Search Results (878)

Multidrug-resistant (MDR) strains of Klebsiella pneumoniae present an acute threat as they continue to disseminate globally. Phage therapy has shown promise as a powerful approach to combat MDR infections, but narrow phage host ranges make development of broad acting therapeutics more challenging. The goal of this effort was to use in vitro directed evolution (the “Appelmans protocol”) to isolate K. pneumoniae phages with broader host ranges for improved therapeutic cocktails. Five myophages in the genus Jiaodavirus (family Straboviridae) with complementary activity were mixed and passaged against a panel of 11 bacterial strains including a permissive host and phage-resistant clinical isolates. Following multiple rounds of training, we collected phage variants displaying altered specificity or expanded host ranges compared with parental phages when tested against a 100 strain diversity panel of K. pneumoniae. Some phage variants gained the ability to lyse previously phage-resistant strains but lost activity towards previously phage-susceptible strains, while several variants had expanded activity. Whole-genome sequencing identified mutations and recombination events impacting genes associated with host tropism including tail fiber genes that most likely underlie the observed changes in host ranges. Evolved phages with broader activity are promising candidates for improved K. pneumoniae therapeutic phage cocktails. Full article

Nipah virus (NiV) is a highly pathogenic bat-borne zoonotic pathogen that poses a significant threat to human and animal health, with fatality rates exceeding 70% in some outbreaks. Despite its significant public health impact, there are currently no licensed vaccines or specific therapeutics available. Various virological tools—such as reverse genetics systems, replicon particles, VSV-based pseudoviruses, and recombinant Cedar virus chimeras—have been widely used to study the molecular mechanisms of NiV and to support vaccine development. Building upon these platforms, we developed a replication-competent recombinant vesicular stomatitis virus (rVSVΔG-eGFP-NiV_BD F/G) expressing NiV attachment (G) and fusion (F) glycoproteins. This recombinant virus serves as a valuable tool for investigating NiV entry mechanisms, cellular tropism, and immunogenicity. The virus was generated by replacing the VSV G protein with NiV F/G through reverse genetics, and protein incorporation was confirmed via immunofluorescence and electron microscopy. In vitro, the virus exhibited robust replication, characteristic cell tropism, and high viral titers in multiple cell lines. Neutralization assays showed that monoclonal antibodies HENV-26 and HENV-32 effectively neutralized the recombinant virus. Furthermore, immunization of golden hamsters with inactivated rVSVΔG-eGFP-NiV_BD F/G induced potent neutralizing antibody responses, demonstrating its robust immunogenicity. These findings highlight rVSVΔG-eGFP-NiV_BD F/G as an effective platform for NiV research and vaccine development. Full article

Bone metastasis remains a significant cause of morbidity and diminished quality of life in patients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 and RASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to cancer cell plasticity and facilitates epithelial-to-mesenchymal transition (EMT). Key histone modifiers, including KLF5, EZH2, and the demethylases KDM4/6, regulate osteoclastogenic signaling pathways and the transition between metastatic dormancy and reactivation. Simultaneously, SWI/SNF chromatin remodelers such as BRG1 and BRM reconfigure enhancer–promoter interactions that promote bone tropism. Non-coding RNAs, including miRNAs, lncRNAs, and circRNAs (e.g., miR-34a, NORAD, circIKBKB), circulate via exosomes to modulate the RANKL/OPG axis, thereby conditioning the bone microenvironment and fostering the formation of a pre-metastatic niche. These mechanistic insights have accelerated the development of epigenetic therapies. DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling. Inhibitors targeting EZH2, BET proteins, and KDM1A are now advancing through early-phase clinical trials, often in combination with bisphosphonates or immune checkpoint inhibitors. Moreover, novel approaches such as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies offer locus-specific reprogramming potential. Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases. Full article

Cardiac arrhythmias remain a major source of morbidity and mortality, often stemming from molecular and structural abnormalities that are insufficiently addressed by current pharmacologic and interventional therapies. Gene therapy has emerged as a transformative approach, offering precise and durable interventions that directly target the arrhythmogenic substrate. Across the spectrum of inherited and acquired arrhythmias—including long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, atrial fibrillation, and post-infarction ventricular tachycardia—gene-based strategies such as allele-specific silencing, gene replacement, CRISPR-mediated editing, and suppression-and-replacement constructs are showing growing translational potential. Advances in delivery platforms, including cardiotropic viral vectors, lipid nanoparticle-encapsulated mRNA, and non-viral reprogramming tools, have further enhanced the specificity and safety of these approaches. Additionally, innovative applications such as biological pacemaker development and mutation-agnostic therapies underscore the versatility of genetic modulation. Nonetheless, significant challenges remain, including vector tropism, immune responses, payload limitations, and the translational gap between preclinical models and human electrophysiology. Integration of patient-derived cardiomyocytes, computational simulations, and large-animal studies is expected to accelerate clinical translation. This review provides a comprehensive synthesis of the mechanistic rationale, therapeutic strategies, delivery platforms, and translational frontiers of gene therapy for cardiac arrhythmias. Full article

Herpes simplex virus type 1 (HSV-1) is associated with eye infections. Specifically, the acute consequences of eye infections have been extensively studied. This review gathers information on possible collateral damage caused by HSV-1 in the retina, such as age-related macular degeneration (AMD), a neurodegenerative disease. The synthesis and accumulation of Amyloid-β peptide (Aβ) is a key hallmark in these types of pathologies. AMD is a disease of multifactorial origin, and viral infections play an important role in its development. It is known that once this virus has entered the eye, it can infect adjacent cells, thus having the ability to infect almost any cell type with great tropism. In the retina, retinal pigment epithelial (RPE) cells are primarily involved in AMD. This work reviews publications that show that RPE can produce Aβ, and once they are infected by HSV-1, the release is promoted. Also, all the information available in the literature that explains how these events may be interconnected has been compiled. This information is valuable when planning new treatments for multifactorial neurodegenerative diseases. Full article

With the rise in immunocompromised individuals and patients with immune-related comorbidities such as COVID-19, the rate of fungal infections is growing. This increase, along with the current plateau in antifungal drug development, has made understanding the pathogenesis and dissemination of these organisms more pertinent than ever. The mouse model of fungal infection, while informative on a basic scientific level, has severe limitations in terms of translation to the human disease. Here we present data supporting the implementation of the human cerebral organoid model, which is generated from human embryonic stem cells and accurately recapitulates relevant brain cell types and structures, to study fungal infection and dissemination to the central nervous system (CNS). This approach provides direct insight into the relevant pathogenesis of specific fungal organisms in human tissues where in vivo models are impossible. With this model system we assessed the specific brain tropisms and cellular effects of fungal pathogens known to cross the blood–brain barrier (BBB), such as Cryptococcus neoformans. We determined the effects of this fungal pathogen on the overall gross morphology, cellular architecture, and cytokine release from these model organoids. Furthermore, we demonstrated that C. neoformans penetrates and invades the organoid tissue and remains present throughout the course of infection. These results demonstrate the utility of this new model to the field and highlight the potential for this system to elucidate fungal pathogenesis to develop new therapeutic strategies to prevent and treat the disseminated stages of fungal diseases such as cryptococcal meningitis. Full article

Adeno-associated virus (AAV) vectors have emerged as powerful tools for in vivo gene therapy, enabling long-term transgene expression in targeted tissues with minimal pathogenicity. This review examines the AAV serotypes used in clinical gene therapy trials for neurodegenerative (central nervous system, CNS) diseases, highlighting their tropisms, engineering advances, and translational progress. We discuss how capsid modifications, cell-specific promoters, and novel delivery routes are enhancing AAV tropism and reducing immunogenicity to overcome current limitations. Key clinical trials in neurodegenerative disorders (such as Parkinson’s, Alzheimer’s, and Huntington’s disease) are summarized, including delivery methods (intravenous, intracoronary, intrathecal, etc.) and outcomes. We further outline the regulatory landscape with recent approvals of AAV-based therapies and ongoing efforts to address safety challenges like immune responses and vector dose toxicity. A more translational, forward-looking perspective is adopted to consider combination therapies (e.g., AAV with immune modulation or genome editing) and strategic directions to improve the next generation of AAV vectors. Overall, continued innovation in AAV vector design and delivery, alongside careful clinical evaluation, is accelerating the translation of gene therapies for neurodegenerative diseases. Full article

Particulate matter (PM), mainly PM_0.5, represents a significant concern for human health, particularly relating to lung homeostasis, and more research is required to ascertain its tissue tropism and the molecular pathways involved. In this study, we first focus on classical in vitro toxicological endpoints (cytotoxicity and cell growth) in human bronchial and alveolar epithelial cell lines mimicking the two pulmonary target tissues. Air samples were collected in five Italian cities (Brescia, Lecce, Perugia, Pisa, Turin) during winter and spring. To better decipher the PM_0.5 effects on pulmonary cells, a further winter sampling was performed in Brescia, and studies were extended to assess tumour promotion, oxidative stress, and the activity of Matrix metalloproteases (MMP). The results confirmed that the effect of air pollution is linked to the seasons (winter is usually more cytotoxic than spring) and is correlated with the peculiar characteristics of the cities studied (meteoclimatic conditions, economic/anthropogenic activities). Alveolar cells were often less sensitive than bronchial cells. All PM samples from Brescia inhibited intercellular communication mediated by gap junctions (GJIC), increased the total content in glutathione, and decreased the reduced form of glutathione, whereas the Reactive Oxygen Species (ROS) content was almost constant. Long-term treatments at higher doses of PM decreased MMP2 and MMP9 activity. Taken together, the results confirmed that PM is cytotoxic and can potentially act as tumour promoters, but the mechanisms involved in oxidative stress and lung homeostasis are dose- and time-dependent and quite complex. Full article

Anseriformes (waterfowl) and Charadriiformes (shorebirds) are well-recognized natural reservoirs of low pathogenic (LP) influenza A viruses (IAVs). Historically, LP IAVs circulate among healthy individuals during seasonal, and often transcontinental, migrations. However, following the introduction of clade 2.3.4.4b highly pathogenic (HP) A/Goose/Guangdong/1/1996 lineage H5 IAV to North America in 2021, countless wild birds succumbed to fatal infections across the Western Hemisphere. Due to their small size and cryptic plumage patterns, opportunities for carcass recovery and postmortem evaluation in sanderlings (Calidris alba) and other shorebirds are rare. A multispecies mortality event in coastal Virginia, USA, in March–April 2024 included sanderlings among other wild bird species. Nine sanderlings underwent postmortem evaluation and clade 2.3.4.4b H5 IAV RNA was detected in pooled oropharyngeal-cloacal swabs from 11/11 individuals by real-time reverse transcription polymerase chain reaction. Histopathology was similar to that in waterfowl and included necrosis in the pancreas and brain and less commonly in the gonad, adrenal gland, spleen, liver, and intestine. Immunohistochemistry revealed IAV antigen labeling in necrotic neurons of the brain (neurotropism) and epithelial cells of the pancreas, gonad, and adrenal gland (epitheliotropism). Describing HP IAV-attributed pathology in shorebirds is key to understanding ecoepidemiology and population health threats in order to further document and compare pathogenesis among avian species. Full article

The parasitic dinoflagellate Hematodinium is an infectious pathogen that causes severe enzootic in numerous economically important marine crustaceans worldwide. Previous research has focused on investigating the identification and life stages of Hematodinium parasites, while the parasite abundance and tissue proliferation process of Hematodinium in naturally infected crustacean hosts need to be further studied. In the present study, the tissue tropisms and intensity of H. perezi were investigated in the naturally infected Chinese swimming crabs Portunus trituberculatus by both the qualitative (hemolymph assay, histology) and quantitative analysis (cell count, quantitative PCR). The results showed that in P. trituberculatus with infection level I (4 ± 2 parasites in 200× microscopic field), filamentous trophonts were observed in the hemolymph and stomach tissues, with the average parasite number and ITS 1 copy number of H. perezi quantitatively detected in hemolymph (1.0 × 10² parasites/mL) and stomach tissues (1.7 × 10³ cells/g), respectively. H. perezi trophonts were observed in the hemolymph (4.3 × 10⁴ parasites/mL) and exhibited broad distribution in multiple tissues with its highest abundance of H. perezi in pereiopod muscles (1.1 × 10⁴ cells/g) followed by that in stomach (4.8 × 10³ cells/g) in P. trituberculatus with infection level II (80 ± 10 parasites in 200× microscopic field). In P. trituberculatus with infection level III (200 ± 35 parasites in 200× microscopic field), a high abundance of H. perezi sporoblasts was found in the hemolymph (3.1 × 10⁷ parasites/mL) and all of the other examined tissues, with its highest abundance detected in pereiopod muscles (3.5 × 10⁴ cells/g). In addition, the number of host’s hemocytes was significantly decreased during the Hematodinium infection. This study provides a comprehensive quantitative characterization of the tissue distribution and abundance of H. perezi in its natural crab host which will contribute to better understanding of the crustacean host–Hematodinium interactions. Full article

Mesenchymal stem cells (MSCs) have recently shown great promise as potential anticancer drug delivery carriers. MSCs exhibit tropism to inflammatory sites, such as tumor beds, and resistance to chemotherapeutics. The aim of this study was to examine the efficacy of gemcitabine (GEM) conjugated with flurbiprofen (FLU) as a potential agent enhancing the GEM cytotoxic effect. Pancreatic cancer cell lines (PCCs), including PANC-1, AsPC-1, and BxPC-3, were studied meticulously. Moreover, the usefulness of bone-marrow-derived mesenchymal stem cells (BM-MSCs) treated with GEM and FLU, and the conditioned media from above these cells (CM) as elements supporting the in vitro action of GEM, inducing apoptosis, necrosis, and inhibiting the cell cycle, was tested. The results showed that CM-GEM exhibited higher cytotoxicity towards the selected PCCs compared to GEM alone. Furthermore, the obtained data revealed lower sensitivity of these cells to treatment, which promotes the utilization of BM-MSCs as potential drug carriers. Based on the presented findings, it seems that applying FLU in the antiproliferative effect of GEM might be regarded as an effective strategy in the therapy of pancreatic cancer, especially in the inhibition of proliferation and induction of cancer cell death. Full article

Adaptive vehicle control systems are crucial for enhancing safety, performance, and efficiency in modern transportation, particularly as vehicles become increasingly automated and responsive to dynamic environments. This review explores the advancements in bio-inspired actuators and their potential applications in adaptive vehicle control systems. Bio-inspired actuators, which mimic natural mechanisms such as muscle movement and plant tropism, offer unique advantages, including flexibility, adaptability, and energy efficiency. This paper categorizes these actuators based on their mechanisms, focusing on shape memory alloys, dielectric elastomers, ionic polymer–metal composites, polyvinylidene fluoride-based electrostrictive actuators, and soft pneumatic actuators. The review highlights the properties, operating principles, and potential applications for each mechanism in automotive systems. Additionally, it investigates the current uses of these actuators in adaptive suspension, active steering, braking systems, and human–machine interfaces for autonomous vehicles. The review further outlines the advantages of bio-inspired actuators, including their energy efficiency and adaptability to road conditions, while addressing key challenges like material limitations, response times, and integration with existing automotive control systems. Finally, this paper discusses future directions, including the integration of bio-inspired actuators with machine learning and advancements in material science, to enable more efficient and responsive adaptive vehicle control systems. Full article

The avian influenza virus poses an emerging public health risk due to its ability to cross the species barrier and infect a broad spectrum of hosts, including humans. The aim of this study was to investigate the molecular mechanisms and evolutionary dynamics underlying the spillover, using a bioinformatics approach to viral sequences. Eight viral proteins involved in the process of adaptation to new hosts were selected, and 156 amino acid mutations potentially associated with interspecies transmission were analyzed. The sequences, obtained from the NCBI Virus database, were aligned with the BLASTP1.4.0 tool and compared through phylogenetic analysis. The results show significant evolutionary proximity between human and animal viral strains, and the identification of shared mutations suggests the presence of conserved mechanisms in spillover. The identification of hosts that share mutations with human strains highlights the potential role of these animals as reservoirs or vectors. This study contributes to the understanding of viral adaptation and provides a starting point for targeted preventive strategies, including molecular surveillance and the development of containment and prevention measures. Full article

African swine fever virus (ASFV), the causative agent of African swine fever (ASF), poses a catastrophic threat to global swine industries through its capacity for immune subversion and rapid evolution. Multigene family genes (MGFs)-encoded proteins serve as molecular hubs governing viral evolution, immune evasion, cell tropism, and disease pathogenesis. This review synthesizes structural and functional evidence demonstrating that MGFs-encoded proteins suppress both interferon signaling and inflammasome activation, while their genomic plasticity in variable terminal regions drives strain diversification and adaptation. Translationally, targeted deletion of immunomodulatory MGFs enables the rational design of live attenuated vaccines that improve protective efficacy while minimizing residual virulence. Moreover, hypervariable MGFs provide strain-specific signatures for PCR-based diagnostics and phylogeographic tracking, directly addressing outbreak surveillance challenges. By unifying virology with translational innovation, this review establishes MGFs as priority targets for next-generation ASF countermeasures. Full article

Nanotechnology is transforming contemporary medicine by providing cutting-edge tools for the treatment and diagnosis of complex disorders. Advanced techniques such as bioimaging and photodynamic therapy (PDT) combine early diagnosis and targeted therapy, offering a more precise approach than conventional treatments. However, a significant obstacle for PDT is the need to selectively deliver photosensitizers to disease sites while minimizing systemic side effects. In this context, mesenchymal stem cells have emerged as promising biological carriers due to their natural tropism towards tumors, low immunogenicity, and their ability to overcome biological barriers. In this study, two push–pull compounds, NPI-PTZ and BTZ-PTZ, phenothiazine derivatives featuring aggregation-induced emission (AIE) abilities, were analyzed. These molecules proved to be excellent fluorescent probes and photosensitizing agents. When administered to human bone marrow-derived multipotent stromal cells (hBM-MSCs) and human adipose multipotent stem cells (hASCs), the compounds were efficiently internalized, maintained a stable fluorescent emission for several days, and showed phototoxicity after irradiation, without inducing major cytotoxic effects under normal conditions. These results highlight the potential of NPI-PTZ and BTZ-PTZ combined with mesenchymal stem cells as theranostic tools, bridging bioimaging and PDT, and suggest new possibilities for advanced therapeutic approaches in clinical applications. Full article