Prevalence, Clinical Characteristics, and Treatment Status of Hepatitis C Virus Infection among People Who Use Drugs in South Korea: A Prospective Multicenter Study.

Background/aims: Data on hepatitis C virus (HCV) infection among people who use drugs (PWUD) in South Korea is limited. This study investigated the prevalence, clinical characteristics, and treatment rates of HCV infection among PWUD.

Methods: From August 2022 to May 2024, 342 PWUD were prospectively enrolled in four hospitals covering 95% of PWUD care in Korea.

Combined clinical, structural and cellular studies discriminate pathogenic and benign TRPV4 variants.

Dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) cause diverse and largely distinct channelopathies, including inherited forms of neuromuscular disease, skeletal dysplasias and arthropathy. Pathogenic TRPV4 mutations cause gain of ion channel function and toxicity that can be rescued by small molecule TRPV4 antagonists in cellular and animal models, suggesting that TRPV4 antagonism could be therapeutic for patients. Numerous variants in TRPV4 have been detected with targeted and whole exome/genome sequencing, but for the vast majority, their pathogenicity remains unclear.

Stabilization of activated mast cells by ORAI1 inhibitor suppresses peanut-induced anaphylaxis and acute diarrhea.

Mast cell (MC) activation triggered by immunoglobulin E (IgE)-antigen crosslinking involves intracellular Ca influx through the ORAI1 channel, which precedes granule exteriorization and de novo synthesis of mediators. Pharmacologically suppressing MCs via the inhibition of the ORAI1 Ca channel may represent a potential strategy for preventing anaphylaxis. This study demonstrated that peanut-induced anaphylaxis in sensitized mice resulted in significant hypothermia and acute diarrhea.

In vitro production of N-degron fused proteins and its application.

The N-degron pathway, first discovered several decades ago by Varshavsky's laboratory, controls the half-life of target proteins depending on their N-terminal residues. In vivo cell biology studies have established the physiological role of the N-degron pathway. However, in vitro studies such as biochemical assays and structural biology studies are relatively limited.

TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease.

Crosstalk between ion channels and small GTPases is critical during homeostasis and disease, but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, calcium-permeable cation channel that has emerged as a potential therapeutic target in multiple conditions. Gain-of-function mutations also cause hereditary neuromuscular disease.

Structural insights into TRPV4-Rho GTPase signaling complex function and disease.

Crosstalk between ion channels and small GTPases is critical during homeostasis and disease , but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, calcium-permeable cation channel that has emerged as a potential therapeutic target in multiple conditions . Gain-of-function mutations also cause hereditary neuromuscular disease .

A cross-species approach using an in vivo evaluation platform in mice demonstrates that sequence variation in human RABEP2 modulates ischemic stroke outcomes.

Ischemic stroke, caused by vessel blockage, results in cerebral infarction, the death of brain tissue. Previously, quantitative trait locus (QTL) mapping of cerebral infarct volume and collateral vessel number identified a single, strong genetic locus regulating both phenotypes. Additional studies identified RAB GTPase-binding effector protein 2 (Rabep2) as the casual gene.

Vanilloid-dependent TRPV1 opening trajectory from cryoEM ensemble analysis.

Single particle cryo-EM often yields multiple protein conformations within a single dataset, but experimentally deducing the temporal relationship of these conformers within a conformational trajectory is not trivial. Here, we use thermal titration methods and cryo-EM in an attempt to obtain temporal resolution of the conformational trajectory of the vanilloid receptor TRPV1 with resiniferatoxin (RTx) bound. Based on our cryo-EM ensemble analysis, RTx binding to TRPV1 appears to induce intracellular gate opening first, followed by selectivity filter dilation, then pore loop rearrangement to reach the final open state.

Heat-dependent opening of TRPV1 in the presence of capsaicin.

Transient receptor potential vanilloid member 1 (TRPV1) is a Ca-permeable cation channel that serves as the primary heat and capsaicin sensor in humans. Using cryo-EM, we have determined the structures of apo and capsaicin-bound full-length rat TRPV1 reconstituted into lipid nanodiscs over a range of temperatures. This has allowed us to visualize the noxious heat-induced opening of TRPV1 in the presence of capsaicin.

Structural basis for the N-degron specificity of ClpS1 from Arabidopsis thaliana.

The N-degron pathway determines the half-life of proteins in both prokaryotes and eukaryotes by precisely recognizing the N-terminal residue (N-degron) of substrates. ClpS proteins from bacteria bind to substrates containing hydrophobic N-degrons (Leu, Phe, Tyr, and Trp) and deliver them to the caseinolytic protease system ClpAP. This mechanism is preserved in organelles such as mitochondria and chloroplasts.

Targeted Degradation of Transcription Coactivator SRC-1 through the N-Degron Pathway.

Aberrantly elevated steroid receptor coactivator-1 (SRC-1) expression and activity are strongly correlated with cancer progression and metastasis. Here we report, for the first time, the development of a proteolysis targeting chimera (PROTAC) that is composed of a selective SRC-1 binder linked to a specific ligand for UBR box, a unique class of E3 ligases recognizing N-degrons. We showed that the bifunctional molecule efficiently and selectively induced the degradation of SRC-1 in cells through the N-degron pathway.

Hypofractionated stereotactic radiosurgery for large-sized skull base meningiomas.

Purpose: Although stereotactic radiosurgery (SRS) has been proven to be effective and safe for treating intracranial meningiomas, concerns have been raised about the use of SRS for large-sized tumors involving the skull base that frequently encroach onto adjacent critical neural structures. The purpose of this study was to investigate the role of hypofractionated SRS as a therapeutic option for large-sized skull base meningiomas.

Methods: Thirty-one consecutive patients (median age: 55 years, 9 men and 22 women) who had been treated with hypofractionated SRS using CyberKnife for large-sized skull base meningiomas (> 10 cm in volume, median of 18.

Radiosurgery for Cerebral Arteriovenous Malformation (AVM) : Current Treatment Strategy and Radiosurgical Technique for Large Cerebral AVM.

Arteriovenous malformations (AVMs) are congenital anomalies of the cerebrovascular system. AVM harbors 2.2% annual hemorrhage risk in unruptured cases and 4.

Development and validation of a risk scoring model for postoperative adult moyamoya disease.

Objective: The current grading system for moyamoya disease (MMD) is focused on angiographic studies with limited clinical application. The authors aimed to determine relevant factors that may impact postoperative outcome and establish a scoring system to predict the functional outcome.

Methods: Adult patients with MMD who underwent treatment between 1998 and 2016 were included.

Role of gamma knife radiosurgery for recurrent or residual World Health Organization grade II and III intracranial meningiomas.

To analysis the role of gamma knife radiosurgery (GKRS) in treatment of the recurrent or residual World Health Organization (WHO) grade II and III meningiomas. Between 1995 and 2015, a total of 1163 meningioma patients were treated with GKRS at our single institute; 26 atypical and 6 anaplastic meningiomas were enrolled. The group consisted of 16 men and 16 women with a median age of 59.

Use of the LC3B-fusion technique for biochemical and structural studies of proteins involved in the N-degron pathway.

The N-degron pathway, formerly the N-end rule pathway, is a protein degradation process that determines the half-life of proteins based on their N-terminal residues. In contrast to the well-established studies over decades, studies of this pathway, including biochemical characterization and high-resolution structures, are relatively limited. In this study, we have developed a unique fusion technique using microtubule-associated protein 1A/1B light chain 3B, a key marker protein of autophagy, to tag the N terminus of the proteins involved in the N-degron pathway, which enables high yield of homogeneous target proteins with variable N-terminal residues for diverse biochemical studies including enzymatic and binding assays and substrate identification.

Impact of clinicopathologic features on leptomeningeal metastasis from lung adenocarcinoma and treatment efficacy with epidermal growth factor receptor tyrosine kinase inhibitor.

Background: We investigated the risk factors for leptomeningeal carcinomatosis (LMC) and compared clinical efficacies of various treatment modalities including intrathecal (IT) chemotherapy in patients with lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations.

Methods: Using clinical research data from the Asan Medical Center, we retrospectively analyzed data of patients diagnosed with LMC, confirmed via cerebrospinal fluid (CSF) analysis from January 2008 to December 2017.

Results: We identified 1189 patients with lung adenocarcinoma harboring EGFR mutations.

Single-fraction versus hypofractionated stereotactic radiosurgery for medium-sized brain metastases of 2.5 to 3 cm.

Purpose: Given recently suggested utility of hypofractionated stereotactic radiosurgery (SRS) in treating large brain metastases (BMs) > 3 cm, we sought to prospectively control tumor size variable to investigate the efficacy and safety of hypofractionated SRS for medium-sized BMs (2.5 to 3 cm) compared with single-fraction SRS.

Methods: Between 2011 and 2015, a total of 100 patients with newly diagnosed BMs (n = 105) of 2.

Endoribonucleolytic Cleavage of mA-Containing RNAs by RNase P/MRP Complex.

N-methyladenosine (mA) is the most abundant internal modification in RNAs and plays regulatory roles in a variety of biological and physiological processes. Despite its important roles, the molecular mechanism underlying mA-mediated gene regulation is poorly understood. Here, we show that mA-containing RNAs are subject to endoribonucleolytic cleavage via YTHDF2 (mA reader protein), HRSP12 (adaptor protein), and RNase P/MRP (endoribonucleases).

Pediatric Intracranial Aneurysms: Favorable Outcomes Despite Rareness and Complexity.

Objective: Pediatric intracranial aneurysms (IAs) are rare and differ from their adult counterparts in terms of their aneurysmal characteristics, presentation, treatment, and outcomes. Their treatment is often more difficult and complex compared with that of adults. However, studies outlining the clinical effect of pediatric IAs remain sparse.

eIF4A3 Phosphorylation by CDKs Affects NMD during the Cell Cycle.

Exon junction complexes (EJCs) loaded onto spliced mRNAs during splicing serve as molecular markers for various post-transcriptional gene-regulatory processes, including nonsense-mediated mRNA decay (NMD). Although the composition and structure of EJCs are well characterized, the mechanism regulating EJC deposition remains unknown. Here we find that threonine 163 (T163) within the RNA-binding motif of eIF4A3 (a core EJC component) is phosphorylated by cyclin-dependent protein kinases 1 and 2 in a cell cycle-dependent manner.

Long-Term Efficacy and Tolerability of Gamma Knife Radiosurgery for Growth Hormone-Secreting Adenoma: A Retrospective Multicenter Study (MERGE-001).

Objective: Little is known about the long-term efficacy, prognostic factors, and tolerability of gamma knife radiosurgery (GKS) for acromegaly. The aim of this study was to investigate long-term hormonal effects, prognostic factors, and tolerability of GKS in patients with growth hormone-secreting adenoma.

Methods: A retrospective multicenter study over 25 years with a median follow-up of 85.

Cyberknife Dosimetric Planning Using a Dose-Limiting Shell Method for Brain Metastases.

Objective: We investigated the effect of optimization in dose-limiting shell method on the dosimetric quality of CyberKnife (CK) plans in treating brain metastases (BMs).

Methods: We selected 19 BMs previously treated using CK between 2014 and 2015. The original CK plans (CKoriginal) had been produced using 1 to 3 dose-limiting shells : one at the prescription isodose level (PIDL) for dose conformity and the others at lowisodose levels (10-30% of prescription dose) for dose spillage.

pH-dependent regulation of SQSTM1/p62 during autophagy.

During macroautophagy/autophagy, SQSTM1/p62 plays dual roles as a key mediator of cargo selection and as an autophagic substrate. SQSTM1 links N-degrons and/or ubiquitinated cargoes to the autophagosome by forming homo- or hetero-oligomers, although its N-degron recognition and oligomerization mechanisms are not well characterized. We recently found that SQSTM1 is a novel type of N-recognin whose ZZ domain provides a negatively-charged binding pocket for Arg-charged N-degron (Nt-Arg), a prototype type-1 substrate.