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Arenicolide Family Macrolides Provide a New Therapeutic Lead Combating Multidrug-Resistant Tuberculosis
No full textThe emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (Mtb) poses a significant threat to health globally. During searching for new chemical entities regulating MDR- and XDR-Mtb, chemical investigation of the black oil beetle gut bacterium Micromonospora sp. GR10 led to the discovery of eight new members of arenicolides along with the identification of arenicolide A (Ar-A, 1), which was a previously reported macrolide with incomplete configuration. Genomic analysis of the bacterial strain GR10 revealed their putative biosynthetic pathway. Quantum mechanics-based computation, chemical derivatizations, and bioinformatic analysis established the absolute stereochemistry of Ar-A and arenicolides D-K (Ar-D-K, 2-9) completely for the first time. Biological studies of 1-9 revealed their antimicrobial activity against MDR and XDR strains of Mtb. Ar-A had the most potent in vitro antimicrobial efficacy against MDR- and XDR-Mtb. Mechanistically, Ar-A induced ATP depletion and destabilized Mtb cell wall, thereby inhibiting growth. Notably, Ar-A exerted a significant antimicrobial effect against Mtb in macrophages, was effective in the treatment of Mtb infections, and showed a synergistic effect with amikacin (AMK) in a mouse model of MDR-Mtb lung infection. Collectively, our findings indicate Ar-A to be a promising drug lead for drug-resistant tuberculosis.Y
Dimension estimates for badly approximable affine forms
No full textFor given & varepsilon;>0 and b is an element of R-m, we say that a real mxn matrix A is & varepsilon;-badly approximable for the target b if lim inf(q is an element of Zn,& Vert;q & Vert;->infinity)& Vert;q & Vert;(n)< Aq-b >(m)>=& varepsilon;, where <& sdot;> denotes the distance from the nearest integral vector. In this article, we obtain upper bounds for the Hausdorff dimensions of the set of & varepsilon;-badly approximable matrices for fixed target b and the set of & varepsilon;-badly approximable targets for fixed matrix A. Moreover, we give a Diophantine condition of A equivalent to the full Hausdorff dimension of the set of & varepsilon;-badly approximable targets for fixed A. The upper bounds are established by effectivizing entropy rigidity in homogeneous dynamics, which is of independent interest. For the A-fixed case, our method also works for the weighted setting where the supremum norms are replaced by certain weighted quasinorms.Y
Unraveling membrane protein localization and interactions in nanodiscs
No full textNanodiscs, consisting of a lipid bilayer surrounded by membrane scaffold proteins (MSPs), are extensively used to study membrane proteins (MPs) because they provide a stable lipid environment. However, the precise mechanism governing MP behavior within the nanodisc remains elusive. Here, we examined the cryo-EM structures of various MPs reconstituted in nanodiscs from EMPIAR. By analyzing the heterogeneity and interactions in the nanodiscs, we discovered that MPs display a distinct spatial preference toward the edges of the nanodisc shells. Furthermore, MPs can establish direct, amphipathic interactions with the MSPs, causing a reduction in local protein dynamics. These interactions may rearrange MSP-MSP interactions into MP-MSP interactions. Collectively, we provide structural insights into how nanodiscs contribute to MP structural behavior and dynamics.Impact statement Nanodiscs are used to study membrane proteins (MPs), but the mechanisms governing the behavior of MPs within nanodiscs remain elusive. Here, we provide structural insights into how nanodiscs contribute to the behavior of MPs, which will aid the interpretation of cryo-EM studies performed using nanodiscs.N
New species and new records of Cosmolaelaps Berlese (Acari: Laelapidae) from the Republic of Korea, with a review of the Korean species of the genus
No full textThis paper reports on six species of the genus Cosmolaelaps (Laelapidae) in the Republic of Korea: Cosmolaelaps brevipedestra (Karg) and C. robustochaetes Ma & Lin collected from soil-litter, and Cosmolaelaps cavosternalis sp. nov., C. hallasanensis sp. nov., C. oedipus sp. nov., C. sansungensis sp. nov. collected in association with ants or their nests. The new species are described and illustrated based on morphological characteristics of the adults and immature stages and compared with closely related species. We provide additional morphological information and new illustrations for two other species to facilitate species delimitation. An identification key to all known Korean Cosmolaelaps species is presented, and ambiguities on the identification of C. koreicus Che & Seo are discussed.N
Clinical Characterization, Natural History, and Detailed Phenotyping of NMNAT1-Associated Leber Congenital Amaurosis
No full textPurpose: To characterize the clinical phenotype and disease progression in patients with NMNAT1-associated Leber congenital amaurosis (LCA) within the Korean population. Design: Retrospective, observational case series. Subjects: Fourteen patients with LCA with biallelic variants of NMNAT1 at a single tertiary referral center. Methods: Electronic medical records were reviewed for medical history, ophthalmic examinations, and molecular diagnoses, both cross-sectionally and longitudinally. Main Outcome Measures: Ophthalmic examination findings were evaluated and retinal phenotypic characteristics were assessed using multimodal imaging. Results: All patients exhibited early-onset, rapidly progressive bilateral retinal degeneration with pronounced central involvement. The condition was characterized by multiple atrophic lesions that coalesced into a large central retinal scar by age 2. The condition stabilized around 4 years of age. Fluorescein angiography demonstrated central hypofluorescence with visible choroidal vasculature. Optical coherence tomography showed significant retinal thinning, outer retinal layer disruption, and retinal pigment epithelial atrophy. Most patients maintained light perception vision or better, with minimal deterioration of visual acuity after the age of 2. All patients were hyperopic and exhibited undetectable electroretinography and visual-evoked potential responses. Conclusions: NMNAT1-associated LCA is characterized by severe, early-onset retinal degeneration with rapid progression, followed by stabilization. This distinct temporal pattern of disease progression suggests a potential therapeutic window in early childhood, emphasizing the importance of early diagnosis and regular monitoring for potential interventions.N
Dual Nozzle-Assisted Deterministic Encapsulation of Triple Particles for Screening NK-Cell Cytotoxicity Against Circulating Tumor Cell Clusters
No full textCirculating tumor cell (CTC) clusters represent formidable precursors of cancer metastasis due to their heightened immune resistance against natural killer (NK) cells. Despite this, the cytotoxicity of NK cells against CTC clusters, particularly their interaction with other immune cells such as neutrophils, remains inadequately examined. This study introduces a dual-nozzle integrated droplet microfluidic chip (dual-nozzle chip) designed to facilitate the deterministic encapsulation of three distinct cell types-CTCs, NK cells, and neutrophils-to monitor the dynamic cytotoxicity between immune cells and target cells. The dual-nozzle chip comprises double-spiral channels and a serpentine channel for inertial cell focusing, alongside dual-nozzle oil phases employed to generate monodisperse droplets at high flow rates. Utilizing Rayleigh-Plateau instability, the focused cell streams, characterized by high inertia, undergo pinching off into monodisperse droplets at the flow-focusing junction, where dual-nozzle oil phases are introduced. Consequently, triple cells are paired at the desired ratios, overcoming the intrinsic challenge posed by the Poisson distribution. A droplet-based assay demonstrates that NK cell-mediated cytotoxicity varies depending on the type of cancer cells and the presence of suppressor cells. The design strategy of the dual-nozzle chip exhibits promises for broader applications, emphasizing its potential for analyzing diverse cell-to-cell interactions.N
The KAPARD guidelines for atopic dermatitis in children and adolescents: Part II. Systemic treatment, novel therapeutics, and adjuvant therapy
No full textAtopic dermatitis is the most common chronic inflammatory skin disease in children and adolescents. The Korean Academy of Pediatric Allergy and Respiratory Disease published the Atopic Dermatitis Treatment Guideline in 2008, which has been helpful in atopic dermatitis treatment until now. Various reports on the development and effectiveness of new drugs have suggested that there is a need to develop and revise old treatment guidelines. Part 1 aimed to provide evidence-based recommendations for skin care management and topical treatment for atopic dermatitis. Part 2 focuses on systemic treatment, novel therapeutics, and adjuvant therapy. The goal of this guideline is intended to assist front-line doctors treating pediatric and adolescent atopic dermatitis patients make safer, more effective, and more rational decisions regarding systemic treatment, novel therapeutics, and adjuvant therapy by providing evidence-based recommendations with a clear level of evidence and benefit regarding treatment.Y
Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Primary Results From TROPION-Breast01
No full textPURPOSE The global, phase 3, open-label, randomized TROPION-Breast01 study assessed the trophoblast cell surface antigen 2-directed antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) versus investigator's choice of chemotherapy (ICC) in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. METHODS Adult patients with inoperable/metastatic HR+/HER2- breast cancer, who had disease progression on endocrine therapy, for whom endocrine therapy was unsuitable, and had received one to two previous lines of chemotherapy in the inoperable/metastatic setting, were randomly assigned 1:1 to Dato-DXd (6 mg/kg once every 3 weeks) or ICC (eribulin/vinorelbine/capecitabine/gemcitabine). Dual primary end points were progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). RESULTS Patients were randomly assigned to Dato-DXd (n = 365) or ICC (n = 367). Dato-DXd significantly reduced the risk of progression or death versus ICC (PFS by BICR hazard ratio [HR], 0.63 [95% CI, 0.52 to 0.76]; P < .0001). Consistent PFS benefit was observed across subgroups. Although OS data were not mature, a trend favoring Dato-DXd was observed (HR, 0.84 [95% CI, 0.62 to 1.14]). The rate of grade >= 3 treatment-related adverse events (TRAEs) with Dato-DXd was lower than ICC (20.8% v 44.7%). The most common TRAEs (any grade; grade >= 3) were nausea (51.1%; 1.4%) and stomatitis (50%; 6.4%) with Dato-DXd and neutropenia (grouped term, 42.5%; 30.8%) with ICC. CONCLUSION Patients receiving Dato-DXd had statistically significant and clinically meaningful improvement in PFS and a favorable and manageable safety profile, compared with ICC. Results support Dato-DXd as a novel treatment option for patients with inoperable/metastatic HR+/HER2- breast cancer who have received one to two previous lines of chemotherapy in this setting.N
Nanoscale gradient interface for efficient heat transfer
No full textColloidal liquid metals with gradient heterointerfaces offer a scalable and cost-effective solution to the persistent challenges of thermal management in high-performance electronics.N
RNA N6-Methyladenosine-Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN-γ Signaling in Gastric Cancer
No full textImmunotherapy holds potential as a treatment for gastric cancer (GC), though immune checkpoint inhibitor (ICI) resistance remains an obstacle. One resistance mechanism involves defects in interferon-γ (IFN-γ) signaling, in which IFN-γ is linked to improved responsiveness to ICIs. Herein, the roles of RNA N6-methyladenosine (m6A) modifications in regulation of IFN-γ signaling and the responsiveness to ICIs are unveiled. The m6A-binding protein YTH N6-methyladenosine RNA-binding protein F1 (YTHDF1) is overexpressed in GC tissues, correlating with the suppression of cancer immunity and poorer survival rates. YTHDF1 overexpression impaired the responsiveness to IFN-γ in GC cells, and knockdown studies indicated the redundant effects of YTHDF2 and YTHDF3 with YTHDF1 in IFN-γ responsiveness. RNA immunoprecipitation sequencing revealed YTHDFs directly target interferon regulatory factor 1 (IRF1) mRNA, a master regulator of IFN-γ signaling, leading to reduced RNA stability and consequent downregulation of IFN-γ signaling. Furthermore, in mouse syngeneic tumor models, Ythdf1 depletion in cancer cells resulted in reduced tumor growth and increased tumor-infiltrating lymphocytes, which are attributed to the augmentation of IFN-γ signaling. Collectively, these findings highlight how YTHDFs modulate cancer immunity by influencing IFN-γ signaling through IRF1 regulation, suggesting their viability as therapeutic targets in cancer immunotherapy.Y