Search Results (70)

Background/Objectives: Achondroplasia is the most common genetic skeletal dysplasia associated with disproportionate short stature and is primarily caused by gain-of-function variants in the fibroblast growth factor receptor 3 (FGFR3) gene. Constitutive FGFR3 activation disrupts growth plate homeostasis and endochondral ossification through complex alterations in chondrocyte proliferation, differentiation, hypertrophy, extracellular matrix organization, and intracellular signaling. The increasing understanding of these mechanisms has enabled the transition from exclusively supportive management toward disease-modifying and precision-based therapeutic strategies. This narrative review aimed to critically synthesize current evidence on the genetic basis, molecular pathogenesis, growth plate abnormalities, and current and emerging targeted therapies in achondroplasia. Methods: A narrative literature review was conducted using PubMed/MEDLINE, Scopus, and Web of Science Core Collection, with Google Scholar used as a supplementary source, together with manual screening of the reference lists of relevant original studies, clinical trials, reviews, consensus documents, and clinical guidelines. The principal literature search covered publications from January 2010 to March 2026, while selected seminal primary studies published before 2010 were included when necessary to document the original identification of pathogenic FGFR3 variants and foundational mechanisms of FGFR3-mediated growth plate regulation. Particular emphasis was placed on FGFR3 variants, receptor activation mechanisms, growth plate dysfunction, intracellular signaling pathways, vosoritide, C-type natriuretic peptide-based therapies, FGFR3 inhibitors, ligand–receptor blockade, drug repurposing, Wnt/β-catenin modulation, and gene-based therapeutic approaches. Results: Achondroplasia is characterized by marked molecular homogeneity, with the recurrent p.Gly380Arg substitution accounting for most cases. Mutant FGFR3 displays sustained activity through partial ligand independence, enhanced receptor dimerization and kinase activation, increased receptor stability, and reduced degradation. Excessive signaling through MAPK/ERK, STAT, PI3K/AKT, IHH/PTHrP, and related pathways impairs chondrocyte proliferation and hypertrophic differentiation, alters extracellular matrix turnover, disrupts primary cilium function, and reduces longitudinal bone growth. Vosoritide provides clinical proof that pharmacological modulation of FGFR3-related signaling can improve growth velocity. Additional therapeutic strategies under clinical or preclinical investigation include long-acting CNP analogues, selective FGFR inhibitors, decoy receptors, RNA aptamers, repurposed drugs, Wnt/DKK1 pathway modulation, and gene- or enhancer-targeted interventions. Conclusions: Achondroplasia is increasingly understood as a disorder of dysregulated growth plate signaling rather than solely a condition of reduced stature. Although vosoritide has established the feasibility of disease-modifying treatment, substantial uncertainty remains regarding final adult height, skeletal proportionality, cranio-spinal development, orthopedic outcomes, and long-term safety. Future progress will depend on mechanistically informed therapeutic combinations, improved biomarkers, advanced cellular and animal models, and long-term clinical and real-world evidence. Full article

Antimicrobial peptides (AMPs) occur naturally in living organisms and play an essential role in defense against pathogens. Consequently, these peptides are significant in public health research as alternatives in addressing microbial resistance. Here, we present the proteomic profile of Cryptococcus neoformans treated with RcAlb-PepII, an AMP derived from the 2S albumin of Ricinus communis seed cake. This research is noteworthy, as C. neoformans is an emerging fungal pathogen classified by the World Health Organization (WHO) as a critical threat. Proteomic analysis revealed depletion of proteins involved in DNA and RNA metabolism, reduced protein biosynthesis, and mitochondrial damage-associated proteins in C. neoformans following RcAlb-PepII treatment. These findings advance the understanding of the therapeutic profile of AMPs and underscore their importance in combating critical pathogens. Full article

Leishmaniases are infections caused by Leishmania parasites and transmitted through the bite of infected female Phlebotomus (Old World) and Lutzomyia (New World) sandflies. The disease disproportionately affects marginalized communities with limited healthcare access. With no approved human vaccines available, leishmaniasis treatment and prevention depend heavily on chemotherapeutics that face growing drug resistance challenges alongside toxicity concerns. The development of safe, effective and affordable vaccines against human leishmaniasis remains a global health priority for disease control and elimination, mostly in resource-limited settings. This review synthesizes progress in leishmaniasis vaccine platforms including live-attenuated parasites, whole-killed parasites, DNA, protein subunit, peptide-based and chimeric/multiepitope vaccines and their homogenous and heterogenous efficacy. Live-attenuated and whole-parasite vaccines have been accounted to elicit robust cellular immunity but pose safety risks, particularly in immunocompromised hosts. While both second- and third-generation vaccines exemplified by LEISH-F1/F3 polyproteins, elicit strong Th1-biased T cell responses in preclinical models, their efficacy in humans remains limited. However, the highlighted collective efforts are pivotal in steering the rational development of future research using various formulations for multiple management of leishmaniasis through cross-protection. Furthermore, emerging strategies including mRNA platforms, nanoparticle delivery, reverse vaccinology, and immunoinformatics offer promising avenues for accelerating vaccine discovery and advancing the development of novel and effective human vaccines. Full article

The discovery of Asgard archaea has reshaped our understanding of eukaryotic origins, supporting a two-domain tree of life in which eukaryotes emerged from Archaea. Building on this revised framework, we propose the Pre-prokaryotic Organismal Lifeforms Existing Today (POLET) hypothesis, which suggests that relic pre-prokaryotic life forms—termed POLETicians—may persist in deep, anoxic, energy-limited environments. These organisms could represent a living bridge to the RNA world and other origin-of-life models, utilizing racemic oligoribonucleotides and peptides, non-enzymatic catalysis, and mineral-assisted compartmentalization. POLETicians might instead rely on radical-based redox chemistry or radiolysis for energy and maintenance. These biomolecules may be racemic or noncanonical, eluding conventional detection. New detection methods are required to determine such life. We propose generalized nanopore sequencing of any linear polymer—including mirror RNAs, mirror DNAs, or any novel genetic material—as a potential strategy to overcome chirality bias in modern sequencing technologies. These approaches, combined with chiral mass spectrometry and stereoisomer-resolved analytics, may enable the detection of molecular signatures from non-phylogenetic primitive lineages. POLETicians challenge the assumption that all life must follow familiar biochemical constraints and offer a compelling extension to our search for both ancient and extant forms of life hidden within Earth’s most extreme environments. Full article

The virus-first theory presents a model in which viral lineages emerged before cells. This proposal aims to give the theory greater relevance by offering a plausible evolutionary framework that explains both (i) the origin of viruses from prebiotic chemistry and (ii) how viruses contributed to the emergence of cells. Here, we propose that viruses should be understood as a distinct class of ribonucleoprotein (RNP) systems, some of which evolved directly from the RNP-world. In our model, simple progenotes produced capsid-like particles through the evolution of a single gene encoding a self-assembling peptide. This allowed the formation of icosahedral shells around RNA genomes, as observed today in certain viral families whose capsids consist of ~60 identical subunits derived from a single gene product. These early capsids enabled mobility and protection, representing key intermediates toward biological complexity. Over time, some of those populations acquired additional peptides and evolved more elaborate architectures. Finally, the incorporation of lipid-binding domains in those capsid-like peptides allowed the formation of proteolipidic membranes akin to those found in modern cells. This model provides a gradualistic and logically coherent evolutionary path from the RNP-world to the emergence of cellular life, emphasizing the foundational role of viruses in early evolution. Full article

(1) Background: Previous theoretical studies have provided arguments for the existence of a circular or hairpin RNA that could have served as a primitive informational and functional molecule at the origin of life. The present article consists of searching in current genomes for RNAs closest to this primitive RNA in terms of the occurrence of similar nucleotide motifs. (2) Methods: In searching for the smallest possible RNA capable of interacting with amino acids in the construction of the peptides of the primitive living world, we found a circular docosamer RNA molecule (length 22), which we called AL (for ALpha or Archetypal Loop). Then, we started to systematically track AL relics in current genomes in the form of motifs like pentamers or pairs of consecutive codons in common with AL. (3) Results: The sequence correspondence between AL and RNA sequences of organisms from different kingdoms of life (Archaea, Bacteria, and Eukarya) was found with high statistical significance, with a frequency gradient depending on both the antiquity of the species and the functional necessity of the genes. (4) Conclusions: Considering the suitability of AL as a candidate for being a primitive sequence, and the evolution of the different species considered, we can consider the AL RNA as a possible actor that favored the appearance of life on Earth. Full article

Metabolism, the network of biochemical reactions that powers life, arose under conditions radically different from those on Earth today. Investigating its origins reveals how initially simple chemical processes gradually integrated nucleic acid and then protein catalysts, becoming progressively more complex and regulated until they evolved into the enzyme-rich systems observed in modern organisms. Here, we integrate multiple perspectives on the origin of metabolism, focusing primarily on an evolutionary trajectory from an RNA-based world, where ribozymes, metal ions, coenzymes, small peptides, and other small organic molecules worked in concert, to enzyme-driven metabolic networks. We also address the longstanding debates on whether these early metabolic pathways were largely autotrophic or heterotrophic, and consider so-called “pre-metabolisms” (non-enzymatic networks) as an alternative conceptual framework. We discuss key examples such as the Wood–Ljungdahl (W–L) pathway and the reverse tricarboxylic acid (TCA) cycle, both posited to function under early Earth conditions. Finally, we examine how the environment (e.g., minerals, clays, hydrothermal vents) shaped early metabolism, describe unresolved questions about the Last Common Ancestor’s catalytic repertoire and propose future directions that link geochemical insights with molecular biology and synthetic approaches. Full article

The COVID-19 pandemic has underscored the need for effective and affordable antiviral drugs. Anthropogenic activities have increased interactions among humans, animals, and wildlife, contributing to the emergence of new and re-emerging viral diseases. RNA viruses pose significant challenges due to their rapid mutation rates, high transmissibility, and ability to adapt to host immune responses and antiviral treatments. The World Health Organization has identified several diseases (COVID-19, Ebola, Marburg, Zika, and others), all caused by RNA viruses, designated as being of priority concern as potential causes of future pandemics. Despite advances in antiviral treatments, many viruses lack specific therapeutic options, and more importantly, there is a paucity of broad-spectrum antiviral drugs. Additionally, the high costs of current treatments such as Remdesivir and Paxlovid highlight the need for more affordable antiviral drugs. Cyclic peptides from natural sources or designed through molecular modeling have shown promise as antiviral drugs with stability, low toxicity, high target specificity, and low antiviral resistance properties. This review emphasizes the urgent need to develop specific and broad-spectrum antiviral drugs and highlights cyclic peptides as a sustainable solution to combat future pandemics. Further research into these compounds could provide a new weapon to combat RNA viruses and address the gaps in current antiviral drug development. Full article

Wheat (Triticum aestivum L.) is a primary crop globally. Among the numerous pathogens affecting wheat production, Puccinia striiformis f. sp. tritici (Pst) is a significant biotic stress agent and poses a major threat to world food security by causing stripe rust or yellow rust disease. Understanding the molecular basis of plant–pathogen interactions is crucial for developing new means of disease management. It is well established that the effector proteins play a pivotal role in pathogenesis. Therefore, studying effector proteins has become an important area of research in plant biology. Our previous work identified differentially expressed candidate secretory effector proteins of stripe rust based on transcriptome sequencing data from susceptible wheat (Avocet S) and resistant wheat (Avocet YR10) infected with Pst. Among the secreted effector proteins, PSTG_14090 contained an ancient double-psi beta-barrel (DPBB) fold, which is conserved in the rare lipoprotein A (RlpA) superfamily. This study investigated the role of PSTG_14090 in plant immune responses, which encodes a protein, here referred to as Pst-DPBB, having 131 amino acids with a predicted signal peptide (SP) of 19 amino acids at the N-terminal end, and the DNA sequence of this effector is highly conserved among different stripe rust races. qRT-PCR analysis indicated that expression levels are upregulated during the early stages of infection. Subcellular localization studies in Nicotiana benthamiana leaves and wheat protoplasts revealed that it is distributed in the cytoplasm, nucleus, and apoplast. We demonstrated that Pst-DPBB negatively regulates the immune response by functioning in various compartments of the plant cells. Based on Co-IP and structural predictions and putative interaction analyses by AlphaFold 3, we propose the probable biological function(s). Pst-DPBB behaves as a papain inhibitor of wheat cysteine protease; Pst-DPBB has high structural homology to kiwellin, which is known to interact with chorismate mutase, suggesting that Pst-DPBB inhibits the native function of the host chorismate mutase involved in salicylic acid synthesis. The DPBB fold is also known to interact with DNA and RNA, which may suggest its possible role in regulating the host gene expression. Full article

Inflammatory bowel disease (IBD) is increasing among mammals around the world, and domestic dogs are no exception. There is no approved cure for canine IBD with limited treatment options. Novel probiotic bacteria discovery from free-ranging animals for the treatment of IBD in domestic pets can likely yield promising probiotic candidates. Consequently, the overall aim was to isolate bacteria from free-ranging animals that could potentially be utilized as novel probiotics. Two bacteria identified as unique Paenibacillus spp. strains by small ribosomal RNA (16S) gene sequencing were isolated from the gastrointestinal tract of a North American Gray Wolf (Canis lupus). The bacteria were typed as Gram-variable, and both were catalase/oxidase positive as well as sensitive to commonly used antibiotics. The bacteria digested complex carbohydrates and lipids by standard assays. The isolated bacteria also inhibited the growth of Staphylococcus aureus and Micrococcus luteus. The whole genome sequence (WGS) length of bacterial isolate ClWae17B was 6,939,193 bp, while ClWae19 was 7,032,512 bp, both similar in size to other Paenibacillus spp. The genomes of both bacteria encoded enzymes involved with the metabolism of complex starches and lipids, such as lyases and pectinases, along with encoding antimicrobials such as lanthipeptides, lasso peptides, and cyclic-lactone-autoinducers. No pernicious virulence genes were identified in the WGS of either bacterial isolate. Phylogenetically, the most closely related bacteria based on 16S gene sequences and WGS were P. taichungensis for ClWae17B and P. amylolyticus for ClWae19. WGS analyses and phenotypic assays supported the hypothesis that the isolates described constitute two novel candidate probiotic bacteria for potential use in dogs. Full article

Plant diseases diminish crop yields and put the world’s food supply at risk. Plant elicitor peptides (Peps) are innate danger signals inducing defense responses both naturally and after external application onto plants. Pep-triggered defense networks are compatible with pattern-triggered immunity (PTI). Nevertheless, in complex regulatory pathways, there is crosstalk among different signaling pathways, involving noncoding RNAs in the natural response to pathogen attack. Here, we used Prunus persica, PpPep2 and a miRNA-Seq approach to show for the first time that Peps regulate, in parallel with a set of protein-coding genes, a set of plant miRNAs (~15%). Some PpPep2-regulated miRNAs have been described to participate in the response to pathogens in various plant–pathogen systems. In addition, numerous predicted target mRNAs of PpPep2-regulated miRNAs are themselves regulated by PpPep2 in peach trees. As an example, peach miRNA156 and miRNA390 probably have a role in plant development regulation under stress conditions, while others, such as miRNA482 and miRNA395, would be involved in the regulation of resistance (R) genes and sulfate-mediated protection against oxygen free radicals, respectively. This adds to the established role of Peps in triggering plant defense systems by incorporating the miRNA regulatory network and to the possible use of Peps as sustainable phytosanitary products. Full article

Approximately one-third of the entire world’s food resources are deemed to be wasted. Palm kernel meal (PKM), a product that is extensively generated by the palm oil industry, exhibits a unique nutrient-rich composition. However, its recycling is seldom prioritized due to numerous factors. To evaluate the impact of enzymatic pretreatment and Lactobacillus plantarum and Lactobacillus reuteri fermentation upon the antioxidant activity of PKM, we implemented integrated metagenomics and metabolomics approaches. The substantially enhanced (p < 0.05) property of free radicals scavenging, as well as total flavonoids and polyphenols, demonstrated that the biotreated PKM exhibited superior antioxidant capacity. Non-targeted metabolomics disclosed that the Lactobacillus fermentation resulted in substantial (p < 0.05) biosynthesis of 25 unique antioxidant biopeptides, along with the increased (p < 0.05) enrichment ratio of the isoflavonoids and secondary metabolites biosynthesis pathways. The 16sRNA sequencing and correlation analysis revealed that Limosilactobacillus reuteri, Pediococcus acidilactici, Lacticaseibacillus paracasei, Pediococcus pentosaceus, Lactiplantibacillus plantarum, Limosilactobacillus fermentum, and polysaccharide lyases had significantly dominated (p < 0.05) proportions in PMEL, and these bacterial species were strongly (p < 0.05) positively interrelated with antioxidants peptides. Fermented PKM improves nutritional value by enhancing beneficial probiotics, enzymes, and antioxidants and minimizing anti-nutritional factors, rendering it an invaluable feed ingredient and gut health promoter for animals, multifunctional food elements, or as an ingredient in sustainable plant-based diets for human utilization, and functioning as a culture substrate in the food sector. Full article

The evolution of the translation system is a fundamental issue in the quest for the origin of life. A feasible evolutionary scenario necessitates the autonomous emergence of a protoribosome capable of catalyzing the synthesis of the initial peptides. The peptidyl transferase center (PTC) region in the modern ribosomal large subunit is believed to retain a vestige of such a prebiotic non-coded protoribosome, which would have self-assembled from random RNA chains, catalyzed peptide bond formation between arbitrary amino acids, and produced short peptides. Recently, three research groups experimentally demonstrated that several distinct dimeric constructs of protoribosome analogues, derived predicated on the approximate 2-fold rotational symmetry inherent in the PTC region, possess the ability to spontaneously fold, dimerize, and catalyze the formation of peptide bonds and of short peptides. These dimers are examined, aiming at retrieving information concerned with the characteristics of a prebiotic protoribosome. The analysis suggests preconditions for the laboratory re-creation of credible protoribosome analogues, including the preference of a heterodimer protoribosome, contradicting the common belief in the precedence of homodimers. Additionally, it derives a dynamic process which possibly played a role in the spontaneous production of the first bio-catalyzed peptides in the prebiotic world. Full article

Traumatic brain injury (TBI) is a major cause of mortality and disability around the world, for which no treatment has been found. Nociceptin/Orphanin FQ (N/OFQ) and the nociceptin opioid peptide (NOP) receptor are rapidly increased in response to fluid percussion, stab injury, and controlled cortical impact (CCI) TBI. TBI-induced upregulation of N/OFQ contributes to cerebrovascular impairment, increased excitotoxicity, and neurobehavioral deficits. Our objective was to identify changes in N/OFQ and NOP receptor peptide, protein, and mRNA relative to the expression of injury markers and extracellular regulated kinase (ERK) 24 h following mild (mTBI) and moderate TBI (ModTBI) in wildtype (WT) and NOP receptor-knockout (KO) rats. N/OFQ was quantified by radioimmunoassay, mRNA expression was assessed using real-time PCR and protein levels were determined by immunoblot analysis. This study revealed increased N/OFQ mRNA and peptide levels in the CSF and ipsilateral tissue of WT, but not KO, rats 24 h post-TBI; NOP receptor mRNA increased after ModTBI. Cofilin-1 activation increased in the brain tissue of WT but not KO rats, ERK activation increased in all rats following ModTBI; no changes in injury marker levels were noted in brain tissue at this time. In conclusion, this study elucidates transcriptional and translational changes in the N/OFQ-NOP receptor system relative to TBI-induced neurological deficits and initiation of signaling cascades that support the investigation of the NOP receptor as a therapeutic target for TBI. Full article

Deciphering the origins of life on a molecular level includes unravelling the numerous interactions that could occur between the most important biomolecules being the lipids, peptides and nucleotides. They were likely all present on the early Earth and all necessary for the emergence of cellular life. In this study, we intended to explore conditions that were at the same time conducive to chemical reactions critical for the origins of life (peptide–oligonucleotide couplings and templated ligation of oligonucleotides) and compatible with the presence of prebiotic lipid vesicles. For that, random peptides were generated from activated amino acids and analysed using NMR and MS, whereas short oligonucleotides were produced through solid-support synthesis, manually deprotected and purified using HPLC. After chemical activation in prebiotic conditions, the resulting mixtures were analysed using LC-MS. Vesicles could be produced through gentle hydration in similar conditions and observed using epifluorescence microscopy. Despite the absence of coupling or ligation, our results help to pave the way for future investigations on the origins of life that may gather all three types of biomolecules rather than studying them separately, as it is still too often the case. Full article