Search Results (3,534)

Background: Solid organ transplantation is hindered by immune-mediated chronic graft dysfunction and the side effects of immunosuppressive therapy. Regulatory T cells (Tregs) are crucial for modulating immune responses post-transplantation; however, the transfer of polyspecific Tregs alone is insufficient to induce allotolerance in rodent models. Methods: To enhance the efficacy of adoptive Treg therapy, we investigated different immune interventions in the recipients. By utilizing an immunogenic skin transplant model and existing transplantation medicine reagents, we facilitated the clinical translation of our findings. Specifically, antigen-specific Tregs were used. Results: Our study demonstrated that combining the available induction therapies with drug-induced T-cell proliferation due to lymphopenia effectively increased the Treg/T effector ratios. This results in significant Treg accumulation within the graft, leading to long-term tolerance after the transfer of antigen-specific Tregs. Importantly, all the animals achieved operational tolerance, which boosted the presence of adoptively transferred Tregs within the graft. Conclusions: This protocol offers a means to establish tolerance by utilizing antigen-specific Tregs. These results have promising implications for future trials involving adoptive Treg therapy in organ transplantation. Full article

Virus-like nanoparticles (VNP) are regarded as efficient vaccination platforms and have proven to be useful for the non-anaphylactogenic delivery of allergen-specific immunotherapy in preclinical models previously. Herein, we sought to determine the mode of VNP uptake by antigen presenting cells (APC). Accordingly, we screened a collection of substances known to inhibit different uptake pathways by APC. The human leukemia monocytic cell line THP-1 and the murine dendritic cell line DC 2.4 were examined for the uptake of fluorescently labelled VNP in the presence or absence of inhibitors. The inhibitory effect of candidate substances that blocked VNP uptake in APC lines was subsequently evaluated in studies with primary APC present in splenocyte and lung cell homogenates in vitro and upon intratracheal application of VNP in vivo. The uptake of allergen-specific VNP in vitro and in vivo was mainly observed by macrophages and CD103⁺ dendritic cells and was sensitive to inhibitors that block macropinocytosis, such as hyperosmolarity induced by sucrose or the polyphenol compound Rottlerin at low micromolar concentrations but not by other inhibitors. Also, T-cell proliferation induced by allergen-specific VNP was significantly reduced by both substances. In contrast, substances that stimulate macropinocytosis, such as Heparin and phorbol myristate acetate (PMA), increased VNP-uptake and may, thus, help modulate allergen-specific T-cell responses. We have identified macropinocytosis as the principal uptake mechanism of APC for allergen-specific VNP in vitro and in vivo, paving the way for further improvement of VNP-based therapies, especially those that can be used for tolerance induction in allergy, in the future. Full article

Bone loss is a major burden for society and impacts people’s health all over the world. In a changing world looking toward a more conscious use of raw materials, efforts are being made to increasingly consider new promising biomaterials that account for, on one side, the ability to provide specific functional biological activities and, on the other, the feature of being well tolerated. In this regard, the use of phenolic compounds in the field of bone-related bioengineering shows a rising interest in the development of medical solutions aimed at taking advantage of the multiple beneficial properties of these plant molecules. In this work, the anti-bacterial and anti-inflammatory power of a biphasic calcium phosphate synthetic bone filler coated with a mixture of phenolic compounds was investigated by evaluating the minimal inhibitory concentration (MIC) value against Streptococcus mutans and Porphyromonas gingivalis and the expression of genes involved in inflammation and autophagy by real-time reverse transcription polymerase chain reaction (RT-qPCR) on J774a.1 murine macrophage cells. Results show a MIC of 0.8 μg/mL, a neat anti-inflammatory effect, and induction of autophagy key genes compared to a ceramic bone filler. In conclusion, functionalization with a polyphenol-rich extract confers to a ceramic bone filler anti-bacterial and anti-inflammatory properties. Full article

Osmotic stress is a major threaten to the growth and yield stability of Brassica napus. Post-translational modification with O-linked β-N-acetylglucosamine (O-GlcNAc) is ubiquitous in plants, and participates in a variety of signal transduction and metabolic regulation. However, studies on the role of O-GlcNAc transferase (OGT) in osmotic stress tolerance of plants are limited. In previous study, a O-glycosyltransferase, named BnaC09.OGT, was identified from the B. napus variety ‘Zhongshuang 11’ by yeast one hybrid with promoter of BnaA01.GPAT9. It was found that BnaC09.OGT localized in both nucleus and cytoplasm. The spatiotemporal expression pattern of BnaC09.OGT exhibited tissue specificity in developmental seed, especially in 15 days after pollination. In view of osmotic stress inducing, the BnaC09.OGT overexpression and knockout transgenic lines were constructed for biological function study. Phenotypic analysis of BnaC09.OGT overexpression seedlings demonstrated that BnaC09.OGT could enhance osmotic stress tolerance than WT and knockout lines in euphylla stage under 15% PEG6000 treatment after 7 days. In addition, compared with WT and knockout lines, overexpression of BnaC09.OGT had significantly higher activities of antioxidant enzymes (SOD and POD), higher content of soluble saccharide, and while significantly less content of malondialdehyde, proline and anthocyanidin under 15% PEG6000 treatment after 7 days. On the other hand, the unsaturated fatty acid content of BnaC09.OGT overexpression was significantly higher than that of WT and knockout lines, so it is speculated that the BnaC09.OGT could increase unsaturated fatty acid biosynthesis for osmotic stress tolerance by promoting the expression of BnaA01.GPAT9 in glycerolipid biosynthesis. In summary, the above results revealed that the function of BnaC09.OGT provides new insight for the analysis of the pathway of O-glycosylation in regulating osmotic stress tolerance in B. napus. Full article

Adenosine kinase (ADK) is a key enzyme widely distributed in plants, playing an important role in maintaining cellular energy homeostasis and regulating plant growth, development, and responses to environmental stresses. However, research on ADK genes in cotton (Gossypium hirsutum), an economically significant crop, has been limited. This study identified 92 ADK genes from four cotton species (G. arboreum, G. raimondii, G. hirsutum, and G. barbadense) using HMMER and Local BLASTP methods and classified them into six groups. Chromosomal localization revealed a random distribution of ADK genes in G. hirsutum, with 13 genes located on the At subgenome and 14 genes on the Dt subgenome. Gene structure analysis showed consistency in exon–intron organization within subgroups, while conserved motif analysis identified subgroup-specific motifs, indicating functional diversity. Synteny and collinearity mapping analysis revealed that the primary expansion mechanisms of the ADK gene family in cotton are polyploidy and segmental duplication. Cis-regulatory elements in GhADK promoters were classified into light response, hormone response, developmental regulation, and stress response. We also analyzed the expression patterns of GhADK genes under a low temperature (4 °C) and drought conditions. Most GhADK genes responded to cold stress with different expression patterns, indicating their roles in rapid response and long-term cold adaptation. Under drought stress, expression patterns varied, with some genes showing sustained high expression levels. The qRT-PCR validation of transcriptomic data confirmed the stress-induced expression patterns of selected GhADK genes. Functional analysis through the VIGS silencing of GhADK25 demonstrated its importance in cold and drought stress responses, with silencing resulting in poor growth under stress, highlighting its significance in stress tolerance. This study provides a basis for further understanding the evolutionary relationships and functions of the cotton ADK gene family. Full article

Nuclear factor Ys (NF-Ys) are heterotrimeric transcription factors that specifically bind to CCAAT boxes present in numerous eukaryotic promoters. In plants, NF-Y proteins consist of the following three subunits: NF-YA, NF-YB, and NF-YC, each encoded by a gene family. Accumulating evidence underscores the crucial roles of NF-Y proteins in various plant development processes and stress responses, such as embryogenesis, flowering time control, drought tolerance, and heat tolerance. Despite this, a comprehensive genome-wide overview of the NF-Y gene family in strawberries is lacking. To bridge this gap, this study was conducted to identify and characterize the NF-Ys in Fragaria vesca. The investigation revealed the presence of six NF-YA, twelve NF-YB, and five NF-YC members in F. vesca. Furthermore, a comprehensive analysis of the FveNF-Ys was performed, including their phylogenetic relationships, gene structures, chromosomal locations, and conserved domains. MiRNA target site prediction found that there were 30 miRNA target sites in 12 (52.2%) FveNF-Y genes. Additionally, the expression profiles of different tissues and developmental stages demonstrated tissue-specific expression patterns among certain members of each NF-Y subfamily. This observation suggests that specific NF-Y subfamily members may play unique roles in different tissues or stages of development. Furthermore, the transient expression assay demonstrated that three selected FveNF-Ys were localized in the nucleus. Our study represents a pioneering effort in the systemic analyses of FveNF-Y genes and will be useful in understanding the functional characterization of NF-Y genes in Fragaria species. Full article

In order to meet the increasing requirements of speed and distance, an advanced digital signal processing (DSP) algorithm is preferred without changing the system structure in intensity modulation and the direct detection (IM/DD) system. As the transmission distance increases, the power fading induced by dispersion must be mitigated. In addition, linear and nonlinear inter symbol interference (ISI) introduced by bandwidth limitation and device imperfections becomes an obstacle to achieving higher capacity. The Gerchberg–Saxton (GS) algorithm was recently used to compensate for dispersion. In this paper, GS-based pre- and post-compensation schemes in the IM/DD system with nonlinearity were investigated. We investigated and compared the performance of the GS-based pre- and post-compensation algorithm in a 28 GB aud four-level pulse amplitude modulation (PAM-4) transmission over 40 km standard single-mode fiber (SSMF). The bit error rate (BER) achieved a threshold of 3.8 × 10⁻³ using look-up-table (LUT), FFE, and the GS-based pre-compensation algorithm without iterations. Turning to the GS-based post-compensation scheme, 80 iterations are needed. However, the demand for FFE is reduced. The algorithm selection depends on the tolerance of the transmitter or receiver complexity in specific scenarios. The joint LUT and GS-based pre-compensation algorithm may be a preferable approach in scenarios where a low-complexity receiver is desired. Full article

Growing evidence suggests that many patients with high-risk non-muscle invasive urothelial carcinoma (NMIUC) can undergo bladder-sparing management with salvage intravesical therapies. However, inherent or developed disease resistance, particularly after multiple lines of prior salvage therapy, implores the continued pursuit of new treatment combinations. Herein, we describe the outcomes of 26 patients (31 treated units; 24 lower tract, 7 upper tract) with high-risk NMIUC treated with sequential intravesical gemcitabine and cabazitaxel with concomitant intravenous pembrolizumab (GCP) at the University of Iowa from August 2020 to February 2023. Median (IQR) follow-up was 30 (IQR: 17–35) months. Treated units had a history of high-risk NMIUC with a median of four prior endoluminal inductions. Overall, 87% of units presented with CIS or positive urine cytology. The 1- and 2-year recurrence-free survival was 77% (CI: 58–88%) and 52% (CI: 30–70%), respectively. The 2-year progression-free and cancer-specific survival was 70% (CI: 44–85%) and 96% (CI: 75–99%), respectively. In total, 22/26 (85%) patients reported any adverse event and 5/26 (19%) reported a grade ≥3 adverse event; however, all patients tolerated a full induction course. These results suggest that GCP is an effective and tolerable treatment option for patients with recurrent high-risk NMIUC. Full article

Background: Misophonia is a chronic condition in which the exposure to specific sounds increases the arousal and recurrence of specific intense negative emotions. We hypothesized that misophonia may be strongly related to maladaptive interpersonal schemas that create difficulties in interpersonal relationships. Subjects with maladaptive interpersonal schemas think that other people try to subjugate, criticize, dominate, exploit, deceive, disregard, and humiliate them. Furthermore, these patients typically endorse a representation of self as mistreated, constricted, harmed, damaged, humiliated, impotent, inadequate, or fragile. Methods: We describe the course of a treatment of Metacognitive Interpersonal Therapy (MIT) in a young man presenting misophonia and co-occurrent obsessive–compulsive personality disorder (OCPD) and avoidant personality disorder (AvPD), with narcissistic traits and normal hearing. We collected qualitative and quantitative data at the beginning of the intervention and at 2 years follow-up. Results: The therapy aimed at increasing awareness of maladaptive interpersonal schemas and promoting a healthy self. The results reported a significant decrease in misophonia; behavioural experiments were used to increase the quality of social relationships and tolerance to the trigger sounds. Conclusions: MIT can be an effective therapy for the treatment of misophonia. Full article

While tolerance is recognised as important, especially to diverse societies, understanding tolerance poses complexities, both theoretically and in practical application. Tolerance is relevant in different social contexts, yet these pose distinct challenges to measurement. Thus, understanding the measurement of tolerance is important. This study provides a systematic review of tolerance scales, with the procedure based on the PRISMA statement. The initial collection of over 1600 papers through the systematic review process yielded a set of 11 papers. These papers trace the development of tolerance scales to encompass distinct social contexts over time, including political, cultural, ethnic and racial, racial and religious, gender and sexual, and social. Correspondingly, the approaches reflect particular challenges relevant to these domains for understanding and measuring tolerance. In contrast, some recent contributions aim to develop broader, less context-specific means to assess tolerance. Notwithstanding the breadth of articles included, this systematic review yielded articles that covered only selected Western-centric geographies: this indicates the opportunity for further research to access and integrate non-English-language articles to broaden the geographical and cultural perspectives on tolerance. Full article

Biofilm-associated infections pose a significant challenge in healthcare, constituting 80% of bacterial infections and often leading to persistent, chronic conditions. Conventional antibiotics struggle with efficacy against these infections due to the high tolerance and resistance induced by bacterial biofilm barriers. Two-dimensional nanomaterials, such as those from the graphene family, boron nitride, molybdenum disulfide (MoS₂), MXene, and black phosphorus, hold immense potential for combating biofilms. These nanomaterial-based antimicrobial strategies are novel tools that show promise in overcoming resistant bacteria and stubborn biofilms, with the ability to circumvent existing drug resistance mechanisms. This review comprehensively summarizes recent developments in two-dimensional nanomaterials, as both therapeutics and nanocarriers for precision antibiotic delivery, with a specific focus on nanoplatforms coupled with photothermal/photodynamic therapy in the elimination of bacteria and penetrating and/or ablating biofilm. This review offers important insight into recent advances and current limitations of current antibacterial nanotherapeutic approaches, together with a discussion on future developments in the field, for the overall benefit of public health. Full article

Although studies have revealed the significant impact of dietary fiber on growth performance and nutrient digestibility, the specific characteristics of the intestinal microbiota and gene regulation in pigs capable of digesting high-fiber diets remained unclear. To investigate the traits associated with roughage tolerance in the Chinese indigenous pig breed, we conducted comparative analysis of growth performance, apparent fiber digestibility, intestinal microbiota, SCFA concentrations and intestinal transcriptome in Tunchang pigs, feeding them diets with different wheat bran levels. The results indicated that the growth performance of Tunchang pigs was not significantly impacted, and the apparent total tract digestibility of crude fiber was significantly improved with increasing dietary fiber content. High-fiber diets altered the diversity of intestinal microbiota, and increased the relative abundance of Prevotella, CF231, as well as the concentrations of isobutyrate, valerate and isovalerate. The LDA analysis identified potential microbial biomarkers that could be associated with roughage tolerance, such as Prevotella stercorea, and Eubacterium biforme. In addition, appropriate high-fiber diets containing 4.34% crude fiber upregulated the mRNA expressions of PYY, AQP8, and SLC5A8, while downregulating the mRNA expressions of CKM and CNN1.This indicated that appropriate high-fiber diets may inhibit intestine motility and increase the absorption of water and SCFAs. Full article

Alfalfa (Medicago sativa L.) is a vitally important perennial fodder legume worldwide. Given their particular traits, alfalfa crop wild relatives (CWRs) could be used to develop cultivars that can tolerate extreme environmental and climatic conditions. Until now, researchers have overlooked the composition and structure of bacterial communities in the root zone of alfalfa and its relevant CWRs and their influence on forage performance under actual field conditions. In this study, high-throughput sequencing of 16S rRNA analysis was performed to investigate the diversity and assemblies of bacterial communities in the bulk soil and in the root zone of individual field-grown Medicago plants arranged in a honeycomb selection design. The plants used in this study were M. sativa × M. arborea hybrids (Genotypes 6 and 8), the closely-related M. sativa nothosubsp. varia (Martyn) Arcang. (Genotype 13), and M. sativa ssp. sativa (Genotype 20). The bacterial communities in the root-zone samples and the assemblies in the bulk soil differed significantly. Genotype 13 was found to have distinct bacterial assemblies from the other genotypes while exhibiting the lowest forage productivity. These findings suggest that plant productivity may influence the composition of bacterial communities in the root zone. Biomarker analysis conducted using linear discriminant analysis (LDA) revealed that only members of the Rhizobiales order were enriched in the M. sativa nothosubsp. varia root zone whereas taxa belonging to Sphingomonas and various Bacteriodota were enriched in the other genotypes. Of the shared taxa identified in the root zone of the Medicago lines, the abundance of specific taxa, namely, Flavisolibacter, Stenotrophomonas, and Sphingomonas, were positively associated with forage yield. This pioneering study, in which the root zones of individual Medicago plants under actual field conditions were examined, offers evidence of differences in the bacterial composition of alfalfa genotypes with varying genetic backgrounds. Its findings indicate that particular bacterial taxa may favorably influence plant performance. This study covered the first six months of crop establishment and paves the way for further investigations to advance understanding of how shifts in bacterial assemblies in alfalfa roots affect plant performance over time. Full article

Background: This study aims to evaluate pregnant women’s knowledge of antenatal ultrasound in Saudi Arabia and its correlation with demographic factors like age and education to enhance prenatal care. Methods: A cross-sectional study was conducted in six Saudi Arabian hospitals, involving 22 questions split between sociodemographic information and knowledge of antenatal ultrasound. Descriptive statistics were used to characterize the participants’ demographics and responses. Additionally, inferential statistics were employed to analyze the relationships and differences among the study variables. Results: Among the 531 pregnant women in the study, most demonstrated a good understanding of antenatal ultrasound, identifying its various uses. Specifically, they recognized its roles in evaluating fetal growth (82.5%), placental location (81.7%), amniotic fluid volume (67%), and fetal morphology (65%), predicting the delivery date (79%), and determining the baby’s sex (89%). A majority viewed ultrasound as important (89.3%), safe (82.3%), and tolerable (76.3%) for prenatal care. Additionally, 66.7% felt adequately informed, mainly through clinical staff and doctors. Younger age, lower education, lack of prior ultrasound experience, and first pregnancy were linked to lower knowledge. Approximately 65% were uncertain about the nonionizing radiation properties of ultrasound. Conclusions: The study found that while most pregnant women in Saudi Arabia understand the objectives of antenatal ultrasonography, there are gaps in their knowledge about its nonionizing properties. Younger age, lower education, lack of prior ultrasound experience, and first pregnancy contribute to lower knowledge. Full article

Chimeric antigen receptor T-cell (CAR-T) therapy is a novel anticancer therapy using autologous or allogeneic T-cells. To date, six CAR-T therapies for specific B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin lymphomas (NHL), and multiple myeloma (MM) have been approved by the Food and Drug Administration (FDA). Significant barriers to the effectiveness of CAR-T therapy include cytokine release syndrome (CRS), neurotoxicity in the case of Allogeneic Stem Cell Transplantation (Allo-SCT) graft-versus-host-disease (GVHD), antigen escape, modest antitumor activity, restricted trafficking, limited persistence, the immunosuppressive microenvironment, and senescence and exhaustion of CAR-Ts. Furthermore, cancer drug resistance remains a major problem in clinical practice. CAR-T therapy, in combination with checkpoint blockades and bispecific T-cell engagers (BiTEs) or other drugs, appears to be an appealing anticancer strategy. Many of these agents have shown impressive results, combining efficacy with tolerability. Biomarkers like extracellular vesicles (EVs), cell-free DNA (cfDNA), circulating tumor (ctDNA) and miRNAs may play an important role in toxicity, relapse assessment, and efficacy prediction, and can be implicated in clinical applications of CAR-T therapy and in establishing safe and efficacious personalized medicine. However, further research is required to fully comprehend the particular side effects of immunomodulation, to ascertain the best order and combination of this medication with conventional chemotherapy and targeted therapies, and to find reliable predictive biomarkers. Full article