensure that they are used in conjunction with human expertise and judgment.
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China and rapidly spread worldwide. To prevent SARS-CoV-2 ...dissemination, understanding the in vivo characteristics of SARS-CoV-2 is a high priority. We report a ferret model of SARS-CoV-2 infection and transmission that recapitulates aspects of human disease. SARS-CoV-2-infected ferrets exhibit elevated body temperatures and virus replication. Although fatalities were not observed, SARS-CoV-2-infected ferrets shed virus in nasal washes, saliva, urine, and feces up to 8 days post-infection. At 2 days post-contact, SARS-CoV-2 was detected in all naive direct contact ferrets. Furthermore, a few naive indirect contact ferrets were positive for viral RNA, suggesting airborne transmission. Viral antigens were detected in nasal turbinate, trachea, lungs, and intestine with acute bronchiolitis present in infected lungs. Thus, ferrets represent an infection and transmission animal model of COVID-19 that may facilitate development of SARS-CoV-2 therapeutics and vaccines.
Display omitted
•SARS-CoV-2-infected ferrets exhibit elevated body temperature and virus replication•SARS-CoV-2 is shed in nasal washes, saliva, urine and feces•SARS-CoV-2 is effectively transmitted to naive ferrets by direct contact•SARS-CoV-2 infection leads acute bronchiolitis in infected ferrets
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spreads, leading to a pandemic infection. Kim et al. show that ferrets are highly susceptible to SARS-CoV-2 infection and effectively transmit the virus by direct or indirect contact, recapitulating human infection and transmission.
Human ferritins are emerging platforms for non‐toxic protein‐based drug delivery, owing to their intrinsic or acquirable targeting abilities to cancer cells and hollow cage structures for drug ...loading. However, reliable strategies for high‐level drug encapsulation within ferritin cavities and prompt cellular drug release are still lacking. Ferritin nanocages were developed with partially opened hydrophobic channels, which provide stable routes for spontaneous and highly accumulated loading of FeII‐conjugated drugs as well as pH‐responsive rapid drug release at endoplasmic pH. Multiple cancer‐related compounds, such as doxorubicin, curcumin, and quercetin, were actively and heavily loaded onto the prepared nicked ferritin. Drugs on these minimally modified ferritins were effectively delivered inside cancer cells with high toxicity.
Spontaneous and high‐level uptake of diverse drugs onto a ferritin nanocage was achieved by fractionally opening hydrophobic channels of ferritin. Drug–FeII complexes were actively and stably accumulated in this nicked ferritin and delivered inside cells by the cell targeting ability of ferritin in a pH‐responsive manner.
According to recent international consensus conferences, pure laparoscopic donor hepatectomy (PLDH), particularly right and left hepatectomies, is not yet considered a standard practice because ...studies remain limited. Thus, we present the outcomes of more than 500 PLDH patients, mostly receiving a right hepatectomy. To our knowledge, this is the largest study to date on PLDH. Data from all living liver donors who underwent PLDH at 5 centers in Korea until June 2018 were retrospectively analyzed. The outcomes of both donors and recipients were included. Pearson correlation analysis was used to explore the relationship between the duration of surgery and cumulative experience at each center, which reflects the learning curve. Overall, 545 PLDH cases were analyzed, including 481 right hepatectomies, 25 left hepatectomies, and 39 left lateral sectionectomies (LLS). The open conversion was necessary for 10 (1.8%) donors, and none of the donors died or experienced irreversible disability. Notably, there were 25 (4.6%) patients with major complications (higher than Clavien‐Dindo grade 3). All centers except one showed a significant decrease in surgery duration as the number of cases accumulated. Regarding recipient outcomes, there were 110 cases (20.2%) of early major complications and 177 cases (32.5%) of late major complications. This study shows the early and late postoperative outcomes of 545 donors and corresponding recipients, including 481 right hepatectomies and 25 left hepatectomies, from 5 experienced centers. Although the results are comparable to those of previously reported open donor hepatectomy series, further studies are needed to consider PLDH a new standard practice.
Due to the urgent need of a therapeutic treatment for coronavirus (CoV) disease 2019 (COVID-19) patients, a number of FDA-approved/repurposed drugs have been suggested as antiviral candidates at ...clinics, without sufficient information. Furthermore, there have been extensive debates over antiviral candidates for their effectiveness and safety against severe acute respiratory syndrome CoV 2 (SARS-CoV-2), suggesting that rapid preclinical animal studies are required to identify potential antiviral candidates for human trials. To this end, the antiviral efficacies of lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir for SARS-CoV-2 infection were assessed in the ferret infection model. While the lopinavir-ritonavir-, hydroxychloroquine sulfate-, or emtricitabine-tenofovir-treated group exhibited lower overall clinical scores than the phosphate-buffered saline (PBS)-treated control group, the virus titers in nasal washes, stool specimens, and respiratory tissues were similar between all three antiviral-candidate-treated groups and the PBS-treated control group. Only the emtricitabine-tenofovir-treated group showed lower virus titers in nasal washes at 8 days postinfection (dpi) than the PBS-treated control group. To further explore the effect of immune suppression on viral infection and clinical outcome, ferrets were treated with azathioprine, an immunosuppressive drug. Compared to the PBS-treated control group, azathioprine-immunosuppressed ferrets exhibited a longer period of clinical illness, higher virus titers in nasal turbinate, delayed virus clearance, and significantly lower serum neutralization (SN) antibody titers. Taken together, all antiviral drugs tested marginally reduced the overall clinical scores of infected ferrets but did not significantly affect
virus titers. Despite the potential discrepancy of drug efficacies between animals and humans, these preclinical ferret data should be highly informative to future therapeutic treatment of COVID-19 patients.
The SARS-CoV-2 pandemic continues to spread worldwide, with rapidly increasing numbers of mortalities, placing increasing strain on health care systems. Despite serious public health concerns, no effective vaccines or therapeutics have been approved by regulatory agencies. In this study, we tested the FDA-approved drugs lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir against SARS-CoV-2 infection in a highly susceptible ferret infection model. While most of the drug treatments marginally reduced clinical symptoms, they did not reduce virus titers, with the exception of emtricitabine-tenofovir treatment, which led to diminished virus titers in nasal washes at 8 dpi. Further, the azathioprine-treated immunosuppressed ferrets showed delayed virus clearance and low SN titers, resulting in a prolonged infection. As several FDA-approved or repurposed drugs are being tested as antiviral candidates at clinics without sufficient information, rapid preclinical animal studies should proceed to identify therapeutic drug candidates with strong antiviral potential and high safety prior to a human efficacy trial.
Olfactory projection neurons convey information from the insect antennal lobe (AL) to higher brain centers. Previous reports have demonstrated that pheromone‐responsive projection neurons with cell ...bodies in the moth medial cell cluster (mcPNs) predominantly have dendritic arborizations in the sexually dimorphic macroglomerular complex (MGC) and send an axon from the AL to the calyces of the mushroom body (CA) as well as the lateral horn (LH) of the protocerebrum via the medial AL tract. These neurons typically exhibit a narrow odor tuning range related to the restriction of their dendritic arbors within a single glomerulus (uniglomerular). In this study, we report on the diverse physiological and morphological properties of a group of pheromone‐responsive olfactory projection neurons with cell bodies in the AL lateral cell cluster (MGC lcPNs) of two closely related moth species. All pheromone‐responsive lcPNs appeared to exhibit “basket‐like” dendritic arborizations in two MGC compartments and made connections with various protocerebral targets including ventrolateral and superior neuropils via projections primarily through the lateral AL tract and to a lesser extent the mediolateral antennal lobe tract. Physiological characterization of MGC lcPNs also revealed a diversity of response profiles including those either enhanced by or reliant upon presentation of a pheromone blend. These responses manifested themselves as higher maximum firing rates and/or improved temporal resolution of pulsatile stimuli. MGC lcPNs therefore participate in conveying diverse olfactory information relating to qualitative and temporal facets of the pheromone stimulus to a more expansive number of protocerebral targets than their mcPN counterparts.
Olfactory output neurons from the moth antennal lobe transmit pheromone information to a variety of higher brain centers along several distinct pathways. Pheromone blend‐sensitive multiglomerular neurons originating in the lateral cluster send information directly to lateral and dorsal targets where integration with other olfactory pathways and sensory modalities may occur.
Abstract
Insulin-like growth factors (IGFs) have pleiotropic roles in embryonic and postnatal growth and differentiation. Most serum IGFs are bound in a ternary complex with IGF-binding protein 3 ...(IGFBP3) and acid-labile subunit (ALS), extending the serum half-life of IGFs and regulating their availability. Here, we report cryo-EM structure of the human IGF1/IGFBP3/ALS ternary complex, revealing the detailed architecture of a parachute-like ternary complex and crucial determinants for their sequential and specific assembly. In vitro biochemical studies show that proteolysis at the central linker domain of IGFBP3 induces release of its C-terminal domain rather than IGF1 release from the ternary complex, yielding an intermediate complex that enhances IGF1 bioavailability. Our results provide mechanistic insight into IGF/IGFBP3/ALS ternary complex assembly and its disassembly upon proteolysis for IGF bioavailability, suggesting a structural basis for human diseases associated with
IGF1
and
IGFALS
gene mutations such as complete ALS deficiency (ACLSD) and IGF1 deficiency.
PBI membranes are recently discussed as stable, well performing membranes for vanadium redox flow batteries (VRFB). Blending meta-PBI with an anion exchange polymer (FAA3i) slightly reduces the ...coulomb efficiency from 99.7 to 97.8%, but strongly increases the voltage efficiency from 82.5 to 88.2%, leading to an increased energy efficiency (86.2% at 80 mA cm−2), exceeding that of meta-PBI (82.2%) and N212 (83%). Apparently, since the conductivity of sulfuric acid has a maximum around a concentration of 3.8 M, the concentration of the absorbed acid has a dominant influence on the conductivity. Addition of FAA3i decreases the concentration of the acid absorbed by PBI membranes. Furthermore, an ex-situ stability test in 1.5 M V5+ solutions in 2 M sulfuric acid for 87 days showed a very high stability for meta-PBI and Nafion 212, while the commercial FAA3 membrane disintegrated into pieces. Blending of meta-PBI and FAA3 decreased the stability, as proven by formation of V4+, but all tested blend membranes retained their membrane shape and could still be handled. Blending with FAA3 reduces the tensile strength and Young's modulus of meta-PBI, and doping with sulfuric acid leads to a further decrease in the mechanical strength. However, an acid doped PF-21 still showed a tensile strength of 37 MPa and a Young's modulus of 0.7 GPa.
Display omitted
•PBI and FAA3 (an AEM) were blended and doped with sulfuric acid for use in VRFB.•Coulomb efficiency slightly decreased, but voltage efficiency strongly increased.•Energy efficiency at 80 mA/cm2 reached 86.2%, higher than that of Nafion 212 (83%).•Stability of blends against VO2+ increases with amount of PBI in the blends.•Doping decreases the tensile strength, but acid doped PF-21 still had a TS of 37 MPa.
Although numerous studies have used systemic approaches to identify prognostic predictors in oral squamous cell carcinoma (OSCC), the effectiveness of these approaches has not been assessed ...clinically. Further, the mechanism underlying malignant behaviors in OSCC is poorly characterized. This study aimed to develop and verify accurate prognostic predictors for OSCC patients and assess the associated biology. We identified an OSCC‐recurrence‐related gene signature (ORGS) using a Cox regression analysis. Functional enrichment analysis was used to identify enriched pathways and biological processes to reveal the underlying mechanism of OSCC malignant behavior. The ORGS successfully divided OSCC patients into low‐ and high‐risk groups with significantly different overall survivals. Pathway analysis revealed oxidative phosphorylation (OXPHOS) as a signaling pathway associated with the ORGS in OSCC. Interestingly, high OXPHOS status was strongly associated with poor overall survival in OSCC patients. Mediator complex subunit 30 (MED30) was a predicted upstream regulator of OXPHOS, and knockdown of MED30 reduced histone acetylation. We identified that the ORGS was strongly correlated with OXPHOS regulatory processes, suggesting OXPHOS as a key mechanism leading to poor prognosis in OSCC.
Here, we define a gene signature from oral squamous cell carcinoma (OSCC) patients which could stratify patients into low and high‐risk groups with different overall survival. We highlight oxidative phosphorylation (OXPHOS) as a signaling pathway associated with this signature. Finally, we demonstrate that MED30‐induced OXPHOS gene transcription depolarizes mitochondrial membrane potential and inhibits ROS‐dependent apoptosis of cancer cells.
PDF
