Search Results (84)

Piston–cylinder pairs are very common in industrial mechanisms. While a piston is primarily designed for axial reciprocating motion, the occurrence of secondary motions—lateral and rotational—due to the small clearance between the piston and the cylinder may lead to frictional contact, energy loss, wear and an increase in unwanted leakage. This study focuses on mitigating the secondary motion of a ringless piston. The influence of a Rayleigh step bearing and partial surface texturing with numerous micro-dimples on the dynamic stability of the secondary motion is studied. A linear model was used to obtain the trajectory of the secondary motion and Floquet theory was applied to analyze the stability and draw stability maps. The influence of various texturing and step parameters, including the dimple area density and aspect ratio for partial texturing, as well as the length and depth of treatment for both partial texturing and step profiles, on the stability of the secondary motion was examined. The normalization method is presented, enabling the expansion of the results for various operating conditions and geometries. Conclusions and guidelines regarding the optimal parameters, in terms of a wider stability range and higher decay rate, are formulated. Full article

Currently, the field of microgear manufacturing faces various processing challenges, particularly in terms of size reduction; these challenges increase the complexity and costs of manufacturing. In this study, a technique for microgear manufacturing is aimed at reducing subsequent processing steps and enhancing material utilization. This technique involves the use of trough dies with extrusion-cutting processing, which enables workpieces to undergo forming in a negative clearance state, thus reducing subsequent processing time for micro products. We conducted finite element simulations using microgear dies, measuring stress, velocity, and flow during the forming process of four types of dies-flat, internal-trough, external-trough, and double-trough dies. The results indicated that the buffering effect of the troughs reduced the rate of increase in the material’s internal stress. In the cavity, the material experiences a significant increase in hydrostatic pressure, leading to the formation of a “hydrostatic pressure wall”. This pressure barrier imposes substantial constraints on the flow of the material during dynamic processes, making it difficult for the material to move into the remaining areas. This effectively enhances the blockage of material flow, demonstrating the critical role of hydrostatic pressure in controlling material distribution and movement. In addition, combining the characteristics of both into a double-trough die enhances the overall stability of forming velocity, reduces forming load and energy consumption, and maximizes material utilization. Results further revealed that microgears manufactured using double-trough dies exhibited defect-free surfaces, with a dimensional error of less than 5 μm and tolerances ranging from IT5 to IT6. Overall, this study offers new insights into the traditional field of microgear manufacturing, highlighting potential solutions for the challenges encountered in current microstamping processes. Full article

Apolipoprotein-CIII (apo-CIII) inhibits the clearance of triglycerides from circulation and is associated with an increased risk of diabetes complications. It exists in four main proteoforms: O-glycosylated variants containing either zero, one, or two sialic acids and a non-glycosylated variant. O-glycosylation may affect the metabolic functions of apo-CIII. We investigated the associations of apo-CIII glycosylation in blood plasma, measured by mass spectrometry of the intact protein, and genetic variants with micro- and macrovascular complications (retinopathy, nephropathy, neuropathy, cardiovascular disease) of type 2 diabetes in a DiaGene study (n = 1571) and the Hoorn DCS cohort (n = 5409). Mono-sialylated apolipoprotein-CIII (apo-CIII₁) was associated with a reduced risk of retinopathy (β = −7.215, 95% CI −11.137 to −3.294) whereas disialylated apolipoprotein-CIII (apo-CIII₂) was associated with an increased risk (β = 5.309, 95% CI 2.279 to 8.339). A variant of the GALNT2-gene (rs4846913), previously linked to lower apo-CIII_0a, was associated with a decreased prevalence of retinopathy (OR = 0.739, 95% CI 0.575 to 0.951). Higher apo-CIII₁ levels were associated with neuropathy (β = 7.706, 95% CI 2.317 to 13.095) and lower apo-CIII_0a with macrovascular complications (β = −9.195, 95% CI −15.847 to −2.543). In conclusion, apo-CIII glycosylation was associated with the prevalence of micro- and macrovascular complications of diabetes. Moreover, a variant in the GALNT2-gene was associated with apo-CIII glycosylation and retinopathy, suggesting a causal effect. The findings facilitate a molecular understanding of the pathophysiology of diabetes complications and warrant consideration of apo-CIII glycosylation as a potential target in the prevention of diabetes complications. Full article

Gastrin-releasing peptide receptor (GRPR)-antagonists have served as motifs in the development of theranostic radioligands for prostate cancer. Our efforts have been focused on the development of radiolabeled RM26 (H-DPhe⁶–Gln⁷–Trp⁸–Ala⁹–Val¹⁰–Gly¹¹–His¹²–Sta¹³–Leu¹⁴–NH₂) analogs, such as [¹¹¹In]In-DOTAGA-PEG2-RM26. We recently showed that its Gly¹¹/Sar¹¹-substituted version, [¹¹¹In]In-AU-RM26-M1, resisted degradation by neprilysin (NEP) while in circulation and achieved higher tumor uptake in mice. We herein introduce the following three new AU-RM26-M1 mimics labeled with In-111, with basic residues in the linker: (i) AU-RM26-M2 (PEG2-Pip), (ii) AU-RM26-M3 (PEG2-Arg), and (iii) AU-RM26-M4 (Arg-Arg-Pip). These analogs were compared in PC-3 cells and animal models vs. AU-RM26-M1 (reference). The new analogs showed high affinity and specificity for the GRPR, exhibiting an uptake and distribution pattern in PC-3 cells typical for a radiolabeled GRPR-antagonist. They showed high stability in peripheral mice blood, except for [¹¹¹In]In-AU-RM26-M3. AU-RM26-M4 achieved the highest tumor uptake and promising background clearance, followed by [¹¹¹In]In-RM26-M2, showing lower background levels. These findings were confirmed for [¹¹¹In]In-AU-RM26-M2 and [¹¹¹In]In-AU-RM26-M4 by micro-SPECT/CT at 4 and 24 h post-injection. Hence, the type of positively charged residues in the linker of AU-RM26-M1 mimics strongly influenced biological behavior. The analogs with Pip next to DPhe⁶ demonstrated the best overall characteristics and warrant further investigation. Full article

Human papillomavirus (HPV) is the second most common infectious agent causing cancer. Persistent infection with high-risk (HR)-HPV can lead to cervical intra-epithelial neoplasia and cervical carcinomas (CC). While host immune response is necessary for viral clearance, chronic immune activation contributes to a low-grade inflammation that can ultimately lead to carcinogenesis. The micro-immunotherapy medicine (MIM) 2LPAPI^® could be a valuable tool to manage the clearance of the virus and reduce the risk of developing CC. In this in vitro study, we aimed to investigate its mode of action. We showed that actives from the MIM increased the IL-6, IFN-γ, and IP-10 secretion in human peripheral blood mononuclear cells (PBMCs) exposed to peptides derived from the HPV-16 capsid (HPV16_(L1)). This could reflect an increase in the immune activity toward HPV-16. At the same time, some active substances reduced the lympho-proliferation and the expression of T-cell activation markers. Finally, some of the MIM actives displayed antiproliferative effects in CC-derived HeLa cells under serum-starvation conditions. Altogether, this body of data highlighted for the first time the dual effect of MIM in the framework of HR-HPV infections as a potential (i) immune modulator of HPV16_(L1)-treated PBMCs and (ii) antiproliferative agent of HPV-positive CC cells. Full article

Addressing the challenge of efficient drug delivery to the lungs, a nano-structured, microparticulate carrier system with defined and customizable dimensions has been developed. Utilizing a template-assisted approach and capillary forces, particles were rapidly loaded and stabilized. The system employs a biocompatible alginate gel as a stabilizing matrix, facilitating the breakdown of the carrier in body fluids with the subsequent release of its nano-load, while also mitigating long-term accumulation in the lung. Different gel strengths and stabilizing steps were applied, allowing us to tune the release kinetics, as evaluated by a quantitative method based on a flow-imaging system. The micro-cylinders demonstrated superior aerodynamic properties in Next Generation Impactor (NGI) experiments, such as a smaller median aerodynamic diameter (MMAD), while yielding a higher fine particle fraction (FPF) than spherical particles similar in critical dimensions. They exhibited negligible toxicity to a differentiated macrophage cell line (dTHP-1) for up to 24 h of incubation. The kinetics of the cellular uptake by dTHP-1 cells was assessed via fluorescence microscopy, revealing an uptake-rate dependence on the aspect ratio (AR = l/d); cylinders with high AR were phagocytosed more slowly than shorter rods and comparable spherical particles. This indicates that this novel drug delivery system can modulate macrophage uptake and clearance by adjusting its geometric parameters while maintaining optimal aerodynamic properties and featuring a biodegradable stabilizing matrix. Full article

The respiratory mucus, a viscoelastic gel, effectuates a primary line of the airway defense when operated by the mucociliary clearance. In chronic respiratory diseases (CRDs), such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), the mucus is overproduced and its solid content augments, changing its structure and viscoelastic properties and determining a derangement of essential defense mechanisms against opportunistic microbial (virus and bacteria) pathogens. This ensues in damaging of the airways, leading to a vicious cycle of obstruction and infection responsible for the harsh clinical evolution of these CRDs. Here, we review the essential features of normal and pathological mucus (i.e., sputum in CF, COPD, and asthma), i.e., mucin content, structure (mesh size), micro/macro-rheology, pH, and osmotic pressure, ending with the awareness that sputum biomarkers (mucins, inflammatory proteins and peptides, and metabolites) might serve to indicate acute exacerbation and response to therapies. There are some indications that old and novel treatments may change the structure, viscoelastic properties, and biomarker content of sputum; however, a wealth of work is still needed to embrace these measures as correlates of disease severity in association with (or even as substitutes of) pulmonary functional tests. Full article

Cannabidiol (CBD) has multiple therapeutic benefits that need to be maximized by optimizing its bioavailability. Numerous formulations are therefore being developed and their pharmacokinetics need to be studied, requiring analytical methods and data from intravenous administration. As CBD is susceptible to hepatic metabolism, the requirement of any method is to quantify metabolites such as 7-COOH-CBD. We demonstrated that CBD and 7-COOH-CBD could be simultaneously and correctly quantified in piglet plasma by using an UHPLC–MS/MS technique. The validated method allowed for an accurate bioanalysis of an intravenously injected solution consisting of CBD-HPβCD complexes. The experimental pharmacokinetic profile of CBD showed multi-exponential decay characterized by a fast apparent distribution half-life (0.25 h) and an elimination half-life of two hours. The profile of 7-COOH-CBD was not linked with the first-pass metabolism, since 80% of the maximum metabolite concentration was reached at the first sampling time point, without any decrease during the period of study. A two-compartment model was optimal to describe the experimental CBD profile. This model allowed us to calculate macro–micro constants and volumes of distribution (V_ss = 3260.35 ± 2286.66 mL) and clearance (1514.5 ± 261.16 mL·h⁻¹), showing that CBD is rapidly distributed to peripheral tissues once injected and slowly released into the bloodstream. Full article

Pulmonary inflammations such as chronic obstructive pulmonary disease and cystic fibrosis are widespread and can be fatal, especially when they are characterized by abnormal mucus accumulation. Inhaled corticosteroids are commonly used for lung inflammations despite their considerable side effects. By utilizing particle engineering techniques, a combined dry powder inhaler (DPI) comprising nanosized ketoprofen-embedded mannitol-coated microparticles was developed. A nanoembedded microparticle system means a novel advance in pulmonary delivery by enhancing local pulmonary deposition while avoiding clearance mechanisms. Ketoprofen, a poorly water-soluble anti-inflammatory drug, was dispersed in the stabilizer solution and then homogenized by ultraturrax. Following this, a ketoprofen-containing nanosuspension was produced by wet-media milling. Furthermore, co-spray drying was conducted with L-leucine (dispersity enhancer) and mannitol (coating and mucuactive agent). Particle size, morphology, dissolution, permeation, viscosity, in vitro and in silico deposition, cytotoxicity, and anti-inflammatory effect were investigated. The particle size of the ketoprofen-containing nanosuspension was ~230 nm. SEM images of the spray-dried powder displayed wrinkled, coated, and nearly spherical particles with a final size of ~2 µm (nano-in-micro), which is optimal for pulmonary delivery. The mannitol-containing samples decreased the viscosity of 10% mucin solution. The results of the mass median aerodynamic diameter (2.4–4.5 µm), fine particle fraction (56–71%), permeation (five-fold enhancement), and dissolution (80% release in 5 min) confirmed that the system is ideal for local inhalation. All samples showed a significant anti-inflammatory effect and decreased IL-6 on the LPS-treated U937 cell line with low cytotoxicity. Hence, developing an innovative combined DPI comprising ketoprofen and mannitol by employing a nano-in-micro approach is a potential treatment for lung inflammations. Full article

Human bacterial infections significantly contribute to the increase in healthcare-related burdens. This scenario drives the study of novel techniques for the early and precise diagnosis of infectious processes. Some alternatives include Nuclear Medicine- and Molecular Imaging-based strategies. However, radiopharmaceuticals that are available for routine assessments are not specific to differentiating infectious from aseptic inflammatory processes. In this context, [⁶⁸Ga]Ga-DOTA-Ubiquicidin_29-41 was synthesized using an automated module and radiochemical; in vivo and in vitro studies were performed. The radiopharmaceutical remained stable in saline (up to 180 min) and in rodent serum (up to 120 min) with radiochemical purities > 99 and 95%, respectively. Partition coefficient and serum protein binding at 60 min were determined (−3.63 ± 0.17 and 44.06 ± 1.88%, respectively). Ex vivo biodistribution, as well as in vivo microPET/CT images in mice, showed rapid blood clearance with renal excretion and reduced uptake in other organs in Staphylococcus aureus-infected animals. Higher uptake was observed in the target as compared to the non-target tissue (p < 0.0001) at 60 min post administration. The presented in-human clinical case demonstrates uptake of the radiopharmaceutical by Staphyloccocus aureus bacteria. These results indicate the potential of [⁶⁸Ga]Ga-DOTA-Ubiquicidin_29-41 as a radiopharmaceutical that can be obtained in a hospital radiopharmacy for the diagnosis of infectious processes using PET/CT. Full article

We developed a Parsimonious Multi-dimensional Moving Window (PMMW) algorithm that only requires Digital Elevation Model (DEM) data of a watershed to efficiently locate potentially optimal hydropower sites. The methodology requires only open source DEM data; therefore, it can be used even in remotest watersheds of the world where in situ measurements are scarce or not available at all. We used three parameters in this algorithm, and tested the method using the Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) and the Shuttle Radar Topography Mission (SRTM) derived DEMs. Our case study on the Morony Watershed, Montana, USA shows that (1) along with 6 out of the 7 existing hydropower plants being successfully located, 12 new potential hydropower sites were also identified, using a clearance of 1 km, diversion of 90 m, and Hydropower Index (HI) threshold of 10⁹ m as the criteria. For the 12 new potential hydropower sites, 737.86 Megawatts (MW) ± 84.56 MW untapped hydropower potential in the Morony Watershed was also derived; (2) SRTM DEM is more suitable for determining the potential hydropower sites; (3) although the ASTER and SRTM DEMs provide elevation data with high accuracy, micro-scale elevation differences between them at some locations may have a profound impact on the HI. Full article

Effective viral clearance requires fine-tuned immune responses to minimize undesirable inflammatory responses. Circular RNAs (circRNAs) are a class of non-coding RNAs that are abundant and highly stable, formed by backsplicing pre-mRNAs, and expressed ubiquitously in eukaryotic cells, emerging as critical regulators of a plethora of signaling pathways. Recent progress in high-throughput sequencing has enabled a better understanding of the physiological and pathophysiological functions of circRNAs, overcoming the obstacle of the sequence overlap between circRNAs and their linear cognate mRNAs. Some viruses also encode circRNAs implicated in viral replication or disease progression. There is increasing evidence that viral infections dysregulate circRNA expression and that the altered expression of circRNAs is critical in regulating viral infection and replication. circRNAs were shown to regulate gene expression via microRNA and protein sponging or via encoding small polypeptides. Recent studies have also highlighted the potential role of circRNAs as promising diagnostic and prognostic biomarkers, RNA vaccines and antiviral therapy candidates due to their higher stability and lower immunogenicity. This review presents an up-to-date summary of the mechanistic involvement of circRNAs in innate immunity against viral infections, the current understanding of their regulatory roles, and the suggested applications. Full article

Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are established prognostic biomarkers for patients with gastric cancer. However, their potential as predictive markers for neoadjuvant chemotherapy (NACT) efficacy has not been fully elucidated. Methods: We conducted a retrospective analysis to determine values of CEA and CA19-9 prior to NACT (pre-NACT) and after NACT (post-NACT) in 399 patients with locally advanced gastric cancer (LAGC) who received intended NACT and surgery. Results: Among the 399 patients who underwent NACT plus surgery, 132 patients (33.1%) had elevated pre-NACT CEA/CA19-9 values. Furthermore, either pre-NACT or post-NACT CEA /CA19-9 levels were significantly associated with prognosis (p = 0.0023) compared to patients with non-elevated levels. Moreover, among the patients, a significant proportion (73/132, 55.3%) achieved normalized CEA/CA19-9 following NACT, which is a strong marker of a favorable treatment response and survival benefits. In addition, the patients with normalized CEA/CA19-9 also had a prolonged survival compared to those who underwent surgery first (p = 0.0140), which may be attributed to the clearance of micro-metastatic foci. Additionally, the magnitude of CEA/CA19-9 changes did not exhibit a statistically significant prognostic value. Conclusions: Normalization of CEA/CA19-9 is a strong biomarker for the effectiveness of treatment, and can thus be exploited to prolong the long-term survival of patients with LAGC. Full article

MicroRNAs (miRNAs) are important regulators of embryonic stem cell (ESC) biology, and their study has identified key regulatory mechanisms. To find novel pathways regulated by miRNAs in ESCs, we undertook a bioinformatics analysis of gene pathways differently expressed in the absence of miRNAs due to the deletion of Dicer, which encodes an RNase that is essential for the synthesis of miRNAs. One pathway that stood out was Ca²⁺ signaling. Interestingly, we found that Dicer^−/− ESCs had no difference in basal cytoplasmic Ca²⁺ levels but were hyperresponsive when Ca²⁺ import into the endoplasmic reticulum (ER) was blocked by thapsigargin. Remarkably, the increased Ca²⁺ response to thapsigargin in ESCs resulted in almost no increase in apoptosis and no differences in stress response pathways, despite the importance of miRNAs in the stress response of other cell types. The increased Ca²⁺ response in Dicer^−/− ESCs was also observed during purinergic receptor activation, demonstrating a physiological role for the miRNA regulation of Ca²⁺ signaling pathways. In examining the mechanism of increased Ca²⁺ responsiveness to thapsigargin, neither store-operated Ca²⁺ entry nor Ca²⁺ clearance mechanisms from the cytoplasm appeared to be involved. Rather, it appeared to involve an increase in the expression of one isoform of the IP₃ receptors (Itpr2). miRNA regulation of Itpr2 expression primarily appeared to be indirect, with transcriptional regulation playing a major role. Therefore, the miRNA regulation of Itpr2 expression offers a unique mechanism to regulate Ca²⁺ signaling pathways in the physiology of pluripotent stem cells. Full article

The International Thermonuclear Experiment Reactor (ITER) Thermal shield (TS) serves as a cryogenic heat exchanger to maintain the thermal stability of the ITER superconducting magnet coil, which is critical to the control of the plasma during the operation of the ITER device. The TS is composed of long-length 316L stainless steel (SS) and copper as brazed joints. In this case, a feasible fabrication design for the CCS TS is presented, accomplished by three kinds of joining processes (vacuum brazing, friction stir weld, and TIG weld). In the reliable fabrication design, the brazing quality of the as-brazed long-distance 316L SS and copper joints plays a critical role in the thermal conductivity performance of the ITER thermal shield. Therefore, a high-quality vacuum brazing process of long-length SS/Cu joints applied in a low-temperature superconductor magnet system was first studied. The macro metallography analysis demonstrates the braze ratio of the samples is 100%, and no crack or defect is observed in the samples. The microstructural characterization reveals the brazing seams are composed of silver-based Ag-rich eutectic. The micro-shear test indicates that the shear strength of the 316L tube and copper joint is 205 MPa, with the fracture position located on the copper side; this zone will be the most vulnerable zone of the joints. In addition, the SEM results illustrated that the shear fracture morphology displayed a ductile fracture feature. The test results demonstrated that the highly precise depth drilling employed in this paper ensured a good control of the brazing clearance, resulting in a 100% braze ratio for the long-length SS/Cu joints. Therefore, it can be concluded that the brazing process can be applied in the ITER TS for the good thermal conductivity performance of long-length SS/Cu-brazing joints. Full article