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Search Results (225)

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Keywords = mutation and glycosylation

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20 pages, 4049 KiB  
Article
ADMET-Guided Docking and GROMACS Molecular Dynamics of Ziziphus lotus Phytochemicals Uncover Mutation-Agnostic Allosteric Stabilisers of the KRAS Switch-I/II Groove
by Abdessadek Rahimi, Oussama Khibech, Abdessamad Benabbou, Mohammed Merzouki, Mohamed Bouhrim, Mohammed Al-Zharani, Fahd A. Nasr, Ashraf Ahmed Qurtam, Said Abadi, Allal Challioui, Mostafa Mimouni and Maarouf Elbekay
Pharmaceuticals 2025, 18(8), 1110; https://doi.org/10.3390/ph18081110 - 25 Jul 2025
Viewed by 319
Abstract
Background/Objectives: Oncogenic KRAS drives ~30% of solid tumours, yet the only approved G12C-specific drugs benefit ≈ 13% of KRAS-mutant patients, leaving a major clinical gap. We sought mutation-agnostic natural ligands from Ziziphus lotus, whose stereochemically rich phenolics may overcome this limitation by occupying [...] Read more.
Background/Objectives: Oncogenic KRAS drives ~30% of solid tumours, yet the only approved G12C-specific drugs benefit ≈ 13% of KRAS-mutant patients, leaving a major clinical gap. We sought mutation-agnostic natural ligands from Ziziphus lotus, whose stereochemically rich phenolics may overcome this limitation by occupying the SI/II (Switch I/Switch II) groove and locking KRAS in its inactive state. Methods: Phytochemical mining yielded five recurrent phenolics, such as (+)-catechin, hyperin, astragalin, eriodictyol, and the prenylated benzoate amorfrutin A, benchmarked against the covalent inhibitor sotorasib. An in silico cascade combined SI/II docking, multi-parameter ADME/T (Absorption, Distribution, Metabolism, Excretion, and Toxicity) filtering, and 100 ns explicit solvent molecular dynamics simulations. Pharmacokinetic modelling predicted oral absorption, Lipinski compliance, mutagenicity, and acute-toxicity class. Results: Hyperin and astragalin showed the strongest non-covalent affinities (−8.6 kcal mol−1) by forging quadridentate hydrogen-bond networks that bridge the P-loop (Asp30/Glu31) to the α3-loop cleft (Asp119/Ala146). Catechin (−8.5 kcal mol−1) balanced polar anchoring with entropic economy. ADME ranked amorfrutin A the highest for predicted oral absorption (93%) but highlighted lipophilic solubility limits; glycosylated flavonols breached Lipinski rules yet remained non-mutagenic with class-5 acute-toxicity liability. Molecular dynamics trajectories confirmed that hyperin clamps the SI/II groove, suppressing loop RMSF below 0.20 nm and maintaining backbone RMSD stability, whereas astragalin retains pocket residence with transient re-orientation. Conclusions: Hyperin emerges as a low-toxicity, mutation-agnostic scaffold that rigidifies inactive KRAS. Deglycosylation, nano-encapsulation, or soft fluorination could reconcile permeability with durable target engagement, advancing Z. lotus phenolics toward broad-spectrum KRAS therapeutics. Full article
(This article belongs to the Section Natural Products)
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18 pages, 11606 KiB  
Article
Emerging Highly Pathogenic Avian Influenza H5N1 Clade 2.3.4.4b Causes Neurological Disease and Mortality in Scavenging Ducks in Bangladesh
by Rokshana Parvin, Sumyea Binta Helal, Md Mohi Uddin, Shadia Tasnim, Md. Riabbel Hossain, Rupaida Akter Shila, Jahan Ara Begum, Mohammed Nooruzzaman, Ann Kathrin Ahrens, Timm Harder and Emdadul Haque Chowdhury
Vet. Sci. 2025, 12(8), 689; https://doi.org/10.3390/vetsci12080689 - 23 Jul 2025
Viewed by 423
Abstract
Scavenging domestic ducks significantly contribute to the transmission and maintenance of highly pathogenic H5N1 clade 2.3.4.4b avian influenza viruses in Bangladesh, a strain of growing global concern due to its broad host range, high pathogenicity, and spillover potential. This study investigates the molecular [...] Read more.
Scavenging domestic ducks significantly contribute to the transmission and maintenance of highly pathogenic H5N1 clade 2.3.4.4b avian influenza viruses in Bangladesh, a strain of growing global concern due to its broad host range, high pathogenicity, and spillover potential. This study investigates the molecular epidemiology and pathology of HPAI H5N1 viruses in unvaccinated scavenging ducks in Bangladesh, with the goal of assessing viral evolution and associated disease outcomes. Between June 2022 and March 2024, 40 scavenging duck flocks were investigated for HPAI outbreaks. Active HPAIV H5N1 infection was detected in 35% (14/40) of the flocks using RT-qPCR. Affected ducks exhibited clinical signs of incoordination, torticollis, and paralysis. Pathological examination revealed prominent meningoencephalitis, encephalopathy and encephalomalacia, along with widespread lesions in the trachea, lungs, liver, and spleen, indicative of systemic HPAIV infection. A phylogenetic analysis of full-genome sequences confirmed the continued circulation of clade 2.3.2.1a genotype G2 in these ducks. Notably, two samples of 2022 and 2023 harbored HPAIV H5N1 of clade 2.3.4.4b, showing genetic similarity to H5N1 strains circulating in Korea and Vietnam. A mutation analysis of the HA protein in clade 2.3.4.4b viruses revealed key substitutions, including T156A (loss of an N-linked glycosylation site), S141P (antigenic site A), and E193R/K (receptor-binding pocket), indicating potential antigenic drift and receptor-binding adaptation compared to clade 2.3.2.1a. The emergence of clade 2.3.4.4b with the first report of neurological and systemic lesions suggests ongoing viral evolution with increased pathogenic potential for ducks. These findings highlight the urgent need for enhanced surveillance and biosecurity to control HPAI spread in Bangladesh. Full article
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22 pages, 498 KiB  
Review
The XEC Variant: Genomic Evolution, Immune Evasion, and Public Health Implications
by Alaa A. A. Aljabali, Kenneth Lundstrom, Altijana Hromić-Jahjefendić, Nawal Abd El-Baky, Debaleena Nawn, Sk. Sarif Hassan, Alberto Rubio-Casillas, Elrashdy M. Redwan and Vladimir N. Uversky
Viruses 2025, 17(7), 985; https://doi.org/10.3390/v17070985 - 15 Jul 2025
Viewed by 718
Abstract
Narrative review synthesizes the most current literature on the SARS-CoV-2 XEC variant, focusing on its genomic evolution, immune evasion characteristics, epidemiological dynamics, and public health implications. To achieve this, we conducted a structured search of the literature of peer-reviewed articles, preprints, and official [...] Read more.
Narrative review synthesizes the most current literature on the SARS-CoV-2 XEC variant, focusing on its genomic evolution, immune evasion characteristics, epidemiological dynamics, and public health implications. To achieve this, we conducted a structured search of the literature of peer-reviewed articles, preprints, and official surveillance data from 2023 to early 2025, prioritizing virological, clinical, and immunological reports related to XEC and its parent lineages. Defined by the distinctive spike protein mutations, T22N and Q493E, XEC exhibits modest reductions in neutralization in vitro, although current evidence suggests that mRNA booster vaccines, including those targeting JN.1 and KP.2, retain cross-protective efficacy against symptomatic and severe disease. The XEC strain of SARS-CoV-2 has drawn particular attention due to its increasing prevalence in multiple regions and its potential to displace other Omicron subvariants, although direct evidence of enhanced replicative fitness is currently lacking. Preliminary analyses also indicated that glycosylation changes at the N-terminal domain enhance infectivity and immunological evasion, which is expected to underpin the increasing prevalence of XEC. The XEC variant, while still emerging, is marked by a unique recombination pattern and a set of spike protein mutations (T22N and Q493E) that collectively demonstrate increased immune evasion potential and epidemiological expansion across Europe and North America. Current evidence does not conclusively associate XEC with greater disease severity, although additional research is required to determine its clinical relevance. Key knowledge gaps include the precise role of recombination events in XEC evolution and the duration of cross-protective T-cell responses. New research priorities include genomic surveillance in undersampled regions, updated vaccine formulations against novel spike epitopes, and long-term longitudinal studies to monitor post-acute sequelae. These efforts can be augmented by computational modeling and the One Health approach, which combines human and veterinary sciences. Recent computational findings (GISAID, 2024) point to the potential of XEC for further mutations in under-surveilled reservoirs, enhancing containment challenges and risks. Addressing the potential risks associated with the XEC variant is expected to benefit from interdisciplinary coordination, particularly in regions where genomic surveillance indicates a measurable increase in prevalence. Full article
(This article belongs to the Special Issue Translational Research in Virology)
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17 pages, 695 KiB  
Review
Genetic Diseases of Fucosylation: Insights from Model Organisms
by Muhammad T. Ameen and Curtis R. French
Genes 2025, 16(7), 800; https://doi.org/10.3390/genes16070800 - 3 Jul 2025
Viewed by 790
Abstract
Fucosylation plays a fundamental role in maintaining cellular functions and biological processes across all animals. As a form of glycosylation, it involves the biochemical addition of fucose, a six-carbon monosaccharide, to biological molecules like lipids, proteins, and glycan chains. This modification is essential [...] Read more.
Fucosylation plays a fundamental role in maintaining cellular functions and biological processes across all animals. As a form of glycosylation, it involves the biochemical addition of fucose, a six-carbon monosaccharide, to biological molecules like lipids, proteins, and glycan chains. This modification is essential for optimizing cellular interactions required for receptor-ligand binding, cell adhesion, immune responses, and development. Disruptions in cellular fucose synthesis or in the mechanisms enabling its transfer to other molecules have been linked to human disease. Inherited defects in the fucosylation pathway are rare, with about thirty patients described. Through genome-wide association studies (GWAS), variants in fucosylation pathway genes have been associated with complex diseases such as glaucoma and stroke, and somatic mutations are often found in cancers. Recent studies have applied targeted genetic animal models to elucidate the mechanisms through which disruptions in fucosylation contribute to disease pathogenesis and progression. Key focus areas include GDP-fucose synthesis through de novo or salvage pathways, GDP-fucose transport into the Golgi and endoplasmic reticulum (ER), and its transfer by fucosyltransferases (FUTs) or protein O-fucosyltransferases (POFUTs) onto acceptor molecules. Loss or gain of function fucosylation gene mutations in animal models such as mice, zebrafish, and invertebrates have provided insights into some fucosylation disease pathogenesis. This review aims to bring together these findings, summarizing key insights from existing animal studies to possibly infer fucosylation disease mechanisms in humans. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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15 pages, 802 KiB  
Article
Plant Lectin, MoMo30, Pressures HIV-1 to Select for Variants with Deleted N-Linked Glycosylation Sites
by Morgan I. Coleman, Mahfuz B. Khan, Erick Gbodossou, Amad Diop, Kenya DeBarros, Vincent C. Bond, Virginia Floyd, Kofi Kondwani, Valerie Montgomery Rice and Michael D. Powell
Viruses 2025, 17(7), 910; https://doi.org/10.3390/v17070910 - 27 Jun 2025
Viewed by 297
Abstract
Momordica balsamina, a plant traditionally used in African medicine, contains a 30 kDa protein, MoMo30, previously identified by our group as an anti-HIV agent that binds glycan residues on the gp120 envelope protein, thereby acting as an entry inhibitor. In this study, we [...] Read more.
Momordica balsamina, a plant traditionally used in African medicine, contains a 30 kDa protein, MoMo30, previously identified by our group as an anti-HIV agent that binds glycan residues on the gp120 envelope protein, thereby acting as an entry inhibitor. In this study, we investigated whether prolonged exposure to MoMo30 exerts selective pressure on HIV-1 and induces mutations in the viral envelope (env) gene. T-lymphocyte cells were infected with HIV-1NL4-3 and continuously treated with MoMo30 over a 24-day period. Viral RNA was isolated at regular intervals, and env genes were sequenced using the Illumina platform. RNA sequence variant calling was performed using iVar, which uses a frequency-based binomial test with a default allele frequency threshold of 3% and a minimum base quality of 20 and applies Bonferroni correction for multiple testing. The infectivity of the MoMo30-exposed virus was assessed using MAGI-CXCR4 cells, visualized by β-galactosidase staining, and compared to untreated controls. Statistical significance was determined via two-way ANOVA. MoMo30-treated HIV-1 exhibited multiple detrimental mutations in gp120 and gp41, including missense, nonsense, and frameshift changes. Notably, 32% of N-linked glycosylation sites were deleted in the treated virus, while no such changes were observed in controls. Functionally, the MoMo30-treated virus demonstrated a sixfold reduction in infectivity compared to untreated HIV-1NL4-3. These findings suggest that MoMo30 imposes genetic pressure on HIV-1NL4-3, selecting for mutations that reduce viral fitness. Full article
(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)
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18 pages, 5210 KiB  
Article
In Silico Analysis of Phosphomannomutase-2 Dimer Interface Stability and Heterodimerization with Phosphomannomutase-1
by Bruno Hay Mele, Jessica Bovenzi, Giuseppina Andreotti, Maria Vittoria Cubellis and Maria Monticelli
Molecules 2025, 30(12), 2599; https://doi.org/10.3390/molecules30122599 - 15 Jun 2025
Viewed by 498
Abstract
Phosphomannomutase 2 (PMM2) catalyzes the interconversion of mannose-6-phosphate and mannose-1-phosphate, a key step in the biosynthesis of GDP-mannose for N-glycosylation. Its deficiency is the most common cause of congenital disorders of glycosylation (CDGs), accounting for the subtype known as PMM2-CDG. PMM2-CDG is a [...] Read more.
Phosphomannomutase 2 (PMM2) catalyzes the interconversion of mannose-6-phosphate and mannose-1-phosphate, a key step in the biosynthesis of GDP-mannose for N-glycosylation. Its deficiency is the most common cause of congenital disorders of glycosylation (CDGs), accounting for the subtype known as PMM2-CDG. PMM2-CDG is a rare autosomal recessive disease characterized by multisystemic dysfunction, including cerebellar atrophy, peripheral neuropathy, developmental delay, and coagulation abnormalities. The disease is associated with a spectrum of pathogenic missense mutations, particularly at residues involved in dimerization and catalytic function (i.e., p.Phe119Leu and p.Arg141His). The dimerization of PMM2 is considered essential for enzymatic activity, although it remains unclear whether this supports structural stability alone, or whether both subunits are catalytically active—a distinction that may affect how mutations in each monomer contribute to overall enzyme function and disease phenotype. PMM2 has a paralog, phosphomannomutase 1 (PMM1), which shares substantial structural similarity—including obligate dimerization—and displays mutase activity in vitro, but does not compensate for PMM2 deficiency in vivo. To investigate potential heterodimerization between PMM1 and PMM2 and the effect of interface mutations over PMM2 dimer stability, we first assessed the likelihood of their co-expression using data from GTEx and the Human Protein Atlas. Building on this expression evidence, we modeled all possible dimeric combinations between the two paralogs using AlphaFold3. Models of the PMM2 and PMM1 homodimers were used as internal controls and aligned closely with their respective reference biological assemblies (RMSD < 1 Å). In contrast, the PMM2/PMM1 heterodimer model, the primary result of interest, showed high overall confidence (pLDDT > 90), a low inter-chain predicted alignment error (PAE∼1 Å), and robust interface confidence scores (iPTM = 0.80). Then, we applied PISA, PRODIGY, and mmCSM-PPI to assess interface energetics and evaluate the impact of missense variants specifically at the dimerization interface. Structural modeling suggested that PMM2/PMM1 heterodimers were energetically viable, although slightly less stable than PMM2 homodimers. Interface mutations were predicted to reduce dimer stability, potentially contributing to the destabilizing effects of disease-associated variants. These findings offer a structural framework for understanding PMM2 dimerization, highlighting the role of interface stability, paralogs co-expression, and sensitivity to disease-associated mutations. Full article
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19 pages, 7002 KiB  
Article
Physiological and Transcriptomic Analysis of a Sepal Mutant in Phalaenopsis
by Yu Qi, Yenan Wang, Fei Dong, Jiao Zhu and Xiaohui Lv
Agronomy 2025, 15(6), 1361; https://doi.org/10.3390/agronomy15061361 - 31 May 2025
Viewed by 479
Abstract
MADS-box transcription factors have undergone in-depth investigations regarding their function in regulating the development of plant floral organs. Flower type mutants serve as critical biological models for investigating the regulatory mechanisms of MADS-box genes in floral organ development, while simultaneously constituting essential genetic [...] Read more.
MADS-box transcription factors have undergone in-depth investigations regarding their function in regulating the development of plant floral organs. Flower type mutants serve as critical biological models for investigating the regulatory mechanisms of MADS-box genes in floral organ development, while simultaneously constituting essential genetic resources for molecular breeding programs. In this work, we examined a lip-like sepal of the peloric mutant in Phalaenopsis ‘Huayang’, which exhibited changes in both the morphology and color of the sepals. Our cryo-SEM investigations revealed that the mutation type belonged to a sepal labellum-like variation in Phalaenopsis ‘Huayang’. Nine glycosylated anthocyanins were identified and their contents were significantly upregulated in the Se-red of mutant flowers. Transcriptomic analysis identified 9408 differentially expressed genes, including 4934 upregulated and 4474 downregulated genes. In addition, 57 MADS-box genes were identified and classed into five groups (Mα, Mβ, Mγ, MIKC*, and MIKCC) according to a phylogenetic comparison with Arabidopsis homologs. Furthermore, 29 MADS genes were screened from the MIKCC group, and these genes may play a crucial role in the regulation of floral organ development. Through real-time PCR analysis and protein interaction analysis, we identified three genes that were upregulated in the mutant, which may be involved in sepal development. The subcellular localization results demonstrated that three genes were found within the nucleus. Taken together, our results elucidated the molecular mechanism of sepal variation in Phalaenopsis ‘Huayang’. Our results could enhance our comprehension of the regulatory mechanisms underlying floral patterning and promote the molecular breeding process of Phalaenopsis. Full article
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21 pages, 2768 KiB  
Article
Glucosylceramide Synthase, a Key Enzyme in Sphingolipid Metabolism, Regulates Expression of Genes Accounting for Cancer Drug Resistance
by Md Saqline Mostaq, Lin Kang, Gauri A. Patwardhan, Yunfeng Zhao, Runhua Shi and Yong-Yu Liu
Int. J. Mol. Sci. 2025, 26(11), 5112; https://doi.org/10.3390/ijms26115112 - 26 May 2025
Viewed by 670
Abstract
Emergent cancer drug resistance and further metastasis can mainly be attributed to altered expression levels and functional activities of multiple genes of cancer cells under chemotherapy. In response to challenge with anticancer drugs, enhanced ceramide glycosylation catalyzed by glucosylceramide synthase (GCS) confers drug [...] Read more.
Emergent cancer drug resistance and further metastasis can mainly be attributed to altered expression levels and functional activities of multiple genes of cancer cells under chemotherapy. In response to challenge with anticancer drugs, enhanced ceramide glycosylation catalyzed by glucosylceramide synthase (GCS) confers drug resistance and enrichment with cancer stem cells. p53 mutations, which gain function in tumor progression, are prevalently extant in ovarian cancers. Via integrated gene expression assessments, we characterized GCS-responsive genes in ovarian cancer cells treated with dactinomycin. NCI/ADR-RES cells dominantly expressed a p53 mutant (7 aa deleted in exon-5) and displayed anti-apoptosis; however, silencing GCS expression rendered these cells sensitive to dactinomycin-induced apoptosis. Microarray analyses of NCI/ADR-RES and its GCS transfected sublines found that elevated GCS expression or ceramide glycosylation was associated with altered expression of 41 genes, notably coding for ABCB1, FGF2, ALDH1A3, apolipoprotein E, laminin 2, chemokine ligands, and IL6, with cellular resistance to induced apoptosis and enrichment with cancer stem cells, promoting cancer progression. These findings were further corroborated through integrated genomic analyses of ovarian cancer from The Cancer Genome Atlas (TCGA) and cancer resistance to platinum-based chemotherapy. Altogether, our present study indicates that altered ceramide glycosylation can modulate expression of these GCS-responsive genes and alter cancer cell attributes under chemotherapy. Full article
(This article belongs to the Special Issue Ceramides and Ceramide Kinase)
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14 pages, 9003 KiB  
Article
Isolation and Characterization of Porcine Epidemic Diarrhea Virus G2c Strains Circulating in China from 2021 to 2024
by Xi Lu, Chen Chen, Zixuan Wang and Anding Zhang
Vet. Sci. 2025, 12(5), 444; https://doi.org/10.3390/vetsci12050444 - 6 May 2025
Viewed by 878
Abstract
Porcine epidemic diarrhea virus (PEDV) is a major pathogen responsible for viral diarrhea in pigs, causing particularly high mortality in neonatal piglets. In recent years, genetic variations in PEDV have resulted in alterations in both its virulence and antigenicity, leading to a reduced [...] Read more.
Porcine epidemic diarrhea virus (PEDV) is a major pathogen responsible for viral diarrhea in pigs, causing particularly high mortality in neonatal piglets. In recent years, genetic variations in PEDV have resulted in alterations in both its virulence and antigenicity, leading to a reduced efficacy of existing vaccines. In this study, diarrheal samples were collected from four commercial pig farms in the Hubei, Guangxi, and Jiangxi provinces, China, which experienced vaccine failure. RT-qPCR confirmed PEDV infection, and three PEDV strains, 2021-HBMC, 2024-JXYX, and 2024-JXNC, were successfully isolated. Sequence analysis and phylogenetic tree construction classified these strains into the G2c genotype, the predominant subtype in China. The neutralization assays revealed a significant reduction in the neutralizing titers of these strains against the immune serum compared with the AJ1102 reference strain. Further amino acid sequence analysis of the spike (S) protein identified several mutations in key neutralizing epitopes compared with the AJ1102 strain, including S27L, E57A, N139D, M214T, and P229L in the S-NTD epitope; A520S, F539L, K566N, D569E, G612V, P634S, E636V/K in the COE epitope; and Y1376H in the 2C10 epitope, along with several deletions at N-glycosylation sites (347NSSD and 510NITV). Additionally, whole-genome sequencing and recombination analysis indicated that the 2021-HBMC strain may have resulted from a recombination event. The findings of this study underscore the challenge posed by the continuous genetic evolution of PEDV to vaccine efficacy and provide valuable insights for future vaccine development and control strategies. Full article
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28 pages, 5849 KiB  
Article
Attenuating Mutations in Usutu Virus: Towards Understanding Orthoflavivirus Virulence Determinants and Live Attenuated Vaccine Design
by Johanna M. Duyvestyn, Peter J. Bredenbeek, Marie J. Gruters, Ali Tas, Tessa Nelemans, Marjolein Kikkert and Martijn J. van Hemert
Vaccines 2025, 13(5), 495; https://doi.org/10.3390/vaccines13050495 - 3 May 2025
Viewed by 810
Abstract
Background/Objectives: Understanding virulence determinants can inform safer and more efficacious live attenuated vaccine design. However, applying this knowledge across related viruses does not always result in conserved phenotypes from similar mutants. Methods: Using Usutu virus (USUV), an emerging orthoflavivirus spreading through Europe, we [...] Read more.
Background/Objectives: Understanding virulence determinants can inform safer and more efficacious live attenuated vaccine design. However, applying this knowledge across related viruses does not always result in conserved phenotypes from similar mutants. Methods: Using Usutu virus (USUV), an emerging orthoflavivirus spreading through Europe, we assessed whether the attenuating effect of the mutations described for related orthoflaviviruses is conserved. Candidate attenuating mutations were selected based on previous studies in other orthoflaviviruses and incorporated into USUV. Results: Nine variants, with mutations in the USUV envelope, non-structural (NS) proteins NS1, NS2A, or NS4B were stable and selected for further characterisation. The variants with an attenuating phenotype in cell culture were then compared to the wild-type virus in an Ifnar−/− mouse model. Mutations of the envelope glycosylation sites and glycosaminoglycan binding sites, which were recognised as more-conserved mechanisms of orthoflavivirus attenuation, were attenuating in USUV as well. However, not all the mutations explored in the USUV non-structural proteins exhibited an attenuated phenotype. Instead, the attenuation was either less pronounced, or there was no change in phenotype relative to the wild-type virus at all. Conclusions: In addition to improving our understanding of USUV virulence determinants, these results add to a growing body of literature highlighting the most promising mechanisms to target for the design of safe live attenuated vaccines against emerging orthoflaviviruses. Full article
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21 pages, 1992 KiB  
Article
Comparative Mutational Analysis and the Glycosylation Patterns of a Peruvian Isolated Avian Influenza A Virus H5N1: Exploring Possible Viral Spillover Events Within One Health Approach
by Sandra Landazabal-Castillo, Lucero Alva-Alvarez, Dilan Suarez-Agϋero, Enrique Mamani-Zapana and Egma Mayta-Huatuco
Vet. Sci. 2025, 12(4), 392; https://doi.org/10.3390/vetsci12040392 - 21 Apr 2025
Viewed by 705
Abstract
(1) Background: The ongoing panzootic of highly pathogenic avian influenza virus (HPAIV) of subtype H5N1, clade 2.3.4.4b, has decimated wild/domestic birds and mammals’ populations worldwide with reports of sporadic cases in humans. (2) Methods: This study aimed to compare the mutational profile of [...] Read more.
(1) Background: The ongoing panzootic of highly pathogenic avian influenza virus (HPAIV) of subtype H5N1, clade 2.3.4.4b, has decimated wild/domestic birds and mammals’ populations worldwide with reports of sporadic cases in humans. (2) Methods: This study aimed to compare the mutational profile of H5N1 avian Influenza virus isolated from a Peruvian natural reserve, with recent data from other related international studies made in human and different species of domestic and wild birds and mammals. Briefly, the near complete protein sequences of the Influenza virus coming from a Calidris alba were analyzed at a multisegmented level, together with 55 samples collected between 2022 and 2024 in different countries. Moreover, the glycosylation patterns were also predicted in silico. (3) Results: A total of 603 amino acid changes were found among H5N1 viruses analyzed, underscoring the detection of critical mutations HA:11I, HA:211I, HA:336T, HA:492D, HA:527I, NA:10T, NA:269L, NA:405T, NP:377N, PA:57R, PA:68S, PA:322V/L, PA:432I, PB2:539V, PB1:207R, PB1:375N, PB1:264D, PB1:429R, PA-X:250Q, PB1-F2:65R, and PB1-F2:42Y, as well as PA:13V, PA-X:13V, PA20T, PA-X:20T, PA:36T PA-X:36T, PA:45S, PA-X:45S, PA:57Q, PA-X:57Q, PA:61I, PA-X:61I, PA:68S, PA-X:68S, PA:70V, PA-X:70V, PA:75Q, PA-X:75Q, PA:85T, PA-X:85T, PA:86I, PA-X:86I, PA:100I, PA-X:100I, PA:142E, PA-X:142E, PA:160E, PA-X:160E, PA:211I, PA-X:211Y, among others, considered of importance under the One Health perspective. Similarly, changes in the N-linked glycosylation sites (NLGs) predicted in both HA and NA proteins were found, highlighting the loss/acquisition or changes in some NLGs, such as 209NNTN, 100 NPTT, 302NSSM (HA) and 70NNTN, 68NISS, and 50NGSV (NA). (4) Conclusions: This study provides our understanding about the evolution of current Influenza A viruses H5N1 HPAIV circulating globally. These findings outline the importance of surveillance updating mutational profiles and glycosylation patterns of these highly evolved viruses. Full article
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16 pages, 49683 KiB  
Article
Niemann-Pick C-like Endolysosomal Dysfunction in DHDDS Patient Cells, a Congenital Disorder of Glycosylation, Can Be Treated with Miglustat
by Hannah L. Best, Sophie R. Cook, Helen Waller-Evans and Emyr Lloyd-Evans
Int. J. Mol. Sci. 2025, 26(4), 1471; https://doi.org/10.3390/ijms26041471 - 10 Feb 2025
Viewed by 1253
Abstract
DHDDS (dehydrodolichol diphosphate synthetase) and NgBR (Nogo-B Receptor) collectively form an enzymatic complex important for the synthesis of dolichol, a key component of protein N-glycosylation. Mutations in DHDDS and the gene encoding NgBR (NUS1) are associated with neurodevelopmental disorders that clinically present [...] Read more.
DHDDS (dehydrodolichol diphosphate synthetase) and NgBR (Nogo-B Receptor) collectively form an enzymatic complex important for the synthesis of dolichol, a key component of protein N-glycosylation. Mutations in DHDDS and the gene encoding NgBR (NUS1) are associated with neurodevelopmental disorders that clinically present with epilepsy, motor impairments, and developmental delay. Previous work has demonstrated both DHDDS and NgBR can also interact with NPC2 (Niemann-Pick C (NPC) type 2), a protein which functions to traffic cholesterol out of the lysosome and, when mutated, can cause a lysosomal storage disorder (NPC disease) characterised by an accumulation of cholesterol and glycosphingolipids. Abnormal cholesterol accumulation has also been reported in cells from both individuals and animal models with mutations in NUS1, and suspected lipid storage has been shown in biopsies from individuals with mutations in DHDDS. Our findings provide further evidence for overlap between NPC2 and DHDDS disorders, showing that DHDDS patient fibroblasts have increased lysosomal volume, store cholesterol and ganglioside GM1, and have altered lysosomal Ca2+ homeostasis. Treatment of DHDDS cells, with the approved NPC small molecule therapy, miglustat, improves these disease-associated phenotypes, identifying a possible therapeutic option for DHDDS patients. These data suggest that treatment options currently approved for NPC disease may be translatable to DHDDS/NUS1 patients. Full article
(This article belongs to the Special Issue The Role of Lipids in Health and Diseases)
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18 pages, 1948 KiB  
Article
Genetic and Molecular Characterization of Avian Influenza A(H9N2) Viruses from Live Bird Markets (LBM) in Senegal
by Mamadou Malado Jallow, Moussa Moise Diagne, Marie Henriette Dior Ndione, Mamadou Aliou Barry, Ndiendé Koba Ndiaye, Davy Evrard Kiori, Marie Pedapa Mendy, Déborah Goudiaby, Gamou Fall, Malick Fall and Ndongo Dia
Viruses 2025, 17(1), 73; https://doi.org/10.3390/v17010073 - 8 Jan 2025
Cited by 1 | Viewed by 2183
Abstract
Despite extensive experience with influenza surveillance in humans in Senegal, there is limited knowledge about the actual situation and genetic diversity of avian influenza viruses (AIVs) circulating in the country, hindering control measures and pandemic risk assessment. Therefore, as part of the “One [...] Read more.
Despite extensive experience with influenza surveillance in humans in Senegal, there is limited knowledge about the actual situation and genetic diversity of avian influenza viruses (AIVs) circulating in the country, hindering control measures and pandemic risk assessment. Therefore, as part of the “One Health” approach to influenza surveillance, we conducted active AIV surveillance in two live bird markets (LBMs) in Dakar to better understand the dynamics and diversity of influenza viruses in Senegal, obtain genetic profiles of circulating AIVs, and assess the risk of emergence of novel strains and their transmission to humans. Cloacal swabs from poultry and environmental samples collected weekly from the two LBMs were screened by RT-qPCR for H5, H7, and H9 AIVs. Subsequently, a subset of H9-positive samples was selected for whole sequencing. From December 2023 to October 2024, 499 samples were tested, and AIV was detected in 58.3% of them. Among these, A/H9N2 was the only subtype detected in both markets, with a detection rate of 47.7% (82/172) in Thiaroye and 35.3% (42/119) in Tilene, resulting in an overall positivity rate of 42.6% (124/291). Genome sequencing of 22 A/H9N2 isolates, including 11 poultry drinking water samples, 7 carcass wash water samples, 3 fecal samples, and 1 cloacal swab, yielded 7 complete and 15 partial genomic sequences. Phylogenetic analyses of the resulting sequences showed that the A/H9N2 isolates obtained in this study formed a monophyletic cluster and were closely related to the Senegalese human strain (A/Senegal/0243/2019) identified through the national influenza sentinel surveillance program. These strains were also closely related to the A/H9N2 viruses of the G1 lineage circulating in neighboring countries, suggesting cross-border transmission. The A/H9N2 strains carried the low pathogenicity RSSR/GLF motif at the HA cleavage site and possessed several key amino acid mutations, including HA-I155T and HA-Q226L, which are associated with human host adaptation, PB2-T105V, PB2-A661T, and PB2-A588V, which are linked to the human-to-human transmission and increased polymerase activity, NS2-T14M, NS2-M100I, NS1-I106M, NS1-V222M, NS1-E223A, NS1-I226V, NS1-E227G, and NS1-P228S, which are known to alter virulence (increased or reduced) in humans or mice, and M2-S31N, which promotes drug resistance. Seven potential N-glycosylation sites were predicted in the HA protein and six in the NA protein. The selection pressure analysis revealed that the A/H9N2 isolates were primarily under neutral evolution or purifying selection pressure. Overall, our findings highlight the potential for cross-species transmission of Senegalese A/H9N2 viruses, emphasizing the need for sustained monitoring of these viruses in both animal and human populations. Full article
(This article belongs to the Special Issue Controlling Zoonotic Viral Diseases from One Health Perspective 2025)
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9 pages, 3029 KiB  
Case Report
Two Different Brain Injury Patterns Associated with Compound Heterozygosis of the PIGO Gene in a Term Newborn: A Case Report
by Francesco Dellepiane, Giulia Moltoni, Sara Ronci, Alessia Guarnera, Maria Camilla Rossi-Espagnet, Maria Cristina Digilio, Diego Martinelli, Francesca Campi and Daniela Longo
Biomedicines 2024, 12(12), 2779; https://doi.org/10.3390/biomedicines12122779 - 6 Dec 2024
Viewed by 1137
Abstract
The glycosylphosphatidylinositol (GPI) is a glycol–lipid that anchors several proteins to the cell surface. The GPI-anchor pathway is crucial for the correct function of proteins involved in cell function, and it is fundamental in early neurogenesis and neural development. The PIG gene family [...] Read more.
The glycosylphosphatidylinositol (GPI) is a glycol–lipid that anchors several proteins to the cell surface. The GPI-anchor pathway is crucial for the correct function of proteins involved in cell function, and it is fundamental in early neurogenesis and neural development. The PIG gene family is a group of genes involved in this pathway with six genes identified so far, and defects in these genes are associated with a rare inborn metabolic disorder manifesting with a spectrum of clinical phenotypes in newborns and children. Among them, the PIGO gene encodes for phosphatidylinositol glycan anchor biosynthesis class O protein (PIGO), an enzyme participating in this cascade, and the loss of its function often leads to a severe clinical picture characterized by global developmental delay, seizures, Hirschsprung disease, and other congenital malformations. To date, 19 patients with confirmed PIGO deficiency have been described in the literature with a host of clinical and radiological manifestations. We report a case of a male term newborn with two compound heterozygous variants of the PIGO genes, presenting with encephalopathy, drug-resistant epilepsy, and gastrointestinal abnormalities. Brain MRI first showed diffusion restriction in the ponto-medullary tegmentum, ventral mesencephalon, superior cerebellar peduncles, cerebral peduncles, and globi pallidi. This pattern of lesion distribution has been described as part of the neuroradiological spectrum of PIG genes-related disorders. However, after one month of life, he also showed a previously undescribed MRI pattern characterized by extensive cortical and subcortical involvement of the brain hemispheres. The presence of two different mutations in both the PIGO genes may have been responsible for the particularly severe clinical picture and worse outcome, leading to the death of the newborn in the sixth month of life despite therapeutic attempts. This case expands the neuroradiological spectrum and may bring new insights on glycosylation-related disorders brain manifestations. Full article
(This article belongs to the Special Issue Understanding Diseases Affecting the Central Nervous System)
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28 pages, 5414 KiB  
Article
Autism-Linked Mutations in α2δ-1 and α2δ-3 Reduce Protein Membrane Expression but Affect Neither Calcium Channels nor Trans-Synaptic Signaling
by Sabrin Haddad, Manuel Hessenberger, Cornelia Ablinger, Clarissa Eibl, Ruslan Stanika, Marta Campiglio and Gerald J. Obermair
Pharmaceuticals 2024, 17(12), 1608; https://doi.org/10.3390/ph17121608 - 28 Nov 2024
Cited by 1 | Viewed by 1458
Abstract
Background: α2δ proteins regulate membrane trafficking and biophysical properties of voltage-gated calcium channels. Moreover, they modulate axonal wiring, synapse formation, and trans-synaptic signaling. Several rare missense variants in CACNA2D1 (coding for α2δ-1) and CACNA2D3 (coding for α2δ-3) [...] Read more.
Background: α2δ proteins regulate membrane trafficking and biophysical properties of voltage-gated calcium channels. Moreover, they modulate axonal wiring, synapse formation, and trans-synaptic signaling. Several rare missense variants in CACNA2D1 (coding for α2δ-1) and CACNA2D3 (coding for α2δ-3) genes were identified in patients with autism spectrum disorder (ASD). However, the pathogenicity of these variants is not known, and the molecular mechanism by which α2δ proteins may contribute to the pathophysiology of autism is, as of today, not understood. Therefore, in this study we functionally characterized two heterozygous missense variants in α2δ-1 (p.R351T) and α2δ-3 (p.A275T), previously identified in patients with ASD. Methods: Electrophysiological recordings in transfected tsA201 cells were used to study specific channel-dependent functions of mutated α2δ proteins. Membrane expression, presynaptic targeting, and trans-synaptic signaling of mutated α2δ proteins were studied upon expression in murine cultured hippocampal neurons. Results: Homologous expression of both mutated α2δ proteins revealed a strongly reduced membrane expression and synaptic localization compared to the corresponding wild type α2δ proteins. Moreover, the A275T mutation in α2δ-3 resulted in an altered glycosylation pattern upon heterologous expression. However, neither of the mutations compromised the biophysical properties of postsynaptic L-type (CaV1.2 and CaV1.3) and presynaptic P/Q-type (CaV2.1) channels when co-expressed in tsA201 cells. Furthermore, presynaptic expression of p.R351T in the α2δ-1 splice variant lacking exon 23 did not affect trans-synaptic signaling to postsynaptic GABAA receptors. Conclusions: Our data provide evidence that the pathophysiological mechanisms of ASD-causing mutations of α2δ proteins may not involve their classical channel-dependent and trans-synaptic functions. Alternatively, these mutations may induce subtle changes in synapse formation or neuronal network function, highlighting the need for future α2δ protein-linked disease models. Full article
(This article belongs to the Special Issue Calcium Channels as Therapeutic Targets)
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