Effect of Remimazolam- versus Propofol-Based Total Intravenous General Anesthesia on Intraoperative Hemodynamic Stability for Major Spine Surgery in the Prone Position: A Randomized Controlled Trial.

Background and Objectives: Remimazolam offers advantages over propofol in terms of hemodynamic stability. However, it remains unclear whether remimazolam-based total intravenous anesthesia (TIVA) can reduce intraoperative hypotension compared to propofol-based TIVA, especially after prone positioning. In this study, we compared the effects of remimazolam- and propofol-based TIVA on intraoperative hemodynamic stability in patients undergoing surgery in the prone position. Materials and Methods: This study randomly assigned patients undergoing major spinal surgery in the prone position to the propofol or remimazolam group. Target-controlled infusion (2-3.5 µg/mL for induction and 2-3 µg/mL for maintenance) was used in the propofol group and continuous infusion (6 mg/kg/h for induction and 1-2 mg/kg/h for maintenance) was used in the remimazolam group; target-controlled infusion (3-5 ng/mL) of remifentanil was performed in both groups. The primary outcomes were the incidence of hypotensive episodes during the first hour after prone positioning. The secondary outcomes included the incidence of severe hypotension and the total amount of inotropic or vasopressor medication. Systolic and mean arterial pressure, heart rate, cardiac index and output, stroke volume, stroke volume variation, and pleth variability index were also evaluated. These variables were recorded per minute for the first 10 min after prone positioning, and every 10 min thereafter. Results: The study enrolled 94 patients (47 patients in each group). The incidence of hypotension or severe hypotension did not differ significantly between the two groups during the first hour after prone positioning. The total amount of ephedrine administered during the first hour after prone positioning was lesser (p = 0.020) and the mean arterial pressure during the initial 10 min after prone positioning was higher in the remimazolam group (p = 0.003). Conclusions: Our study uncovered no significant differences in the incidence of hypotension between remimazolam- and propofol-based TIVA in patients undergoing major spine surgery in prone position.

Effective remimazolam loading dose for adequate sedation in regional anesthesia.

PURPOSE: Remimazolam is a novel ultrashort-acting sedative considered appropriate for continuous infusion during surgical procedures. Nevertheless, information regarding its loading dose for sedation during surgery is limited. We aimed to determine the 90% effective dose (ED90) of the remimazolam loading dose for sedation in patients undergoing limb surgery under regional anesthesia. METHODS: We included 50 patients aged 19-80 yr undergoing limb surgery under regional anesthesia. After regional anesthesia, remimazolam besylate was administered at the assigned dose. For ten minutes after the initiation of loading, the level of sedation was evaluated using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale. The primary outcome was the ED90 based on whether patients reached a MOAA/S score of ≤ 3 points (loss of response to verbal command) within ten minutes. The secondary outcomes were the ED50 and the estimated effect site and plasma concentration at the time of achieving successful sedation. RESULTS: In total, 49 patients were included in the final analysis, and adequate sedation with the assigned loading dose was successful in 42 patients. The log-logistic function showed that the ED90 and ED50 were 0.617 mg·kg-1·hr-1 (95% confidence interval [CI], 0.511 to 0.722; 98% CI, 0.492 to 0.741) and 0.438 mg·kg-1·hr-1 (95% CI, 0.335 to 0.541; 98% CI, 0.315 to 0.560), respectively. CONCLUSION: The ED90 of the remimazolam loading dose to achieve adequate sedation in patients undergoing limb surgery under regional anesthesia was 0.617 mg·kg-1·hr-1 (95% CI, 0.511 to 0.722; 98% CI, 0.492 to 0.741). STUDY REGISTRATION: ClinicalTrials.gov (NCT05340335); first posted 22 April 2022.

RéSUMé: OBJECTIF: Le remimazolam est un nouveau sédatif à action ultracourte considéré comme approprié pour la perfusion continue pendant les interventions chirurgicales. Néanmoins, les informations concernant sa dose de charge pour la sédation pendant la chirurgie sont limitées. Notre objectif était de déterminer la dose efficace à 90 % (DE90) de la dose de charge de remimazolam pour la sédation chez la patientèle bénéficiant d'une chirurgie d'un membre sous anesthésie régionale. MéTHODE: Cinquante personnes âgées de 19 à 80 ans bénéficiant d'une chirurgie des membres sous anesthésie régionale ont été incluses. Après l'anesthésie régionale, du bésylate de remimazolam a été administré à la dose assignée. Pendant dix minutes après le début de la charge, le niveau de sédation a été évalué à l'aide de l'échelle modifiée d'évaluation de la vigilance/sédation par l'observateur (MOAA/S). Le critère d'évaluation principal était la DE90 selon que les patient·es ont atteint un score MOAA/S de ≤ 3 points (perte de réponse à la commande verbale) dans les dix minutes. Les critères d'évaluation secondaires étaient la DE50 et l'estimation du site d'effet et de la concentration plasmatique au moment de l'obtention d'une sédation réussie. RéSULTATS: Au total, 49 personnes ont été incluses dans l'analyse finale, et une sédation adéquate avec la dose de charge assignée a été couronnée de succès chez 42 d'entre elles. La fonction log-logistique a montré que les DE90 et DE50 étaient de 0,617 mg·kg−1·h−1 (intervalle de confiance [IC] à 95 %, 0,511 à 0,722; IC 98 %, 0,492 à 0,741) et 0,438 mg·kg−1·h−1 (IC 95 %, 0,335 à 0,541; IC 98 %, 0,315 à 0,560), respectivement. CONCLUSION: La DE90 de la dose de charge de remimazolam pour obtenir une sédation adéquate chez les personnes bénéficiant d'une chirurgie des membres sous anesthésie régionale était de 0,617 mg·kg−1·h−1 (IC 95 %, 0,511 à 0,722; IC 98 %, 0,492 à 0,741). ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT05340335); première publication le 22 avril 2022.

Gene Therapy Using Efficient Direct Lineage Reprogramming Technology for Neurological Diseases.

Gene therapy is an innovative approach in the field of regenerative medicine. This therapy entails the transfer of genetic material into a patient's cells to treat diseases. In particular, gene therapy for neurological diseases has recently achieved significant progress, with numerous studies investigating the use of adeno-associated viruses for the targeted delivery of therapeutic genetic fragments. This approach has potential applications for treating incurable diseases, including paralysis and motor impairment caused by spinal cord injury and Parkinson's disease, and it is characterized by dopaminergic neuron degeneration. Recently, several studies have explored the potential of direct lineage reprogramming (DLR) for treating incurable diseases, and highlighted the advantages of DLR over conventional stem cell therapy. However, application of DLR technology in clinical practice is hindered by its low efficiency compared with cell therapy using stem cell differentiation. To overcome this limitation, researchers have explored various strategies such as the efficiency of DLR. In this study, we focused on innovative strategies, including the use of a nanoporous particle-based gene delivery system to improve the reprogramming efficiency of DLR-induced neurons. We believe that discussing these approaches can facilitate the development of more effective gene therapies for neurological disorders.

Factors Related to Depression According to the Degree of Loneliness in Adolescents with Severe Friend-Relationship Stress.

This study attempted to identify factors affecting depression in relation to loneliness among adolescents. The study participants were 2668 adolescents aged 12 to 18 years who felt stressed and lonely. The variables in this study were classified into sociodemographic and psychological characteristics based on the 16th Korea Youth Risk Behavior Web-Based Survey items. Results revealed that sex, smoking, suicidal ideation, suicide planning, and anxiety were significantly related to depression (p < 0.05) in the group that reported less loneliness. Economic level, alcohol consumption, suicidal ideation, suicide planning, subjective body type, and anxiety were significantly related factors (p < 0.05) in the group that reported feeling very lonely. This study is significant in providing basic data for developing evidence-based strategies to ameliorate depression in adolescents.

Effects of wastewater effluent-borne nutrients on phytoplankton off the coast of Jeju Island.

The spatiotemporal distributions of nutrients in coastal waters surrounding eight wastewater treatment plants (WWTPs) in four seasons were investigated to determine the effects of WWTP effluents on seawater off Jeju Island, Korea. The highest concentrations of nutrients were observed in the outlets of WWTPs with relatively high ammonium concentrations among dissolved inorganic nitrogen (DIN). The reduced DIN (NO2- and NH4+)/total DIN ratios are used as a potential short-term index for marine environmental conditions. In seawater surrounding the WWTPs, relatively low nutrient concentrations were observed in spring and fall, due to enhanced biological production, which is closely linked to decreased N/P ratios. Because the highest WWTP effluent fluxes of ammonium in this study were similar to the fluxes of nutrients from submarine groundwater discharge, diffusion from bottom sediments, and discharge from land-based fish farm wastewater, WWTP effluent-derived nutrients are potentially important in oligotrophic environments and can be readily utilized by phytoplankton.

Effect of Temperature, pH, and Media on the Mycelial Growth of Tuber koreanum.

Members of the genus Tuber are ectomycorrhizal fungi; this genus includes more than 180 species worldwide. In the present study, the optimal pH, temperature, and medium suitable for the mycelial growth of the Korean truffle, Tuber koreanum, were determined. Mycelium of T. koreanum, isolated from fruiting bodies collected in Korea, was used to investigate the effects of these environmental factors. The results showed that malt extract agar and potato dextrose agar were the most suitable for the mycelial growth of T. koreanum when cultured at a pH of 6.0 at 25 °C for 30 days.

Elongated nanoporous Au networks improve somatic cell direct conversion into induced dopaminergic neurons for Parkinson's disease therapy.

The efficient production of dopaminergic neurons via the direct conversion of other cell types is of interest as a potential therapeutic approach for Parkinson's disease. This study aimed to investigate the use of elongated porous gold nanorods (AuNpRs) as an enhancer of cell fate conversion. We observed that AuNpRs promoted the direct conversion of fibroblasts into dopaminergic neurons in vivo and in vitro. The extent of conversion of fibroblasts into dopaminergic neurons depended on the porosity of AuNpRs, as determined by their aspect ratio. The mechanism underlying these results involves specific AuNpR-induced transcriptional changes that altered the expression of antioxidant-related molecules. The generation of dopaminergic neurons via the direct conversion method will open a new avenue for developing a therapeutic platform for Parkinson's disease treatment. STATEMENT OF SIGNIFICANCE: In this study, we applied modified gold nanoporous materials (AuNpRs) to the direct lineage reprogramming of dopaminergic neurons. The cell reprogramming process is energy-intensive, resulting in an excess of oxidative stress. AuNpRs facilitated the direct conversion of dopaminergic neurons by ameliorating oxidative stress during the reprogramming process. We have found this mechanistic clue from high throughput studies in this research work.

Mycorrhization of Quercus spp. with Tuber huidongense and T. himalayense Collected in Korea.

Fungi of the genus Tuber are ectomycorrhizal fungi that form a symbiotic relationship mainly with oak and hazel trees. Tuber spp. exhibit a highly selective host plant preference; thus, for cultivation purposes it is important to select an appropriate host plant for successful mycorrhization. In addition, as mycorrhizal characteristics differ according to Tuber spp., it is necessary to understand the differences in mycorrhizae according to the fungal species. Tuber huidongense and Tuber himalayense were recently discovered in Korea; therefore, we used spore suspensions from these two species to inoculate two species of oak trees, Quercus acutissima and Quercus dentata, to compare colonization rates and morphologies of the mycorrhizae. The colonization rates demonstrated that the different Tuber spp. favored different host plant species. In addition, unique morphological and anatomical characteristics were observed for T. huidongense and T. himalayense depending on the host species. These findings can lead to new economically important agricultural activities related to truffle cultivation in Korea.

Stretchable and Self-Healable Poly(styrene-co-acrylonitrile) Elastomer with Metal-Ligand Coordination Complexes.

Recently, soft electronics have attracted significant attention for various applications such as flexible devices, artificial electronic skins, and wearable devices. For practical applications, the key requirements are an appropriate electrical conductivity and excellent elastic properties. Herein, using the cyano-silver complexes resulting from coordination bonds between the nitrile group of poly(styrene-co-acrylonitrile) (SAN) and Ag ions, a self-healing elastomer demonstrating electrical conductivity is obtained. Because of these coordination complexes, the Ag-SAN elastomer possesses elasticity, compared with pristine SAN. The fracture strain of the Ag-SAN elastomers increased with the amount of added Ag ions, reaching up to 1000%. Additionally, owing to the presence of reversible coordination bonds, the elastomer exhibits self-healing properties at room temperature and electrical conductivity, thereby improving the possibility of its utilization in novel applications wherein elastic materials are generally exposed to external stimuli.

Report on a New Truffle Species, Tuber koreanum sp. nov., from Korea.

The truffle and ectomycorrhizal roots formed by Tuber sp. were collected from the rhizosphere of Quercus aliena in Korea. The morphological characteristics of the ascoma, and molecular phylogenetic analysis using sequences from the internal transcribed spacer (ITS) and large subunit (LSU) of ribosomal DNA, translation elongation factor 1-alpha (TEF), and RNA polymerase second largest subunit (RPB2) regions confirmed the distinct morphology of the truffle. This truffle belongs to a monophyletic clade among the other Tuber species in the phylogeny. This study describes the truffle, Tuber koreanum, as a new species reported from Korea.

Large-Scale Assembly of Peptide-Based Hierarchical Nanostructures and Their Antiferroelectric Properties.

An effective strategy is developed to create peptide-based hierarchical nanostructures through the meniscus-driven self-assembly in a large area and fabricate antiferroelectric devices based on these nanostructures for the first time. The diphenylalanine hierarchical nanostructures (FF-HNs) are self-assembled by vertically pulling a substrate from a diphenylalanine (FF) solution dissolved in a miscible solvent under precisely controlled conditions. Owing to the unique structural properties of FF nanostructures, including high crystallinity and α-helix structures, FF-HNs possess a net electrical dipole moment, which can be switched in an external electric field. The mass production of antiferroelectric devices based on FF-HNs can be successfully achieved by means of this biomimetic assembly technique. The devices show an evident antiferroelectric to ferroelectric transition under dark conditions, while the ferroelectricity is found to be tunable by light. Notably, it is discovered that the modulation of antiferroelectric behaviors of FF-HNs under glutaraldehyde exposure is due to the FF molecules that are transformed into cyclophenylalanine by glutaraldehyde. This work provides a stepping stone toward the mass production of self-assembled hierarchical nanostructures based on biomolecules as well as the mass fabrication of electronic devices based on biomolecular nanostructures for practical applications.

Carbon monoxide ameliorates acetaminophen-induced liver injury by increasing hepatic HO-1 and Parkin expression.

Acetaminophen (APAP) is widely used as an antifebrile and analgesic drug at recommended doses, whereas an overdose of APAP can cause severe liver damage. The molecular mechanisms underlying APAP-induced liver damage remain incompletely understood. Carbon monoxide (CO), an end-product of heme oxygenase (HO)-1 activity, can confer anti-inflammatory and antiapoptotic properties in cellular models of toxicity via regulation of mitochondrial function. The objective of this study was to evaluate the effects of CO on APAP-induced hepatotoxicity and CO's relationship to regulation of endoplasmic reticulum (ER) stress and mitochondrial signaling using CO-releasing molecules or low concentrations of CO applied as pretreatment or posttreatment. Using genetic deletion or knockdown approaches in alpha mouse liver cells or primary hepatocytes, respectively, we investigated the role of HO-1 and the mitophagy regulator protein Parkin on APAP-induced expression of the ER stress-associated apoptosis regulator cytosine-cytosine-adenosine-adenosine-thymidine (CCAAT)/enhancer-binding protein homologous protein (CHOP). We found that CO induced Parkin expression in hepatocytes via the protein kinase RNA-like ER kinase/eukaryotic translation initiation factor 2-α/activating transcription factor-4 signaling pathway. Additionally, CO gas inhalation significantly alleviated APAP-induced liver damage in vivo and correspondingly reduced serum alanine aminotransferase and aspartate aminotransferase levels as well as proinflammatory cytokines and reduced the expression of CHOP in liver tissues while dramatically increasing hepatic HO-1 and Parkin expression. We found that the protective effects of CO on APAP-induced liver damage were mediated by down-regulation of CHOP at a transcriptional and post-translational level via induction of HO-1 and Parkin, respectively, and associated with decreases in reactive oxygen species production and JNK phosphorylation. We conclude that CO may represent a promising therapeutic agent for APAP-induced liver injury.-Chen, Y., Park, H.-J., Park, J., Song, H.-C., Ryter, S. W., Surh, Y.-J., Kim, U.-H., Joe, Y., Chung, H. T. Carbon monoxide ameliorates acetaminophen-induced liver injury by increasing hepatic HO-1 and Parkin expression.

Nac1 facilitates pluripotency gene activation for establishing somatic cell reprogramming.

Transcription factors play a central role in pluripotency transcription circuitry for establishing pluripotent reprogramming. Master transcription factors Oct4, Nanog, and Sox2 are known to form the core of the pluripotency transcription network. Other transcription factors also play critical roles for further refining the core circuitry for pluripotency in induced pluripotent stem (iPS) cells. Here, we reported that Nac1 interacted with the master pluripotent factors Oct4 and Nanog co-occupies gene promoters bound by these transcriptional factors for establishing pluripotency. Moreover, this interaction coordinates gene expression with H3K4me3 in the somatic cell reprogramming. Knockdown of Nac1 suppressed somatic cell reprogramming, whereas overexpression of Nac1 resulted in enhanced efficiency of induced pluripotent cell generation. Altogether, these results reveal the genome wide role for Nac1 in the contribution to the pluripotency circuitry and the regulation of the establishing pluripotent state.

Modeling G2019S-LRRK2 Sporadic Parkinson's Disease in 3D Midbrain Organoids.

Recent advances in generating three-dimensional (3D) organoid systems from stem cells offer new possibilities for disease modeling and drug screening because organoids can recapitulate aspects of in vivo architecture and physiology. In this study, we generate isogenic 3D midbrain organoids with or without a Parkinson's disease-associated LRRK2 G2019S mutation to study the pathogenic mechanisms associated with LRRK2 mutation. We demonstrate that these organoids can recapitulate the 3D pathological hallmarks observed in patients with LRRK2-associated sporadic Parkinson's disease. Importantly, analysis of the protein-protein interaction network in mutant organoids revealed that TXNIP, a thiol-oxidoreductase, is functionally important in the development of LRRK2-associated Parkinson's disease in a 3D environment. These results provide proof of principle for the utility of 3D organoid-based modeling of sporadic Parkinson's disease in advancing therapeutic discovery.

FGF21 induced by carbon monoxide mediates metabolic homeostasis via the PERK/ATF4 pathway.

The prevalence of metabolic diseases, including type 2 diabetes, obesity, and cardiovascular disease, has rapidly increased, yet the molecular mechanisms underlying the metabolic syndrome, a primary risk factor, remain incompletely understood. The small, gaseous molecule carbon monoxide (CO) has well-known anti-inflammatory, antiproliferative, and antiapoptotic effects in a variety of cellular- and tissue-injury models, whereas its potential effects on the complex pathways of metabolic disease remain unknown. We demonstrate here that CO can alleviate metabolic dysfunction in vivo and in vitro. We show that CO increased the expression and section of the fibroblast growth factor 21 (FGF21) in hepatocytes and liver. CO-stimulated PERK activation and enhanced the levels of FGF21 via the eIF2α-ATF4 signaling pathway. The induction of FGF21 by CO attenuated endoreticulum stress- or diet-induced, obesity-dependent hepatic steatosis. Moreover, CO inhalation lowered blood glucose levels, enhanced insulin sensitivity, and promoted energy expenditure by stimulating the emergence of beige adipose cells from white adipose cells. In conclusion, we suggest that CO acts as a potent inducer of FGF21 expression and that CO critically depends on FGF21 to regulate metabolic homeostasis.-Joe, Y., Kim, S., Kim, H. J., Park, J., Chen, Y., Park, H.-J., Jekal, S.-J., Ryter, S. W., Kim, U. H., Chung, H. T. FGF21 induced by carbon monoxide mediates metabolic homeostasis via the PERK/ATF4 pathway.

Pterostilbene 4'-ß-Glucoside Protects against DSS-Induced Colitis via Induction of Tristetraprolin.

Pterostilbene, a dimethyl ester analog of resveratrol, has anti-inflammatory and antioxidative effects and alters cell proliferation. Tristetraprolin (TTP) promotes the degradation of proinflammatory mediators via binding to adenosine and uridine- (AU-) rich elements (ARE) located in the 3'-untranslated regions of mRNAs. Here, we utilized pterostilbene 4'-ß-glucoside (4-PG), a compound derived from pterostilbene, to investigate whether it has anti-inflammatory effects on dextran sulfate sodium- (DSS-) induced colitis via TTP enhancement. TTP expression was increased in 4-PG dose- and time-dependent manners in RAW264.7 cells. The production of proinflammatory cytokine, such as TNF-α, was reduced by 4-PG in vitro. To investigate the role of TTP in the anti-inflammatory effects of 4-PG, we used DSS-induced colitis in TTP WT and KO mice as models. The expression levels of TTP and proinflammatory cytokines were determined in serum and colon tissue. 4-PG increased the expression of TTP while suppressing proinflammatory cytokines both in vitro and in vivo. These findings suggest that treatment with 4-PG mediates the anti-inflammatory effects of 4-PG on DSS-induced colitis via enhancing TTP expression.

Effects of Arbuscular Mycorrhizal Fungi and Soil Conditions on Crop Plant Growth.

We investigated the effects on various crops of inoculation with species of arbuscular mycorrhizal fungi (AMF) in soils from different sources and selected AMF species suitable for domestic environment-friendly farming. Effects on plants varied with the AMF species used. In carrot, Scutellospora heterogama, Acaulospora longula, and Funneliformis mosseae had a positive effect on growth of the host, whereas AMF had only weak effects on the growth of red pepper and leek. AMF inoculation had positive effects on the growth of carrot and sorghum. The results of this study indicate the nature of the relationship between soil, plants, and AMF; this study therefore has important implications for the future use of AMF in environment-friendly agriculture.

Two Endophytic Diaporthe Species Isolated from the Leaves of Astragalus membranaceus in Korea.

We characterized two endophyte fungi from the leaves of Astragalus membranaceus in Korea. The isolated strains were identified on the basis of the morphological characters and sequences analysis of the internal transcribed spacer and large subunit regions of the rDNA and ß-tubulin gene. To the best of our knowledge, this is the first report of Diaporthe oncostoma and Diaporthe infecunda in Korea, and we have provided descriptions and figures.

Early postoperative albumin level following total knee arthroplasty is associated with acute kidney injury: A retrospective analysis of 1309 consecutive patients based on kidney disease improving global outcomes criteria.

Hypoalbuminemia has been reported to be an independent risk factor for acute kidney injury (AKI). However, little is known about the relationship between the albumin level and the incidence of AKI in patients undergoing total knee arthroplasty (TKA). The aim of our study was to assess incidence and risk factors for AKI and to evaluate the relationship between albumin level and AKI following TKA.The study included a retrospective review of medical records of 1309 consecutive patients who underwent TKA between January 2008 and December 2014. The patients were divided into 2 groups according to the lowest serum albumin level within 2 postoperative days (POD2_alb level < 3.0 g/dL vs ≥3.0 g/dL). Multivariate logistic regression analysis was used to assess risk factors for AKI. A comparison of incidence of AKI, hospital stay, and overall mortality in the 2 groups was performed using propensity score analysis.Of 1309 patients, 57 (4.4%) developed AKI based on Kidney Disease Improving Global Outcomes criteria. Factors associated with AKI included age (odds ratio [OR] 1.05; 95% confidence interval [CI] 1.01-1.09; P = 0.030), diabetes (OR 3.12; 95% CI 1.65-5.89; P < 0.001), uric acid (OR 1.51; 95% CI 1.26-1.82; P < 0.001), beta blocker use (OR 2.65; 95% CI 1.48-4.73; P = 0.001), diuretics (OR 16.42; 95% CI 3.08-87.68; P = 0.001), and POD2_alb level < 3.0 g/dL (OR 1.92; 95% CI 1.09-3.37; P = 0.023). After propensity score analysis, POD2_alb level<3.0 g/dL was associated with AKI occurrence (OR 1.82; 95% CI 1.03-3.24, P = 0.041) and longer hospital stay (P = 0.001).In this study, we demonstrated that POD2_alb level<3.0 g/dL was an independent risk factor for AKI and lengthened hospital stay in patients undergoing TKA.