Expression of nuclear receptors and glucose metabolic pathway proteins in sebaceous carcinoma: Androgen receptor and monocarboxylate transporter 1 have a key role in disease progression.

Standard systemic treatments are not consistently effective for treating unresectable or advanced sebaceous carcinoma (SC). The present study investigated the pathogenic roles of nuclear receptors (NRs), glucose metabolic dysregulation and immune checkpoint proteins in SC as prognostic markers or therapeutic targets. Patients with pathologically confirmed SC between January 2002 and December 2019 at three university hospitals in South Korea were included in the present study. Immunohistochemistry was performed on paraffin-embedded tumor tissues for glucocorticoid receptors (GR), androgen receptors (AR), estrogen receptors (ER), progesterone receptors (PR), glucose transporter 1 (GLUT1), monocarboxylate transporters (MCT1 and MCT4), CD147, phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) and the immune checkpoint protein, programmed cell death-ligand 1 (PD-L1). The results were semi-quantitatively assessed and the associations of these proteins with various clinicopathological parameters were determined. A total of 39 cases of SC comprising 19 periocular and 20 extraocular tumors were enrolled. NRs were frequently detected in the tumor nuclei, with GR having the highest frequency (89.7%), followed by AR, ER (both 51.3%) and PR (41.0%). Regarding glucose metabolism, CD147, GLUT1 and MCT1 were highly expressed at 100, 89.7 and 87.2%, respectively, whereas MCT4 and pAMPK expression levels were relatively low at 38.5 and 35.9%, respectively. Membranous expression of PD-L1 was detected in five cases (12.8%), four of which were extraocular. In the multivariate analysis, advanced stage, low AR positivity and high MCT1 expression were independent poor prognostic factors for metastasis-free survival (all P<0.05). The present results suggested that hormonal and metabolic dysregulation may be associated with the pathogenesis of SC, and that AR and MCT1 in particular may serve as prognostic indicators and potential therapeutic targets. Additionally, ~10% of SC cases exhibited PD-L1 expression within the druggable range, and these patients are expected to benefit from treatment with immune checkpoint inhibitors.

Whole genome sequencing of Lacticaseibacillus casei KACC92338 strain with strong antioxidant activity, reveals genes and gene clusters of probiotic and antimicrobial potential.

Lacticaseibacillus casei KACC92338 was originally isolated from Korean raw milk. The antioxidant activities and protective effect in vitro of this strain were evaluated extensively. The results showed that KACC92338 can tolerate hydrogen peroxide up to 2 mM and cell-free supernatant (CFS) had higher scavenging rates for DPPH, hydroxyl radical, reducing power, and iron chelating activities with 95.61 ± 1.59%, 34.10 ± 1.93%, 2.220 ± 0.82 and 81.06 ± 1.06%, respectively. Meanwhile, the CFS showed a protective effect on yeast cells against 10 mM hydrogen peroxide with a survival rate of 76.05 ± 5.65%. To explore the probiotic potential of KACC92338, whole genome assembly and gene clusters with probiotic properties were further analyzed. The genome size was 3,050,901 bp with a 47.96% GC ratio, and 63 contigs. The genome contains 3,048 genes composed of 2,981 coding sequences and 67 RNAs (including 57 tRNAs +9 rRNAs +1 tmRNA). Average Nucleotide Identity and genome-based taxonomy showed that the KACC92338 genome had close similarity with L. casei strains with 96% ANI. Functional annotation by EggNOG and KEGG revealed the presence of numerous genes putatively involved in carbohydrate- and amino acid-transport and metabolism, genetic information processing, and signaling and cellular processes. Additionally, several genes conferring probiotic characteristics such as tolerance to stress, heat, cold, acid, bile salts, oxidative stress, immunomodulation, and adhesion to intestinal epithelium were identified. Notably absent were acquired antibiotic resistance genes, virulence, and pathogenic factors, that prove KACC92338 is a safe strain. Besides, the defense mechanisms of KACC92338 include six prophage regions and three clustered regularly interspaced short palindromic repeat (CRISPR) arrays as acquired immune systems against mobile elements. Further, the BAGEL4 database determined antimicrobial bacteriocin clusters of class IIb: sakacin-P, Enterolysin_A, sactipeptides, and Enterocin X, which suggests the strain could exhibit a wide range of antimicrobial functions. Together, these findings show that the L. casei KACC92338 strain can be a potential probiotic candidate in producing functional fermented foods-, health care- and skin care products- with antioxidant properties. However, a few more mechanistic studies are necessary on the safety assurance and potential application of the strain as a probiotic agent.

A fluorite-structured HfO2/ZrO2/HfO2 superlattice based self-rectifying ferroelectric tunnel junction synapse.

A self-rectifying ferroelectric tunnel junction that employs a HfO2/ZrO2/HfO2 superlattice (HZH SL) combined with Al2O3 and TiO2 layers is proposed. The 6 nm-thick HZH SL effectively suppresses the formation of non-ferroelectric phases while increasing remnant polarization (Pr). This enlarged Pr modulates the energy barrier configuration, consequently achieving a large on/off ratio of 1273 by altering the conduction mechanism from off-state thermal injection to on-state Fowler-Nordheim tunneling. Moreover, the asymmetric Schottky barriers at the top TiN/TiO2 and bottom HfO2/Pt interfaces enable a self-rectifying property with a rectifying ratio of 1550. Through calculations and simulations it is found that the device demonstrates potential for achieving an integrated array size exceeding 7k while maintaining a 10% read margin, and shows potential for application in artificial synapses for neuromorphic computing with an image recognition accuracy above 92%. Finally, the self-rectifying behavior and device-to-device variation reliability are confirmed in a 9 × 9 crossbar array structure.

Dysbiotic signatures and diagnostic potential of gut microbial markers for inflammatory bowel disease in Korean population.

Fecal samples were collected from 640 individuals in Korea, including 523 patients with IBD (223 with Crohn's disease [CD] and 300 with ulcerative colitis [UC]) and 117 healthy controls. The samples were subjected to cross-sectional gut metagenomic analysis using 16 S rRNA sequencing and bioinformatics analysis. Patients with IBD, particularly those with CD, exhibited significantly lower alpha diversities than the healthy subjects. Differential abundance analysis revealed dysbiotic signatures, characterized by an expansion of the genus Escherichia-Shigella in patients with CD. Functional annotations showed that functional pathways related to bacterial pathogenesis and production of hydrogen sulfide (H2S) were strongly upregulated in patients with CD. A dysbiosis score, calculated based on functional characteristics, highly correlated with disease severity. Markers distinguishing between healthy subjects and patients with IBD showed accurate classification based on a small number of microbial taxa, which may be used to diagnose ambiguous cases. These findings confirm the taxonomic and functional dysbiosis of the gut microbiota in patients with IBD, especially those with CD. Taxa indicative of dysbiosis may have significant implications for future clinical research on the management and diagnosis of IBD.

Cumulative impact of hypotension during intermittent hemodialysis on kidney recovery in critically ill patients with AKI-D.

BACKGROUND: Intermittent hemodialysis (IHD) is commonly implemented in patients with AKI-D, irrespective of the initial kidney replacement therapy (KRT) modality. However, concerns remain regarding the hemodynamic instability during IHD. This study aimed to assess the association between hypotensive episodes during IHD and kidney recovery in AKI-D patients. METHODS: We retrospectively enrolled AKI-D survivors who received IHD in the intensive care units of a tertiary care hospital in Korea from January 2018 to February 2024. RESULTS: A total of 1791 IHD sessions from 209 AKI-D survivors were analyzed. The patients underwent a median of 7 IHD sessions (interquartile range [IQR] 3-11), with an incidence of intradialytic hypotension (IDH) of 16.8 % per patient. Of these, 43.1 % were dialysis-dependent at hospital discharge. The number of IDH was a significant predictor of dialysis dependence (odds ratio [OR] 1.56; 95 % confidence interval [CI] 1.16-2.22). Patients experiencing ≥3 IDH episodes had a substantially higher risk of dialysis dependence compared to those without IDH (OR 9.41; 95 % CI 2.41-41.69). In per-session analysis, the target ultrafiltration rate was identified as an independent risk factor for IDH occurrence. CONCLUSIONS: Our study revealed that IHD-related hypotension during hospitalization has a cumulative negative impact on kidney recovery in AKI-D survivors.

Abrupt increase in Arctic-Subarctic wildfires caused by future permafrost thaw.

Unabated 21st-century climate change will accelerate Arctic-Subarctic permafrost thaw which can intensify microbial degradation of carbon-rich soils, methane emissions, and global warming. The impact of permafrost thaw on future Arctic-Subarctic wildfires and the associated release of greenhouse gases and aerosols is less well understood. Here we present a comprehensive analysis of the effect of future permafrost thaw on land surface processes in the Arctic-Subarctic region using the CESM2 large ensemble forced by the SSP3-7.0 greenhouse gas emission scenario. Analyzing 50 greenhouse warming simulations, which capture the coupling between permafrost, hydrology, and atmosphere, we find that projected rapid permafrost thaw leads to massive soil drying, surface warming, and reduction of relative humidity over the Arctic-Subarctic region. These combined processes lead to nonlinear late-21st-century regime shifts in the coupled soil-hydrology system and rapid intensification of wildfires in western Siberia and Canada.

Identification of acrolein as a novel diagnostic odor biomarker for 1,2,3-trichloropropane-induced hepatotoxicity in Sprague Dawley rats.

Body odor is considered a diagnostic indicator of various infectious and chronic diseases. But, few studies have examined the odor markers for various toxic effects in the mammalian system. This study attempted to identify the novel diagnostic odor biomarkers for chemical-induced hepatotoxicity in animals. The changes in the concentration of odors were analyzed in the urine of Sprague Dawley (SD) rats treated with two dosages (100 or 200 mg/kg) of 1,2,3-trichloropropane (TCP) using gas chromatography-mass spectrometry (GC-MS). The TCP treatment induced significant toxicity, including a decrease in body weight, an increase in serum biochemical factors, and histopathological changes in the liver of SD rats. During this hepatotoxicity, the concentrations of six odors (ethyl alcohol, acrolein (2-propenal), methanesulfonyl chloride, methyl ethyl ketone, cyclotrisiloxane, and 2-heptanone) in urine changed significantly after the TCP treatment. Among them, acrolein, an acrid and pungent compound, showed the highest rate of increase in the TCP-treated group compared to the Vehicle-treated group. In addition, this increase in acrolein was accompanied by enhanced spermine oxidase (SMOX) expression, an acrolein metabolic enzyme, and the increased level of IL-6 transcription as a regulator factor that induces SMOX production. The correlation between acrolein and other parameters was conformed using correlagram analyses. These results provide scientific evidence that acrolein have potential as a novel diagnostic odor biomarker for TCP-induced hepatotoxicity. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-024-00253-0.

Novel Role of the ALPI Gene Associated with Constipation Caused by Complement Component 3 Deficiency.

Complement component 3 (C3) deficiency has recently been reported as one of the novel causes of constipation. To identify a unique gene specific to constipation caused by C3 deficiency, the total RNA extracted from the mid colon of C3 knockout (C3 KO) mice was hybridized to oligonucleotide microarrays, and the function of the candidate gene was verified in in vitro and in vivo models. C3 KO mice used for microarrays showed definite phenotypes of constipation. Overall, compared to the wild type (WT), 1237 genes were upregulated, and 1292 genes were downregulated in the C3 KO mice. Of these, the major genes included were lysine (K)-specific demethylase 5D (KDM5D), olfactory receptor 870 (Olfr870), pancreatic lipase (PNLIP), and alkaline phosphatase intestinal (ALPI). Specifically, the ALPI gene was selected as a novel gene candidate based on alterations during loperamide (Lop)-induced constipation and intestinal bowel disease (IBD). The upregulation of ALPI expression treated with acetate recovered the expression level of mucin-related genes in primary epithelial cells of C3 KO mice as well as most phenotypes of constipation in C3 KO mice. These results indicate that ALPI plays an important role as the novel gene associated with C3 deficiency-induced constipation.

Enhancing Wound Healing and Anti-Inflammatory Effects by Combination of CIGB-258 and Apolipoprotein A-I against Carboxymethyllysine Toxicity in Zebrafish: Insights into Structural Stabilization and Antioxidant Properties.

CIGB-258 is known to exert anti-inflammatory activity via structural stabilization of apolipoprotein A-I (apoA-I) and functional enhancement of high-density lipoproteins (HDL) against acute toxicity of carboxymethyllysine (CML). The co-presence of CIGB-258 in reconstituted HDL (rHDL) formed larger rHDL particles and enhanced anti-inflammatory activity in a dose-dependent manner of apoA-I:CIGB-258, 1:0, 1:0.1, 1:0.5, and 1:1 of molar ratio, in the synthesis of the rHDL. However, no study has evaluated the enhancement of HDL functionality by the co-presence of lipid-free apoA-I and CIGB-258. The present study was therefore designed to compare the structural stabilization and functional improvement of HDL in the presence of lipid-free apoA-I and CIGB-258 in molar ratios of 1:0, 1:0.1, 1:0.5, and 1:1 within both HDL2 and HDL3. As the concentration of CIGB-258 increased, it effectively inhibited the cupric-ion-induced oxidation of HDL, thereby safeguarding apoA-I from proteolytic degradation. Additionally, the wound-healing activity of zebrafish was significantly (p < 0.01) enhanced by the co-addition of apoA-I:CIGB-258 (1:1) up to 1.6-fold higher than apoA-I alone (1:0) under the presence of CML. ApoA-I:CIGB-258 (1:1) treatment exhibited the lowest apoptosis and production of reactive oxygen species against CML-induced damage in the wound site. Also, an increase in wounded tissue granulation and epidermis thickness was observed with increasing concentration of CIGB-258 during 48 h post-treatment via the healing process. Intraperitoneal injection of apoA-I:CIGB-258 mixture remarkably ameliorated the acute paralysis and restored zebrafish swimming ability impaired by the acute toxicity of CML. The increase of CIGB-258 content, especially co-injection of apoA-I:CIGB-258 (1:1), leads to a significant 2.3-fold (p < 0.001) and 4.1-fold (p < 0.001) higher zebrafish survivability and recovery of swimming ability, respectively, than those of CML-control. In the apoA-I:CIGB-258 (1:1) group, neutrophil infiltration and interleukin (IL)-6 production was lowest in the hepatic tissue with the least cellular damage and apoptosis. Additionally, the group treated with apoA-I:CIGB-258 (1:1) demonstrated the lowest plasma levels of total cholesterol (TC) and triglycerides (TG), along with minimal damage to the kidney, ovary, and testicular cells. Conclusively, co-treatment of CIGB-258 with apoA-I effectively mitigated acute inflammation in zebrafish, safeguarded vital organs, structurally stabilized apoA-I, and enhanced HDL functionality.

Novel Therapeutic Effects of Euphorbia heterophylla L. Methanol Extracts in Macular Degeneration Caused by Blue Light in A2E-Laden ARPE-19 Cells and Retina of BALB/c Mice.

Natural products with high antioxidant activity are considered as innovative prevention strategies to effectively prevent age-related macular degeneration (AMD) in the early stage because the generation of reactive oxygen species (ROS) leading to the development of drusen is reported as an important cause of this disease. To investigate the prevention effects of the methanol extracts of Euphorbia heterophylla L. (MEE) on AMD, its effects on the antioxidant activity, inflammatory response, apoptosis pathway, neovascularization, and retinal tissue degeneration were analyzed in N-retinylidene-N-retinylethanolamine (A2E)-landed spontaneously arising retinal pigment epithelia (ARPE)-19 cells and BALB/c mice after exposure to blue light (BL). The MEE contained 10 active components and showed high free radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and nitric oxide (NO) radicals. The pretreatments of high-dose MEE remarkably suppressed the production of intracellular ROS (88.2%) and NO (25.2%) and enhanced (SOD) activity (84%) and the phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2) in A2E + BL-treated ARPE-19 cells compared to Vehicle-treated group. The activation of the inducible nitric oxide synthase (iNOS)-induced cyclooxygenase-2 (COX-2) mediated pathway, inflammasome activation, and expression of inflammatory cytokines was significantly inhibited in A2E + BL-treated ARPE-19 cells after the MEE pretreatment. The activation of the apoptosis pathway and increased expression of neovascular proteins (36% for matrix metalloproteinase (MMP)-9) were inhibited in the MEE pretreated groups compared to the Vehicle-treated group. Furthermore, the thickness of the whole retina (31%), outer nuclear layer (ONL), inner nuclear layer (INL), and photoreceptor layer (PL) were significantly increased by the MEE pretreatment of BALB/c mice with BL-induced retinal degeneration. Therefore, these results suggest that the MEE, with its high antioxidative activity, protects against BL-induced retinal degeneration through the regulation of the antioxidative system, inflammatory response, apoptosis, and neovascularization in the AMD mouse model.

Comparative Assessment of Beeswax Alcohol and Coenzyme Q10 (CoQ10) to Prevent Liver Aging, Organ Damage, and Oxidative Stress in Hyperlipidemic Zebrafish Exposed to D-Galactose: A 12-Week Dietary Intervention.

The current study was designed to compare in vivo efficacy between beeswax alcohol (BWA) and coenzyme Q10 (CoQ10) to treat fatty liver changes, oxidative stress, and damages in major organs of zebrafish by 12 weeks with high-cholesterol (HC) and galactose (Gal) supplementation. At week 12, the HC control and HC+Gal control groups showed 96% and 92% survivability, respectively, while co-supplementation of the 0.5% BWA and 1.0% BWA groups exhibited 96% and 100% survivability. However, co-supplementation of the 0.5% CoQ10 and 1.0% CoQ10 groups revealed the lowest survivability, around 92% and 89%, respectively. The 0.5% BWA and 1.0% BWA groups showed 21% (p < 0.001) and 41% (p < 0.001), respectively, lower total cholesterol (TC) than the HC+Gal control, while the 1.0% CoQ10 group showed only 15% lower TC than the control. Interestingly, the 0.5% BWA and 1.0% BWA groups showed 22% (p < 0.001) and 38% (p < 0.001), respectively, lower triglyceride (TG) than the HC+Gal control. However, both the 0.5% CoQ10 and 1.0% CoQ10 groups showed similar TG levels as the control, suggesting that CoQ10 supplementation had no effect on lowering serum TG. The 1.0% BWA group showed the highest plasma HDL-C and HDL-C/TC (%) up to 3.2-fold and 5.5-fold, respectively, higher than those of the HC+Gal control, while the 1.0% CoQ10 group showed 2.4-fold and 2.8-fold higher plasma HDL-C and HDL-C/TC (%), respectively, than the control. The plasma aspartate transaminase (AST) and alanine transaminase (ALT) levels were lowest in the 1.0% BWA group, 51% and 72%, respectively, lower than HC+Gal control, suggesting the lowest extent of hepatic damage. In hepatic tissue, neutrophil infiltration and interleukin (IL)-6 production were the lowest in the 1.0% BWA group, around 67% and 85%, respectively, lower than the HC+Gal control. Fatty liver change, cellular apoptosis, and cell senescence in hepatic tissue were remarkably lowered in the 1.0% BWA group, while the CoQ10 group showed much less effect than the BWA group. In kidney, ovary, and testis tissue, the 1.0% BWA group showed the lowest production of reactive oxygen species, the extent of cellular senescence, and cellular apoptosis with the healthiest cell morphology. In conclusion, supplementation of BWA remarkably protected the liver, kidney, ovary, and testis from oxidative damage by cholesterol and galactose consumption, with the least serum AST and ALT levels, inflammatory parameters, and senescence markers.

Histopathological correlations of CT-based radiomics imaging biomarkers in native kidney biopsy.

BACKGROUND: Kidney biopsy is the standard of care for the diagnosis of various kidney diseases. In particular, chronic histopathologic lesions, such as interstitial fibrosis and tubular atrophy, can provide prognostic information regarding chronic kidney disease progression. In this study, we aimed to evaluate historadiological correlations between CT-based radiomic features and chronic histologic changes in native kidney biopsies and to construct and validate a radiomics-based prediction model for chronicity grade. METHODS: We included patients aged ≥ 18 years who underwent kidney biopsy and abdominal CT scan within a week before kidney biopsy. Left kidneys were three-dimensionally segmented using a deep learning model based on the 3D Swin UNEt Transformers architecture. We additionally defined isovolumic cortical regions of interest near the lower pole of the left kidneys. Shape, first-order, and high-order texture features were extracted after resampling and kernel normalization. Correlations and diagnostic metrics between extracted features and chronic histologic lesions were examined. A machine learning-based radiomic prediction model for moderate chronicity was developed and compared according to the segmented regions of interest (ROI). RESULTS: Overall, moderate correlations with statistical significance (P < 0.05) were found between chronic histopathologic grade and top-ranked radiomic features. Total parenchymal features were more strongly correlated than cortical ROI features, and texture features were more highly ranked. However, conventional imaging markers, including kidney length, were poorly correlated. Top-ranked individual radiomic features had areas under receiver operating characteristic curves (AUCs) of 0.65 to 0.74. Developed radiomics models for moderate-to-severe chronicity achieved AUCs of 0.89 (95% confidence interval [CI] 0.75-0.99) and 0.74 (95% CI 0.52-0.93) for total parenchymal and cortical ROI features, respectively. CONCLUSION: Significant historadiological correlations were identified between CT-based radiomic features and chronic histologic changes in native kidney biopsies. Our findings underscore the potential of CT-based radiomic features and their prediction model for the non-invasive assessment of kidney fibrosis.

Integrating, Validating, and Expanding Information Space in Single-Molecule Surface-Enhanced Raman Spectroscopy for Biomolecules.

Single-molecule surface-enhanced Raman spectroscopy (SM-SERS) is an ultrahigh-resolution spectroscopic method for directly obtaining the complex vibrational mode information on individual molecules. SM-SERS offers a wide range of submolecular information on the hidden heterogeneity in its functional groups and varying structures, dynamics of conformational changes, binding and reaction kinetics, and interactions with the neighboring molecule and environment. Despite the richness in information on individual molecules and potential of SM-SERS in various detection targets, including large and complex biomolecules, several issues and practical considerations remain to be addressed, such as the requirement of long integration time, challenges in forming reliable and controllable interfaces between nanostructures and biomolecules, difficulty in determining hotspot size and shape, and most importantly, insufficient signal reproducibility and stability. Moreover, utilizing and interpreting SERS spectra is challenging, mainly because of the complexity and dynamic nature of molecular fingerprint Raman spectra, and this leads to fragmentary analysis and incomplete understanding of the spectra. In this Perspective, we discuss the current challenges and future opportunities of SM-SERS in views of system approaches by integrating molecules of interest, Raman dyes, plasmonic nanostructures, and artificial intelligence, particularly for detecting and analyzing biomolecules to realize the validation and expansion of information space in SM-SERS.

Reciprocal regulation of oxidative stress and mitochondrial fission augments parvalbumin downregulation through CDK5-DRP1- and GPx1-NF-κB signaling pathways.

Loss of parvalbumin (PV) expressing neurons (PV neurons) is relevant to the underlying mechanisms of the pathogenesis of neurological and psychiatric diseases associated with the dysregulation of neuronal excitatory networks and brain metabolism. Although PV modulates mitochondrial morphology, volume and dynamics, it is largely unknown whether mitochondrial dynamics affect PV expression and what the molecular events are responsible for PV neuronal degeneration. In the present study, L-buthionine sulfoximine (BSO, an inhibitor of glutathione synthesis) did not degenerate PV neurons under physiological condition. However, BSO-induced oxidative stress decreased PV expression and facilitated cyclin-dependent kinase 5 (CDK5) tyrosine (Y) 15 phosphorylation, dynamin-related protein 1 (DRP1)-mediated mitochondrial fission and glutathione peroxidase-1 (GPx1) downregulation in PV neurons. Co-treatment of roscovitine (a CDK5 inhibitor) or mitochondrial division inhibitor-1 (Mdivi-1, an inhibitor of mitochondrial fission) attenuated BSO-induced PV downregulation. WY14643 (an inducer of mitochondrial fission) reduced PV expression without affecting CDK5 Y15 phosphorylation. Following status epilepticus (SE), CDK5 Y15 phosphorylation and mitochondrial fission were augmented in PV neurons. These were accompanied by reduced GPx1-mediated inhibition of NF-κB p65 serine (S) 536 phosphorylation. N-acetylcysteine (NAC), roscovitine and Mdivi-1 ameliorated SE-induced PV neuronal degeneration by mitigating CDK5 Y15 hyperphosphorylation, aberrant mitochondrial fragmentation and reduced GPx1-mediated NF-κB inhibition. Furthermore, SN50 (a NF-κB inhibitor) alleviated SE-induced PV neuronal degeneration, independent of dysregulation of mitochondrial fission, CDK5 hyperactivation and GPx1 downregulation. These findings provide an evidence that oxidative stress may activate CDK5-DRP1- and GPx1-NF-κB-mediated signaling pathways, which would be possible therapeutic targets for preservation of PV neurons in various diseases.

Leveraging volatile memristors in neuromorphic computing: from materials to system implementation.

Inspired by the functions of biological neural networks, volatile memristors are essential for implementing neuromorphic computing. These devices enable large-scale and energy-efficient data processing by emulating neural functionalities through dynamic resistance changes. The threshold switching characteristics of volatile memristors, which are driven by various mechanisms in materials ranging from oxides to chalcogenides, make them versatile and suitable for neuromorphic computing systems. Understanding these mechanisms and selecting appropriate devices for specific applications are crucial for optimizing the performance. However, the existing literature lacks a comprehensive review of switching mechanisms, their compatibility with different applications, and a deeper exploration of the spatiotemporal processing capabilities and inherent stochasticity of volatile memristors. This review begins with a detailed analysis of the operational principles and material characteristics of volatile memristors. Their diverse applications are then explored, emphasizing their role in crossbar arrays, artificial receptors, and neurons. Furthermore, the potential of volatile memristors in artificial inference systems and reservoir computing is discussed, due to their spatiotemporal processing capabilities. Hardware security applications and probabilistic computing are also examined, where the inherent stochasticity of the devices can improve the system robustness and adaptability. To conclude, the suitability of different switching mechanisms for various applications is evaluated, and future perspectives for the development and implementation of volatile memristors are presented. This review aims to fill the gaps in existing research and highlight the potential of volatile memristors to drive innovation in neuromorphic computing, paving the way for more efficient and powerful computational paradigms.

GPx1-ERK1/2-CREB pathway regulates the distinct vulnerability of hippocampal neurons to oxidative stress via modulating mitochondrial dynamics following status epilepticus.

Glutathione peroxidase-1 (GPx1) and cAMP/Ca2+ responsive element (CRE)-binding protein (CREB) regulate neuronal viability by maintaining the redox homeostasis. Since GPx1 and CREB reciprocally regulate each other, it is likely that GPx1-CREB interaction may play a neuroprotective role against oxidative stress, which are largely unknown. Thus, we investigated the underlying mechanisms of the reciprocal regulation between GPx1 and CREB in the male rat hippocampus. Under physiological condition, L-buthionine sulfoximine (BSO)-induced oxidative stress increased GPx1 expression, extracellular signal-regulated kinase 1/2 (ERK1/2) activity and CREB serine (S) 133 phosphorylation in CA1 neurons, but not dentate granule cells (DGC), which were diminished by GPx1 siRNA, U0126 or CREB knockdown. GPx1 knockdown inhibited ERK1/2 and CREB activations induced by BSO. CREB knockdown also decreased the efficacy of BSO on ERK1/2 activation. BSO facilitated dynamin-related protein 1 (DRP1)-mediated mitochondrial fission in CA1 neurons, which abrogated by GPx1 knockdown and U0126. CREB knockdown blunted BSO-induced DRP1 upregulation without affecting DRP1 S616 phosphorylation ratio. Following status epilepticus (SE), GPx1 expression was reduced in CA1 neurons and DGC. SE also decreased CREB activity CA1 neurons, but not DGC. SE degenerated CA1 neurons, but not DGC, accompanied by mitochondrial elongation. These post-SE events were ameliorated by N-acetylcysteine (NAC, an antioxidant), but deteriorated by GPx1 knockdown. These findings indicate that a transient GPx1-ERK1/2-CREB activation may be a defense mechanism to protect hippocampal neurons against oxidative stress via maintenance of proper mitochondrial dynamics.

Histologic improvement predicts endoscopic remission in patients with ulcerative colitis.

Limited research has been performed to determine if histologic improvement serves as a prognosticator for endoscopic remission, a key therapeutic target for ulcerative colitis (UC). The primary aim of the study was to evaluate if histological activity could predict endoscopic remission in UC patients with Mayo endoscopic subscores (MES) of 0 or 1. In addition, we compared the clinical outcomes between histologic improvement group and active group. This research encompassed 492 individuals with UC with MES of 0 or 1, who underwent histological assessment as per the established protocol of Samsung Medical Center between January 2018 and December 2020. Participants were categorized into two cohorts based on the degree of histological activity: those showing histologic improvement and those with ongoing histologic activity. The endoscopic activity was assessed during follow-up, and the primary outcome was endoscopic remission according to histologic activity. Out of the total participants, endoscopic activity was scrutinized in 435 patients during the colonoscopic follow-up and in 146 during the subsequent one. The histologic improvement group at the index colonoscopy was more likely achieve endoscopic remission than the histologic active group. Clinical relapse was more likely in the histologic active group than in the histologic improvement group.

Comparison of the In Vivo Efficacy of Cuban (Raydel®) and Chinese (BOC Science) Policosanol in Alleviating Dyslipidemia and Inflammation via Safeguarding Major Organs and Reproductive Health in Hyperlipidemic Zebrafish: A Twelve-Week Consumption Study.

Policosanol is a blend of long-chain aliphatic alcohols (LCAAs) and is well-known for several health-beneficial activities; however, the functionality of policosanol varied substantially based on the composition of LCAAs. In this study, two distinct policosanols, Raydel® (extracted from Cuban sugarcane wax) and BOC Sciences (extracted from Chinese sugarcane wax), were dietarily supplemented (0.1% w/w) for 12 weeks in hyperlipidemic zebrafish to examine their influence on the blood lipid profile and functionality of the liver, kidney, and reproductive organs. The results demonstrated a noteworthy impact of both policosanols on preventing high-cholesterol diet (HCD, 4% w/w)-induced dyslipidemia by decreasing total cholesterol (TC) and triglyceride (TG) levels in the plasma. However, compared to BOC Sciences, the Raydel® policosanol exhibited a significantly (p < 0.05) higher efficacy in reducing HCD-induced TC and TG levels. A substantial effect was observed exclusively with the Raydel® policosanol in mitigating HCD-impaired low-density-lipoprotein cholesterol (LDL-C) and high-density-lipoprotein cholesterol (HDL-C) levels. Hepatic histology and immunohistochemistry (IHC) analysis revealed the higher efficacy of Raydel® policosanol over BOC Sciences policosanol to prevent HCD-provoked fatty liver changes, cellular senescence, oxidative stress, and interleukin (IL)-6 production. Consistently, a significantly higher effect of Raydel® over BOC Sciences policosanol was observed on the protection of kidney, testis, and ovary morphology hampered by HCD consumption. In addition, Raydel® policosanol exhibited a notably stronger effect (~2-fold, p < 0.05) on the egg-laying ability of the zebrafish compared to policosanol from BOC Sciences. Furthermore, Raydel® policosanol plays a crucial role in improving embryo viability and mitigating developmental defects caused by the intake of an HCD. Conclusively, Raydel® policosanol displayed a substantially higher efficacy over BOC Sciences policosanol to revert HCD-induced dyslipidemia, the functionality of vital organs, and the reproductive health of zebrafish.

The degree of respiratory depression according to the effect-site concentration in remimazolam target-controlled infusion: A randomised controlled trial.

BACKGROUND: Remimazolam is not only associated with a lower incidence of respiratory depression than propofol but also in itself has the risk of respiratory depression. OBJECTIVE: We investigated respiratory depression following remimazolam infusion, targeting different effect-site concentrations using target-controlled infusion. DESIGN: A prospective, double-blind, randomised controlled study. SETTING: Tertiary hospital, Suwon, South Korea, from April 2022 to November 2022. PARTICIPANTS: One hundred and seven patients scheduled for general anaesthesia were randomised into three groups targeting remimazolam effect-site concentrations of 500 (RMZ-500) ( n  = 36), 1000 (RMZ-1000) ( n  = 35) and 1500 ng ml -1 (RMZ-1500) ( n  = 36). INTERVENTIONS: Remimazolam was solely infused for 10 min according to target effect-site concentrations. According to the degree of SpO 2 decrease, oxygen desaturations were managed with the following respiratory supports: jaw-thrust for SpO 2 less than 97%, 100% oxygen delivery for SpO 2 less than 93% and assisted ventilation for SpO 2 less than 90%. MAIN OUTCOME MEASURES: The incidence of each respiratory support, along with respiratory variables (at baseline, 5 min and 10 min after remimazolam infusion) and loss of consciousness were observed for 10 min after remimazolam target-controlled infusion. RESULTS: Both RMZ-1000 and RMZ-1500 required more frequent respiratory support than RMZ-500 (both P  < 0.001), with nearly identical frequencies between RMZ-1000 and RMZ-1500. In terms of respiratory support, the incidence of assisted ventilation was significantly lower in RMZ-500 (2.8%) than RMZ-1000 (48.6%) and RMZ-1500 (50%) ( P  < 0.001). RMZ-1000 and RMZ-1500 achieved loss of consciousness in all patients; RMZ-500 only achieved loss of consciousness in 86.1% of patients ( P  = 0.010). In patients who maintained spontaneous respiration, tidal volume decreased by 41 to 48% and respiratory rate increased by 118 to 158% at 5 and 10 min, significantly compared to baseline in all groups ( P  < 0.001). CONCLUSIONS: Remimazolam infusion, like that of other benzodiazepines, led to respiratory depression, which was more prominent at higher target effect-site concentrations. Therefore, appropriate countermeasures should be developed to prevent oxygen desaturation. TRIAL REGISTRATION: CRIS ( https://cris.nih.go.kr ), identifier: KCT0006952.

Analgesic Effect of SKI306X on Chronic Postischemic Pain and Spinal Nerve Ligation-Induced Neuropathic Pain in Mice.

Neuropathic pain (NP) results from lesions or diseases affecting the peripheral or central somatosensory system. However, there are currently no drugs that are particularly effective in treating this condition. SKI306X is a blend of purified extracts of three oriental herbs (Clematis mandshurica, Trichosanthes kirilowii, and Prunella vulgaris) commonly used to treat osteoarthritis for their chondroprotective effects. Chronic postischemic pain (CPIP) and spinal nerve ligation (SNL) models were created by binding the upper left ankle of mice with an O-ring for 3 h and ligating the L5 spinal nerve, respectively. Mice with allodynia were injected intraperitoneally with 0.9% normal saline (NS group) or different doses (25, 50, or 100 mg/kg) of SKI306X (SKI groups). We assessed allodynia using von Frey filaments before injection and 30, 60, 90, 120, 180, and 240 min and 24 h after injection to confirm the antiallodynic effect of SKI306X. We also measured glial fibrillary acidic protein (GFAP) levels in the spinal cord and dorsal root ganglia to confirm the change of SKI306X administration. Both models exhibited significant mechanical allodynia. The intraperitoneal injection of SKI306X significantly increased the paw withdrawal threshold in a dose-dependent manner, as the paw withdrawal threshold was significantly increased after SKI306X administration compared with at baseline or after NS administration. GFAP levels in the SKI group decreased significantly (p < 0.05). Intraperitoneal administration of SKI306X dose-dependently attenuated mechanical allodynia and decreased GFAP levels, suggesting that GFAP is involved in the antiallodynic effect of SKI306X in mice with CPIP and SNL-induced NP.