Investigation of Planckian behavior in a high-conductivity oxide: PdCrO2.

The layered delafossite metal PdCrO[Formula: see text] is a natural heterostructure of highly conductive Pd layers Kondo coupled to localized spins in the adjacent Mott insulating CrO[Formula: see text] layers. At high temperatures, T, it has a T-linear resistivity which is not seen in the isostructural but nonmagnetic PdCoO[Formula: see text]. The strength of the Kondo coupling is known, as-grown crystals are extremely high purity and the Fermi surface is both very simple and experimentally known. It is therefore an ideal material platform in which to investigate "Planckian metal" physics. We do this by means of controlled introduction of point disorder, measurement of the thermal conductivity and Lorenz ratio, and studying the sources of its high-temperature entropy. The T-linear resistivity is seen to be due mainly to elastic scattering and to arise from a sum of several scattering mechanisms. Remarkably, this sum leads to a scattering rate within 10[Formula: see text] of the Planckian value of k[Formula: see text]T/[Formula: see text].

A novel biguanide (IM1761065) inhibits bioenergetics of glioblastoma tumorspheres.

PURPOSE: Glioblastoma (GBM) is a rapidly growing tumor in the central nervous system with altered metabolism. Depleting the bioenergetics of tumors with biguanides have been suggested as an effective therapeutic approach for treating GBMs. The purpose of this study was to determine the effects of IM1761065, a novel biguanide with improved pharmacokinetics, on GBM-tumorspheres (TSs). METHODS: The biological activities of IM1761065 on GBM-TSs, including their effects on viability, ATP levels, cell cycle, stemness, invasive properties, and transcriptomes were examined. The in vivo efficacy of IM1761065 was tested in a mouse orthotopic xenograft model. RESULTS: IM1761065 decreased the viability and ATP levels of GBM-TSs in a dose-dependent manner, and reduced basal and spare respiratory capacity in patient-derived GBM-TS, as measured by the oxygen consumption rate. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TSs were also significantly suppressed by IM1761065. A gene-ontology comparison of IM1761065-treated groups showed that the expression levels of stemness-related, epithelial mesenchymal transition-related, and mitochondrial complex I genes were also significantly downregulated by IM1761065. An orthotopic xenograft mouse model showed decreased bioluminescence in IM1761065-treated cell-injected mice at 5 weeks. IM1761065-treated group showed longer survival than the control group (P = 0.0289, log-rank test). CONCLUSION: IM1761065 is a potent inhibitor of oxidative phosphorylation. The inhibitory effect of IM1761065 on the bioenergetics of GBM-TS suggests that this novel compound could be used as a new drug for the treatment of GBM.

Dual inhibition of CPT1A and G6PD suppresses glioblastoma tumorspheres.

PURPOSE: Limited treatment options are currently available for glioblastoma (GBM), an extremely lethal type of brain cancer. For a variety of tumor types, bioenergetic deprivation through inhibition of cancer-specific metabolic pathways has proven to be an effective therapeutic strategy. Here, we evaluated the therapeutic effects and underlying mechanisms of dual inhibition of carnitine palmitoyltransferase 1A (CPT1A) and glucose-6-phosphate dehydrogenase (G6PD) critical for fatty acid oxidation (FAO) and the pentose phosphate pathway (PPP), respectively, against GBM tumorspheres (TSs). METHODS: Therapeutic efficacy against GBM TSs was determined by assessing cell viability, neurosphere formation, and 3D invasion. Liquid chromatography-mass spectrometry (LC-MS) and RNA sequencing were employed for metabolite and gene expression profiling, respectively. Anticancer efficacy in vivo was examined using an orthotopic xenograft model. RESULTS: CPT1A and G6PD were highly expressed in GBM tumor tissues. Notably, siRNA-mediated knockdown of both genes led to reduced viability, ATP levels, and expression of genes associated with stemness and invasiveness. Similar results were obtained upon combined treatment with etomoxir and dehydroepiandrosterone (DHEA). Transcriptome analyses further confirmed these results. Data from LC-MS analysis showed that this treatment regimen induced a considerable reduction in the levels of metabolites associated with the TCA cycle and PPP. Additionally, the combination of etomoxir and DHEA inhibited tumor growth and extended survival in orthotopic xenograft model mice. CONCLUSION: Our collective findings support the utility of dual suppression of CPT1A and G6PD with selective inhibitors, etomoxir and DHEA, as an efficacious therapeutic approach for GBM.

FKBP8 LIRL-dependent mitochondrial fragmentation facilitates mitophagy under stress conditions.

Mitochondrial quality control maintains mitochondrial function by regulating mitochondrial dynamics and mitophagy. Despite the identification of mitochondrial quality control factors, little is known about the crucial regulators coordinating both mitochondrial fission and mitophagy. Through a cell-based functional screening assay, FK506 binding protein 8 (FKBP8) was identified to target microtubule-associated protein 1 light chain 3 (LC3) to the mitochondria and to change mitochondrial morphology. Microscopy analysis revealed that the formation of tubular and enlarged mitochondria was observed in FKBP8 knockdown HeLa cells and the cortex of Fkbp8 heterozygote-knockout mouse embryos. Under iron depletion-induced stress, FKBP8 was recruited to the site of mitochondrial division through budding and colocalized with LC3. FKBP8 was also found to be required for mitochondrial fragmentation and mitophagy under hypoxic stress. Conversely, FKBP8 overexpression induced mitochondrial fragmentation in HeLa cells, human fibroblasts and mouse embryo fibroblasts (MEFs), and this fragmentation occurred in Drp1 knockout MEF cells, FIP200 knockout HeLa cells and BNIP3/NIX double knockout HeLa cells, but not in Opa1 knockout MEFs. Interestingly, we found an LIR motif-like sequence (LIRL), as well as an LIR motif, at the N-terminus of FKBP8 and LIRL was essential for both inducing mitochondrial fragmentation and binding of FKBP8 to OPA1. Together, we suggest that FKBP8 plays an essential role in mitochondrial fragmentation through LIRL during mitophagy and this activity of FKBP8 together with LIR is required for mitophagy under stress conditions.

A Fluorescent Probe for Stimulated Emission Depletion Super-Resolution Imaging of Vicinal-Dithiol-Proteins on Mitochondrial Membrane.

Realizing the significant roles of vicinal-dithiol proteins (VDPs) in maintaining the cellular redox homeostasis and their implication in many diseases, we synthesized a smart arsenate based fluorescent probe 1 which can preferentially target the mitochondrial membrane-bound vicinal dithiol proteins (VDPs), especially voltage-dependent anion channel (VDAC2). The probe targetability was demonstrated by in vitro studies such as colocalization, stimulated emission depletion (STED) super-resolution imaging, proteomic MS/MS analysis, and Western blot analysis. The probe represents a rare example of fluorescence labeling of mitochondrial membrane-bound VDPs and can provide a new way to construct VDPs-specific fluorescent probes to gain deeper understanding of their roles in mitochondrial-related disorders.

Observation of the Anomalous Hall Effect in a Layered Polar Semiconductor.

Progress in magnetoelectric materials is hindered by apparently contradictory requirements for time-reversal symmetry broken and polar ferroelectric electronic structure in common ferromagnets and antiferromagnets. Alternative routes can be provided by recent discoveries of a time-reversal symmetry breaking anomalous Hall effect (AHE) in noncollinear magnets and altermagnets, but hitherto reported bulk materials are not polar. Here, the authors report the observation of a spontaneous AHE in doped AgCrSe2 , a layered polar semiconductor with an antiferromagnetic coupling between Cr spins in adjacent layers. The anomalous Hall resistivity 3 µ Ω c m $\mu \Omega \, \textnormal {cm}$ is comparable to the largest observed in compensated magnetic systems to date, and is rapidly switched off when the angle of an applied magnetic field is rotated to ≈80° from the crystalline c-axis. The ionic gating experiments show that the anomalous Hall conductivity magnitude can be enhanced by modulating the p-type carrier density. They also present theoretical results that suggest the AHE is driven by Berry curvature due to noncollinear antiferromagnetic correlations among Cr spins, which are consistent with the previously suggested magnetic ordering in AgCrSe2 . The results open the possibility to study the interplay of magnetic and ferroelectric-like responses in this fascinating class of materials.

Structural characterization of de novo designed L5K5W model peptide isomers with potent antimicrobial and varied hemolytic activities.

In an effort to develop short antimicrobial peptides with simple amino acid compositions, we generated a series of undecapeptide isomers having the L(5)K(5)W formula. Amino acid sequences were designed to be perfectly amphipathic when folded into a helical conformation by converging leucines onto one side and lysines onto the other side of the helical axis. The single tryptophans, whose positions were varied in the primary structures, were located commonly at the critical amphipathic interface in the helical wheel projection. Helical conformations and the tryptophanyl environments of the 11 L(5)K(5)W peptides were confirmed and characterized by circular dichroism, fluorescence and nuclear magnetic resonance spectroscopy. All of the isomers exhibited a potent, broad-spectrum of antibacterial activity with just a slight variance in individual potency, whereas their hemolytic activities against human erythrocytes were significantly diversified. Interestingly, helical dispositions and fluorescence blue shifts of the peptides in aqueous trifluoroethanol solutions, rather than in detergent micelles, showed a marked linear correlation with their hemolytic potency. These results demonstrate that our de novo design strategy for amphipathic helical model peptides is effective for developing novel antimicrobial peptides and their hemolytic activities can be estimated in correlation with structural parameters.

Does COVID-19 Infection within 1 Week after Total Knee Arthroplasty Affect Patients' Early Clinical Outcomes? A Matched Case-Control Study.

Recent studies have reported the impact of previous COVID-19 infection on the early clinical outcome after total knee arthroplasty (TKA). However, the timing of infection before the surgery was not constant and a study on patients with COVID-19 infection within 1 week after TKA is lacking. This study aimed to determine the effect of COVID-19 infection within one week after TKA on the postoperative outcomes and to compare the early clinical outcomes to those who were not infected with COVID-19 before and after surgery. No significant differences were observed between the two groups in terms of clinical outcomes or complications. The length of the hospital stay (LOS) was significantly longer for the COVID-19 group than for the non-COVID-19 group (p < 0.05). The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were higher for the study group on postoperative days 9 and 12 than for those in the control group (p < 0.05). However, D-dimer levels were not significantly different between the two groups. We should cautiously consider that COVID-19 infection within 1 week after TKA may be associated with increased ESR, CRP levels, and length of hospital stay, but they are not associated with the worsening of early clinical outcomes or the occurrence of complications.

Shelf Life Prediction of Vacuum-Packaged Grilled Mackerel.

The current study aimed to establish the shelf life of vacuum-packaged grilled mackerel stored at 5, -5, and -20°C for 70 days. To this end, physicochemical analyses, which involved determining the pH, volatile basic nitrogen, amino nitrogen, trimethylamine (TMA), and thiobarbituric acid levels; microbiological analyses (aerobic plate count and coliform); and sensory quality determination were performed. Regression analysis on the relationship between physicochemical properties and storage time at various temperatures revealed TMA level was the most suitable parameter (R2=0.9769) for predicting changes in the quality of grilled mackerel during storage, with a quality limit value of 8.74 mg/100 g. The shelf life of vacuum-packaged grilled mackerel according to temperature was 21, 53, 62, and 75 days for 5, -5, -15, and -20°C, respectively, with the use-by date being 23 days at 5°C and 74 days at -5°C. In conclusion, TMA was the most suitable parameter for predicting changes in the quality of grilled mackerel during storage.

Pathogenic Role of RAGE in Tau Transmission and Memory Deficits.

BACKGROUND: In tauopathies, brain regions with tau accumulation strongly correlate with clinical symptoms, and spreading of misfolded tau along neural network leads to disease progression. However, the underlying mechanisms by which tau proteins enter neurons during pathological propagation remain unclear. METHODS: To identify membrane receptors responsible for neuronal propagation of tau oligomers, we established a cell-based tau uptake assay and screened complementary DNA expression library. Tau uptake and propagation were analyzed in vitro and in vivo using a microfluidic device and stereotactic injection. The cognitive function of mice was assessed using behavioral tests. RESULTS: From a genome-wide cell-based functional screening, RAGE (receptor for advanced glycation end products) was isolated to stimulate the cellular uptake of tau oligomers. Rage deficiency reduced neuronal uptake of pathological tau prepared from rTg4510 mouse brains or cerebrospinal fluid from patients with Alzheimer's disease and slowed tau propagation between neurons cultured in a 3-chamber microfluidic device. RAGE levels were increased in the brains of rTg4510 mice and tau oligomer-treated neurons. Rage knockout decreased tau transmission in the brains of nontransgenic mice after injection with Alzheimer's disease patient-derived tau and ameliorated memory loss after injection with GFP-P301L-tau-AAV. Treatment of RAGE antagonist FPS-ZM1 blocked transsynaptic tau propagation and inflammatory responses and alleviated cognitive impairment in rTg4510 mice. CONCLUSIONS: These results suggest that in neurons and microglia, RAGE binds to pathological tau and facilitates neuronal tau pathology progression and behavioral deficits in tauopathies.

Highly Stretchable Sensor Based on Fluid Dynamics-Assisted Graphene Inks for Real-Time Monitoring of Sweat.

Graphene inks have recently attracted attention for the development of printed wearable and flexible electronics and sensors not only because of their high conductivity and low cost but also because they are suitable for high-speed printing. Although reliable and scalable printing technologies are well established, further improvement in graphene inks in terms of electrical conductivity, stretchability/flexibility, and mass production is necessary for sensors for real-time monitoring. Herein, highly stretchable and conductive graphene inks were prepared by an efficient and scalable fluid dynamics-assisted exfoliation of graphite and a mixing process with elastomeric Ecoflex. After printing inks onto textile substrates, the serpentine-patterned conductors exhibited high conductivity and stable resistance even under a mechanically stretched state (a strain of 150%). Electrochemical sensors that detect sodium ions were fabricated on this conducting platform. These sensors indicated high potentiometric sensing ability under different mechanical deformations. To demonstrate the on-body performance of the developed sensors, real-time monitoring of sodium-ion concentration in the sweat of a human subject was carried out during an indoor stationary cycling exercise.

A lignan from Alnus japonica inhibits glioblastoma tumorspheres by suppression of FOXM1.

Forkhead Box M1 (FOXM1) is known to regulate cell proliferation, apoptosis and tumorigenesis. The lignan, (-)-(2R,3R)-1,4-O-diferuloylsecoisolariciresinol (DFS), from Alnus japonica has shown anti-cancer effects against colon cancer cells by suppressing FOXM1. The present study hypothesized that DFS can have anti-cancer effects against glioblastoma (GBM) tumorspheres (TSs). Immunoprecipitation and luciferase reporter assays were performed to evaluate the ability of DFS to suppress nuclear translocation of ß-catenin through ß-catenin/FOXM1 binding. DFS-pretreated GBM TSs were evaluated to assess the ability of DFS to inhibit GBM TSs and their transcriptional profiles. The in vivo efficacy was examined in orthotopic xenograft models of GBM. Expression of FOXM1 was higher in GBM than in normal tissues. DFS-induced FOXM1 protein degradation blocked ß-catenin translocation into the nucleus and consequently suppressed downstream target genes of FOXM1 pathways. DFS inhibited cell viability and ATP levels, while increasing apoptosis, and it reduced tumorsphere formation and the invasiveness of GBM TSs. And DFS reduced the activities of transcription factors related to tumorigenesis, stemness, and invasiveness. DFS significantly inhibited tumor growth and prolonged the survival rate of mice in orthotopic xenograft models of GBM. It suggests that DFS inhibits the proliferation of GBM TSs by suppressing FOXM1. DFS may be a potential therapeutic agent to treat GBM.

Identification of a novel recombinant mutation in Korean patients with Gaucher disease using a long-range PCR approach.

Gaucher disease (GD) is an autosomal recessive, lysosomal disorder caused by mutations in the gene for the ß-glucocerebrosidase (GBA) enzyme. Presence of the non-functional GBAP pseudogene, which shares high sequence similarity with the functional GBA gene, has made it difficult to carry out molecular analyses of GD, especially recombinant mutations. Using a long-range PCR approach that has been skillfully devised for the easy detection of GBA recombinant mutations, we identified four recombinant mutations including two gene conversion alleles, Rec 1a and Rec 8a, one reciprocal gene fusion allele, Rec 1b, and one reciprocal gene duplication allele, Rec 7b, in Korean patients with GD. Rec 8a, in which the GBAP pseudogene sequence from intron 5 to exon 11 is substituted for the GBA gene is a novel recombinant mutation. All mutations were confirmed by full sequencing of PCR amplicons and/or Southern blot analysis. These results indicate that the usage of long-range PCR may allow the rapid and accurate detection of GBA recombinant mutations and contribute to the improvement of genotyping efficiency in GD patients.

Gene expression profiles of rat olfactory bulb at developmental stage.

Microarray analysis may be a useful tool to identify some candidate genes related to the development of olfactory bulbs. In the present study, gene expression profiles of olfactory bulbs from postnatal day 1 (P1) rats and postnatal day 35 (P35) rats were analyzed by oligonucleotide-microarray and expression levels of some selected genes were also confirmed by RT-PCR and in situ hybridization. 9146 genes were commonly identified in six microarray chips. Among these genes, 76 were up-regulated and 130 were down-regulated three-folds or more at P1 olfactory bulbs. Out of these 76 up-regulated genes, 24 genes were annotated based on the NCBI database of reference sequences and expression levels of these 24 genes were confirmed by RT-PCR. Among them, 2 interesting genes (neurogenic differentiation 1 and retinoid acid receptor alpha) were localized in the P1 olfactory bulb by the use of in situ hybridization technique. Our results may provide basic information to identify genes associated with functional growth of olfactory bulbs.

Binary Drug Reinforced First Small-Molecule-Based Prodrug for Synergistic Anticancer Effects.

We developed a small-molecule-based binary drug delivery system (BDDS) with two anticancer drugs, SN-38 and 5'-DFUR. The drug release from the prodrug BDDS can be achieved upon its reaction with intracellular H2O2, overexpressed in cancer cells. The efficacy of BDDS was demonstrated by a comparative study along with that of a single drug conjugate (SDDS), bearing SN-38 alone.

Spatial Disparity in Food Environment and Household Economic Resources Related to Food Insecurity in Rural Korean Households with Older Adults.

Different contextual factors of a household and a community, such as access to resources and transportation, may influence the level of food insecurity. The objective of this study was to identify how food environmental factors and economic resources were related to food insecurity in Korean older adults residing in different contexts of rural areas. Face-to-face interviews with 248 older adults residing in land (n = 149) and mountain (n = 99) rural areas were performed. In both areas, risk of food insecurity was increased for households with limited community food accessibility measured by having difficulties in food purchasing due to food stores far from home. There were discrepancies in factors related to increased risks of food insecurity between households in land and mountain areas. The experience of reducing food expenditure resulting from burden of heating costs during the winter in households in a mountain area whereas the percent proportion of housing fee and household cook's physical disability in households residing in the land area were found to be factors associated with increased risks of food insecurity. For households residing in mountain areas, the risk of food insecurity was decreased when economic resources measured by average monthly income for the last one year was increased and there was farming or home gardening activity. Such spatial disparity might affect household food insecurity in rural areas. In addition, food environmental factors and economic resources may affect household food insecurity differently according to the diverse contexts of rural areas. Better understanding of spatial challenges in food insecurity faced by seniors in a large rural area would help prepare programs or policy change to strengthen and improve their food environments.

GNI Corpus Version 1.0: Annotated Full-Text Corpus of Genomics & Informatics to Support Biomedical Information Extraction.

Genomics & Informatics (NLM title abbreviation: Genomics Inform) is the official journal of the Korea Genome Organization. Text corpus for this journal annotated with various levels of linguistic information would be a valuable resource as the process of information extraction requires syntactic, semantic, and higher levels of natural language processing. In this study, we publish our new corpus called GNI Corpus version 1.0, extracted and annotated from full texts of Genomics & Informatics, with NLTK (Natural Language ToolKit)-based text mining script. The preliminary version of the corpus could be used as a training and testing set of a system that serves a variety of functions for future biomedical text mining.

Glycyrrhetinic acid as a hepatocyte targeting unit for an anticancer drug delivery system with enhanced cell type selectivity.

Herein, we report the potential of glycyrrhetinic acid (GA) as an active targeting ligand for hepatocellular carcinoma (HCC) for the development of diagnosis/therapy using small-molecule based approaches. Our preliminary results demonstrated that GA-conjugation to diagnostic/therapeutic counterparts significantly enhanced their HCC targeting ability and excellent therapeutic efficacy.

Modulating the GSH/Trx selectivity of a fluorogenic disulfide-based thiol sensor to reveal diminished GSH levels under ER stress.

We synthesized a fluorogenic disulfide-based naphthalimide thiol probe (ER-Naph) with a hydrophilic endoplasmic reticulum (ER)-guiding glibenclamide unit. Its ER targeting ability and high selectivity to GSH over thioredoxin, a potent competitor, were clearly demonstrated, both in solution and in vitro. Finally, a confocal microscopic investigation revealed that GSH levels in the ER were dramatically decreased under thapsigargin, brefeldin A, and tunicamycin-induced ER stress models.

Differential gene expression profiles in salicylate ototoxicity of the mouse.

CONCLUSION: This study demonstrated differential gene expression profiles in salicylate ototoxicity with oligonucleotide microarray. This study may also provide basic information on candidate genes associated with hearing loss and/or tinnitus or recovery after salicylate-induced cochlear dysfunction. OBJECTIVES: Salicylate ototoxicity is accompanied by temporary hearing loss and tinnitus. The purpose of the present study was to evaluate the gene expression profiles in the mouse cochlea with salicylate ototoxicity using DNA microarray. MATERIALS AND METHODS: The subject mice were injected intraperitoneally with 400 mg/kg of sodium salicylate; an approximate 30 dB threshold shift that was observed by auditory brainstem response was achieved 3 h after an injection of sodium salicylate and the hearing threshold returned to within normal range at 3 days. Differential gene expression profiles at 3 h after salicylate injection in comparison to the normal cochlea were analyzed with DNA microarray technology. RESULTS: No ultrastructural changes in the mice cochlea were observed by TEM at 3 h after salicylate injection. Microarray revealed that 87 genes were up-regulated twofold or more in the mouse cochlea with salicylate ototoxicity in comparison to the normal cochlea. Among these genes, increased expression levels of 30 functional genes were confirmed by semi-quantitative RT-PCR.