Eucalyptol Ameliorates Retinal Microvascular Defects through Modulating ER Stress and Angiopoietin-Tie Signaling in Diabetic Eyes.

Loss of the inner blood-retinal barrier (BRB) integrity is a main feature of ocular diseases such as diabetic macular edema. However, there is a lack of clarity on how inner BRB function is modulated within the diabetic retina. The current study examined whether eucalyptol inhibited inner BRB destruction and aberrant retinal angiogenesis in 33 mM glucose-exposed human retinal microvascular endothelial (RVE) cells and db/db mice. This study further examined the molecular mechanisms underlying endothelial dysfunction including retinal endoplasmic reticulum (ER) stress and angiopoietin (Ang)/Tie axis in conjunction with vascular endothelial growth factor (VEGF). Eucalyptol is a naturally occurring monoterpenoid and an achiral aromatic component of many plants including eucalyptus leaves. Nontoxic eucalyptol reduced the production of amyloid-ß (Aß) protein in glucose-loaded RVE cells and in diabetic mice. This natural compound blocked apoptosis of Aß-exposed RVE cells in diabetic mouse eyes by targeting ER stress via the inhibition of PERK-eIF2α-ATF4-CHOP signaling. Eucalyptol promoted activation of the Ang-1/Tie-2 pathway and dual inhibition of Ang-2/VEGF in Aß-exposed RVE cells and in diabetic eyes. Supply of eucalyptol reversed the induction of junction proteins in glucose/Aß-exposed RVE cells within the retina and reduced permeability. In addition, oral administration of eucalyptol reduced vascular leaks in diabetic retinal vessels. Taken together, these findings clearly show that eucalyptol inhibits glucose-induced Aß-mediated ER stress and manipulates Ang signaling in diabetic retinal vessels, which ultimately blocks abnormal angiogenesis and loss of inner BRB integrity. Therefore, eucalyptol provides new treatment strategies for diabetes-associated RVE defects through modulating diverse therapeutic targets including ER stress, Ang-1/Tie-2 signaling, and Ang-2/VEGF.

Impact of vehicles at the roadside of expressway in urban area: Simultaneous measurement of particle size distribution and positive matrix factorization.

This study conducted real-time monitoring of size-resolved particle concentrations ranging from 9 nm to 10 µm simultaneously at four sites on the park ground and the roof of a five-story apartment buildings in the upwind and downwind areas of the Olympic Expressway next to apartment complex areas of Seoul, Korea. Using a positive matrix factorization model for source apportionment, eight factors were resolved at each monitoring site: four exhaust emissions of vehicles, one non-exhaust emission of vehicle, two regional sources, and one unknown source. After categorizing monitoring data into three cases by wind conditions, impact and contribution of each vehicle-related source on the local road to the roadside pollution was quantified and characterized by subtracting the urban background concentrations. Throughout the measurement period, the contribution of vehicle-related sources to the particle number concentration at each monitoring site ranged from 61 % to 69 %, while that to the particle mass concentration ranged from 39 % to 87 %. During periods of steady traffic flow and wind blowing from the road to three downwind sites at speeds exceeding >0.5 m/s during working hours, the particle number concentrations at the downwind sites were 2.2-2.5 times higher than the average levels. Among vehicle-related sources, gasoline vehicles with multiple injections or high-emitting diesel vehicles showed the highest contribution to particle number concentrations at all sites. As wind speed increased, the number concentrations of particles from vehicle exhaust and non-exhaust emissions decreased and increased, respectively, probably due to enhanced dilution and transport, respectively. In addition, particle number concentrations showed a parabolic curve-like trend with traffic volumes increasing to approximately 10,000 vehicles/h, and then decreasing for both vehicle exhaust and non-exhaust emissions. These results can be utilized in numerical modeling studies and in establishing traffic-related environmental policies to reduce seasonal and temporal particle exposure near the roadsides.

Clinical performance of the Roche Cobas Liat SARS-CoV-2 & influenza A/B assay: A systematic review and meta-analysis.

Respiratory tract infections caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses are persistent and critical. The Cobas Liat SARS-CoV-2 & influenza A/B assay (Multiplex Liat), the FDA-authorized point-of-care reverse transcriptase polymerase chain reaction (RT-PCR) assay, has a turnaround time of 20 min and high accuracy. This study evaluates the pooled performance of this assay to provide practical information. This meta-analysis was registered in PROSPERO (registration number: CRD42023467579). A systematic literature search was conducted within PubMed, Ovid-EMBASE, and the Cochrane Library for articles evaluating the accuracy of the Multiplex Liat assay through September 2023. A random-effects model was used to calculate the pooled diagnostic values with real-time RT-PCR (rRT-PCR) as a reference test. A total of 4,705 samples from eight studies were included in the primary meta-analysis. The overall pooled sensitivity and specificity of Multiplex Liat were 100.0 % (95 % confidence interval [CI] = 96.7 %-100.0 %) and 99.7 % (95 % CI = 98.7 %-99.9 %), respectively. The presence of variants of concern or in-house rRT-PCR assays as reference standards did not significantly affect the pooled diagnostic performance of the Multiplex Liat. When 5,333 samples from nine studies were assessed for sensitivity, the pooled sensitivity was 100.0 % (95 % CI = 85.8 %-100.0 %) without a significant difference. This meta-analysis demonstrates the usefulness of Multiplex Liat for the detection of SARS-CoV-2 based on pooled diagnostic values. These practical findings may facilitate appropriate settings for the diagnosis and management of patients with respiratory tract infections.

Assessment of Deep Learning-Based Triage Application for Acute Ischemic Stroke on Brain MRI in the ER.

RATIONALE AND OBJECTIVES: To assess a deep learning application (DLA) for acute ischemic stroke (AIS) detection on brain magnetic resonance imaging (MRI) in the emergency room (ER) and the effect of T2-weighted imaging (T2WI) on its performance. MATERIALS AND METHODS: We retrospectively analyzed brain MRIs taken through the ER from March to October 2021 that included diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) sequences. MRIs were processed by the DLA, and sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUROC) were evaluated, with three neuroradiologists establishing the gold standard for detection performance. In addition, we examined the impact of axial T2WI, when available, on the accuracy and processing time of DLA. RESULTS: The study included 947 individuals (mean age ± standard deviation, 64 years ± 16; 461 men, 486 women), with 239 (25%) positive for AIS. The overall performance of DLA was as follows: sensitivity, 90%; specificity, 89%; accuracy, 89%; and AUROC, 0.95. The average processing time was 24 s. In the subgroup with T2WI, T2WI did not significantly impact MRI assessments but did result in longer processing times (35 s without T2WI compared to 48 s with T2WI, p < 0.001). CONCLUSION: The DLA successfully identified AIS in the ER setting with an average processing time of 24 s. The absence of performance acquire with axial T2WI suggests that the DLA can diagnose AIS with just axial DWI and FLAIR sequences, potentially shortening the exam duration in the ER.

Performances and properties of steel and composite prestressed tendons - A review.

The primary drawback of concrete lies in its low tensile strength, prompting the development of various solutions to enhance this aspect. A notable approach is the utilization of Prestressed Reinforced Concrete (PRC) with tendons, aimed at bolstering its tensile strength. As the use of diverse tendon types in the PRC continues to surge, a review becomes imperative to delve into this evolution. Therefore, this study delved into the engineering characteristics, performance, and evolution of different tendon varieties, encompassing both steel and composite options. Despite certain drawbacks associated with employing composite materials such as Fiber Reinforced Polymer (FRP) tendons - such as heightened costs, limited availability of composite materials, and intricate manufacturing processes - there are distinct advantages and merits to incorporating FRP composite tendons in the realm of construction. In this respect, Carbon FRP tendons exhibited superior strength, comparable to their steel counterparts. Glass FRP tendons, lacking metallic components, possessed non-magnetic properties, rendering them resistant to corrosion. Additionally, Aramid FRP tendons boasted low flammability and exceptional resistance to elevated temperatures. Lastly, Basalt FRP tendons offered sustainability, rust resistance, and non-corrosiveness. The findings derived from this review study serve as a valuable resource for researchers seeking to advance the applications of steel tendons and FRP composite materials within the construction industry.

Chemically Driven Clearance of Amyloid Aggregates by Polyfunctionalized Furo[2,3-b:4,5-b']dipyridine-Chalcone Hybrids to Ameliorate Memory in an Alzheimer Mouse Model.

The aberrant assembly of amyloid-ß (Aß) is implicated in Alzheimer's disease (AD). Recent clinical outcomes of Aß-targeted immunotherapy reinforce the notion that clearing Aß burden is a potential therapeutic approach for AD. Herein, to develop drug candidates for chemically driven clearance of Aß aggregates, we synthesized 51 novel polyfunctionalized furo[2,3-b:4,5-b']dipyridine-chalcone hybrid compounds. After conducting two types of cell-free anti-Aß functional assays, Aß aggregation prevention and Aß aggregate clearance, we selected YIAD-0336, (E)-8-((1H-pyrrol-2-yl)methylene)-10-(4-chlorophenyl)-2,4-dimethyl-7,8-dihydropyrido[3',2':4,5]furo[3,2-b]quinolin-9(6H)-one, for further in vivo investigations. As YIAD-0336 exhibited a low blood-brain barrier penetration profile, it was injected along with aggregated Aß directly into the intracerebroventricular region of ICR mice and ameliorated spatial memory in Y-maze tests. Next, YIAD-0336 was orally administered to 5XFAD transgenic mice with intravenous injections of mannitol, and YIAD-0336 significantly removed Aß plaques from the brains of 5XFAD mice. Collectively, YIAD-0336 dissociated toxic aggregates in the mouse brain and hence alleviated cognitive deterioration. Our findings indicate that chemically driven clearance of Aß aggregates is a promising therapeutic approach for AD.

One Health Landscape of Antimicrobial Resistance in Bacteria Isolated from Virginia between 2007-2021.

The emergence of antimicrobial-resistant (AMR) bacteria has become a critical global One Health issue, mainly attributed to the extensive use of antimicrobial agents in human and agricultural settings. Regional and local AMR surveillance data is essential for implementing awareness and mitigation strategies. This article assesses AMR frequency in 1604 bacterial isolates consisting of Escherichia coli (E. coli) and Salmonella spp. isolated from diverse sources in Virginia, including farm animals, wildlife, environment, and food samples from 2007 to 2021. The results are based on the Kirby-Bauer disc diffusion assessment method of susceptibility to select antimicrobial agents, spanning nine distinct categories approved by the US Food and Drug Administration for clinical use. Streptomycin (STR) and tetracycline (TCY) exhibited the highest frequency of resistance in E. coli (39.1%) and Salmonella (25.2%), respectively. Multidrug resistance (MDR) was evident in 6.6% of E. coli and 10.9% of Salmonella isolates. Notably, 51% of E. coli and 36% of Salmonella isolates demonstrated resistance to more than one antimicrobial. None of the tested antimicrobials guaranteed effectiveness against the bacteria isolated from the surveyed sources and regions. The study found heightened MDR and distinct AMR patterns in bacteria isolated from food products compared to other sampled sources. These findings are vital for comprehending the current AMR landscape, prompting the development of strategies to mitigate the emergence of AMR bacteria, and advocating prudent antimicrobial use from a One Health perspective.

Cross-domain Denoising for Low-dose Multi-frame Spiral Computed Tomography.

Computed tomography (CT) has been used worldwide as a non-invasive test to assist in diagnosis. However, the ionizing nature of X-ray exposure raises concerns about potential health risks such as cancer. The desire for lower radiation doses has driven researchers to improve reconstruction quality. Although previous studies on low-dose computed tomography (LDCT) denoising have demonstrated the effectiveness of learning-based methods, most were developed on the simulated data. However, the real-world scenario differs significantly from the simulation domain, especially when using the multi-slice spiral scanner geometry. This paper proposes a two-stage method for the commercially available multi-slice spiral CT scanners that better exploits the complete reconstruction pipeline for LDCT denoising across different domains. Our approach makes good use of the high redundancy of multi-slice projections and the volumetric reconstructions while leveraging the over-smoothing issue in conventional cascaded frameworks caused by aggressive denoising. The dedicated design also provides a more explicit interpretation of the data flow. Extensive experiments on various datasets showed that the proposed method could remove up to 70% of noise without compromised spatial resolution, while subjective evaluations by two experienced radiologists further supported its superior performance against state-of-the-art methods in clinical practice. Code is available at https://github.com/YCL92/TMD-LDCT.

Difficult endotracheal intubation in a patient with progressed tracheobronchopathia osteoplastica: A case report.

Tracheobronchopathia osteoplastica is a rare condition involving large airways with multiple bone and cartilage nodules in the tracheobronchial submucosa. This can cause tracheal stenosis, leading to difficulty in endotracheal intubation. A 79-year-old female patient, who had a history of successful endotracheal intubation for general anesthesia 8 years prior, was scheduled for abdominal surgery. Preoperative chest computed tomography and bronchoscopy revealed slight progression of tracheobronchopathia osteoplastica. Attempts to intubate with a smaller endotracheal tube failed; even the smaller endotracheal tube could barely pass. Mechanical ventilation was successfully administered and the surgery was completed without complications. The use of a smaller endotracheal tube may be beneficial for managing difficult airways in patients with tracheobronchopathia osteoplastica. Chest CT and bronchoscopic examination may be beneficial for evaluating the airway and determining the most appropriate airway management strategy. However, relying solely on these measures may lead to unexpected challenges because there is no established method to evaluate airway in patient with tracheobronchopathia osteoplastica. It is crucial for anesthesiologists to be aware of the potential existence of rare conditions such as tracheobronchopathia osteoplastica and be prepared to handle anticipated or unanticipated difficult airway management.

Enhancing the anticancer effect of androgen deprivation therapy by monocarboxylate transporter 1 inhibitor in prostate cancer cells.

BACKGROUND: Tumor initiation and progression necessitate a metabolic shift in cancer cells. Consequently, the progression of prostate cancer (PCa), a leading cause of cancer-related deaths in males globally, involves a shift from lipogenic to glycolytic metabolism. Androgen deprivation therapy (ADT) serves as the standard treatment for advanced-stage PCa. However, despite initial patient responses, castrate resistance emerges ultimately, necessitating novel therapeutic approaches. Therefore, in this study, we aimed to investigate the role of monocarboxylate transporters (MCTs) in PCa post-ADT and evaluate their potential as therapeutic targets. METHODS: PCa cells (LNCaP and C4-2 cell line), which has high prostate-specific membrane antigen (PSMA) and androgen receptor (AR) expression among PCa cell lines, was used in this study. We assessed the expression of MCT1 in PCa cells subjected to ADT using charcoal-stripped bovine serum (CSS)-containing medium or enzalutamide (ENZ). Furthermore, we evaluated the synergistic anticancer effects of combined treatment with ENZ and SR13800, an MCT1 inhibitor. RESULTS: Short-term ADT led to a significant upregulation in folate hydrolase 1 (FOLH1) and solute carrier family 16 member 1 (SLC16A1) gene levels, with elevated PSMA and MCT1 protein levels. Long-term ADT induced notable changes in cell morphology with further upregulation of FOLH1/PSMA and SLC16A1/MCT1 levels. Treatment with ENZ, a nonsteroidal anti-androgen, also increased PSMA and MCT1 expression. However, combined therapy with ENZ and SR13800 led to reduced PSMA level, decreased cell viability, and suppressed expression of cancer stem cell markers and migration indicators. Additionally, analysis of human PCa tissues revealed a positive correlation between PSMA and MCT1 expression in tumor regions. CONCLUSIONS: Our results demonstrate that ADT led to a significant upregulation in MCT1 levels. However, the combination of ENZ and SR13800 demonstrated a promising synergistic anticancer effect, highlighting a potential therapeutic significance for patients with PCa undergoing ADT.

Hyaluronic acid stimulation of stem cells for cardiac repair: a cell-free strategy for myocardial infarct.

BACKGROUND: Myocardial infarction (MI), a representative form of ischemic heart disease, remains a huge burden worldwide. This study aimed to explore whether extracellular vesicles (EVs) secreted from hyaluronic acid (HA)-primed induced mesenchymal stem cells (HA-iMSC-EVs) could enhance the cardiac repair after MI. RESULTS: HA-iMSC-EVs showed typical characteristics for EVs such as morphology, size, and marker proteins expression. Compared with iMSC-EVs, HA-iMSC-EVs showed enhanced tube formation and survival against oxidative stress in endothelial cells, while reduced reactive oxygen species (ROS) generation in cardiomyocytes. In THP-1 macrophages, both types of EVs markedly reduced the expression of pro-inflammatory signaling players, whereas HA-iMSC-EVs were more potent in augmenting anti-inflammatory markers. A significant decrease of inflammasome proteins was observed in HA-iMSC-EV-treated THP-1. Further, phospho-SMAD2 as well as fibrosis markers in TGF-ß1-stimulated cardiomyocytes were reduced in HA-iMSC-EVs treatment. Proteomic data showed that HA-iMSC-EVs were enriched with multiple pathways including immunity, extracellular matrix organization, angiogenesis, and cell cycle. The localization of HA-iMSC-EVs in myocardium was confirmed after delivery by either intravenous or intramyocardial route, with the latter increased intensity. Echocardiography revealed that intramyocardial HA-iMSC-EVs injections improved cardiac function and reduced adverse cardiac remodeling and necrotic size in MI heart. Histologically, MI hearts receiving HA-iMSC-EVs had increased capillary density and viable myocardium, while showed reduced fibrosis. CONCLUSIONS: Our results suggest that HA-iMSC-EVs improve cardiac function by augmenting vessel growth, while reducing ROS generation, inflammation, and fibrosis in MI heart.

A review of utilization of industrial waste materials as cement replacement in pervious concrete: An alternative approach to sustainable pervious concrete production.

Around 8% of the global carbon dioxide emissions, are generated during cement manufacturing, which also involves significant use of raw materials, leading to adverse environmental effects. Consequently, extensive research is being conducted worldwide to explore the feasibility of utilizing different industrial waste by-products as alternatives to cement in concrete production. Fly ash (FA), Metakaolin (MK), Silica fume (SF), and ground granulated blast furnace slag (GGBS) are potential industrial materials that can serve as cement substitutes in pervious concrete. However, there exist conflicting findings in the literature regarding the impact of industrial supplementary cementitious materials (ISCMs) as partial cement replacements on the physical, mechanical, and durability properties of pervious concrete. The aim of this review is to investigate the feasibility and potential benefits of using ISCMs and compare them as partial cement replacements in the production of pervious concrete. The analysis primarily examines the effect of ISCMs as partial cement replacements on cementitious properties, including properties of ISMCs, mechanical properties, and durability of pervious concrete. The influence of ISCMs primarily stems from their pozzolanic reaction and filler characteristics. SF has the highest reactivity due to its high surface area and amorphous structure, resulting in a rapid pozzolanic reaction. GGBS and FA have moderate reactivity, while MK has relatively low reactivity due to its crystalline structure. Results from various studies indicate that the addition of FA, SF, and MK up to approximately 20% leads to a reduction in porosity and permeability while improving compressive strength and durability due to the filler effect of SF and MK. Incorporating GGBS increases permeability slightly while causing a slight decrease in compressive strength. The range of permeability and compressive strength for pervious concrete incorporating FA, SF, GGBS and MK were 0.17-1.46 cm/s and 4-35 MPa, 0.56-2.28 cm/s and 3.1-35 MPa, 0.19-0.64 cm/s and 8-42 MPa, 0.10-1.28 cm/s and 5.5-41 MPa, respectively, which are in the acceptable range for non-structural application of pervious concrete. In conclusion, it is possible to produce sustainable pervious concrete by substituting up to 20% of cement with FA, SF, GGBS, and MK, thereby reducing cement consumption, carbon footprint, energy usage, and air pollution associated with conventional cement production. However, further research is required to systematically assess the durability properties, long-term behavior, and, develop models for analyzing CO2 emissions and cost considerations of pervious concrete containing ISMCs.

Initial experience with the enhanced recovery after surgery (ERAS) protocols in gynecologic surgery at an urban academic tertiary medical center.

Background: The enhanced recovery after surgery (ERAS) protocols have been consistently associated with improved patient experience and surgical outcomes. Despite the release of ERAS Society guidelines specific to gynecologic oncology, the adoption of ERAS in gynecology on global level has been disappointingly low and some centers have shown minimal improvement in clinical outcomes after adopting ERAS. The aim of this study is to describe the development and early experience of ERAS protocols in gynecologic surgery at an urban academic tertiary medical center. Methods: This was an observational prospective cohort study. The target patient population included those with low comorbidities who were scheduled to undergo various types of gynecologic surgeries for both benign and malignant diseases between October 2020 and February 2021. Two attending surgeons implemented the protocols for their patients (ERAS cohort) while three attending surgeons maintained the conventional perioperative care for their patients (non-ERAS cohort). Baseline characteristics, surgical outcomes and patients' answers to a 12-question survey were compared. A case-matched comparative analysis was also performed between the ERAS cohort and the historical non-ERAS cohort (those who received the same types of surgical procedures from the two ERAS attending surgeons prior to the implementation of the protocols). Results: A total of 244 patients were evaluated (122 in the ERAS cohort vs. 122 in the non-ERAS cohort). The number of vials of opioid analgesia used during the first two postoperative days was significantly lower whereas the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen was more frequent in the ERAS cohort group. The patients in the ERAS group reported less postoperative pain, feelings of hunger and thirst, and greater amount of exercise postoperatively. These benefits of the ERAS cohort were more pronounced in the patients who underwent laparotomic surgeries than those who underwent laparoscopic surgeries. The case-matched comparative analysis also showed similar results. The length of hospital stay did not differ between those who underwent the ERAS protocols and those who did not. Conclusions: The results of the study demonstrated the safety, clinical feasibility and benefits of the ERAS protocols for patients undergoing gynecologic surgeries for both benign and malignant indications.

Substitution Effect of a Single Nitrogen Atom on π-Electronic Systems of Linear Polycyclic Aromatic Hydrocarbons (PAHs): Theoretically Visualized Coexistence of Mono- and Polycyclic π-Electron Delocalization.

We theoretically investigated the nitrogen substitution effect on the molecular structure and π-electron delocalization in linear nitrogen-substituted polycyclic aromatic hydrocarbons (N-PAHs). Based on the optimized molecular structures and magnetic field-induced parameters of fused bi- and tricyclic linear N-PAHs, we found that the local π-electron delocalization of subcycles (e.g., mono- and bicyclic constituent moieties) in linear N-PAHs is preserved, despite deviation from ideal structures of parent monocycles. The introduction of a fused five-membered ring with a pyrrolic N atom (N-5MR) in linear N-PAHs significantly perturbs the π-electronic condition of the neighboring fused six-membered ring (6MR). Monocyclic pyrrole exhibits substantial bond length alternations, strongly influencing the π-electronic systems of both the fused N-5MR and 6MR in linear N-PAHs, depending on the location of shared covalent bonds. A fused six-membered ring with a graphitic N atom in an indolizine moiety cannot generate monocyclic π-electron delocalization but instead contributes to the formation of polycyclic π-electron delocalization. This is evidenced by bifurcated diatropic ring currents induced by an external magnetic field. In conclusion, the satisfaction of Hückel's 4n + 2 rule for both mono- and polycycles is crucial for understanding the overall π-electron delocalization. It is crucial to consider the unique characteristics of the three types of substituted N atoms and the spatial arrangement of 5MR and 6MR in N-PAHs.

Prediction of complications in diabetes mellitus using machine learning models with transplanted topic model features.

Purpose: This study aims to predict the progression of Diabetes Mellitus (DM) from the clinical notes through machine learning based on latent Dirichlet allocation (LDA) topic modeling. Particularly, 174,427 clinical notes of DM patients were collected from the electronic medical record (EMR) system of the Seoul National University Hospital outpatient clinic. Method: We developed a model to predict the development of DM complications. Topics developed by the topic model were exploited as the key feature of our machine-learning model. The proposed model generalized a correlation between topic structures and complications. Results: The model provided acceptable predictive performance for all four types of complications (diabetic retinopathy, diabetic nephropathy, nonalcoholic fatty liver disease, and cerebrovascular accident). Upon employing extreme gradient boosting (XGBoost), we obtained the F1 scores of the predictions for each complication type as 0.844, 0.921, 0.831, and 0.762. Conclusion: This study shows that a machine learning project based on topic modeling can effectively predict the progress of a disease. Furthermore, a unique way of topic model transplanting, which matches the dimension of the topic structures of the two data sets, is presented. Supplementary Information: The online version contains supplementary material available at 10.1007/s13534-023-00322-7.

Pan PPAR agonist stimulation of induced MSCs produces extracellular vesicles with enhanced renoprotective effect for acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) has a complex pathophysiology and imposes serious health concerns worldwide. Extracellular vesicles (EVs) derived from induced mesenchymal stem cells (iMSCs) have been recognized as novel cell-free therapeutics for various inflammatory and degenerative disorders. In this study, we investigated whether iMSCs stimulated with a pan-peroxisome proliferator-activated receptor (PPAR) agonist could enhance the therapeutic efficacy of EVs against AKI. METHODS: Human iMSCs were primed with or without lanifibranor, a PPAR agonist for 24 h, and EVs were collected after an additional 24 h. The basic characteristics of EVs were evaluated using cryo-transmission electron microscopy imaging, immunoblot detection of EV markers, nanoparticle tracking analysis, and localization in AKI kidneys. In vitro, the potential of the EVs to promote the growth and survival of HK-2 cells undergoing cisplatin-induced apoptosis and anti-inflammatory effects in M1-polarized THP-1 was compared. Subsequently, AKI was induced in BALB/c mice using cisplatin. After 8 and 24 h of cisplatin treatment, iMSC-EVs or pan-PPAR-iMSC-EVs were injected intravascularly. At 96 h after cisplatin administration, the renoprotective effects of iMSC-EVs or pan-PPAR-iMSC-EVs in inhibiting inflammation and apoptosis were compared using serum biochemistry, histology, immunohistochemistry, and gene expression analysis by qPCR. RESULTS: Both EV types expressed EV markers and had typical EV morphology, and their localization in the renal tissue was confirmed. The proliferation and survival of HK-2 cells were higher in pan-PPAR-iMSC-EVs than those in iMSC-EVs. In M1-polarized THP-1 cells, the reduction in the mRNA expression of inflammatory cytokines was more significant in pan-PPAR-iMSC-EVs than that in iMSC-EVs. In the mouse model of cisplatin-induced AKI, pan-PPAR-iMSC-EVs markedly enhanced renoprotective effects compared to iMSC-EVs. Specifically, pan-PPAR-iMSC-EVs reduced tissue inflammation, immune cell infiltration, and apoptosis. Pan-PPAR-iMSC-EVs also increased renal capillary density. CONCLUSION: Priming iMSCs with a PPAR agonist significantly improved the therapeutic potential of EVs by reducing inflammation and apoptosis. The reported strategy may contribute to the development of a novel cell-free option for AKI treatment. TRIAL REGISTRATION: Not applicable.

Impact of glucose metabolism on PD-L1 expression in sorafenib-resistant hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related mortality worldwide. Programmed cell death ligand-1 (PD-L1) is an immune checkpoint protein that binds to programmed cell death-1 (PD-1), which is expressed in activated T cells and other immune cells and has been employed in cancer therapy, including HCC. Recently, PD-L1 overexpression has been documented in treatment-resistant cancer cells. Sorafenib is a multikinase inhibitor and the only FDA-approved treatment for advanced HCC. However, several patients exhibit resistance to sorafenib during treatment. This study aimed to assess the effect of glucose deprivation on PD-L1 expression in HCC cells. We used PD-L1-overexpressing HepG2 cells and IFN-γ-treated SK-Hep1 cells to explore the impact of glycolysis on PD-L1 expression. To validate the correlation between PD-L1 expression and glycolysis, we analyzed data from The Cancer Genome Atlas (TCGA) and used immunostaining for HCC tissue analysis. Furthermore, to modulate PD-L1 expression, we treated HepG2, SK-Hep1, and sorafenib-resistant SK-Hep1R cells with rapamycin. Here, we found that glucose deprivation reduced PD-L1 expression in HCC cells. Additionally, TCGA data and immunostaining analyses confirmed a positive correlation between the expression of hexokinase II (HK2), which plays a key role in glucose metabolism, and PD-L1. Notably, rapamycin treatment  decreased the expression of PD-L1 and HK2 in both high PD-L1-expressing HCC cells and sorafenib-resistant cells. Our results suggest that the modulation of PD-L1 expression by glucose deprivation may represent a strategy to overcome PD-L1 upregulation in patients with sorafenib-resistant HCC.

Extracellular vesicles from induced pluripotent stem cell-derived mesenchymal stem cells enhance the recovery of acute kidney injury.

BACKGROUND AIMS: To investigate whether the extracellular vesicles (EVs) from mesenchymal stem cell-like cells derived from induced pluripotent stem cells (iMSC-EVs) can inhibit the progression of acute kidney injury (AKI). METHODS: The characteristics of iMSC-EVs were confirmed by immunoblotting, cryo-transmission electron microscopy, nanoparticle tracking analysis, and their localization in kidneys. Using human renal epithelial cells, the potential of iMSC-EVs to stimulate the growth and survival of HK-2 cells undergoing cisplatin-induced cell death was investigated. The anti-inflammatory effects of iMSC-EVs was examined in M1-polarized THP-1 macrophages. Subsequently, the therapeutic potential of iMSC-EVs was assessed in cisplatin-induced acute kidney injury in BALB/c mice. The anti-apoptotic and anti-inflammatory effect of iMSC-EVs was evaluated using serum biochemistry, histology, immunohistochemistry, and gene expression analysis. RESULTS: iMSC-EVs promoted the growth of renal epithelial cell (HK-2) and enhanced the survival of HK-2 undergoing cisplatin-induced cell death. In cisplatin-induced mice with AKI, iMSC-EVs alleviated AKI, as shown by reduced blood nitrogen urea/creatinine and increased body weight. Also, iMSC-EVs enhanced renal tissue integrity and the number of proliferating cell nuclear antigen-positive tubules. iMSC-EVs decreased the infiltration of immune cells, reduced the expression of inflammatory genes in M1-induced THP-1 cells and enhanced capillary density in the kidney of AKI mice. Real-time quantitative polymerase chain reaction analysis showed that the expression of inflammatory genes in the kidney of AKI mice was reduced compared with that received vehicle. Immunoblotting revealed that iMSC-EVs led to a decreased protein expression of key inflammatory genes. Also, iMSC-EVs reversed the activation of ERK1/2 signaling induced by AKI. Finally, iMSC-EVs inhibited the apoptosis of HK-2 cells induced by cisplatin as well as that of renal tissue of AKI mice. CONCLUSIONS: Our data suggest that iMSC-EVs have potential to become a novel, cell-free therapeutic for cisplatin-induced AKI.

Quantum spin nematic phase in a square-lattice iridate.

Spin nematic is a magnetic analogue of classical liquid crystals, a fourth state of matter exhibiting characteristics of both liquid and solid1,2. Particularly intriguing is a valence-bond spin nematic3-5, in which spins are quantum entangled to form a multipolar order without breaking time-reversal symmetry, but its unambiguous experimental realization remains elusive. Here we establish a spin nematic phase in the square-lattice iridate Sr2IrO4, which approximately realizes a pseudospin one-half Heisenberg antiferromagnet in the strong spin-orbit coupling limit6-9. Upon cooling, the transition into the spin nematic phase at TC ≈ 263 K is marked by a divergence in the static spin quadrupole susceptibility extracted from our Raman spectra and concomitant emergence of a collective mode associated with the spontaneous breaking of rotational symmetries. The quadrupolar order persists in the antiferromagnetic phase below TN ≈ 230 K and becomes directly observable through its interference with the antiferromagnetic order in resonant X-ray diffraction, which allows us to uniquely determine its spatial structure. Further, we find using resonant inelastic X-ray scattering a complete breakdown of coherent magnon excitations at short-wavelength scales, suggesting a many-body quantum entanglement in the antiferromagnetic state10,11. Taken together, our results reveal a quantum order underlying the Néel antiferromagnet that is widely believed to be intimately connected to the mechanism of high-temperature superconductivity12,13.

Comparative Effects of Bivalent, Quadrivalent, and Nonavalent Human Papillomavirus Vaccines in The Prevention of Genotype-Specific Infection: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Human papillomavirus (HPV) infection is a major global disease burden and the main cause of cervical cancer. Certain HPV genotypes, with are the most common etiologic pathogens and cause a significant disease burden, are being targeted for vaccine development. However, few studies have focused on the comparative effectiveness of the bivalent HPV (2v-HPV), quadrivalent HPV (4v-HPV), and nonavalent HPV (9v-HPV) vaccines against HPV strain-specific infection. This study investigated the comparative effects of these vaccines against genotype-specific infection. MATERIALS AND METHODS: We conducted a pairwise and network meta-analysis of published randomized clinical trials of HPV vaccines according to sex and HPV infection status for nine HPV genotypes (HPV 6/11/16/18/31/33/45/52/58). RESULTS: Overall, 10 randomized controlled trials (12 articles) were included in this study. In the network meta-analysis, no statistically significant differences were observed in the prevention of carcinogenic HPV strains (16/18/31/33/45/52/58) between the 2v-HPV and 4v-HPV vaccines in female HPV infection-naïve populations. However, the 9v-HPV vaccine showed a significantly superior effect compared with 2v-HPV and 4v-HPV vaccines in preventing HPV 31/33/45/52/58 infections. Although 2v-HPV and 4v-HPV vaccines provided some cross-protection against HPV 31/33/45/52/58 infections, the effect was significant only on HPV 31 infection. For HPV 16 and 18, neither statistically significant nor small differences were found in the prevention of HPV infection among the 2v-HPV, 4v-HPV, and 9v-HPV vaccines. CONCLUSION: Our study complements previous understanding of how the effect of HPV vaccines differs according to the HPV genotype. This is important because HPV genotype prevalence varies among countries. We advocate for continued efforts in vaccinating against HPV, while public health agencies should consider the difference in the vaccine effect and HPV genotype prevalence when implementing HPV vaccination in public vaccination programs.