Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes.

Steroid receptors activate gene transcription by recruiting coactivators to initiate transcription of their target genes. For most nuclear receptors, the ligand-dependent activation function domain-2 (AF-2) is a primary contributor to the nuclear receptor (NR) transcriptional activity. In contrast to other steroid receptors, such as ERα, the activation function of androgen receptor (AR) is largely dependent on its ligand-independent AF-1 located in its N-terminal domain (NTD). It remains unclear why AR utilizes a different AF domain from other receptors despite that NRs share similar domain organizations. Here, we present cryoelectron microscopy (cryo-EM) structures of DNA-bound full-length AR and its complex structure with key coactivators, SRC-3 and p300. AR dimerization follows a unique head-to-head and tail-to-tail manner. Unlike ERα, AR directly contacts a single SRC-3 and p300. The AR NTD is the primary site for coactivator recruitment. The structures provide a basis for understanding assembly of the AR:coactivator complex and its domain contributions for coactivator assembly and transcriptional regulation.

RNA polymerase III transcription as a disease factor.

RNA polymerase (Pol) III is responsible for transcription of different noncoding genes in eukaryotic cells, whose RNA products have well-defined functions in translation and other biological processes for some, and functions that remain to be defined for others. For all of them, however, new functions are being described. For example, Pol III products have been reported to regulate certain proteins such as protein kinase R (PKR) by direct association, to constitute the source of very short RNAs with regulatory roles in gene expression, or to control microRNA levels by sequestration. Consistent with these many functions, deregulation of Pol III transcribed genes is associated with a large variety of human disorders. Here we review different human diseases that have been linked to defects in the Pol III transcription apparatus or to Pol III products imbalance and discuss the possible underlying mechanisms.

Tissue-specific compensatory mechanisms maintain tissue architecture and body size independent of cell size in polyploid zebrafish.

Genome duplications and ploidy transitions have occurred in nearly every major taxon of eukaryotes, but they are far more common in plants than in animals. Due to the conservation of the nuclear:cytoplasmic volume ratio increased DNA content results in larger cells. In plants, polyploid organisms are larger than diploids as cell number remains relatively constant. Conversely, vertebrate body size does not correlate with cell size and ploidy as vertebrates compensate for increased cell size to maintain tissue architecture and body size. This has historically been explained by a simple reduction in cell number that matches the increase in cell size maintaining body size as ploidy increases, but here we show that the compensatory mechanisms that maintain body size in triploid zebrafish are tissue-specific: A) erythrocytes respond in the classical pattern with a reduced number of larger erythrocytes in circulation, B) muscle, a tissue comprised of polynucleated muscle fibers, compensates by reducing the number of larger nuclei such that myofiber and myotome size in unaffected by ploidy, and C) vascular tissue compensates by thickening blood vessel walls, possibly at the expense of luminal diameter. Understanding the physiological implications of ploidy on tissue function requires a detailed description of the specific mechanisms of morphological compensation occurring in each tissue to understand how ploidy changes affect development and physiology.

Exploring intricate connectivity patterns for cognitive functioning and neurological disorders: incorporating frequency-domain NC method into fMRI analysis.

This study extends the application of the frequency-domain new causality method to functional magnetic resonance imaging analysis. Strong causality, weak causality, balanced causality, cyclic causality, and transitivity causality were constructed to simulate varying degrees of causal associations among multivariate functional-magnetic-resonance-imaging blood-oxygen-level-dependent signals. Data from 1,252 groups of individuals with different degrees of cognitive impairment were collected. The frequency-domain new causality method was employed to construct directed efficient connectivity networks of the brain, analyze the statistical characteristics of topological variations in brain regions related to cognitive impairment, and utilize these characteristics as features for training a deep learning model. The results demonstrated that the frequency-domain new causality method accurately detected causal associations among simulated signals of different degrees. The deep learning tests also confirmed the superior performance of new causality, surpassing the other three methods in terms of accuracy, precision, and recall rates. Furthermore, consistent significant differences were observed in the brain efficiency networks, where several subregions defined by the multimodal parcellation method of Human Connectome Project simultaneously appeared in the topological statistical results of different patient groups. This suggests a significant association between these fine-grained cortical subregions, driven by multimodal data segmentation, and human cognitive function, making them potential biomarkers for further analysis of Alzheimer's disease.

Mot1, Ino80C, and NC2 Function Coordinately to Regulate Pervasive Transcription in Yeast and Mammals.

Pervasive transcription initiates from cryptic promoters and is observed in eukaryotes ranging from yeast to mammals. The Set2-Rpd3 regulatory system prevents cryptic promoter function within expressed genes. However, conserved systems that control pervasive transcription within intergenic regions have not been well established. Here we show that Mot1, Ino80 chromatin remodeling complex (Ino80C), and NC2 co-localize on chromatin and coordinately suppress pervasive transcription in S. cerevisiae and murine embryonic stem cells (mESCs). In yeast, all three proteins bind subtelomeric heterochromatin through a Sir3-stimulated mechanism and to euchromatin via a TBP-stimulated mechanism. In mESCs, the proteins bind to active and poised TBP-bound promoters along with promoters of polycomb-silenced genes apparently lacking TBP. Depletion of Mot1, Ino80C, or NC2 by anchor away in yeast or RNAi in mESCs leads to near-identical transcriptome phenotypes, with new subtelomeric transcription in yeast, and greatly increased pervasive transcription in both yeast and mESCs.

Collagen IV of basement membranes: II. Emergence of collagen IVα345 enabled the assembly of a compact GBM as an ultrafilter in mammalian kidneys.

The collagen IVα345 (Col-IVα345) scaffold, the major constituent of the glomerular basement membrane (GBM), is a critical component of the kidney glomerular filtration barrier. In Alport syndrome, affecting millions of people worldwide, over two thousand genetic variants occur in the COL4A3, COL4A4, and COL4A5 genes that encode the Col-IVα345 scaffold. Variants cause loss of scaffold, a suprastructure that tethers macromolecules, from the GBM or assembly of a defective scaffold, causing hematuria in nearly all cases, proteinuria, and often progressive kidney failure. How these variants cause proteinuria remains an enigma. In a companion paper, we found that the evolutionary emergence of the COL4A3, COL4A4, COL4A5, and COL4A6 genes coincided with kidney emergence in hagfish and shark and that the COL4A3 and COL4A4 were lost in amphibians. These findings opened an experimental window to gain insights into functionality of the Col-IVα345 scaffold. Here, using tissue staining, biochemical analysis and TEM, we characterized the scaffold chain arrangements and the morphology of the GBM of hagfish, shark, frog, and salamander. We found that α4 and α5 chains in shark GBM and α1 and α5 chains in amphibian GBM are spatially separated. Scaffolds are distinct from one another and from the mammalian Col-IVα345 scaffold, and the GBM morphologies are distinct. Our findings revealed that the evolutionary emergence of the Col-IVα345 scaffold enabled the genesis of a compact GBM that functions as an ultrafilter. Findings shed light on the conundrum, defined decades ago, whether the GBM or slit diaphragm is the primary filter.

Collagen IV of basement membranes: IV. Adaptive mechanism of collagen IV scaffold assembly in Drosophila.

Collagen IV is an essential structural protein in all metazoans. It provides a scaffold for the assembly of basement membranes, a specialized form of extracellular matrix, which anchors and signals cells and provides microscale tensile strength. Defective scaffolds cause basement membrane destabilization and tissue dysfunction. Scaffolds are composed of α-chains that coassemble into triple-helical protomers of distinct chain compositions, which in turn oligomerize into supramolecular scaffolds. Chloride ions mediate the oligomerization via NC1 trimeric domains, forming an NC1 hexamer at the protomer-protomer interface. The chloride concentration-"chloride pressure"-on the outside of cells is a primordial innovation that drives the assembly and dynamic stabilization of collagen IV scaffolds. However, a Cl-independent mechanism is operative in Ctenophora, Ecdysozoa, and Rotifera, which suggests evolutionary adaptations to environmental or tissue conditions. An understanding of these exceptions, such as the example of Drosophila, could shed light on the fundamentals of how NC1 trimers direct the oligomerization of protomers into scaffolds. Here, we investigated the NC1 assembly of Drosophila. We solved the crystal structure of the NC1 hexamer, determined the chain composition of protomers, and found that Drosophila adapted an evolutionarily unique mechanism of scaffold assembly that requires divalent cations. By studying the Drosophila case we highlighted the mechanistic role of chloride pressure for maintaining functionality of the NC1 domain in humans. Moreover, we discovered that the NC1 trimers encode information for homing protomers to distant tissue locations, providing clues for the development of protein replacement therapy for collagen IV genetic diseases.

Collagen IV of basement membranes: III. Chloride pressure is a primordial innovation that drives and maintains the assembly of scaffolds.

Collagen IV scaffold is a primordial innovation enabling the assembly of a fundamental architectural unit of epithelial tissues-a basement membrane attached to polarized cells. A family of six α-chains (α1 to α6) coassemble into three distinct protomers that form supramolecular scaffolds, noted as collagen IVα121, collagen IVα345, and collagen IVα121-α556. Chloride ions play a pivotal role in scaffold assembly, based on studies of NC1 hexamers from mammalian tissues. First, Cl- activates a molecular switch within trimeric NC1 domains that initiates protomer oligomerization, forming an NC1 hexamer between adjoining protomers. Second, Cl- stabilizes the hexamer structure. Whether this Cl--dependent mechanism is of fundamental importance in animal evolution is unknown. Here, we developed a simple in vitro method of SDS-PAGE to determine the role of solution Cl- in hexamer stability. Hexamers were characterized from 34 animal species across 15 major phyla, including the basal Cnidarian and Ctenophora phyla. We found that solution Cl- stabilized the quaternary hexamer structure across all phyla except Ctenophora, Ecdysozoa, and Rotifera. Further analysis of hexamers from peroxidasin knockout mice, a model for decreasing hexamer crosslinks, showed that solution Cl- also stabilized the hexamer surface conformation. The presence of sufficient chloride concentration in solution or "chloride pressure" dynamically maintains the native form of the hexamer. Collectively, our findings revealed that chloride pressure on the outside of cells is a primordial innovation that drives and maintains the quaternary and conformational structure of NC1 hexamers of collagen IV scaffolds.

Leukocyte-associated immunoglobulin-like receptor-1 blockade in combination with programmed death-ligand 1 targeting therapy mediates increased tumour control in mice.

Collagen expression and structure in the tumour microenvironment are associated with tumour development and therapy response. Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a widely expressed inhibitory collagen receptor. LAIR-2 is a soluble homologue of LAIR-1 that competes for collagen binding. Multiple studies in mice implicate blockade of LAIR-1:collagen interaction in cancer as a promising therapeutic strategy. Here, we investigated the role of LAIR-1 in anti-tumour responses. We show that although LAIR-1 inhibits activation, proliferation, and cytokine production of mouse T cells in vitro, tumour outgrowth in LAIR-1-deficient mice did not differ from wild type mice in several in vivo tumour models. Furthermore, treatment with NC410, a LAIR-2-Fc fusion protein, did not result in increased tumour clearance in tested immunocompetent mice, which contrasts with previous data in humanized mouse models. This discrepancy may be explained by our finding that NC410 blocks human LAIR-1:collagen interaction more effectively than mouse LAIR-1:collagen interaction. Despite the lack of therapeutic impact of NC410 monotherapy, mice treated with a combination of NC410 and anti-programmed death-ligand 1 did show reduced tumour burden and increased survival. Using LAIR-1-deficient mice, we showed that this effect seemed to be dependent on the presence of LAIR-1. Taken together, our data demonstrate that the absence of LAIR-1 signalling alone is not sufficient to control tumour growth in multiple immunocompetent mouse models. However, combined targeting of LAIR-1 and PD-L1 results in increased tumour control. Thus, additional targeting of the LAIR-1:collagen pathway with NC410 is a promising approach to treating tumours where conventional immunotherapy is ineffective.

The RNA helicase DDX3 induces neural crest by promoting AKT activity.

Mutations in the RNA helicase DDX3 have emerged as a frequent cause of intellectual disability in humans. Because many individuals carrying DDX3 mutations have additional defects in craniofacial structures and other tissues containing neural crest (NC)-derived cells, we hypothesized that DDX3 is also important for NC development. Using Xenopus tropicalis as a model, we show that DDX3 is required for normal NC induction and craniofacial morphogenesis by regulating AKT kinase activity. Depletion of DDX3 decreases AKT activity and AKT-dependent inhibitory phosphorylation of GSK3ß, leading to reduced levels of ß-catenin and Snai1: two GSK3ß substrates that are crucial for NC induction. DDX3 function in regulating these downstream signaling events during NC induction is likely mediated by RAC1, a small GTPase whose translation depends on the RNA helicase activity of DDX3. These results suggest an evolutionarily conserved role of DDX3 in NC development by promoting AKT activity, and provide a potential mechanism for the NC-related birth defects displayed by individuals harboring mutations in DDX3 and its downstream effectors in this signaling cascade.

Facilitation of Fenton-Like Reaction of Copper-Nitrogen-Doped Carbon-Based Nanocatalysts by Enhancing Hydroxyl Adsorption on Single-Atom Cu-NxC4- x Sites.

Copper-nitrogen-doped carbon-based nanocatalysts (Cu-NCs), containing atomically dispersed Cu-NxC4- x sites, are efficient in boosting the Fenton-like reaction. However, the mechanisms of the Fenton-like reaction, including the pH effect on the products and the effect of the coordination environment on catalytic activity, remain controversial, restricting the development of Cu-NCs. Cu-NCs are experimentally synthesized with Cu-N4 sites and prove that the Fenton-like reaction generates mainly hydroxyl radicals (·OH) in the acidic but ·OH and superoxide radicals (·O2 -) in the neutral. The density functional theory (DFT) calculations reveal that the catalytic activity of Cu-NCs in the Fenton-like reaction is associated with the adsorption strength of ·OH at the Cu site. Further investigation of the effect of the coordination environment of Cu-NCs indicates that the Cu-N2C2 site, which can enhance the ·OH adsorption strength, is an ideal catalyst site for the Fenton-like reaction. These results open the way to facilitating the catalytic activity of Cu-NCs in the Fenton-like reaction.

Intelligent Reconfiguration-Promoted Cellular Internalization of Core-Shell DNA Nanoprobe Equipped with Successive Dual Stimuli-Responsive Protective Satellites for Amplification Fluorescence Imaging of Tumor Cells.

Although DNA probes have attracted increasing interest for precise tumor cell identification by imaging intracellular biomarkers, the requirement of commercial transfection reagents, limited targeting ligands, and/or non-biocompatible inorganic nanostructures has hampered the clinic translation. To circumvent these shortcomings, a reconfigurable ES-NC (Na+-dependent DNAzyme (E)-based substrate (S) cleavage core/shell DNA nanocluster (NC)) entirely from DNA strands is assembled for precise imaging of cancerous cells in a successive dual-stimuli-responsive manner. This nanoprobe is composed of a strung DNA tetrahedral satellites-based protective (DTP) shell, parallelly aligned target-responsive sensing (PTS) interlayer, and hydrophobic cholesterol-packed innermost layer (HCI core). Tetrahedral axial rotation-activated reconfiguration of DTP shell promotes the exposure of interior hydrophobic moieties, enabling cholesterol-mediated cellular internalization without auxiliary elements. Within cells, over-expressed glutathione triggers the disassembly of the DTP protective shell (first stimulus), facilitating target-stimulated signal transduction/amplification process (second stimuli). Target miRNA-21 is detected down to 10.6 fM without interference from coexisting miRNAs. Compared with transfection reagent-mediated counterpart, ES-NC displays a higher imaging ability, resists nuclease degradation, and has no detectable damage to healthy cells. The blind test demonstrates that the ES-NC is suitable for the identification of cancerous cells from healthy cells, indicating a promising tool for early diagnosis and prediction of cancer.

Evolutionary ecology of denitrifying methanotrophic NC10 bacteria in the deep-sea biosphere.

The NC10 phylum links anaerobic methane oxidation to nitrite denitrification through a unique O2-producing intra-aerobic methanotrophic pathway. Although numerous amplicon-based studies revealed the distribution of this phylum, comprehensive genomic insights and niche characterization in deep-sea environments were still largely unknown. In this study, we extensively surveyed the NC10 bacteria across diverse deep-sea environments, including waters, sediments, cold seeps, biofilms, rocky substrates, and subseafloor aquifers. We then reconstructed and analysed 38 metagenome-assembled genomes (MAGs), and revealed the extensive distribution of NC10 bacteria and their intense selective pressure in these harsh environments. Isotopic analyses combined with gene expression profiling confirmed that active nitrite-dependent anaerobic methane oxidation (n-DAMO) occurs within deep-sea sediments. In addition, the identification of the Wood-Ljungdahl (WL) and 3-hydroxypropionate/4-hydroxybutyrat (3HB/4HP) pathways in these MAGs suggests their capability for carbon fixation as chemoautotrophs in these deep-sea environments. Indeed, we found that for their survival in the oligotrophic deep-sea biosphere, NC10 bacteria encode two branches of the WL pathway, utilizing acetyl-CoA from the carbonyl branch for citric acid cycle-based energy production and methane from the methyl branch for n-DAMO. The observed low ratios of non-synonymous substitutions to synonymous substitutions (pN/pS) in n-DAMO-related genes across these habitats suggest a pronounced purifying selection that is critical for the survival of NC10 bacteria in oligotrophic deep-sea environments. These findings not only advance our understanding of the evolutionary adaptations of NC10 bacteria but also underscore the intricate coupling between the carbon and nitrogen cycles within deep-sea ecosystems, driven by this bacterial phylum.

Cryptic exon inclusion is a molecular signature of LATE-NC in aging brains.

The aggregation, mislocalization, and phosphorylation of TDP-43 are pathologic hallmarks of several neurodegenerative diseases and provide a defining criterion for the neuropathologic diagnosis of Limbic-predominant Age-related TDP-43 Encephalopathy (LATE). LATE neuropathologic changes (LATE-NC) are often comorbid with other neurodegenerative pathologies including Alzheimer's disease neuropathologic changes (ADNC). We examined whether TDP-43 regulated cryptic exons accumulate in the hippocampus of neuropathologically confirmed LATE-NC cases. We found that several cryptic RNAs are robustly expressed in LATE-NC cases with or without comorbid ADNC and correlate with pTDP-43 abundance; however, the accumulation of cryptic RNAs is more robust in LATE-NC with comorbid ADNC. Additionally, cryptic RNAs can robustly distinguish LATE-NC from healthy controls and AD cases. These findings expand our current understanding and provide novel potential biomarkers for LATE pathogenesis.

Identification and bioinformatics analysis of a novel variant in the HERC2 gene in a patient with intellectual developmental disorder.

HERC2-associated neurodevelopmental-disorders(NDD) encompass a cluster of medical conditions that arise from genetic mutations occurring within the HERC2 gene. These disorders can manifest a spectrum of symptoms that impact the brain and nervous system, including delayed psychomotor development, severe mental retardation, seizures and autistic features. Whole-Exome-Sequencing(WES) was performed on a ten-year-old male patient referred to the genetic center for genetic analysis. Blood samples were collected from the proband, his parents, and his sister to extract DNA. PCR-Sanger-sequencing was utilized to validate the findings obtained from WES. In order to obtain a more thorough understanding of the impact of the mutation, an extensive analysis was conducted using bioinformatics tools. WES data analysis identified a homozygous single nucleotide change(C > T) at position c14215 located in exon ninety-two of the HERC2 gene (NC_000015.10(NM_004667.6):c.14215C > T). The absence of this mutation among our cohort composed of four hundred normal healthy adults from the same ethnic group, and its absence in any other population database, confirms the pathogenicity of the mutation. This study revealed that the substitution of arginine with a stop codon within the Hect domain caused a premature stop codon at position 4739(p.Arg4739Ter). This mutation significantly results in the production of a truncated HERC2 protein with an incomplete HECT domain. In the final stage of ubiquitin attachment, HECT E3 ubiquitin ligases play a catalytic role by creating a thiolester intermediate using their conserved catalytic cysteine (Cys4762). This intermediate is formed before ubiquitin is transferred to a substrate protein. The truncation of the HERC2 protein is expected to disrupt its ability to perform this function, which could potentially hinder important regulatory processes related to the development and maintenance of synapses. The identification of a novel pathogenic variant, NC_000015.10(NM_004667.6):c.14215C > T, located within the ninety-two exon of the HERC2 gene, is notable for its association with an autosomal recessive inheritance pattern in cases of Intellectual Developmental Disorder(IDD). In the end, this variant could potentially play a part in the underlying mechanisms leading to the onset of intellectual developmental disorder.

Customized Synthesis of MOF Nanoplates via Molecular Scalpel Strategy for Efficient Oxygen Reduction in Zn-Air Batteries.

The production of metal-organic framework (MOF) nanoplates with well-defined geometric morphology is remarkable for expanding their applications. Herein, the cobalt-based MOF nanoplates with hexagonal channels from a layer-pillared MOF are accomplished, via a molecular scalpel strategy, utilizing monodentate pyridine to replace the bidentate 4,4'-bipyridine. The morphology can be modified from nanorods to nanoplates with controllable thickness tuned by the amounts of pyridine. Succeeding carbonization treatment transforms the MOF nanoplates into Co particles homogeneously encapsulated in the nitrogen-doped carbon layers. The prepared catalyst with a unique platelike morphology displays a high half-wave potential of 0.88 V in oxygen reduction reaction. When used in primary Zn-air batteries, it delivers a high peak power density of 280 mW cm-2 . This work clarifies the structure-morphology-reactivity connection of MOF nanoplates.

NiCo-LDH coupled with 2D ZIF-derived Co nitrogen doped carbon nanosheet arrays as a self-supporting electrocatalyst for detection of formaldehyde.

Formaldehyde is susceptible to illegal addition to foodstuffs to extend their shelf life due to its antimicrobial, preservative and bleaching properties. In this study, a self-supporting "nanosheet on nanosheet" arrays electrocatalyst with core-shell heterostructure was prepared in situ by coupling NiCo layer double hydroxide with 2D ZIF derived Co-nitrogen-doped porous carbon on carbon cloth (Co-N/C@NiCo-LDH NSAs/CC). Co-N/C nanosheet arrays act as a scaffold core with good electrical conductivity, providing more NiCo-LDH nucleation sites to avoid NiCo-LDH agglomeration, thus having fast mass/charge transfer performance. While the NiCo-LDH nanosheet arrays shell with high specific surface area provide more active sites for electrochemical reactions. As an electrocatalytic sensing electrode, Co-N/C@NiCo-LDH NSAs/CC has a wide linear range of 1 µM to 13 mM for formaldehyde detection, and the detection limit is 82 nM. Besides, the sensor has been applied to the detection of formaldehyde in food samples with satisfactory results.

Determinants of confrontation naming deficits on the Boston Naming Test associated with transactive response DNA-binding protein 43 pathology.

OBJECTIVE: To determine whether poorer performance on the Boston Naming Test (BNT) in individuals with transactive response DNA-binding protein 43 pathology (TDP-43+) is due to greater loss of word knowledge compared to retrieval-based deficits. METHODS: Retrospective clinical-pathologic study of 282 participants with Alzheimer's disease neuropathologic changes (ADNC) and known TDP-43 status. We evaluated item-level performance on the 60-item BNT for first and last available assessment. We fit cross-sectional negative binomial count models that assessed total number of incorrect items, number correct of responses with phonemic cue (reflecting retrieval difficulties), and number of "I don't know" (IDK) responses (suggestive of loss of word knowledge) at both assessments. Models included TDP-43 status and adjusted for sex, age, education, years from test to death, and ADNC severity. Models that evaluated the last assessment adjusted for number of prior BNT exposures. RESULTS: 43% were TDP-43+. The TDP-43+ group had worse performance on BNT total score at first (p = .01) and last assessments (p = .01). At first assessment, TDP-43+ individuals had an estimated 29% (CI: 7%-56%) higher mean number of incorrect items after adjusting for covariates, and a 51% (CI: 15%-98%) higher number of IDK responses compared to TDP-43-. At last assessment, compared to TDP-43-, the TDP-43+ group on average missed 31% (CI: 6%-62%; p = .01) more items and had 33% more IDK responses (CI: 1% fewer to 78% more; p = .06). CONCLUSIONS: An important component of poorer performance on the BNT in participants who are TDP-43+ is having loss of word knowledge versus retrieval difficulties.

A Cost-Effective Approach to Resistant AV Fistula Stenosis: Successful Treatment Using Coronary OPN NC® Balloon in a Low-Income Setting.

Stenosis in the anastomotic site or venous limb of an arteriovenous fistula (AVF) is the most frequent cause of AVF failure. Percutaneous angioplasty with a standard or high-pressure balloon is the first-line treatment for AVF stenosis due to its higher technical success rate (90%) and lower complication rate (4%). Almost 20% of stenosis cases are resistant or undilatable by regular-pressure balloon angioplasty due to fibrosis, leading to technical failure or restenosis. Alternative therapies, such as atherectomy devices or cutting balloons, are expensive and difficult to obtain in low-income developing countries. We successfully treated resistant AVF stenosis with a coronary OPN-NC® ultra-high-pressure balloon and produced a good angiographic result with technical success. Coronary hardware is easily available and relatively cheaper compared to dedicated peripheral balloons or devices in our country due to reuse, which can be a boon in such type of cases. According to the standard hospital protocol, Cathlab hardware was reused.

Fermented black ginseng extract prevents UVB-induced inflammation by regulating the nc886-PKR pathway in human keratinocytes.

BACKGROUND: Continuous exposure of the skin to ultraviolet B (UVB) rays can cause inflammation and photodamage. In previous studies, we observed that the upregulation of nc886, a noncoding RNA (ncRNA), can alleviate UVB-induced inflammation through suppression of the protein kinase RNA (PKR) pathway. We aim to investigate the effect of fermented black ginseng extract (FBGE), which has been shown to increase the expression of nc886, on UVB-induced inflammation in keratinocytes. METHODS: To confirm the cytotoxicity of FBGE, MTT assay was performed, and no significant cytotoxicity was found on human keratinocytes. The efficacies of FBGE were assessed through qPCR, Western blotting, and ELISA analysis which confirmed regulation of UVB-induced inflammation. RESULTS: The analysis results showed that FBGE inhibited the decrease in nc886 expression and the increase in the methylated nc886 caused by UVB. It also prevented the UVB-induced increase of metalloproteinase-9 (MMP-9), metalloproteinase-1 (MMP-1), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α). Additionally, FBGE suppressed the PKR-MAPK pathways activated by UVB. CONCLUSION: These results implicate that FBGE can alleviate UVB-induced inflammation through regulation of the nc886-PKR pathway.