Lactobacillus acidophilus KBL409 protects against kidney injury via improving mitochondrial function with chronic kidney disease.

PURPOSE: Recent advances have led to greater recognition of the role of mitochondrial dysfunction in the pathogenesis of chronic kidney disease (CKD). There has been evidence that CKD is also associated with dysbiosis. Here, we aimed to evaluate whether probiotic supplements can have protective effects against kidney injury via improving mitochondrial function. METHODS: An animal model of CKD was induced by feeding C57BL/6 mice a diet containing 0.2% adenine. KBL409, a strain of Lactobacillus acidophilus, was administered via oral gavage at a dose of 1 × 109 CFU daily. To clarify the underlying mechanisms by which probiotics exert protective effects on mitochondria in CKD, primary mouse tubular epithelial cells stimulated with TGF-ß and p-cresyl sulfate were administered with butyrate. RESULTS: In CKD mice, PGC-1α and AMPK, key mitochondrial energy metabolism regulators, were down-regulated. In addition, mitochondrial dynamics shifted toward fission, the number of fragmented cristae increased, and mitochondrial mass decreased. These alterations were restored by KBL409 administration. KBL409 supplementation also improved defects in fatty acid oxidation and glycolysis and restored the suppressed enzyme levels involved in TCA cycle. Accordingly, there was a concomitant improvement in mitochondrial respiration and ATP production assessed by mitochondrial function assay. These favorable effects of KBL409 on mitochondria ultimately decreased kidney fibrosis in CKD mice. In vitro analyses with butyrate recapitulated the findings of animal study. CONCLUSIONS: This study demonstrates that administration of the probiotic Lactobacillus acidophilus KBL409 protects against kidney injury via improving mitochondrial function.

Severus: accurate detection and characterization of somatic structural variation in tumor genomes using long reads.

Most current studies rely on short-read sequencing to detect somatic structural variation (SV) in cancer genomes. Long-read sequencing offers the advantage of better mappability and long-range phasing, which results in substantial improvements in germline SV detection. However, current long-read SV detection methods do not generalize well to the analysis of somatic SVs in tumor genomes with complex rearrangements, heterogeneity, and aneuploidy. Here, we present Severus: a method for the accurate detection of different types of somatic SVs using a phased breakpoint graph approach. To benchmark various short- and long-read SV detection methods, we sequenced five tumor/normal cell line pairs with Illumina, Nanopore, and PacBio sequencing platforms; on this benchmark Severus showed the highest F1 scores (harmonic mean of the precision and recall) as compared to long-read and short-read methods. We then applied Severus to three clinical cases of pediatric cancer, demonstrating concordance with known genetic findings as well as revealing clinically relevant cryptic rearrangements missed by standard genomic panels.

Phased nanopore assembly with Shasta and modular graph phasing with GFAse.

Reference-free genome phasing is vital for understanding allele inheritance and the impact of single-molecule DNA variation on phenotypes. To achieve thorough phasing across homozygous or repetitive regions of the genome, long-read sequencing technologies are often used to perform phased de novo assembly. As a step toward reducing the cost and complexity of this type of analysis, we describe new methods for accurately phasing Oxford Nanopore Technologies (ONT) sequence data with the Shasta genome assembler and a modular tool for extending phasing to the chromosome scale called GFAse. We test using new variants of ONT PromethION sequencing, including those using proximity ligation, and show that newer, higher accuracy ONT reads substantially improve assembly quality.

Nanonization and Deformable Behavior of Fattigated Peptide Drug in Mucoadhesive Buccal Films.

This study was tasked with the design of mucoadhesive buccal films (MBFs) containing a peptide drug, leuprolide (LEU), or its diverse nanoparticles (NPs), for enhanced membrane permeability via self-assembled nanonization and deformable behavior. An LEU-oleic acid conjugate (LOC) and its self-assembled NPs (LON) were developed. Additionally, a deformable variant of LON (d-LON) was originally developed by incorporating l-α-phosphatidylcholine into LON as an edge activator. The physicochemical properties of LON and d-LON, encompassing particle size, zeta potential, and deformability index (DI), were evaluated. MBFs containing LEU, LOC, and NPs (LON, d-LON) were prepared using the solvent casting method by varying the ratio of Eudragit RLPO and hydroxypropyl methylcellulose, with propylene glycol used as a plasticizer. The optimization of MBF formulations was based on their physicochemical properties, including in vitro residence time, dissolution, and permeability. The dissolution results demonstrated that the conjugation of oleic acid to LEU exhibited a more sustained LEU release pattern by cleaving the ester bond of the conjugate, as compared to the native LEU, with reduced variability. Moreover, the LOC and its self-assembled NPs (LON, d-LON), equivalent to 1 mg LEU doses in MBF, exhibited an amorphous state and demonstrated better permeability through the nanonization process than LEU alone, regardless of membrane types. The incorporation of lauroyl-L-carnitine into the films as a permeation enhancer synergistically augmented drug permeability. Most importantly, the d-LON-loaded buccal films showed the highest permeability, due to the deformability of NPs. Overall, MBF-containing peptide NPs and permeation enhancers have the potential to replace parenteral LEU administration by improving LEU druggability and patient compliance.

Gapless assembly of complete human and plant chromosomes using only nanopore sequencing.

The combination of ultra-long Oxford Nanopore (ONT) sequencing reads with long, accurate PacBio HiFi reads has enabled the completion of a human genome and spurred similar efforts to complete the genomes of many other species. However, this approach for complete, "telomere-to-telomere" genome assembly relies on multiple sequencing platforms, limiting its accessibility. ONT "Duplex" sequencing reads, where both strands of the DNA are read to improve quality, promise high per-base accuracy. To evaluate this new data type, we generated ONT Duplex data for three widely-studied genomes: human HG002, Solanum lycopersicum Heinz 1706 (tomato), and Zea mays B73 (maize). For the diploid, heterozygous HG002 genome, we also used "Pore-C" chromatin contact mapping to completely phase the haplotypes. We found the accuracy of Duplex data to be similar to HiFi sequencing, but with read lengths tens of kilobases longer, and the Pore-C data to be compatible with existing diploid assembly algorithms. This combination of read length and accuracy enables the construction of a high-quality initial assembly, which can then be further resolved using the ultra-long reads, and finally phased into chromosome-scale haplotypes with Pore-C. The resulting assemblies have a base accuracy exceeding 99.999% (Q50) and near-perfect continuity, with most chromosomes assembled as single contigs. We conclude that ONT sequencing is a viable alternative to HiFi sequencing for de novo genome assembly, and has the potential to provide a single-instrument solution for the reconstruction of complete genomes.

Nectar Characteristics and Honey Production Potential of Five Rapeseed Cultivars and Two Wildflower Species in South Korea.

The growing beekeeping industry in South Korea has led to the establishment of new honey plant complexes. However, studies on honey production from each species are limited. This study aimed to assess the honey production potential of various Brassica napus cultivars and two wildflower species. The nectar characteristics of B. napus varied significantly among the cultivars. Absolute sugar concentrations differed among the cultivars, but sugar composition ratios were similar. In contrast, the amino acid content remained relatively uniform regarding percentage values, irrespective of the absolute concentrations. Estimations of honey potential production per hectare (kg/ha) resulted in the following ranking among cultivars: 'JM7003' (107.1) > 'YS' (73.0) > 'JM7001' (63.7) > 'TL' (52.7) > 'TM' (42.4). The nectar volume of Pseudolysimachion rotundum var. subintegrum and Leonurus japonicus increased during the flowering stage. P. rotundum var. subintegrum was sucrose-rich and L. japonicus was sucrose-dominant. Both species predominantly contained phenylalanine, P. rotundum var. subintegrum had glutamine as the second most abundant amino acid, and L. japonicus had tyrosine. The honey production potential was 152.4 kg/ha for P. rotundum var. subintegrum and 151.3 kg/ha for L. japonicus. These findings provide a basis for identifying food resources for pollinators and selecting plant species to establish honey plant complexes.

A 25-Year-Old Military Recruit with Isolated Myositis Following Routine Chemoprophylaxis with Intramuscular Benzathine Penicillin G.

BACKGROUND Myositis is an inflammatory myopathy that can be caused by a variety of drugs, diseases, and toxins. The U.S. military uses chemoprophylaxis with intramuscular penicillin G to prevent group A streptococcal infection. We present a case of penicillin G-induced myositis, a rare cause of drug-induced myositis with limited discussion in the medical literature. CASE REPORT A 25-year-old man with no pertinent medical history presented to the Emergency Department with right hip and leg pain after receiving a single dose of intramuscular penicillin G as part of standard prophylaxis for group A streptococcal infection during basic military training. He reported pain and leg weakness that was exacerbated by physical exertion and weight bearing but had no systemic symptoms, such as fevers or chills. Initial radiographs of the hip were normal; however, subsequent magnetic resonance imaging of the hip revealed intramuscular edema and features consistent with myositis of the right proximal thigh and hip musculature. He was admitted for isolated right gluteal myositis, attributed to his preceding local penicillin injection. He recovered with symptomatic care over the following 2 weeks, with return to baseline function. CONCLUSIONS This case highlights a rare complication of intramuscular penicillin G as a cause of acute isolated myositis. It serves to inform physicians of this rare complication and to recommend the consideration of intramuscular penicillin G as a causative etiology in individuals presenting with myositis and recent penicillin G exposure.

Analogous Design of a Microlayered Silicon Oxide-Based Electrode to the General Electrode Structure for Thin-Film Lithium-Ion Batteries.

Development of miniaturized thin-film lithium-ion batteries (TF-LIBs) using vacuum deposition techniques is crucial for low-scale applications, but addressing low energy density remains a challenge. In this work, structures analogous to SiOx-based thin-film electrodes are designed with close resemblance to traditional LIB slurry formulations including active material, conductive agent, and binder. The thin-film is produced using mid-frequency sputtering with a single hybrid target consisting of SiOx nanoparticles, carbon nanotubes, and polytetrafluoroethylene. The thin-film SiOx/PPFC (plasma-polymerized fluorocarbon) involves a combination of SiOx and conductive carbon within the PPFC matrix. This results in enhanced electronic conductivity and superior elasticity and hardness in comparison to a conventional pure SiOx-based thin-film. The electrochemical performance of the half-cell consisting of thin-film SiOx/PPFC demonstrates remarkable cycling stability, with a capacity retention of 74.8% up to the 1000th cycle at 0.5 C. In addition, a full cell using the LiNi0.6Co0.2Mn0.2O2 thin-film as the cathode material exhibits an exceptional initial capacity of ≈120 mAh g-1 at 0.1 C and cycle performance, marked by a capacity retention of 90.8% from the first cycle to the 500th cycle at a 1 C rate. This work will be a stepping stone for the AM/CB/B composite electrodes in TF-LIBs.

Carboxylate-Directed Pd-Catalyzed ß-C(sp3)-H Arylation of N-Methyl Alanine Derivatives for Diversification of Bioactive Peptides.

This study presents a Pd(II)-catalyzed method for the ß-C(sp3)-H arylation of N-Cbz- or N-Fmoc-protected N-methyl alanines, providing ready access to building blocks for N-methylated peptide synthesis. For this transformation, the native carboxylate was exploited as the directing group, attributing its success to the use of a monoprotected amino-pyridine ligand. Its synthetic utility was demonstrated by facile generation of nine analogues of the naturally occurring N-methylated cyclic peptide cycloaspeptide A.

The role of executive function abilities in interleaved vs. blocked learning of science concepts.

This study investigated the relative efficacy of interleaved versus blocked instruction and the role of executive function in governing learning from these instructional sequences. Eighth grade students learned about three rock concepts (igneous, sedimentary, metamorphic) and their attributes (origin, texture, composition). Consistent with prior studies and as predicted by current theoretical accounts, students who received interleaved instruction showed better memory (i.e., accuracy on true-false questions) when tested 2 weeks later, whereas those who received blocked instruction showed better memory when tested on the same day as instruction. Also consistent with prior studies and theoretical accounts, the blocked group showed greater transfer when tested after a retention interval, although this advantage was not significant. Critically, and as predicted, the shifting and inhibition executive function abilities were more predictive of learning from interleaved vs. blocked instruction. These findings lay the groundwork for future studies investigating the role of executive function in learning from different forms of instruction.

Challenge for Trade-Off Relationship between the Mechanical Property and Healing Efficiency of Self-Healable Polyimide.

Polyimide is actively applied in various industrial fields because of its strong mechanical properties, owing to the interactions between the polymer chains. Fully aromatic imide structures exhibit high glass-transition temperatures due to the strong interactions between their chains, which hinder chain mobility. Therefore, preparing a material that exhibits self-healing at a low temperature of ≤100 °C and good mechanical properties is challenging. Thus, we prepared imides with four-component semiaromatic structures by adjusting the contents of 4,4'-(hexafluoroisopropylidene)diphthalic anhydride and 4,4'-(4,4'-isopropylidenediphenoxy)bis(phthalic anhydride) to yield four-component self-healable colorless polyimides (f-SH-CPIs) with novel structures, flexibilities, good mechanical properties, and low healing temperatures. The flexibilities and distances between the polymer chains, as the basis of the trade-off relationship between the mechanical properties and healing efficiency, were controlled. These materials may be used as substrates in wearable devices and multilayer insulation that may protect from space dust, cosmic rays, and satellite fragments.

Syntactic complexity differentially affects auditory sentence comprehension performance for individuals with age-related hearing loss.

Objectives: This study examined whether older adults with hearing loss (HL) experience greater difficulties in auditory sentence comprehension compared to those with typical-hearing (TH) when the linguistic burdens of syntactic complexity were systematically manipulated by varying either the sentence type (active vs. passive) or sentence length (3- vs. 4-phrases). Methods: A total of 22 individuals with HL and 24 controls participated in the study, completing sentence comprehension test (SCT), standardized memory assessments, and pure-tone audiometry tests. Generalized linear mixed effects models were employed to compare the effects of sentence type and length on SCT accuracy, while Pearson correlation coefficients were conducted to explore the relationships between SCT accuracy and other factors. Additionally, stepwise regression analyses were employed to identify memory-related predictors of sentence comprehension ability. Results: Older adults with HL exhibited poorer performance on passive sentences than on active sentences compared to controls, while the sentence length was controlled. Greater difficulties on passive sentences were linked to working memory capacity, emerging as the most significant predictor for the comprehension of passive sentences among participants with HL. Conclusion: Our findings contribute to the understanding of the linguistic-cognitive deficits linked to age-related hearing loss by demonstrating its detrimental impact on the processing of passive sentences. Cognitively healthy adults with hearing difficulties may face challenges in comprehending syntactically more complex sentences that require higher computational demands, particularly in working memory allocation.

All-Solid-State Synaptic Transistors with Lithium-Ion-Based Electrolytes for Linear Weight Mapping and Update in Neuromorphic Computing Systems.

Neuromorphic computing, an innovative technology inspired by the human brain, has attracted increasing attention as a promising technology for the development of artificial intelligence systems. This study proposes synaptic transistors with a Li1-xAlxTi2-x(PO4)3 (LATP) layer to analyze the conductance modulation linearity, which is essential for weight mapping and updating during on-chip learning processes. The high ionic conductivity of the LATP electrolyte provides a large hysteresis window and enables linear weight update in synaptic devices. The results demonstrate that optimizing the LATP layer thickness improves the conductance modulation and linearity of synaptic transistors during potentiation and degradation. A 20 nm-thick LATP layer results in the most nonlinear depression (αd = -6.59), whereas a 100 nm-thick LATP layer results in the smallest nonlinearity (αd = -2.22). Additionally, a device with the optimal 100 nm-thick LATP layer exhibits the highest average recognition accuracy of 94.8% and the smallest fluctuation, indicating that the linearity characteristics of a device play a crucial role in weight update during learning and can significantly affect the recognition accuracy.

ATG14 plays a critical role in hepatic lipid droplet homeostasis.

BACKGROUND & AIMS: Autophagy-related 14 (ATG14) is a key regulator of autophagy. ATG14 is also localized to lipid droplet; however, the function of ATG14 on lipid droplet remains unclear. In this study, we aimed to elucidate the role of ATG14 in lipid droplet homeostasis. METHODS: ATG14 loss-of-function and gain-of-function in lipid droplet metabolism were analyzed by fluorescence imaging in ATG14 knockdown or overexpression hepatocytes. Specific domains involved in the ATG14 targeting to lipid droplets were analyzed by deletion or site-specific mutagenesis. ATG14-interacting proteins were analyzed by co-immunoprecipitation. The effect of ATG14 on lipolysis was analyzed in human hepatocytes and mouse livers that were deficient in ATG14, comparative gene identification-58 (CGI-58), or both. RESULTS: Our data show that ATG14 is enriched on lipid droplets in hepatocytes. Mutagenesis analysis reveals that the Barkor/ATG14 autophagosome targeting sequence (BATS) domain of ATG14 is responsible for the ATG14 localization to lipid droplets. Co-immunoprecipitation analysis illustrates that ATG14 interacts with adipose triglyceride lipase (ATGL) and CGI-58. Moreover, ATG14 also enhances the interaction between ATGL and CGI-58. In vitro lipolysis analysis demonstrates that ATG14 deficiency remarkably decreases triglyceride hydrolysis. CONCLUSIONS: Our data suggest that ATG14 can directly enhance lipid droplet breakdown through interactions with ATGL and CGI-58.

Association of Sustained Low or High Income and Income Changes With Risk of Incident Type 2 Diabetes Among Individuals Aged 30 to 64 Years.

Importance: Evidence of the association between income fluctuation and risk of type 2 diabetes (T2D) is scarce. Objective: To investigate whether sustained low or high income and income changes are associated with incidence of T2D. Design, Setting, and Participants: In this population-based cohort study, more than 7.8 million adults without T2D aged 30 to 64 years from a nationally representative sample from the Korean Health Insurance Service database were enrolled in 2012 and followed up to 2019 (median follow-up, 6.3 years [IQR, 6.1-6.6 years]). Exposures: Twenty quantiles of monthly health insurance premiums determined income levels. Income quartiles were annually analyzed from 2008 to 2012. Beneficiaries of the Medical Aid Program were regarded as those with very low income. A decrease in income was indicated as a reduction of 25% or more in income compared with income in the previous year. Main Outcomes and Measures: The primary outcome was incident T2D based on the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes E11 to E14, 1 or more claims of antidiabetic medication, or a fasting glucose level of 126 mg/dL or higher. Multivariable Cox proportional hazards models were used to assess the association of low- or high-income status and income changes with incidence of T2D. Results: Of 7 821 227 participants (mean [SD] age, 46.4 [9.3] years; 54.9% men), 359 931 (4.6%) developed T2D at least 1 year after enrollment. Individuals who repeatedly experienced low and very low income for 5 years showed 22% (hazard ratio [HR], 1.22 [95% CI, 1.21-1.23]) and 57% (1.57 [95% CI, 1.53-1.62]) higher T2D risk compared with those who never experienced low and very low income, respectively. In contrast, individuals who were repeatedly in high-income quartiles showed lower T2D risk compared with those who never experienced high income (HR, 0.86 [95% CI, 0.85-0.86]). The number of income decreases was associated with elevated T2D risk (≥2 vs 0 income decreases: HR, 1.08 [95% CI, 1.06-1.11]; P < .001 for trend). When income quartile status was compared between 2008 and 2012, individuals who experienced an income increase had lowered T2D risk, while those who experienced an income decrease had elevated T2D risk in each income quartile group. Conclusions and Relevance: This cohort study found that individuals who experienced sustained low-income status or an income decrease had elevated T2D risk, while those who had sustained high-income status or an income increase had lowered T2D risk.

Enhancement of dynamic visual acuity using transcranial alternating current stimulation with gamma burst entrained on alpha wave troughs.

BACKGROUND: Cross-frequency phase-amplitude coupling (PAC) of cortical oscillations is observed within and across cortical regions during higher-order cognitive processes. Particularly, the PAC of alpha and gamma waves in the occipital cortex is closely associated with visual perception. In theory, gamma oscillation is a neuronal representation of visual stimuli, which drives the duty cycle of visual perception together with alpha oscillation. Therefore, it is believed that the timing of entrainment in alpha-gamma PAC may play a critical role in the performance of visual perception. We hypothesized that transcranial alternating current stimulation (tACS) with gamma waves entrained at the troughs of alpha waves would enhance the dynamic visual acuity (DVA). METHOD: We attempted to modulate the performance of DVA by using tACS. The waveforms of the tACS were tailored to target PAC over the occipital cortex. The waveforms contained gamma (80 Hz) waves oscillating at either the peaks or troughs of alpha (10 Hz) waves. Participants performed computerized DVA task before, immediately after, and 10 min after each stimulation sessions. EEG and EOG were recorded during the DVA task to assess inter-trial phase coherence (ITPC), the alpha-gamma PAC at occipital site and the eye movements. RESULTS: tACS with gamma waves entrained at alpha troughs effectively enhanced DVA, while the tACS with gamma waves entrained at alpha peaks did not affect DVA performance. Importantly, analyses of EEG and EOG showed that the enhancement of DVA performance originated solely from the neuromodulatory effects, and was not related to the modulation of saccadic eye movements. Consequently, DVA, one of the higher-order cognitive abilities, was successfully modulated using tACS with a tailored waveform. CONCLUSIONS: Our experimental results demonstrated that DVA performances were enhanced when tACS with gamma bursts entrained on alpha wave troughs were applied over the occipital cortex. Our findings suggest that using tACS with tailored waveforms, modulation of complex neuronal features could effectively enhance higher-order cognitive abilities such as DVA, which has never been modulated with conventional noninvasive brain stimulation methods.

Transcranial alternating current stimulation over multiple brain areas with non-zero phase delays other than 180 degrees modulates visuospatial working memory performance.

While zero-phase lag synchronization between multiple brain regions has been widely observed, relatively recent reports indicate that systematic phase delays between cortical regions reflect the direction of communications between cortical regions. For example, it has been suggested that a non-zero phase delay of electroencephalography (EEG) signals at the gamma frequency band between the bilateral parietal areas may reflect the direction of communication between these areas. We hypothesized that the direction of communication between distant brain areas might be modulated by multi-site transcranial alternating current stimulation (tACS) with specific phase delays other than 0° and 180°. In this study, a new noninvasive brain stimulation (NIBS) method called multi-site multi-phase tACS (msmp-tACS) was proposed. The efficacy of the proposed method was tested in a case study using a visuospatial working memory (VWM) paradigm in which the optimal stimulation conditions including amplitudes and phases of multiple scalp electrodes were determined using finite element analysis adopting phasor representation. msmp-tACS was applied over the bilateral intraparietal sulci (IPS) and showed that 80 Hz tACS with the phase for the right IPS leading that for the left IPS by 90° (= 3.125 ms) partialized VWM performance toward the right visual hemifield. The three stimulation conditions were synchronized, RL, and LR, which refers to stimulation condition with no phase lag, stimulation phase of right IPS (rIPS) leading left IPS (lIPS) by 90° and the stimulation of lIPS leading rIPS by 90°, respectively. The lateralization of VWM significantly shifted towards right visual hemifield under the RL condition compared to the synchronized and LR conditions. The shift in VWM was the result of the stimulation affecting both left and right visual hemifield trials to certain degrees, rather than significantly increasing or decreasing VWM capacity of a specific visual hemifield. Altered brain dynamics caused by msmp-tACS partialized VWM performance, likely due to modulation of effective connectivity between the rIPS and lIPS. Our results suggest that msmp-tACS is a promising NBS method that can effectively modulate cortical networks that cannot be readily modulated with conventional multi-site stimulation methods.

Application of conformational space annealing to the protein structure modeling using cryo-EM maps.

Conformational space annealing (CSA), a global optimization method, has been applied to various protein structure modeling tasks. In this paper, we applied CSA to the cryo-EM structure modeling task by combining the python subroutine of CSA (PyCSA) and the fast relax (FastRelax) protocol of PyRosetta. Refinement of initial structures generated from two methods, rigid fitting of predicted structures to the Cryo-EM map and de novo protein modeling by tracing the Cryo-EM map, was performed by CSA. In the refinement of the rigid-fitted structures, the final models showed that CSA can generate reliable atomic structures of proteins, even when large movements of protein domains were required. In the de novo modeling case, although the overall structural qualities of the final models were rather dependent on the initial models, the final models generated by CSA showed improved MolProbity scores and cross-correlation coefficients to the maps. These results suggest that CSA can accomplish flexible fitting and refinement together by sampling diverse conformations effectively and thus can be utilized for cryo-EM structure modeling.

Soluble receptors for advanced glycation end-products prevent unilateral ureteral obstruction-induced renal fibrosis.

Introduction: The receptor for advanced glycation end products (RAGE) and its ligands, such as high-mobility group protein box 1 (HMGB1), play an important role in the accumulation of extracellular matrix in chronic kidney diseases with tubulointerstitial fibrosis. Blocking RAGE signaling with soluble RAGE (sRAGE) is a therapeutic candidate for renal fibrosis. Methods: NRK-52E cells were stimulated with or without HMGB1 and incubated with sRAGE in vitro. Sprague-Dawley rats were intraperitoneally treated with sRAGE after unilateral ureteral obstruction (UUO) operation in vivo. Results: HMBG1-stimulated NRK-52E cells showed increased fibronectin expression, type I collagen, α-smooth muscle actin, and connective tissue growth factor, which were attenuated by sRAGE. The mitogen-activated protein kinase (MAPK) pathway and nuclear translocation of nuclear factor kappa B (NF-κB) were enhanced in NRK-52E cells exposed to HMBG1, and sRAGE treatment alleviated the activation of the MAPK and NF-κB pathways. In the UUO rat models, sRAGE significantly ameliorated the increased renal fibronectin, type I collagen, and α-smooth muscle actin expressions. Masson's trichrome staining confirmed the anti-fibrotic effect of sRAGE in the UUO rat model. RAGE also significantly attenuated the activation of the MAPK pathway and NF-κB, as well as the increased number of infiltrated macrophages within the tubulointerstitium in the kidney of the UUO rat models. Conclusion: These findings suggest that RAGE plays a pivotal role in the pathogenesis of renal fibrosis and that its inhibition by sRAGE may be a potential therapeutic approach for renal fibrosis.

ß-COP Suppresses the Surface Expression of the TREK2.

K2P channels, also known as two-pore domain K+ channels, play a crucial role in maintaining the cell membrane potential and contributing to potassium homeostasis due to their leaky nature. The TREK, or tandem of pore domains in a weak inward rectifying K+ channel (TWIK)-related K+ channel, subfamily within the K2P family consists of mechanical channels regulated by various stimuli and binding proteins. Although TREK1 and TREK2 within the TREK subfamily share many similarities, ß-COP, which was previously known to bind to TREK1, exhibits a distinct binding pattern to other members of the TREK subfamily, including TREK2 and the TRAAK (TWIK-related acid-arachidonic activated K+ channel). In contrast to TREK1, ß-COP binds to the C-terminus of TREK2 and reduces its cell surface expression but does not bind to TRAAK. Furthermore, ß-COP cannot bind to TREK2 mutants with deletions or point mutations in the C-terminus and does not affect the surface expression of these TREK2 mutants. These results emphasize the unique role of ß-COP in regulating the surface expression of the TREK family.