Search Results (41)

Background: Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene, with a rare juvenile-onset form (JoHD) marked by early, rigid motor symptoms. This study examined cortical and subcortical resting-state connectivity in JoHD, hypothesizing preserved cortical networks but altered striatal connectivity, in line with early subcortical atrophy despite relatively spared cortical volume. Methods: Participants included children and young adults with clinician-confirmed Juvenile-Onset Huntington’s Disease (JoHD; n = 19) and gene-non-expanded (GNE) controls (n = 64), both drawn from longitudinal studies at the University of Iowa. Resting-state functional MRI scans were analyzed to assess canonical cortical network and striatal connectivity, and linear mixed-effects models tested group differences and associations with motor, cognitive, and clinical outcomes. Results: JoHD participants showed reduced connectivity within the left somatomotor network and striatal circuits, despite largely typical cortical network connectivity. Striatal connectivity was associated with disease burden and cognitive ability, while left somatomotor connectivity was unrelated to clinical outcomes. Conclusions: These findings support the hypothesis of antagonistic pleiotropy in JoHD, where early neural advantages—such as relatively preserved or possibly enhanced cortical function—may contribute to later striatal vulnerability and degeneration. The observed left-lateralized somatomotor hypoconnectivity aligns with prior volumetric and gene expression research, highlighting the role of excitotoxic glutamatergic input and the selective vulnerability of high-functioning circuits in disease progression. Full article

Abnormal expression of miRNAs is associated with the occurrence and progression of cancer and other diseases, making miRNAs essential biomarkers for disease diagnosis and prognosis. However, the intrinsic properties of miRNAs, such as short length, low abundance, and high sequence homology, represent great challenges for fast and accurate miRNA detection in clinics. Herein, we developed a novel hybridization chain reaction (HCR)-based electrochemical miRNAs chip (e-miRchip), featured with gold nanostructured electrodes (GNEs) and silver nanoparticle reporters (AgNRs), for sensitive and multiplexed miRNA detection. AgNRs were synthesized and applied on the e-miRchip to generate strong redox signals in the presence of miRNA. The stem–loop capture probe was covalently immobilized on the GNEs, and was opened upon miRNA hybridization to consequently trigger the HCR for signal amplification. The multiple long-repeated DNA helix generated by HCR provides the binding sites for the AgNRs, contributing to the amplification of the electrochemical signals of miRNA hybridization. To optimize the detection sensitivity, GNEs with three distinct structures were electroplated, in which flower-like GNEs were found to be the best electrode morphology for miRNAs analysis. Under optimal conditions, the HCR-based e-miRchip showed an excellent detection performance with an LOD of 0.9 fM and a linear detection range from 1 fM to 10 pM. Moreover, this HCR-based e-miRchip platform was able to effectively distinguish miRNAs from the one- or two-base mismatches. This HCR-based e-miRchip holds great potential as a highly efficient and promising miRNA detection platform for the diagnosis and prognosis of cancer and other diseases in the future. Full article

Objective: Non-small cell lung cancer (NSCLC) is a major cause of cancer-related deaths worldwide. This study investigated the effects and mechanisms of the USP7 inhibitor GNE-6776 on human NSCLC A549 and H1299 cells, providing insights for anti-NSCLC drug development. Methods: USP7 expression was analyzed in lung cancer tissue using data from public databases. RNA sequencing and functional enrichment analyses were conducted to explore differentially expressed genes (DEGs) and potentially related pathways. A549 and H1299 cells were treated with GNE-6776 at different concentrations, and its effects on cell proliferation, migration, invasion, apoptosis, mitochondrial membrane potential, and cell cycle were evaluated. Changes in protein expression following GNE-6776 treatment were assessed by Western blot. A xenograft tumor model in nude mice was used to evaluate the in vivo effects of GNE-6776. Results: GNE-6776 inhibited the proliferation, migration, and invasion of A549 and H1299 cells, induced apoptosis, and caused cells to arrest in the G1 phase in a concentration-dependent manner. GNE-6776 decreased the mitochondrial membrane potential, suppressed epithelial-mesenchymal transition (EMT) markers, and downregulated the PI3K/AKT/mTOR and Wnt/β-catenin signaling pathways. GNE-6776 significantly inhibited tumor growth without affecting body weight, reduced expression of CDK6, C-myc, and N-cadherin, and increased GSK3β expression in tumor tissue. Conclusions: In summary, GNE-6776 demonstrated potent anti-tumor activity in NSCLC both in vitro and in vivo. GNE-6776 suppresses NSCLC cell proliferation, invasion, and migration while promoting apoptosis by inhibiting the EMT and modulating the PI3K/AKT/mTOR and Wnt/β-catenin pathways. These findings support its potential as a therapeutic agent for treating NSCLC. Full article

Fungal infections represent a significant global health challenge. Candida albicans is a particularly widespread pathogen, with both molecular and biofilm-based mechanisms making it resistant to or tolerant of available antifungal drugs. This study reports a combination therapy, active against C. albicans, utilizing terbinafine and essential oils incorporated into a gelatin-based nanoemulsion system (T-GNE). Eugenol and methyl eugenol/terbinafine T-GNEs had an additive efficacy, while carvacrol (CT-GNE) worked synergistically with terbinafine, providing effective antifungal treatment with minimal mammalian cell toxicity. Confocal microscopy demonstrated that CT-GNE penetrated the dense C. albicans biofilm and disrupted the fungal cell membrane. Overall, the combination of essential oils with terbinafine in GNE provided a promising treatment for fungal biofilms. Full article

GNE myopathy, also known as hereditary inclusion body myopathy (HIBM), is a rare genetic muscle disorder marked by a gradual onset of muscle weakness in young adults. GNE myopathy (GNEM) is caused by bi-allelic variants in the UDP-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase)/N-acetylmannosamine kinase (ManNAc kinase) gene (GNE), clinically resulting in the loss of ambulation within 10–20 years from the onset of the initial symptoms. The disease’s mechanism is poorly understood and non-invasive biomarkers are lacking, hindering effective therapy development. Based on the available evidence, we employed a lipidomic approach to study the serum lipid profile of GNE patients. The multivariate statistical analysis revealed a downregulation of carnitines, as well as of lysophosphatidylcholines, in sera samples derived from GNEM patients. Furthermore, we identified lower levels of sphingomyelins and, concomitantly, high levels of ceramides in serum samples from GNEM patients when compared to control samples derived from healthy donors. Moreover, the GNEM serum samples showed the upregulation of Krebs cycle intermediates, in addition to a decrease in oxaloacetic acid. The correlated data gathered in this study can offer a promising diagnostic panel of complex lipids and polar metabolites that can be used in clinic for GNEM in terms of a metabolic fingerprint measurable in a minimally invasive manner. Full article

In this article, a distributed charging strategy problem for plug-in electric vehicles (PEVs) with feeder constraints based on generalized Nash equilibria (GNE) in a novel smart charging station (SCS) is investigated. The purpose is to coordinate the charging strategies of all PEVs in SCS to minimize the energy cost of SCS. Therefore, we build a non-cooperative game framework and propose a new price-driven charging control game by considering the overload constraint of the assigned feeder, where each PEV minimizes the fees it pays to satisfy its optimal charging strategy. On this basis, the existence of GNE is given. Furthermore, we employ a distributed algorithm based on forward–backward operator splitting methods to find the GNE. The effectiveness of the employed algorithm is verified by the final simulation results. Full article

Autosomal recessive Nonaka distal myopathy is a rare autosomal recessive genetic disease characterized by progressive degeneration of the distal muscles, causing muscle weakness and decreased grip strength. It is primarily associated with mutations in the GNE gene, which encodes a key enzyme of sialic acid biosynthesis (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase). This study was performed to find GNE mutations in six independent distal myopathy patients with or without peripheral neuropathy using whole-exome sequencing (WES). In silico pathogenic prediction and simulation of 3D structural changes were performed for the mutant GNE proteins. As a result, we identified five pathogenic or likely pathogenic missense variants: c.86T>C (p.Met29Thr), c.527A>T (p.Asp176Val), c.782T>C (p.Met261Thr), c.1714G>C (p.Val572Leu), and c.1771G>A (p.Ala591Thr). Five affected individuals showed compound heterozygous mutations, while only one patient revealed a homozygous mutation. Two patients revealed unreported combinations of combined heterozygous mutations. We observed some specific clinical features, such as complex phenotypes of distal myopathy with distal hereditary peripheral neuropathy, an earlier onset of weakness in legs than that of hands, and clinical heterogeneity between two patients with the same set of compound heterozygous mutations. Our findings on these genetic causes expand the clinical spectrum associated with the GNE mutations and can help prepare therapeutic strategies. Full article

USP7 is highly expressed in a variety of tumors and is thought to play a major role in cancer development. However, there are no drugs available to target USP7, so there is a need to develop new USP7 inhibitors. In this study, AutoQSAR, multiple linear regression, and Naive Bayesian models were constructed using 543 compounds and used to analyze marine compounds. After selecting 240 small molecules for molecular docking with Maestro, MOE, and GOLD, better small molecules than the positive compound P217564 were screened. The molecular structure of “1, 2-dibromobenzene” was optimized to improve the binding effect of the protein, and 10 optimized compounds in ADMET performed well during the screening process. To study the dynamic combination of protein–ligand effect consistency with static molecular docking, 100ns molecular dynamics simulations of candidate compound 1008-1, reference compound P217564, and negative-positive GNE2917 were conducted. The results of molecular docking and molecular dynamics simulation analysis showed that compound 1008-1 maintained a stable conformation with the target protein. Thus, the comprehensive analysis suggests that compound 1008-1 could provide new possibilities for USP7 covalent inhibitor candidates. Full article

Water in heavy crude oil (W/O) emulsions, which are stubborn mixtures of immiscible heavy crude oil and brine, are a ubiquitous challenge in the petroleum industry. They cause serious corrosion problems, increase the viscosity of petroleum and make the production cost very high. This phenomenon appears during the production of crude oil and should be treated to maximize the overall profitability of oil production and meet transportation requirement. Surfactants are some of the most useful demulsifiers and play a pivotal role in breaking brine/oil emulsions. Herein, we aimed to combine ethyleneamine units and ethyleneoxide units to prepare star-shaped surfactants and test the effect of this combination on the demulsification performance. First, diethylenetriamine reacted with glycidyl 4-nonyl ether (GNE) through an epoxy ring opening to prepare trinonyl phenoxy diethylenetriamine (TNDT). Then, ethylene oxide units were introduced via the interaction of hydroxyl groups with 2-(2-chloroethoxy)ethanol to form ethoxylated trinonyl phenoxy diethylenetriamine (ETNDT). The chemical structures of the surfactants were verified via FTIR and NMR characteristic techniques. The surfactants were applied as demulsifiers for W/O emulsions. It was found that the introduction of the ethyleneoxide units enhanced the solubility of the water and the demulsification performance of the prepared surfactants. The demulsification efficiency was enhanced via ethoxylation and reached 100% for ETNDT for most of the W/O emulsions. Full article

Proteolysis-Targeting Chimeras (PROTACs) are a promising new technology in drug development. They have rapidly evolved in recent years, with several of them in clinical trials. While most of these advances have been associated with monovalent protein degraders, bivalent PROTACs have also entered clinical trials, although progression to market has been limited. One of the reasons is the complex physicochemical properties of the heterobifunctional PROTACs. A promising strategy to improve pharmacokinetics of highly lipophilic compounds, such as PROTACs, is encapsulation in liposome systems. Here we describe liposome systems for intravenous administration to enhance the PK properties of two bivalent PROTAC molecules, by reducing clearance and increasing systemic coverage. We developed and characterized a PROTAC-in-cyclodextrin liposome system where the drug was retained in the liposome core. In PK studies at 1 mg/kg for GNE-01 the PROTAC-in-cyclodextrin liposome, compared to the solution formulation, showed a 80- and a 380-fold enhancement in AUC for mouse and rat studies, respectively. We further investigated the same PROTAC-in-cyclodextrin liposome system with the second PROTAC (GNE-02), where we monitored both lipid and drug concentrations in vivo. Similarly, in a mouse PK study of GEN-02, the PROTAC-in-cyclodextrin liposome system exhibited enhancement in plasma concentration of a 23× increase over the conventional solution formulation. Importantly, the lipid CL correlated with the drug CL. Additionally, we investigated a conventional liposome approach for GNE-02, where the PROTAC resides in the lipid bilayer. Here, a 5× increase in AUC was observed, compared to the conventional solution formulation, and the drug CL was faster than the lipid CL. These results indicate that the different liposome systems can be tailored to translate across multiple PROTAC systems to modulate and improve plasma concentrations. Optimization of the liposomes could further improve tumor concentration and improve the overall therapeutic index (TI). This delivery technology may be well suited to bring novel protein targeted PROTACs into clinics. Full article

Background: The assessment of voice quality can be evaluated perceptually with standard clinical practice, also including acoustic evaluation of digital voice recordings to validate and further interpret perceptual judgments. The goal of the present study was to determine the strongest acoustic voice quality parameters for perceived hoarseness and breathiness when analyzing the sustained vowel [a:] using a new clinical acoustic tool, the VOXplot software. Methods: A total of 218 voice samples of individuals with and without voice disorders were applied to perceptual and acoustic analyses. Overall, 13 single acoustic parameters were included to determine validity aspects in relation to perceptions of hoarseness and breathiness. Results: Four single acoustic measures could be clearly associated with perceptions of hoarseness or breathiness. For hoarseness, the harmonics-to-noise ratio (HNR) and pitch perturbation quotient with a smoothing factor of five periods (PPQ5), and, for breathiness, the smoothed cepstral peak prominence (CPPS) and the glottal-to-noise excitation ratio (GNE) were shown to be highly valid, with a significant difference being demonstrated for each of the other perceptual voice quality aspects. Conclusions: Two acoustic measures, the HNR and the PPQ5, were both strongly associated with perceptions of hoarseness and were able to discriminate hoarseness from breathiness with good confidence. Two other acoustic measures, the CPPS and the GNE, were both strongly associated with perceptions of breathiness and were able to discriminate breathiness from hoarseness with good confidence. Full article

This paper develops an algorithm for solving the generalized Nash equilibrium problem (GNEP) in non-cooperative games. The problem involves a set of players, each with a cost function that depends on their own decision as well as the decisions of other players. The goal is to find a decision vector that minimizes the cost for each player. Unlike most of the existing algorithms for GNEP, which require full information exchange among all players, this paper considers a more realistic scenario where players can only communicate with a subset of players through a connectivity graph. The proposed algorithm enables each player to estimate the decisions of other players and update their own and others’ estimates through local communication with their neighbors. By introducing a network Lagrangian function and applying the Douglas-Rachford splitting method (DR), the GNEP is reformulated as a zero-finding problem. It is shown that the DR method can find the generalized Nash equilibrium (GNE) of the original problem under some mild conditions. Full article

This paper proposes a distributed algorithm for games with shared coupling constraints based on the variational approach and the proximal-point algorithm. The paper demonstrates the effectiveness of the proximal-point algorithm in distributed computing of generalized Nash equilibrium (GNE) problems using local data and communication with neighbors in any networked game. The algorithm achieves the goal of reflecting local decisions in the Nash–Cournot game under partial-decision information while maintaining the distributed nature and convergence of the algorithm. Full article

Protein glycosylation, including sialylation, involves complex and frequent post-translational modifications, which play a critical role in different biological processes. The conjugation of carbohydrate residues to specific molecules and receptors is critical for normal hematopoiesis, as it favors the proliferation and clearance of hematopoietic precursors. Through this mechanism, the circulating platelet count is controlled by the appropriate platelet production by megakaryocytes, and the kinetics of platelet clearance. Platelets have a half-life in blood ranging from 8 to 11 days, after which they lose the final sialic acid and are recognized by receptors in the liver and eliminated from the bloodstream. This favors the transduction of thrombopoietin, which induces megakaryopoiesis to produce new platelets. More than two hundred enzymes are responsible for proper glycosylation and sialylation. In recent years, novel disorders of glycosylation caused by molecular variants in multiple genes have been described. The phenotype of the patients with genetic alterations in GNE, SLC35A1, GALE and B4GALT is consistent with syndromic manifestations, severe inherited thrombocytopenia, and hemorrhagic complications. Full article

The GNE-associated V727M mutation is one of the most prevalent ethnic founder mutations in the Asian HIBM cohort; however, its role in inducing disease phenotype remains largely elusive. In this study, the function of this hotspot mutation was profoundly investigated. For this, V727M mutation-specific altered expression profile and potential networks were explored. The relevant muscular disorder-specific in vivo studies and patient data were further analyzed, and the key altered molecular pathways were identified. Our study found that the GNEV727M mutation resulted in a deregulated lincRNA profile, the majority of which (91%) were associated with a down-regulation trend. Further, in silico analysis of associated targets showed their active role in regulating Wnt, TGF-β, and apoptotic signaling. Interestingly, COL6a3 was found as a key target of these lincRNAs. Further, GSEA analysis showed HIBM patients with variable COL6A3 transcript levels have significant alteration in many critical pathways, including epithelial-mesenchymal-transition, myogenesis, and apoptotic signaling. Interestingly, 12 of the COL6A3 coexpressed genes also showed a similar altered expression profile in HIBM. A similar altered trend in COL6A3 and coexpressed genes were found in in vivo HIBM disease models as well as in multiple other skeletal disorders. Thus, the COL6A3-specific 13 gene signature seems to be altered in multiple muscular disorders. Such deregulation could play a pivotal role in regulating many critical processes such as extracellular matrix organization, cell adhesion, and skeletal muscle development. Thus, investigating this novel COL6A3-specific 13 gene signature provides valuable information for understanding the molecular cause of HIBM and may also pave the way for better diagnosis and effective therapeutic strategies for many muscular disorders. Full article