Search Results (1,136)

Tobamovirus fructirugosum (ToBRFV) and Crinivirus tomatichlorosis (ToCV) are emerging viral threats to tomato production worldwide, with expanding global distribution. Both viruses exhibit distinct biological characteristics and transmission mechanisms that influence their spread. This study aimed to reconstruct the complete genomes of ToBRFV and ToCV from infected tomato plants and wastewater samples in Argentina to explore their global evolutionary dynamics. Additionally, it compared the genetic diversity of ToBRFV in plant tissue and sewage samples. Using metagenomic analysis, the complete genome sequences of two ToBRFV isolates and two ToCV isolates from co-infected tomatoes, along with four ToBRFV isolates from sewage, were obtained. The analysis showed that ToBRFV exhibited higher genetic diversity in environmental samples than in plant samples. Phylodynamic analysis indicated that both viruses had a recent, single introduction in Argentina but predicted different times for ancestral diversification. The evolutionary analysis estimated that ToBRFV began its global diversification in June 2013 in Israel, with rapid diversification and exponential growth until 2020, after which the effective population size declined. Moreover, ToCV’s global expansion was characterized by exponential growth from 1979 to 2010, with Turkey identified as the most probable location with the current data available. This study highlights how sequencing and monitoring plant viruses can enhance our understanding of their global spread and impact on agriculture. Full article

Human mesenchymal stem cells (hMSCs) are widely used in regenerative medicine, but large-scale in vitro expansion alters their function, impacting proliferation and differentiation potential. Currently, a predictive marker to assess these changes is lacking. Here, we used dielectrophoresis (DEP) to characterize the electrical phenotype of hMSCs derived from bone marrow (BM), adipose tissue (AT), and umbilical cord (UC) as they aged in vitro from passage 4 (P4) to passage 9 (P9). The electrical phenotype was defined by the DEP spectra, membrane capacitance, and cytoplasm conductivity. Cell morphology and size, growth characteristics, adipogenic differentiation potential, and osteogenic differentiation potential were assessed alongside label-free biomarker membrane capacitance and cytoplasm conductivity. Differentiation was confirmed by histological staining and RT-qPCR. All hMSCs exhibited typical morphology, though cell size varied, with UC-hMSCs displaying the largest variability across all size metrics. Growth analysis revealed that UC-hMSCs proliferated the fastest. The electrical phenotype varied with cell source and in vitro age, with high passage hMSCs showing noticeable shifts in DEP spectra, membrane capacitance, and cytoplasm conductivity. Correlation analysis revealed that population doubling level (PDL) correlated with membrane capacitance and cytoplasm conductivity, indicating PDL as a more precise marker of in vitro aging than passage number. Additionally, we demonstrate that membrane capacitance correlates with the osteogenic marker COL1A1 and that cytoplasm conductivity correlates with the adipogenic markers ADIPOQ and FABP4, suggesting that DEP-derived electrical properties serve as label-free biomarkers of differentiation potential. While DEP has previously been applied to BM-hMSCs and AT-hMSCs, and more recently to UC-hMSCs, few studies have provided a direct comparison across all three sources or tracked changes across continuous expansion. These findings underscore the utility of DEP as a label-free approach for assessing hMSC aging and function, offering practical applications for optimizing stem cell expansion and stem cell banking in clinical settings. Full article

The “angiogenesis switch”—defined as the active process by which solid tumors develop their own circulation—plays an important role in both tumoral growth and propagation. As the malignant tumor grows and reaches a critical size, the metabolic needs as a function of an ever-increasing distance to the nearest emergent blood vessel, can no longer be covered by the microenvironment of the peritumoral tissue. Although a relatively discrete process, the “angiogenic switch” acts as a limiting stage of tumoral development present from the avascular hyperplasia phase to the vascularized neoplastic phase, providing support for tumor expansion and metastasis. Over time, research has focused on blocking the angiogenetic pathways (such as VEGF/VEGFR signaling axis) leading to the development of targeted therapeutic agents such as Bevacizumab. Objectives: We conducted a review of the molecular principles of tumoral angiogenesis and we tried to follow the history of Bevacizumab from its first approval for human usage 20 years ago to current days, focusing on the impact this agent had in solid tumor therapy. A comprehensive review of clinical trials pertaining to Bevacizumab (from the era of the preclinic trials leading to approval for human usage, to the more recent randomized trial focusing on combination targeted therapy) further details the role of this drug. We aimed to establish if this ancient drug continues to have a place in modern oncology. Conclusions: Bevacizumab, one of the first drugs targeting tumoral microenvironment, remains one of the most important oncologic agents blocking the VEGF/VEGFR angiogenic pathway. otherwise, history of 20 years marked by numerous controversies (ranging from methodological errors of clinical trials to withdrawal of approval for human usage in breast cancer patients, from discussions about severe side effects to resistance to therapy and limited efficacity), Bevacizumab continues to provide an optimal therapeutic option for many solid tumors that previously had little to no means of treatment, improving otherwise bleak outcomes. Even in the era of personalized precision oncology, Bevacizumab continues to be a key element in many therapeutic regimens both as monotherapy and in combination with newer targeted agents. Full article

Background/Objectives: Rapid palatal expansion is commonly used to correct maxillary deficiencies. However, medications like Isotretinoin may influence bone remodeling during treatment. Isotretinoin, a drug used to treat acne, was the focus of this study, which aimed to evaluate its effect on bone repair after rapid palatal suture expansion in rats. Methods: The sample consisted of 40 Wistar rats, divided into two groups: the control group (CG), subjected only to orthodontic movement, and the experimental isotretinoin group (IG), where movement occurred after drug administration. Periods of 0, 7, and 14 days after the installation of the orthodontic device were analyzed, with a force of 30 g applied in all groups using a steel spring. After euthanasia, the maxillae were removed and analyzed via Micro-CT, histologically, and histomorphometrically. Results: The results showed that the expander was effective in promoting the expansion of the palatal suture. After 14 days, the total expansion was 381% (CG) and 299% (IG); the percentage of vessels in the connective tissue increased by 145% in CG and 84% in IG; and bone formation in both groups occupied 52% of the expanded palatal suture. No significant differences were observed between the groups regarding collagen fiber formation. Conclusions: It was concluded that the daily administration of Isotretinoin at the standard dose for the treatment of severe acne does not cause significant alterations in the bone repair process following the opening of the median palatine suture in rats. Full article

Tolerance to foetal tissues in pregnancy depends on the match between mother and child. CD4+Foxp3+ regulatory T cells (Tregs), which are involved in peripheral tolerance, may facilitate this effect. Previous findings have indicated that the number of missing KIR ligands (MSLs) between mother and child correlates with the risk of gestational hypertension (GH) and preeclampsia (PE). This study tested whether Tregs are involved in the pathogenesis of gestational disorders. In total, 57 pregnant women participated, including 39 with hypertensive disorders of pregnancy and 18 healthy controls. Treg phenotypes were evaluated using multicolour flow cytometry. Killer cell immunoglobulin-like receptors (KIRs) and their ligands were assessed using NGS and PCR-SSO typing. The correlation between the MSLs and Treg antigen expression was evaluated. The pregnancy-related hypertensive groups differ from the healthy control group in the frequency of particular Treg subsets. However, there was a correlation between an increasing number of MSLs and only one subset of Tregs, which was PD-1+ Tregs. Surprisingly, women suffering from GH or PE had a significantly higher percentage of PD-1+ Tregs than healthy pregnant women. The percentages of several other populations of Tregs, such as those expressing CCR4, CCR10, CD39, and CD73, were higher in healthy pregnant women than in those with GH or PE, but these numbers did not correlate with MSLs. The exhausted PD-1+ Treg cell subsets may play a crucial role in the pathogenesis of hypertensive disorders of pregnancy. It is also hypothesised that MSLrelated mechanisms trigger PD-1+ Treg expansion, but their increased number fails to provide protection against hypertensive conditions of pregnancy. Full article

Obesity, marked by excessive fat accumulation, especially abdominal, is a global health concern with significant public impact. While obesity-associated chronic unresolved inflammation contributes to metabolic dysfunctions, acute inflammation supports healthy adipose tissue remodeling and expansion. Platelet-activating factor (PAF), a “primitive” signaling molecule, is among the key mediators involved in the acute phase of inflammation and in various pathophysiological processes. This article explores the role of PAF in fat accumulation and obesity by reviewing experimental data from cell cultures, animals, and humans. It proposes an emerging biochemical mechanism in an attempt to explain its dual role in the healthy and obese adipose tissue, including also data on PAF’s potential involvement in epigenetic mechanisms that may be linked to the “obesity memory”. Finally, it highlights the potential of natural PAF modulators in promoting functional adipose tissue, thermogenesis, and obesity prevention through a healthy lifestyle, including a Mediterranean diet rich in PAF weak agonists/PAF receptor antagonists and regular exercise, which help maintain controlled PAF levels. Conversely, in cases of obesity-related systemic inflammation with excessive PAF levels, potent PAF inhibitors like ginkgolide B and rupatadine may help mitigate metabolic dysfunctions with PAFR antagonists potentially enhancing their effects synergistically. Full article

Fragile X-related disorders (FXDs) are caused by the expansion of a CGG repeat tract in the 5’-UTR of the FMR1 gene. The expansion mechanism is likely shared with the 45+ other human diseases resulting from repeat expansion, a process that has been shown to require key mismatch repair (MMR) factors. FANCJ, a DNA helicase involved in unwinding unusual DNA secondary structures, has been implicated in a number of DNA repair processes including MMR. To test the role of FANCJ in repeat expansion, we crossed FancJ-null mice to an FXD mouse model. We found that loss of FANCJ resulted in a trend towards more extensive expansion that was significant for the small intestine and male germline. This finding has interesting implications for the expansion mechanism and raises the possibility that other DNA helicases may be important modifiers of expansion risk in certain cell types. Full article

Cartilage damage is common in sports injuries and cartilage-related diseases, such as degenerative joint and rheumatic disorders. Autologous chondrocyte implantation (ACI) is a widely used cell-based therapy for repairing cartilage damage in clinical practice. In this procedure, a patient’s chondrocytes are isolated, cultured in vitro to expand the cell population, and then implanted into the damaged site. However, in vitro expansion of chondrocytes on standard 2D culture surfaces leads to dedifferentiation (loss of the chondrocyte phenotype), and the delivery of detached cells has proven to be ineffective. To overcome these limitations, the matrix-assisted ACI (MACI) procedure was developed. In MACI, matrices such as hydrogels and microspheres are used as cell carriers or scaffolds to deliver expanded chondrocytes, enhancing cell viability and precision delivery. To streamline the two key steps of MACI—cell expansion and delivery—this study aims to investigate various configurations of gelatin-based hydrogels for their potential to support both cell expansion and delivery as a single step. This study evaluated gelatin microspheres (Gel MS), micronized photo-crosslinked GelMA microparticles (GelMA MP), and bulky GelMA hydrogels containing cells (GelMA HG). Cell growth, maintenance of the chondrocyte phenotype, and cartilage extracellular matrix (ECM) production were assessed in pellet cultures for cells grown on/in these carriers, compared with cells cultured on tissue culture-treated polystyrene (TCP). Our results demonstrate that normal human knee articular chondrocytes exhibit robust growth on Gel MS and form aggregates enriched with glycosaminoglycan-rich ECM. Gel MS outperformed both GelMA MP and GelMA HG as a cell carrier by both supporting long-term cell growth with reduced dedifferentiation and precision delivery. Full article

The TCP transcription factor (TF) family is a vital set of plant-specific regulators involved in plant growth, development, and responses to environmental stresses. Despite the extensive research on TCP transcription factors in numerous plant species, the functions they fulfill in Betula platyphylla are still not well understood. In this study, 21 BpTCP genes were identified via genome-wide analysis. Bioinformatics analysis was used to examine the physicochemical properties of these transcription factors, including molecular weight, isoelectric point, chromosomal distribution, and predicted subcellular localization. We expected that most BpTCP transcription factors would be located in the nucleus. Collinearity analysis revealed that gene fragment duplication events played a major role in the evolutionary expansion and diversification of the BpTCP gene family. Promoter analysis identified diverse cis-acting elements in BpTCP, suggesting that they play a role in stress responses, hormonal regulation, and plant growth and development. qRT-PCR analysis showed that BpTCP genes displayed tissue-specific expression patterns in the roots, stems, and leaves, displaying remarkable differences in expression levels when subjected to abiotic stresses, including drought and high- and low-temperature conditions. Notably, BpTCP17 and BpTCP18 showed markedly higher expression levels under multiple stress conditions. Subcellular localization experiments confirmed that both BpTCP17 and BpTCP18 localize in the nucleus, consistent with bioinformatic predictions. These findings emphasize the potential roles of BpTCP17 and BpTCP18 in mediating abiotic stress responses, highlighting their potential as candidate genes for improving stress tolerance in B. platyphylla. Full article

To better understand diabetic nephropathy (DN), developing accurate animal models is crucial. Current models often fail to fully mimic human DN, showing only mild albuminuria, glomerular hypertrophy, and limited mesangial matrix expansion. Our study aims to develop a more robust model by combining streptozotocin (STZ)-induced diabetes with a high-protein diet (HPD). We divided C57Bl/6J mice into three groups: control, STZ with a standard diet (STZ-SD), and STZ with a HPD (45 kcal% protein) (STZ-HPD) for 12 weeks. Renal function was evaluated using the urinary albumin-to-creatinine ratio, and kidney tissues were analyzed for histological and molecular changes. The STZ-HPD group showed significantly higher albuminuria and more severe glomerular and tubular damage compared to the control and STZ-SD groups. These changes were accompanied by increased inflammatory and oxidative stress markers, highlighting the harmful effects of high-protein intake on renal injury. Our findings suggest that the STZ-HPD model could be a valuable tool for studying DN pathophysiology and evaluating therapeutic interventions, providing a new approach for preclinical research. Full article

Background/Objectives: The GARP transcription factor superfamily is crucial for plant growth, development, and stress responses. This study systematically identified and analyzed the GARP family genes in Populus deltoides to explore their roles in plant development and abiotic stress responses. Methods: A total of 58 PdGARP genes were identified using bioinformatics tools. Their physicochemical properties, genomic locations, conserved motifs, gene structures, and phylogenetic relationships were analyzed. Expression patterns under phosphorus and nitrogen deficiency, as well as tissue-specific expression, were investigated using RT-qPCR. Transgenic RNAi lines were generated to validate the function of GLK genes in chlorophyll biosynthesis. Results: The 58 PdGARP genes were classified into five subfamilies based on their evolutionary relationships and protein sequence similarity. Segmental duplication was found to be the primary driver of the PdGARP family’s expansion. Cis-regulatory elements (CREs) related to light, hormones, and abiotic stresses were identified in the promoters of PdGARP genes. Differential expression patterns were observed for NIGT1/HRS1/HHO and PHR/PHL subfamily members under phosphorus and nitrogen deficiency, indicating their involvement in stress responses. KAN subfamily members exhibited tissue-specific expression, particularly in leaves. Structural analysis of the GLK subfamily revealed conserved α-helices, extended chains, and irregular coils. Transgenic RNAi lines targeting GLK genes showed significant reductions in chlorophyll and carotenoid content. Conclusions: This study provides a comprehensive analysis of the GARP transcription factor superfamily in P. deltoides, highlighting their potential roles in nutrient signaling and stress response pathways. The findings lay the foundation for further functional studies of PdGARP genes and their application in stress-resistant breeding of poplar. Full article

Background/Objectives: The oncofetal membrane protein Claudin 6 (CLDN6) is an attractive target for T cell-based therapies. There is a lack of detailed analyses on the age-dependent expression of CLDN6 in normal tissues is lacking, which limits the expansion of CLDN6 CAR-T cell clinical trials to pediatric populations. Methods: We analyzed CLDN6 expression in extracranial solid tumors and normal tissues of children using RNA-sequencing data from over 500 pediatric solid tumor samples, qRT-PCR and immunohistochemistry (IHC) in more than 100 fresh-frozen tumor samples and, approximately, 250 formalin-fixed paraffin-embedded (FFPE) samples. We examined normal tissue expression via qRT-PCR in 32 different infant tissues and via IHC in roughly 290 tissues from donors across four age groups, as well as in fetal autopsy samples. Results: In fetal tissues, we detected CLDN6 expression primarily in the epithelial cells of several organs, including the skin, lungs, kidneys, intestinal tract, and pancreas, but not in undifferentiated blastemal cells. Postnatally, we found CLDN6-positive epithelial progenitors only during the first few weeks of life. In older-age groups, isolated clusters of CLDN6-positive progenitors were present, but in scarce quantities. In tumor tissues, we found strong and homogeneous CLDN6 expression in desmoplastic small round cell tumors and germ cell tumors. Wilms tumors demonstrated heterogeneous CLDN6 expression, notably absent in the blastemal component. Conclusions: These findings highlight an organ-specific presence of CLDN6-positive epithelial precursors that largely disappear in terminally differentiated epithelia within weeks after birth. Therefore, our data support CLDN6 as a viable therapeutic target in pediatric patients and justify their inclusion in basket studies for anti-CLDN6-based therapies. Full article

Soft tissue sarcomas [STSs] are rare tumors of mesodermal origin that arise in diverse tissues such as muscles, fat, and nerves. There are over 100 subtypes of STS, each with distinct clinical behaviors and responses to treatment. Recent advances in treatment have moved towards histology-specific approaches, emphasizing the integration of pathological, immunohistochemical, and molecular features to guide treatment. Localized STS is primarily treated with surgery, often supplemented by neoadjuvant or adjuvant radiation and/or chemotherapy. However, about half of patients with localized disease will progress to an advanced stage, which is typically managed with systemic therapies including anthracycline-based chemotherapy such as doxorubicin or epirubicin. Despite these treatments, the survival rates for most subtypes of advanced metastatic STS remain relatively low. While anthracycline-based chemotherapy remains the mainstay of treatment, ongoing research into the biology of STSs is enhancing our understanding and approach to these complex tumors with an expansion beyond chemotherapy to include targeted therapy and immunotherapy to improve response rates and survival outcomes. This review focuses on STS other than gastrointestinal stromal tumors [GISTs], examines the current systemic treatment strategies, highlights recent advances, and explores future directions in the systemic therapy of sarcoma patients. Full article

Background: Herpes simplex virus 2 (HSV-2) is the primary cause of sexually transmitted genital ulcerative diseases, for which no effective prophylactic vaccine is currently available. However, the identification of appropriate targets for an HSV-2 mRNA vaccine remains an area requiring further investigation. Methods: The immunogenicity and protective effects of an HSV-2 UL41 mRNA vaccine were evaluated in a BALB/c mouse model. The mice were intramuscularly immunized twice, followed by HSV-2 infection at 28 days post boost. Clinical signs were monitored daily, and the viral load and tissue inflammation were assessed on days 1, 4, and 7 post infection. Dendritic cell (DC) activation in spleen tissue was analyzed via transcriptome sequencing. Results: A comparison of the clinical, immunological, and pathological characteristics of the groups that were immunized with the UL41 mRNA vaccine and then infected with HSV2, along with the control groups, revealed that the vaccine elicited both cellular and humoral immunity, inhibited viral replication, suppressed the inflammatory response, and provided protective effects against the virus in vivo. Furthermore, in vitro assays of DC expansion revealed that the vaccine immunization increased the induction of DCs from splenic cells. Transcriptomic analysis of these DCs revealed the activation of immune signaling pathways. Conclusions: Our study suggests that the UL41 mRNA vaccine may provide effective protection against HSV-2-related diseases and holds promise as a potential mRNA vaccine candidate. Full article

Trihelix transcription factors (TFs) play crucial roles in plant growth, development, and environmental adaptation. However, there have been no systematic studies on the trihelix gene family in watermelon (Citrullus lanatus). A comprehensive study of trihelix genes in watermelon could provide new insights into its evolution and breeding potential. In this study, we identified 29 watermelon trihelix genes and analyzed their genome-wide information, molecular evolution, and expression patterns. The 29 watermelon trihelix genes were distributed across 12 chromosomes and grouped into five subfamilies. Evolutionary analysis revealed that four watermelon trihelix genes were collinear with six trihelix genes in Arabidopsis thaliana, and 20 watermelon trihelix genes were collinear with 20 trihelix genes in cucumber (Cucumis sativus). Gene duplication event analysis suggested that the expansion of the trihelix gene family mainly occurred through segmental duplications. Gene expression analysis showed distinct expression patterns of trihelix genes in watermelon, with evidence of tissue-specific expression. Furthermore, expression pattern analysis of watermelon trihelix genes in response to stress revealed that the Cla97C10G2055470 gene was associated with the response to salt stress, while the Cla97C06G127520 gene was associated with watermelon resistance to SqVYV disease. In conclusion, the phylogenetic, evolutionary, and expression analyses of the trihelix gene family in watermelon provide a solid foundation for future functional studies. Full article