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1.
Medicine (Baltimore) ; 103(38): e39853, 2024 Sep 20.
Article in English | MEDLINE | ID: mdl-39312311

ABSTRACT

To investigate the factors influencing glycemic control in gestational diabetes mellitus (GDM) patients and their impacts on pregnancy outcomes, providing insights for GDM management. Pregnant women diagnosed with GDM at a tertiary hospital in western China in 2019. Participants were categorized based on varying levels of glycemic control during pregnancy. A retrospective analysis was conducted, utilizing univariate and multivariate regression analyses, to identify factors influencing glycemic control in GDM patients. Based on various approaches to manage glucose, subjects were categorized into A1 (diet and exercise guidance alone) and A2 (insulin usage) groups. Based on whether glucose levels met the glycemic target in women with GDM, subjects were further divided into satisfactory and unsatisfactory groups. A total of 2621 women meeting the inclusion criteria were enrolled in the study. Independent factors associated with GDM A2 included higher prepregnancy body mass index (odds ratio [OR] = 1.070, 95% confidence interval [CI]: 1.019-1.122, P = .006), a history of GDM (OR = 1.888, 95% CI: 1.052-3.389, P = .033), elevated fasting plasma glucose (FPG) in early pregnancy (OR = 1.828, 95% CI: 1.320-2.532, P < .001), elevated 1-hour postprandial glucose (1-h PG) (OR = 1.126, 95% CI: 1.0091.256, P = .034), and 2-h PG by oral glucose tolerance test (OGTT) (OR = 1.181, 95% CI: 1.046-1.333, P = .007). Higher FPG by OGTT was an independent risk factor for unsatisfactory glycemic control (OR = 1.590, 95% CI: 1.273-1.985, P < .001). Compared with the A1 group, the A2 group has longer hospitalization, higher rates of cesarean section, placenta previa, and neonatal pneumonia (P < .05). Compared with the satisfactory group, the unsatisfactory group has lower gestational age, lower rates of cesarean section and placenta previa, and higher rates of postpartum hemorrhage for mothers; lower length and weight, and higher rates of premature birth, jaundice, hypoglycemia, pneumonia, respiratory distress syndrome, anemia, hospitalization, and hospitalization for more than 15 days in both pediatric unit and neonatal intensive care unit for newborns (P < .05). Elevated prepregnancy body mass index, FPG in early pregnancy, 1-h and 2-h PG during OGTT, and with a history with GDM are independent factors influencing insulin utilization, while elevated 0-h PG is an independent influencing factor of unsatisfactory glycemic control. Poor glycemic control has negative impacts on both maternal and fetal outcomes under 2 classifications.


Subject(s)
Blood Glucose , Diabetes, Gestational , Glycemic Control , Humans , Female , Pregnancy , Diabetes, Gestational/epidemiology , Diabetes, Gestational/blood , Retrospective Studies , Adult , China/epidemiology , Glycemic Control/methods , Blood Glucose/analysis , Body Mass Index , Pregnancy Outcome/epidemiology , Insulin/therapeutic use , Insulin/blood , Glucose Tolerance Test , Risk Factors
2.
J Am Chem Soc ; 2024 Sep 26.
Article in English | MEDLINE | ID: mdl-39324803

ABSTRACT

C3H6 is a crucial building block for many chemicals, yet separating it from other C3 hydrocarbons presents a significant challenge. Herein, we report a hydrolytically stable Cu4I4-triazolate metal-organic framework (MOF) (JNU-9-CH3) featuring 1D channels decorated with readily accessible iodine and nitrogen atoms from Cu4I4 clusters and triazolate linkers, respectively. The exposed iodine and nitrogen atoms allow for cooperative binding of C3 hydrocarbons, as evidenced by in situ single-crystal crystallography and Raman spectroscopy studies. As a result, JNU-9-CH3 exhibits substantially stronger binding affinity for C3H4, CH2═C═CH2, and C3H8 than that for C3H6. Breakthrough experiments confirm its ability to directly separate C3H6 (≥99.99%) from C3H4/CH2═C═CH2/C3H8/C3H6 mixtures at varying ratios and flow rates. Overall, we illustrate the cooperative binding of C3 hydrocarbons in a Cu4I4-triazolate MOF and its highly efficient C3H6 purification from quaternary C3 mixtures. The study highlights the potential of MOF adsorbents with metal-iodide clusters for cooperative bindings and hydrocarbon separations.

3.
Tissue Barriers ; : 2392361, 2024 Sep 12.
Article in English | MEDLINE | ID: mdl-39264117

ABSTRACT

Impairment of the blood - brain barrier (BBB) and subsequent inflammatory responses contribute to the development of human immunodeficiency virus (HIV)-1-associated neurocognitive disorders (HAND). Apelin-13, the most abundant member of the apelin family, acts as the ligand of the angiotensin receptor-like 1 (APJ). However, its pharmacological function in HAND and its underlying mechanism are unknown. In the current study, we report that the presence of HIV-1 Tat reduced the levels of Apelin-13 and APJ in the cortex tissue of mice. Importantly, Apelin-13 preserved BBB integrity against HIV-1 Tat in mice by increasing the expression of the tight junction protein zonula occludens-1 (ZO-1) and occludin. Interestingly, increased macrophage infiltration, indicated by elevated CD68-positive staining was observed in the cortex after stimulation with HIV-1, which was mitigated by the administration of Apelin-13. Correspondingly, Apelin-13 reduced the expression of monocyte chemoattractant protein-1; (MCP-1). An in vitro two-chamber and two-cell trans-well assay demonstrated that HIV-1 Tat challenge significantly promoted macrophage migration, which was notably attenuated by the introduction of Apelin-13. Accordingly, treatment with Apelin-13 restored the HIV-1 Tat-induced reduction of occludin and ZO-1, while preventing the upregulation of MCP-1 in human brain microvascular endothelial cells (HBMVECs). Our results suggest that Apelin-13 may reduce macrophage infiltration into brain tissues and mitigate BBB dysfunction in patients with HAND.

4.
J Nanobiotechnology ; 22(1): 484, 2024 Aug 13.
Article in English | MEDLINE | ID: mdl-39138477

ABSTRACT

BACKGROUND: Inflammatory bowel disease (IBD) is a progressive and debilitating inflammatory disease of the gastrointestinal tract (GIT). Despite recent advances, precise treatment and noninvasive monitoring remain challenging. METHODS: Herein, we developed orally-administered, colitis-targeting and hyaluronic acid (HA)-modified, core-shell curcumin (Cur)- and cerium oxide (CeO2)-loaded nanoprobes (Cur@PC-HA/CeO2 NPs) for computed tomography (CT) imaging-guided treatment and monitoring of IBD in living mice. RESULTS: Following oral administration, high-molecular-weight HA maintains integrity with little absorption in the upper GIT, and then actively accumulates at local colitis sites owing to its colitis-targeting ability, leading to specific CT enhancement lasting for 24 h. The retained NPs are further degraded by hyaluronidase in the colon to release Cur and CeO2, thereby exerting anti-inflammatory and antioxidant effects. Combined with the ability of NPs to regulate intestinal flora, the oral NPs result in substantial relief in symptoms. Following multiple treatments, the gradually decreasing range of the colon with high CT attenuation correlates with the change in the clinical biomarkers, indicating the feasibility of treatment response and remission. CONCLUSION: This study provides a proof-of-concept for the design of a novel theranostic integration strategy for concomitant IBD treatment and the real-time monitoring of treatment responses.


Subject(s)
Cerium , Curcumin , Hyaluronic Acid , Inflammatory Bowel Diseases , Nanoparticles , Theranostic Nanomedicine , Animals , Inflammatory Bowel Diseases/drug therapy , Mice , Cerium/chemistry , Curcumin/pharmacology , Curcumin/chemistry , Curcumin/therapeutic use , Theranostic Nanomedicine/methods , Administration, Oral , Nanoparticles/chemistry , Hyaluronic Acid/chemistry , Hyaluronoglucosaminidase/metabolism , Tomography, X-Ray Computed , Mice, Inbred C57BL , Colon/diagnostic imaging , Colon/pathology , Colon/metabolism , Humans , Colitis/drug therapy
5.
Nat Commun ; 15(1): 6640, 2024 Aug 05.
Article in English | MEDLINE | ID: mdl-39103324

ABSTRACT

Immune checkpoint inhibitor (ICI)-induced myocarditis involves intensive immune/inflammation activation; however, its molecular basis is unclear. Here, we show that gasdermin-E (GSDME), a gasdermin family member, drives ICI-induced myocarditis. Pyroptosis mediated by GSDME, but not the canonical GSDMD, is activated in myocardial tissue of mice and cancer patients with ICI-induced myocarditis. Deficiency of GSDME in male mice alleviates ICI-induced cardiac infiltration of T cells, macrophages, and monocytes, as well as mitochondrial damage and inflammation. Restoration of GSDME expression specifically in cardiomyocytes, rather than myeloid cells, in GSDME-deficient mice reproduces ICI-induced myocarditis. Mechanistically, quantitative proteomics reveal that GSDME-dependent pyroptosis promotes cell death and mitochondrial DNA release, which in turn activates cGAS-STING signaling, triggering a robust interferon response and myocardial immune/inflammation activation. Pharmacological blockade of GSDME attenuates ICI-induced myocarditis and improves long-term survival in mice. Our findings may advance the understanding of ICI-induced myocarditis and suggest that targeting the GSDME-cGAS-STING-interferon axis may help prevent and manage ICI-associated myocarditis.


Subject(s)
Immune Checkpoint Inhibitors , Membrane Proteins , Myocarditis , Nucleotidyltransferases , Pyroptosis , Animals , Myocarditis/immunology , Myocarditis/pathology , Myocarditis/chemically induced , Myocarditis/metabolism , Membrane Proteins/metabolism , Membrane Proteins/genetics , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/adverse effects , Mice , Male , Humans , Nucleotidyltransferases/metabolism , Nucleotidyltransferases/genetics , Signal Transduction , Mice, Inbred C57BL , Mice, Knockout , DNA, Mitochondrial/metabolism , DNA, Mitochondrial/genetics , Female , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Myocytes, Cardiac/drug effects , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Phosphate-Binding Proteins/metabolism , Phosphate-Binding Proteins/genetics , Gasdermins
6.
Front Pharmacol ; 15: 1431221, 2024.
Article in English | MEDLINE | ID: mdl-39101144

ABSTRACT

Glycyrrhiza uralensis polysaccharides (GUPS) are widely applied in biomedicine and functional food due to their multiple pharmacological activities and low toxicity. Despite their widespread use, the in vivo metabolic profile of GUPS remains poorly understood. To address this gap, we developed a quantitative analysis method that involves labeling GUPS with visible fluorescein (5-DTAF) and near-infrared (NIR) fluorescein (Cy7), resulting in stable conjugates with substitution degrees of 0.81% for 5-DTAF and 0.39% for Cy7. The pharmacokinetic studies showed a biphasic elimination pattern in the blood concentration-time curve following both intravenous and oral administration, consistent with a two-compartment model. Using fluorescence quantification and NIR imaging, we observed that GUPS was distributed to various tissues, exhibiting higher concentrations particularly in liver, kidney and lung. Excretion studies indicated that feces were the major excretion pathway of GUPS after oral administration (60.98%), whereas urine was the main pathway after intravenous administration (31.16%). Notably, GUPS could be absorbed rapidly by gut (Tmax 1 ± 0.61 h) and showed a biological half-time t1/2 26.4 ± 7.72 h after oral administration. Furthermore, the Caco-2 cells uptake studies illustrated that macropinocytosis and clathrin-mediated endocytosis were participated in the transport of GUPS in intestine epithelium. This comprehensive analysis of the in vivo pharmacokinetics of GUPS not only enhances our understanding of its metabolic pathways but also establishes a foundational basis for its clinical application, optimizing its therapeutic potential and safety profile.

7.
MedComm (2020) ; 5(9): e697, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39206413

ABSTRACT

Ovarian cancer is high recurrence and mortality malignant tumor. The most common ovarian cancer was High-Grade Serous Ovarian Cancer. However, High-Grade Serous Ovarian Cancer organoid is rare, which organoid with patient immune microenvironment and blood vessels even absence. Here, we report a novel High-Grade Serous Ovarian Cancer organoid system derived from patient ovarian cancer samples. These organoids recapitulate High-Grade Serous Ovarian Cancer organoids' histological and molecular heterogeneity while preserving the critical immune microenvironment and blood vessels, as evidenced by the presence of CD34 + endothelial cells. Whole exome sequencing identifies key mutations (CSMD3, TP53, GABRA6). Organoids show promise in testing cisplatin sensitivity for patients resistant to carboplatin and paclitaxel, with notable responses in cancer proteoglycans and p53 (TP53) signaling, like ACTG/ACTB1/AKT2 genes and BBC3/MDM2/PERP. Integration of immune microenvironment and blood vessels enhances potential for novel therapies like immunotherapies and angiogenesis inhibitors. Our work may provide a new detection system and theoretical basis for ovarian cancer research and individual therapy.

8.
Biomedicines ; 12(8)2024 Aug 01.
Article in English | MEDLINE | ID: mdl-39200190

ABSTRACT

Prion diseases are neurodegenerative disorders caused by misfolded prion proteins. Although rare, the said diseases are always fatal; they commonly cause death within months of developing clinical symptoms, and their diagnosis is exceptionally difficult pre-mortem. There are no known cures or treatments other than symptomatic care. Given the aggressiveness of prion diseases on onset, therapies after disease onset could be challenging. Prevention to reduce the incidence or to delay the disease onset has been suggested to be a more feasible approach. In this perspective article, we summarize our current understandings of the origin, risk factors, and clinical manifestations of prion diseases. We propose a PCR testing of the blood to identify PRNP gene polymorphisms at codons 129 and 127 in individuals with familial PRNP mutations to assess the risk. We further present the CRISPR/Cas9 gene editing strategy as a perspective preventative approach for these high-risk individuals to induce a polymorphic change at codon 127 of the PRNP gene, granting immunity to prion diseases in selected high-risk individuals, in particular, in individuals with familial PRNP mutations.

9.
Angew Chem Int Ed Engl ; : e202412601, 2024 Aug 28.
Article in English | MEDLINE | ID: mdl-39193911

ABSTRACT

[4-(3,6-dimethyl-9H-carbazol-9yl)butyl]phosphonic acid (Me-4PACz) self-assembly material has been recognized as a highly effective approach for mitigating nickel oxide (NiOx) surface-related challenges in inverted perovskite solar cells (IPSCs). However, its uneven film generation and failure to effectively passivate the buried interface defects limit the device's performance improvement potential. Herein, p-xylylenediphosphonic acid (p-XPA) containing bilateral phosphate groups (-PO3H2) is introduced as an interface layer between the NiOx/Me-4PACz and the perovskite layer. P-XPA can flatten the surface of hole transport layer and optimize interface contact. Meanwhile, p-XPA achieves better energy level alignment and promotes interfacial hole transport. In addition, the bilateral -PO3H2 of p-XPA can chelate with Pb2+ and form hydrogen bond with FA+ (formamidinium cation),  thereby suppressing buried interface non-radiative recombination loss. Consequently, the IPSC with p-XPA buried interface modification achieves champion power conversion efficiency of 25.87% (certified at 25.45%) at laboratory scale (0.0448 cm2). The encapsulated target device exhibits better operational stability. Even after 1100 hours of maximum power point tracking at 50 ℃, its efficiency remains at an impressive 82.7% of the initial efficiency. Molecules featuring bilateral passivation groups optimize interfacial contact and inhibit interfacial recombination, providing an effective approach to enhancing the stability and efficiency of devices.

10.
Pharmaceutics ; 16(8)2024 Aug 16.
Article in English | MEDLINE | ID: mdl-39204418

ABSTRACT

Ulcerative colitis (UC) results in inflammation and ulceration of the colon and the rectum's inner lining. The application of herbal therapy in UC is increasing worldwide. As natural macromolecular compounds, polysaccharides have a significant role in the treatment of UC due to advantages of better biodegradation, good biocompatibility, immunomodulatory activity, and low reactogenicity. Therefore, polysaccharide drug formulation is becoming a potential candidate for UC treatment. In this review, we summarize the etiology and pathogenesis of UC and the therapeutic effects of polysaccharides on UC, such as regulating the expression of cytokines and tight junction proteins and modulating the balance of immune cells and intestinal microbiota. Polysaccharides can also serve as drug delivery carriers to enhance drug targeting and reduce side effects. This review provides a theoretical basis for applying natural plant polysaccharides in the prevention and treatment of UC.

11.
Sensors (Basel) ; 24(16)2024 Aug 11.
Article in English | MEDLINE | ID: mdl-39204890

ABSTRACT

There is a growing demand for indoor positioning systems (IPSs) in a wide range of applications. However, traditional solutions such as GPS face many technical challenges. In recent years, a promising alternative has been emerging, the visible light communication (VLC)-based IPS, which offers a combination of high accuracy, low cost, and energy efficiency. This article presents a comprehensive review of VLC-based IPSs, providing a tutorial-like overview of the system. It begins by comparing various positioning systems and providing background information on their inherent limitations. Experimental results have demonstrated that VLC-based systems can achieve localization accuracy to within 10 cm in controlled environments. The mechanisms of VLC-based IPSs are then discussed, including a comprehensive examination of their performance metrics and underlying assumptions. The complexity, operating range, and efficiency of VLC-based IPSs are examined by analyzing factors such as channel modeling, signal processing, and localization algorithms. To optimize VLC-based IPSs, various strategies are explored, including the design of efficient modulation schemes, the development of advanced encoding and decoding algorithms, the implementation of adaptive power control, and the application of state-of-the-art localization algorithms. In addition, system parameters are carefully examined. These include LED placement, receiver sensitivity, and transmit power. Their impact on energy efficiency and localization accuracy is highlighted. Altogether, this paper serves as a comprehensive guide to VLC IPSs, providing in-depth insights into their vast potential and the challenges that they present.

12.
Langmuir ; 40(26): 13355-13364, 2024 Jul 02.
Article in English | MEDLINE | ID: mdl-38952283

ABSTRACT

Agricultural solid waste has become one of the raw materials for hydrothermal carbon production, promoting resource utilization. This study synthesized two types of ball-milling carbons (Fe-MHBC vs MHBC) with and without FeCl3 modification using wheat straw hydrochars. Cr(VI) adsorption on these two types of ball-milling carbons was investigated. According to Langmuir's maximum adsorption capacity analysis, Fe-MHBC had a capacity of 116.29 mg g-1. The thermodynamic analysis based on isothermal adsorption reveals the spontaneous process of the reaction between the two materials. The adsorption of Cr(VI) on Fe-MHBC exhibited excellent agreement with the pseudo-second-order kinetics model. Furthermore, X-ray photoelectron spectroscopy analysis showed that Fe(II) in the material reduced Cr(VI) when it participated in the reaction. The acidic conditions facilitate the elimination of Cr(VI). The Fe-MHBC has a higher zeta potential, which enhances the electrostatic attraction of Cr(VI) particles. Even with a starting pH of 10, the removal rate can be consistently maintained at over 64%. The adsorption of Cr(VI) was inhibited by various anions and higher ion concentrations. Density functional theory demonstrates that the presence of Fe enhances the adsorption capacity and electron transfer flux of Cr(VI). Fe-MHBC effectively eliminates Cr(VI) by the process of electrostatic adsorption, redox, and complexation reactions. This study demonstrated that hydrochar materials modified by FeCl3 through a ball-milling process show considerable potential as effective adsorbents in the treatment of Cr(VI) pollution, offering a viable and environmentally friendly solution for mitigating this prevalent environmental issue.

13.
Cell Death Differ ; 2024 Jul 16.
Article in English | MEDLINE | ID: mdl-39009654

ABSTRACT

Dysregulated metabolism, cell death, and inflammation contribute to the development of metabolic dysfunction-associated steatohepatitis (MASH). Pyroptosis, a recently identified form of programmed cell death, is closely linked to inflammation. However, the precise role of pyroptosis, particularly gasdermin-E (GSDME), in MASH development remains unknown. In this study, we observed GSDME cleavage and GSDME-associated interleukin-1ß (IL-1ß)/IL-18 induction in liver tissues of MASH patients and MASH mouse models induced by a choline-deficient high-fat diet (CDHFD) or a high-fat/high-cholesterol diet (HFHC). Compared with wild-type mice, global GSDME knockout mice exhibited reduced liver steatosis, steatohepatitis, fibrosis, endoplasmic reticulum stress, lipotoxicity and mitochondrial dysfunction in CDHFD- or HFHC-induced MASH models. Moreover, GSDME knockout resulted in increased energy expenditure, inhibited intestinal nutrient absorption, and reduced body weight. In the mice with GSDME deficiency, reintroduction of GSDME in myeloid cells-rather than hepatocytes-mimicked the MASH pathologies and metabolic dysfunctions, as well as the changes in the formation of neutrophil extracellular traps and hepatic macrophage/monocyte subclusters. These subclusters included shifts in Tim4+ or CD163+ resident Kupffer cells, Ly6Chi pro-inflammatory monocytes, and Ly6CloCCR2loCX3CR1hi patrolling monocytes. Integrated analyses of RNA sequencing and quantitative proteomics revealed a significant GSDME-dependent reduction in citrullination at the arginine-114 (R114) site of dynamin-related protein 1 (Drp1) during MASH. Mutation of Drp1 at R114 reduced its stability, impaired its ability to redistribute to mitochondria and regulate mitophagy, and ultimately promoted its degradation under MASH stress. GSDME deficiency reversed the de-citrullination of Drp1R114, preserved Drp1 stability, and enhanced mitochondrial function. Our study highlights the role of GSDME in promoting MASH through regulating pyroptosis, Drp1 citrullination-dependent mitochondrial function, and energy balance in the intestine and liver, and suggests that GSDME may be a potential therapeutic target for managing MASH.

14.
Reprod Domest Anim ; 59(6): e14631, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38828566

ABSTRACT

This study examines the impact of Notoginsenoside R1 (NGR1), a compound from Panax notoginseng, on the maturation of porcine oocytes and their embryonic development, focusing on its effects on antioxidant levels and mitochondrial function. This study demonstrates that supplementing in vitro maturation (IVM) medium with NGR1 significantly enhances several biochemical parameters. These include elevated levels of glutathione (GSH), nuclear factor erythrocyte 2-related factor 2 (NRF2) and mRNA expression of catalase (CAT) and GPX. Concurrently, we observed a decrease in reactive oxygen species (ROS) levels and an increase in JC-1 immunofluorescence, mitochondrial distribution, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) and nuclear NRF2 mRNA levels. Additionally, there was an increase in ATP production and lipid droplets (LDs) immunofluorescence. These biochemical improvements correlate with enhanced embryonic outcomes, including a higher blastocyst rate, increased total cell count, enhanced proliferative capacity and elevated octamer-binding transcription factor 4 (Oct4) and superoxide dismutase 2 (Sod2) gene expression. Furthermore, NGR1 supplementation resulted in decreased apoptosis, reduced caspase 3 (Cas3) and BCL2-Associated X (Bax) mRNA levels and decreased glucose-regulated protein 78 kD (GRP78) immunofluorescence in porcine oocytes undergoing in vitro maturation. These findings suggest that NGR1 plays a crucial role in promoting porcine oocyte maturation and subsequent embryonic development by providing antioxidant levels and mitochondrial protection.


Subject(s)
Antioxidants , Embryonic Development , Ginsenosides , In Vitro Oocyte Maturation Techniques , Mitochondria , Oocytes , Animals , Antioxidants/pharmacology , Ginsenosides/pharmacology , In Vitro Oocyte Maturation Techniques/veterinary , Mitochondria/drug effects , Embryonic Development/drug effects , Oocytes/drug effects , Female , Swine , Reactive Oxygen Species/metabolism , Embryo Culture Techniques/veterinary
15.
Mol Cell ; 84(12): 2320-2336.e6, 2024 Jun 20.
Article in English | MEDLINE | ID: mdl-38906115

ABSTRACT

2'-O-methylation (Nm) is a prominent RNA modification well known in noncoding RNAs and more recently also found at many mRNA internal sites. However, their function and base-resolution stoichiometry remain underexplored. Here, we investigate the transcriptome-wide effect of internal site Nm on mRNA stability. Combining nanopore sequencing with our developed machine learning method, NanoNm, we identify thousands of Nm sites on mRNAs with a single-base resolution. We observe a positive effect of FBL-mediated Nm modification on mRNA stability and expression level. Elevated FBL expression in cancer cells is associated with increased expression levels for 2'-O-methylated mRNAs of cancer pathways, implying the role of FBL in post-transcriptional regulation. Lastly, we find that FBL-mediated 2'-O-methylation connects to widespread 3' UTR shortening, a mechanism that globally increases RNA stability. Collectively, we demonstrate that FBL-mediated Nm modifications at mRNA internal sites regulate gene expression by enhancing mRNA stability.


Subject(s)
3' Untranslated Regions , RNA Stability , RNA, Messenger , Humans , RNA, Messenger/genetics , RNA, Messenger/metabolism , Methylation , RNA Processing, Post-Transcriptional , Nanopore Sequencing/methods , Transcriptome , Gene Expression Regulation, Neoplastic , Machine Learning
16.
Phys Rev Lett ; 132(22): 223801, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38877932

ABSTRACT

Hybrid microresonators have served an intriguing platform for fundamental research and applied photonics. Here, we study the plasmonics-engineered coupling between degenerate optical whispering gallery modes, which can be tuned in a complex space featuring the dissipative strong, dispersive strong, and weak coupling regimes. Experimentally, the engineering of a single plasmonic resonance to a cavity mode family is examined in a waveguide-integrated high-Q microdisk, from which the complex coupling coefficients are extracted and agree well with theoretical predictions. The coupling strength over 10 GHz is achieved for both dissipative and dispersive interactions, showing a remarkable enhancement compared to that induced by a dielectric scatterer. Furthermore, the far fields of hybridized cavity modes are measured, revealing the coherent interference between the radiative channels. Our results shed light on the engineering of whispering gallery modes through plasmonic resonances, and provide fundamental guidance to practical microcavity devices.

17.
Nat Med ; 30(7): 1898-1904, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38839897

ABSTRACT

Gene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene therapy with dual adeno-associated virus (AAV) serotype 1 carrying human OTOF transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended and approved to allow bilateral gene therapy administration. Here we report an interim analysis of the single-arm trial investigating the safety and efficacy of binaural therapy in five pediatric patients with DFNB9. The primary endpoint was dose-limiting toxicity at 6 weeks, and the secondary endpoint included safety (adverse events) and efficacy (auditory function and speech perception). No dose-limiting toxicity or serious adverse event occurred. A total of 36 adverse events occurred. The most common adverse events were increased lymphocyte counts (6 out of 36) and increased cholesterol levels (6 out of 36). All patients had bilateral hearing restoration. The average auditory brainstem response threshold in the right (left) ear was >95 dB (>95 dB) in all patients at baseline, and the average auditory brainstem response threshold in the right (left) ear was restored to 58 dB (58 dB) in patient 1, 75 dB (85 dB) in patient 2, 55 dB (50 dB) in patient 3 at 26 weeks, and 75 dB (78 dB) in patient 4 and 63 dB (63 dB) in patient 5 at 13 weeks. The speech perception and the capability of sound source localization were restored in all five patients. These results provide preliminary insights on the safety and efficacy of binaural AAV gene therapy for hereditary deafness. The trial is ongoing with longer follow-up to confirm the safety and efficacy findings. Chinese Clinical Trial Registry registration: ChiCTR2200063181 .


Subject(s)
Dependovirus , Genetic Therapy , Humans , Genetic Therapy/methods , Child , Male , Female , Dependovirus/genetics , Child, Preschool , Deafness/genetics , Deafness/therapy , Adolescent , Treatment Outcome , Genes, Recessive , Genetic Vectors/genetics , Evoked Potentials, Auditory, Brain Stem
18.
J Ultrasound ; 2024 Jun 21.
Article in English | MEDLINE | ID: mdl-38904735

ABSTRACT

PURPOSE: This is an extremely rare case of complicated fetal esophageal atresia (EA) with tracheoesophageal fistula (TEF) and interrupted inferior vena cava (IVC) diagnosed by prenatal ultrsonography and successfully treated with surgical repair. METHODS: A 35-year-old pregnant woman was referred to our center for prenatal ultrasound, and the fetus was found to have a series of abnormalities, such as an interrupted IVC associated with a dilated azygos vein, an upper neck pouch sign of the thorax, and polyhydramnios. With suspicion of EA with TEF and interrupted IVC, the infant was born at 39 weeks of gestation, and successfully underwent the surgical operation. RESULTS: The baby was doing well after 21 months of follow-up. CONCLUSION: It is beneficial for the prenatal ultrasonic diagnosis of EA with TEF in optimizing labor care, postpartum treatment, and prompting neonatal management.

19.
Front Endocrinol (Lausanne) ; 15: 1335611, 2024.
Article in English | MEDLINE | ID: mdl-38818507

ABSTRACT

Objective: This research aimed to elucidate the relationship between testosterone levels and serum soluble klotho (S-klotho) concentrations in females aged 40-79 years using the National Health and Nutrition Examination Survey (NHANES) dataset. Design: Associations between testosterone and S-klotho were assessed through multivariable linear regression methodologies, spanning nonadjusted, minimally adjusted, and fully adjusted models. Settings: The investigation was conducted as a cross-sectional analysis utilizing the NHANES database. Participants: From 20,146 NHANES participants between 2013 and 2016, 2,444 females met the stipulated inclusion and exclusion criteria. Results: Free androgen index (FAI) showcased a negative correlation with S-klotho levels across all regression models (nonadjusted: ß -7.08, 95% CI -13.39- -0.76; minimally adjusted: ß -9.73, 95% CI -16.6- -2.84; fully adjusted: ß -7.63, 95% CI -14.75-0.51). Conversely, total testosterone did not exhibit significant associations with S-klotho across the models. In the nonadjusted model, estradiol was positively associated with S-klotho concentrations (ß 0.14, 95% CI 0.05-0.23), but this significance was not retained in subsequent regression models. Conclusion: Findings suggest that in U.S. females aged 40-79 years, FAI negatively correlates with S-klotho concentrations, while there is the lack of significant associations for total testosterone and estradiol.


Subject(s)
Klotho Proteins , Nutrition Surveys , Testosterone , Adult , Aged , Female , Humans , Middle Aged , Biomarkers/blood , Cross-Sectional Studies , Databases, Factual , Glucuronidase/blood , Klotho Proteins/blood , Testosterone/blood
20.
J Nanobiotechnology ; 22(1): 224, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38702709

ABSTRACT

Poorly identified tumor boundaries and nontargeted therapies lead to the high recurrence rates and poor quality of life of prostate cancer patients. Near-infrared-II (NIR-II) fluorescence imaging provides certain advantages, including high resolution and the sensitive detection of tumor boundaries. Herein, a cyanine agent (CY7-4) with significantly greater tumor affinity and blood circulation time than indocyanine green was screened. By binding albumin, the absorbance of CY7-4 in an aqueous solution showed no effects from aggregation, with a peak absorbance at 830 nm and a strong fluorescence emission tail beyond 1000 nm. Due to its extended circulation time (half-life of 2.5 h) and high affinity for tumor cells, this fluorophore was used for primary and metastatic tumor diagnosis and continuous monitoring. Moreover, a high tumor signal-to-noise ratio (up to ~ 10) and excellent preferential mitochondrial accumulation ensured the efficacy of this molecule for photothermal therapy. Therefore, we integrated NIR-II fluorescence-guided surgery and intraoperative photothermal therapy to overcome the shortcomings of a single treatment modality. A significant reduction in recurrence and an improved survival rate were observed, indicating that the concept of intraoperative combination therapy has potential for the precise clinical treatment of prostate cancer.


Subject(s)
Carbocyanines , Mitochondria , Neoplasm Recurrence, Local , Photothermal Therapy , Prostatic Neoplasms , Male , Prostatic Neoplasms/diagnostic imaging , Photothermal Therapy/methods , Humans , Animals , Mitochondria/metabolism , Mitochondria/drug effects , Cell Line, Tumor , Carbocyanines/chemistry , Optical Imaging/methods , Mice , Surgery, Computer-Assisted/methods , Fluorescent Dyes/chemistry , Mice, Nude , Mice, Inbred BALB C , Infrared Rays , Indocyanine Green/chemistry , Indocyanine Green/therapeutic use , Indocyanine Green/pharmacology
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