Search Results (1,219)

Utilizing the immune system as a strategy for disease prevention and treatment is promising, especially with dendritic cells (DCs) playing a central role in adaptive immune responses. The unique properties of DCs drive interest in developing materials for cell-based therapy and immune modulation. Injectable systems require syringe-compatible scaffolds, while hydrogels, like alginate, known for their programmability and biocompatibility, offer a versatile platform for immune medicine enhancement through easy preparation and room-temperature cross-linking. In this study, we synthesized alginate balls loaded with DCs or cytosine–phosphorothioate–guanine deoxyribonucleotide (CpG DNA) microparticles, aiming for long-term immune cell culture with potential immune stimulation effects. Encapsulated DCs exhibited proliferation within the alginate balls for up to 7 days, and CpG MPs were uniformly dispersed, which can facilitate uptake by DCs. This was supported by the result that DCs effectively phagocytosed CpG microparticles in a 2D environment. After the uptake of CpG MPs, the alginate balls with CpG-MP-uptaken DCs were synthesized successfully. The injectable properties of the alginate balls were easily modulated by adjusting the syringe needle gauges. This innovative strategy holds substantial promise for advancing medical treatments, offering effective and comfortable solutions for controlled immune modulation. Full article

Initially described as a triad of immunodeficiency, congenital heart defects and hypoparathyroidism, 22q11.2 deletion syndrome (22q11.2DS) now encompasses a great amount of abnormalities involving different systems. Approximately 85% of patients share a 3 Mb 22q11.2 region of hemizygous deletion in which 46 protein-coding genes are included. However, the hemizygosity of the genes of this region cannot fully explain the clinical phenotype and the phenotypic variability observed among patients. Additional mutations in genes located outside the deleted region, leading to “dual diagnosis”, have been described in 1% of patients. In some cases, the hemizygosity of the 22q11.2 region unmasks autosomal recessive conditions due to additional mutations on the non-deleted allele. Some of the deleted genes play a crucial role in gene expression regulation pathways, involving the whole genome. Typical miRNA expression patterns have been identified in 22q11.2DS, due to an alteration in miRNA biogenesis, affecting the expression of several target genes. Also, a methylation epi-signature in CpG islands differentiating patients from controls has been defined. Herein, we summarize the evidence on the genetic and epigenetic mechanisms implicated in the pathogenesis of the clinical manifestations of 22q11.2 DS. The review of the literature confirms the hypothesis that the 22q11.2DS phenotype results from a network of interactions between deleted protein-coding genes and altered epigenetic regulation. Full article

Background: HOXA1 is a prognostic marker and a potential predictive biomarker for radioresistance in head and neck tumors. Its overexpression has been associated with promoter methylation and a worse prognosis in oral squamous cell carcinoma (OSCC) patients. However, opposite outcomes are also described. The effect of the methylation of this gene on different gene regions, other than the promoter, remains uncertain. We investigated the methylation profile at different genomic regions of HOXA1 in OSCC and correlated differentially methylated CpG sites with clinicopathological data. Methods: The HOXA1 DNA methylation status was evaluated by analyzing data from The Cancer Genome Atlas and three Gene Expression Omnibus datasets. Significant differentially methylated CpG sites were considered with a |∆β| ≥ 0.10 and a Bonferroni-corrected p-value < 0.01. Differentially methylated CpGs were validated by pyrosequencing using two independent cohorts of 15 and 47 OSCC patients, respectively. Results: Compared to normal tissues, we found significantly higher DNA methylation levels in the 3′UTR region of HOXA1 in OSCC. Higher methylation levels in tumor samples were positively correlated with smoking habits and patients’ overall survival. Conclusions: Our findings suggest that HOXA1 gene body methylation is a promising prognostic biomarker for OSCC with potential clinical applications in patient monitoring. Full article

To address the challenges of sinking, imbalance, and complex control systems faced by hexapod robots walking on lunar soil, this study develops an umbrella-shaped foot lunar exploration hexapod robot. The overall structure of the robot is designed to mimic the body structure of insects. By incorporating a four-bar linkage mechanism to replace the commonly used naked joints in traditional hexapod robots, the robot reduces the number of degrees of freedom and simplifies control complexity. Additionally, an extension mechanism is added to the robot’s foot, unfolding into an umbrella shape to provide a larger support area, effectively addressing the issue of foot sinking instability during walking. This study adopts and simplifies the Central Pattern Generator (CPG) model to generate stable periodic control signals for the robot’s legs. Precise control of the extension mechanism’s unfolding period is achieved through mapping functions. A joint simulation platform using Solid Works and Matlab is established to analyze the stability of the robot’s walking. Finally, walking experiments are conducted on the prototype, confirming the smooth walking of the lunar exploration hexapod robot. The results indicate that the designed lunar exploration hexapod robot has a reasonable structure, excellent stability in motion, and the CPG control scheme is feasible. Full article

Information on the dynamics and decline/persistence of antibody titres is important in vaccine development. A recent vaccine trial in malaria-exposed, healthy African adults and children living in a malaria hyperendemic and seasonal area (Ouagadougou, Burkina Faso) was the first study in which BK-SE36/CpG was administered to different age groups. In 5- to 10-year-old children, the risk of malaria infection was markedly lower in the BK-SE36/CpG arm compared to the control arm. We report here data on antibody titres measured in this age-group after the high malaria transmission season of 2021 (three years after the first vaccine dose was administered). At Year 3, 83% of children had detectable anti-SE36 total IgG antibodies. Geometric mean antibody titres and the proportion of children with detectable anti-SE36 antibodies were markedly higher in the BK-SE36/CpG arm than the control (rabies) arm. The information obtained in this study will guide investigators on future vaccine/booster schedules for this promising blood-stage malaria vaccine candidate. Full article

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by degeneration of lower motor neurons (LMNs), causing muscle weakness, atrophy, and paralysis. SMA is caused by mutations in the Survival Motor Neuron 1 (SMN1) gene and can be classified into four subgroups, depending on its severity. Even though the genetic component of SMA is well known, the precise mechanisms underlying its pathophysiology remain elusive. Thus far, there are three FDA-approved drugs for treating SMA. While these treatments have shown promising results, their costs are extremely high and unaffordable for most patients. Thus, more efforts are needed in order to identify novel therapeutic targets. In this context, zebrafish (Danio rerio) stands out as an ideal animal model for investigating neurodegenerative diseases like SMA. Its well-defined motor neuron circuits and straightforward neuromuscular structure offer distinct advantages. The zebrafish’s suitability arises from its low-cost genetic manipulation and optical transparency exhibited during larval stages, which facilitates in vivo microscopy. This review explores advancements in SMA research over the past two decades, beginning with the creation of the first zebrafish model. Our review focuses on the findings using different SMA zebrafish models generated to date, including potential therapeutic targets such as U snRNPs, Etv5b, PLS3, CORO1C, Pgrn, Cpg15, Uba1, Necdin, and Pgk1, among others. Lastly, we conclude our review by emphasizing the future perspectives in the field, namely exploiting zebrafish capacity for high-throughput screening. Zebrafish, with its unique attributes, proves to be an ideal model for studying motor neuron diseases and unraveling the complexity of neuromuscular defects. Full article

In light of the current International Association for the Study of Pain (IASP) clinical practice guidelines (CPGs) and the European Society for Medical Oncology (ESMO) guidelines, the topic of cannabinoids in relation to pain remains controversial, with insufficient research presently available. Cannabinoids are an attractive pain management option due to their synergistic effects when administered with opioids, thereby also limiting the extent of respiratory depression. On their own, however, cannabinoids have been shown to have the potential to relieve specific subtypes of chronic pain in adults, although controversies remain. Among these subtypes are neuropathic, musculoskeletal, cancer, and geriatric pain. Another interesting feature is their effectiveness in chemotherapy-induced peripheral neuropathy (CIPN). Analgesic benefits are hypothesized to extend to HIV-associated neuropathic pain, as well as to lower back pain in the elderly. The aim of this article is to provide an up-to-date review of the existing preclinical as well as clinical studies, along with relevant systematic reviews addressing the roles of various types of cannabinoids in neuropathic pain settings. The impact of cannabinoids in chronic cancer pain and in non-cancer conditions, such as multiple sclerosis and headaches, are all discussed, as well as novel techniques of administration and relevant mechanisms of action. Full article

For several decades, cancers have demonstrably been one of the most frequent causes of death worldwide. In addition to genetic causes, cancer can also be caused by epigenetic gene modifications. Frequently, tumor suppressor genes are epigenetically inactivated due to hypermethylation of their CpG islands, actively contributing to tumorigenesis. Since CpG islands are usually localized near promoters, hypermethylation of the promoter can have a major impact on gene expression. In this study, the potential tumor suppressor gene Receptor Interacting Serine/Threonine Protein Kinase 3 (RIPK3) was examined for an epigenetic regulation and its gene inactivation in melanomas. A hypermethylation of the RIPK3 CpG island was detected by bisulfite pyrosequencing and was accompanied by a correlated loss of its expression. In addition, an increasing RIPK3 methylation rate was observed with increasing tumor stage of melanomas. For further epigenetic characterization of RIPK3, epigenetic modulation was performed using a modified CRISPR/dCas9 (CRISPRa activation) system targeting its DNA hypermethylation. We observed a reduced fitness of melanoma cells by (re-)expression and demethylation of the RIPK3 gene using the epigenetic editing-based method. The tumor suppressive function of RIPK3 was evident by phenotypic determination using fluorescence microscopy, flow cytometry and wound healing assay. Our data highlight the function of RIPK3 as an epigenetically regulated tumor suppressor in melanoma, allowing it to be classified as a biomarker. Full article

An epigenomic approach was used to study the impact of maternal pregestational body mass index (BMI) on the placenta and umbilical cord methylomes and their potential effect on the offspring’s metabolic phenotype. DNA methylome was assessed in 24 paired placenta and umbilical cord samples. The differentially methylated CpGs associated with maternal pregestational BMI were identified and the metabolic pathways and the potentially related diseases affected by their annotated genes were determined. Two top differentially methylated CpGs were studied in 90 additional samples and the relationship with the offspring’s metabolic phenotype was determined. The results showed that maternal pregestational BMI is associated with the methylation of genes involved in endocrine and developmental pathways with potential effects on type 2 diabetes and obesity. The methylation and expression of HADHA and SLC2A8 genes in placenta and umbilical cord were related to several metabolic parameters in the offspring at 6 years (weight SDS, height SDS, BMI SDS, Δ BW-BMI SDS, FM SDS, waist, SBP, TG, HOMA-IR, perirenal fat; all p < 0.05). Our data suggest that epigenetic analysis in placenta and umbilical cord may be useful for identifying individual vulnerability to later metabolic diseases. Full article

Childhood maltreatment is an important risk factor for adult depression and has been associated with changes in the hypothalamic pituitary adrenal (HPA) axis, including cortisol secretion and methylation of the FKBP5 gene. Furthermore, associations between depression and HPA changes have been reported. This study investigated the associations of whole-blood FKBP5 mRNA levels, serum cortisol levels, childhood maltreatment, and depressive symptoms with the whole-blood methylation status (assessed via target bisulfite sequencing) of 105 CpGs at the FKBP5 locus using data from the general population-based Study of Health in Pomerania (SHIP) (N = 203). Both direct and interaction effects with the rs1360780 single-nucleotide polymorphism were investigated. Nominally significant associations of main effects on methylation of a single CpG site were observed at intron 3, intron 7, and the 3′-end of the gene. Additionally, methylation at two clusters at the 3′-end and intron 7 were nominally associated with childhood maltreatment × rs1360780 and depressive symptoms × rs1360780, respectively. The results add to the understanding of molecular mechanisms underlying the emergence of depression and could aid the development of personalised depression therapy and drug development. Full article

Rett syndrome (RTT) is a neurological disorder that mostly affects females, with a frequency of 1 in 10,000 to 20,000 live birth cases. Symptoms include stereotyped hand movements; impaired learning, language, and communication skills; sudden loss of speech; reduced lifespan; retarded growth; disturbance of sleep and breathing; seizures; autism; and gait apraxia. Pneumonia is the most common cause of death for patients with Rett syndrome, with a survival rate of 77.8% at 25 years of age. Survival into the fifth decade is typical in Rett syndrome, and the leading cause of death is cardiorespiratory compromise. Rett syndrome progression has multiple stages; however, most phenotypes are associated with the nervous system and brain. In total, 95% of Rett syndrome cases are due to mutations in the MECP2 gene, an X-linked gene that encodes for the methyl CpG binding protein, a regulator of gene expression. In this review, we summarize the recent developments in the field of Rett syndrome and therapeutics targeting MECP2. Full article

Traveltime picking accuracy is frequently affected by incoherent or random data noise. Within this context, we put forth a new denoising method called iterative interferometric denoising filtering. This method leverages the pseudo-Wigner distribution function to capture the offset and time-symmetric patterns of source wavelets convolved in seismic signals. Incoherent or random noises without this characteristic are eliminated via this approach. The processed data have waveform information distortion and more frequency components. However, the traveltime information can be considered correct, and the improved signal-to-noise ratio makes traveltime picking much more convenient. Our method’s practical applications in a synthetic and in two field datasets show that this technology can increase the signal-to-noise ratio, and the picked traveltime information can be used in traveltime tomography. These two field datasets were collected near the Aqaba Gulf and the Qademah fault, located in King Abdullah Economic City. Full article

DNA methylation is a fundamental mechanism of epigenetic control in cells and its dysregulation is strongly implicated in cancer development. Cancers possess an extensively hypomethylated genome with focal regions of hypermethylation at CPG islands. Due to the highly conserved nature of cancer-specific methylation, its detection in cell-free DNA in plasma using liquid biopsies constitutes an area of interest in biomarker research. The advent of next-generation sequencing and newer computational technologies have allowed for the development of diagnostic and prognostic biomarkers that utilize methylation profiling to diagnose disease and stratify risk. Methylome-based predictive biomarkers can determine the response to anti-cancer therapy. An additional emerging application of these biomarkers is in minimal residual disease monitoring. Several key challenges need to be addressed before cfDNA-based methylation biomarkers become fully integrated into practice. The first relates to the biology and stability of cfDNA. The second concerns the clinical validity and generalizability of methylation-based assays, many of which are cancer type-specific. The third involves their practicability, which is a stumbling block for translating technologies from bench to clinic. Future work on developing pan-cancer assays with their respective validities confirmed using well-designed, prospective clinical trials is crucial in pushing for the greater use of these tools in oncology. Full article

Thymic epithelial tumors (TET) consist of thymomas, thymic carcinoma (TC), and neuroendocrine tumors of the thymus (NECTT). Genetic and epigenetic alterations in TET have been the focus of recent research. In the present study, genome-wide screening was performed on aberrantly methylated CpG islands in TET, and this identified neuronal pentraxin 2 (NTPX2) as a significantly hypermethylated CpG island in TC relative to thymomas. NPTX2 is released from pre-synaptic cells in response to neuronal activity/seizure, and plays a role in host immunity and acute inflammation. TET samples were obtained from 38 thymomas, 25 TC, and 6 NECTT. The DNA methylation, mRNA, and protein expression levels of NPTX2 were examined. The DNA methylation rate of the NPTX2 gene was significantly higher in TC than in the normal thymus and thymomas, except B3. The mRNA expression level of NPTX2 was lower in TC than in the normal thymus. An inverse relationship was observed between mRNA expression levels and methylation levels. Relapse-free survival was shorter in patients with high NPTX2 DNA methylation levels than in those with low DNA methylation levels. NECTT showed very high mRNA and protein expression levels and low DNA methylation levels of NPTX2. NPTX2 may function as a tumor suppressor in TC, and have an oncogenic function in NECTT. Full article

Recent advancements in forensic genetics have facilitated the extraction of additional characteristics from unidentified samples. This study delves into the predictive potential of a five-gene (ELOVL2, FHL2, KLF14, C1orf132, and TRIM59) methylation rate analysis for human age estimation using buccal swabs collected from 60 Italian volunteers. The methylation levels of specific CpG sites in the five genes were analyzed through bisulfite conversion, single-base extension, and capillary electrophoresis. A multivariate linear regression model was crafted on the training set, then the test set was employed to validate the predictive model. The multivariate predictive model revealed a mean absolute deviation of 3.49 years in the test set of our sample. While limitations include a modest sample size, the study provides valuable insights into the potential of buccal swab-based age prediction, aiding in criminal investigations where accurate age determination is crucial. Our results also highlight that it is necessary to investigate the effectiveness of predictive models specific to biological tissues and individual populations, since models already proven effective for other populations or different tissues did not show the same effectiveness in our study. Full article