Search Results (381)

The standard genetic code (SGC) plays a fundamental role in encoding biological information, but its evolutionary origins remain unresolved and widely debated. Thus, we used a methodology based on the evolutionary algorithm to investigate the emergence of stable coding systems. The simulation began with a population of varied primitive genetic codes that ambiguously encoded only a limited set of amino acids (labels). These codes underwent mutation, modeled by dynamic reassignment of labels to codons, gradual incorporation of new amino acids, and information exchange between themselves. Then, the best codes were selected using a specific fitness function F that measured the accuracy of reading genetic information and coding potential. The evolution converged towards stable and unambiguous coding systems with a higher coding capacity facilitating the production of more diversified proteins. A crucial factor in this process was the exchange of encoded information among evolving codes, which significantly accelerated the emergence of genetic systems capable of encoding 21 labels. The findings shed light on key factors that may have influenced the development of the current genetic code structure. Full article

S-nitrosoglutathione (GSNO), a promising S-nitrosothiol, has been recognized for its ability to modulate vascular tone through its vasodilatory, antiplatelet, and antiproliferative effects. However, data on its vasodilatory effects in human vessels remain limited, and its mechanisms of action have yet to be fully elucidated. In this study, we aimed to investigate the vasorelaxant effect of GSNO and its underlying mechanisms, with particular focus on the soluble guanylate cyclase (sGC)/nitric oxide (NO) pathway and potassium channels in isolated human saphenous veins (SVs) obtained from patients undergoing coronary artery bypass grafting (CABG). GSNO (10⁻⁸–10⁻⁴ M) produced concentration-dependent relaxations in SV rings precontracted with phenylephrine. These relaxations were unaffected by NO synthase inhibition with L-NAME (10⁻⁴ M, 30 min) or NO scavenging with PTIO (10⁻⁴ M, 30 min), but were significantly reduced by the sGC inhibitor, ODQ (10⁻⁵ M, 30 min). Inhibition of ATP-sensitive (glibenclamid; 10⁻⁵ M, 30 min.), high-conductance Ca²⁺-activated (charybdotoxin; 10⁻⁷ M, 30 min), small-conductance Ca²⁺-activated (apamin; 10⁻⁶ M, 30 min), or voltage-dependent (4-aminopyridine; 10⁻³ M, 30 min) potassium channels did not alter the maximum relaxant responses to GSNO. Furthermore, pretreatment with GSNO (10⁻⁴ M, 30 min) significantly attenuated both the contractile response and sensitivity to phenylephrine. Collectively, these findings demonstrate that GSNO exerts acute vasorelaxant and modulatory effects in human SV primarily via cGMP-dependent mechanisms, highlighting its potential as a local therapeutic agent for preventing graft spasm in CABG. Full article

Valproic acid (VPA) is a widely prescribed antiepileptic agent whose teratogenic potential has been recognized. In recent years, VPA has been shown to promote neuronal regeneration; however, the exact molecular mechanisms are not fully understood. This study elucidates the pH-dependent pathway through which VPA promotes the differentiation of satellite glial cells (SGCs) into neurons. We observed sustained intracellular pH elevation during the VPA-induced neural differentiation of SGCs, and the modulation of intracellular pH was shown to influence this differentiation process. Then, we found that VPA regulates intracellular pH through NHE1 (sodium–hydrogen exchanger 1), and that the pharmacological inhibition of NHE1 not only attenuated intracellular pH elevation but also substantially impaired VPA-induced neuronal differentiation. Finally, our results showed that the elevated intracellular pH promoted the neuronal differentiation of SGCs by activating β-catenin signaling. These findings provide novel insights into the mechanisms of VPA-induced neurogenesis, advancing our understanding of its pharmacological profile and informing its potential therapeutic application in neuronal regeneration strategies. Full article

Background: Protein arginine methyltransferase 3 (PRMT3), a type I family PRMT, regulates the activity of downstream substrates by catalyzing the asymmetric dimethylation of arginine residues. While PRMT3 activity has been reported to be deregulated in many cancers, including glioblastoma (GBM), the underlying signalling mechanisms that contribute to disease progression are largely unknown. Methods: We tested the efficacy of a PRMT3 chemical probe, SGC707, in a cohort of GBM patient-derived primary and recurrent brain tumour stem cell (BTSC) lines. RNA-sequencing, CRISPR-cas9 knockout, and inducible overexpression methods were used to investigate the molecular mechanisms regulated by the aberrant activity of PRMT3 in different BTSC lines. Results: We show that expression of the tumour suppressor protein 4.1B, a negative regulator of PRMT3, predicts the response of GBM BTSCs to the PRMT3 chemical probe, SGC707. Furthermore, PRMT3 modulates the stability and subcellular localization of the downstream effector, UHRF1, a member of the DNA methylation complex. These findings suggest that UHRF1 and DNMT1 may suppress the expression of 4.1B through the increased promoter methylation of EPB4.1L3. Intriguingly, the inducible overexpression of EPB4.1L3 in the BT248^EPB4.1L3low BTSC line mimicked the effects of the pharmacologic and genetic inhibition of PRMT3. In contrast, knockout of EPB4.1L3 in BT143^EPB4.1L3high cells reduced the interactions between PRMT3 and 4.1B proteins, resulting in increased sensitivity of knockout cells to SGC707 treatment. Conclusions: These findings show that 4.1B, PRMT3, and UHRF1/DNMT1 function together to promote BTSC growth. Thus, targeting PRMT3 or UHRF1/DNMT1, especially in tumours with low endogenous 4.1B protein, may have high therapeutic relevance. Full article

Mansonellosis is a chronic infectious tropical disease that affects hundreds of millions of people worldwide but is not currently targeted for control. In this study, we interviewed 320 residents from Sao Gabriel do Cachoeira (SGC) about their support for soil transmitted helminth (STH) and mansonellosis interventions. Our survey found no significant difference between community support for mansonellosis and STH disease treatment when comparing any equivalent treatment regimen or program, although support for STH treatments was always higher than for mansonellosis treatments. No significant differences were detected when comparing community members’ willingness to participate in treatment programs and their willingness to allow family members to participate in an equivalent program. Our survey did, however, almost always find that significantly more community members were willing to participate in a proposed treatment program if the treatment regimen of that program was shorter than an otherwise equivalent regimen. Although significantly fewer people said they would participate in a curative four-week treatment course for mansonellosis than in a mansonellosis mass drug administration (MDA) program, significantly more community members said they would take a curative mansonellosis treatment course that lasted seven days or less than they would participate in any type of anthelminthic MDA proposed to them. The number of community members who said they would participate in any helminthic treatment program if they knew there was a ≥50% chance that they were infected was significantly higher than the number who said that they would without knowing the regional prevalence rate. Full article

The growing application of soil–geosynthetic composites (SGCs) in geotechnical engineering has highlighted the critical role of reinforcement spacing in enhancing structural performance. This study presents a numerical investigation of the stress–deformation behavior of SGC masses under working stress and failure load conditions, considering both confining and unconfined pressure scenarios. A finite element (FE) model was developed to analyze stress distribution, reinforcement strain profiles at varying depths, and lateral displacement at open facings. Results revealed that vertical stresses in reinforced and unreinforced soil masses were nearly identical, while lateral stresses increased notably in reinforced masses, particularly near reinforcement layers and open facings. Closer reinforcement spacing (0.2 m) effectively reduced lateral displacement and enhanced structural stability compared with wider spacing (0.4 m). In some cases, strengthening reinforcement in the upper portion of the SGC mass proved more effective under failure loads in both confining and unconfined pressure conditions. These findings provide critical insights for optimizing reinforcement spacing in SGC systems, with implications for the design of retaining walls and bridge abutments. Full article

Salivary gland cancers (SGCs) pose a therapeutic challenge due to their aggressive nature and limited treatment options. Ion transporters, particularly the sodium/iodide symporter (SLC5A5), which transport iodine in the form of iodide anion (I⁻) into cells, have emerged as potential therapeutic targets in tumors of glandular origin. Our research indicates that SLC5A5 is expressed predominantly in ductal cells of human and murine SGC cells. We assessed the effects of potassium iodide (KI), a source of iodide ions. KI treatment reduced SGC cell proliferation and viability without impacting migration. KI increased ROS levels and triggered caspase-dependent apoptosis, as indicated by the upregulation of the pro-apoptotic protein BAX, downregulation of the anti-apoptotic protein Bcl-2, and induction of SGC cell shrinkage. KI did not affect NF-κB or TNF-α and SLC5A5 expression. Adding the antioxidant N-acetylcysteine reversed KI-induced growth inhibition, underscoring ROS-induced oxidative stress’s crucial role in growth inhibition. While KI administered in drinking water to mice increased epidermal growth factor (EGF) expression in non-malignant salivary gland tissues, KI decreased EGF receptor (EGFR) expression in malignant SGC cell cultures, where EGFR signaling is frequently dysregulated in SGCs but promoted AKT phosphorylation. Combining KI and anti-EGFR treatment did not yield synergistic anti-SGC cell effects. The study underscores the therapeutic potential of KI as a standalone treatment in vitro for SGC cells. However, the upregulation of EGF in non-malignant tissues and, therefore, the possibility to enhance EGFR-driven signals and AKT phosphorylation after KI treatment in cancer patients could indicate a risk of rendering SGC cells more drug resistant, warranting further investigation to optimize its clinical application. Full article

The role of nitric oxide (NO), soluble guanylate cyclase (sGC), and the cyclic guanosine monophosphate (cGMP) pathway in cardiovascular and renal health and disease is a complex issue. The impact of these biochemical pathways on the vascular tree is well established: the activation of sGC by NO promotes vasodilation and modulates vascular tone. Indeed, additional characteristics exist that lead physicians to believe there is a pleiotropic influence of this pathway on the functional activities and structural characteristics of human tissues and cells. Recently, sGC stimulators have demonstrated clinical efficacy in patients with worsening heart failure with reduced ejection fraction, improving cardiovascular death risk, re-hospitalization for HF, and all-cause mortality. These new outcome data have increased interest in understanding the potential pathophysiological mechanisms. The NO-sGC-cGMP axis may influence endothelial function, kidney performance, and cardiac muscle cell activity. The synergy of these actions could explain the positive effects of vericiguat on worsening HF. The aim of this narrative review was to provide a comprehensive insight into the pathophysiological mechanisms of action of NO-sGC-cGMP axis stimulators on cardiac muscle, endothelial cells, and kidneys. Full article

This paper analyzes phytoplankton communities in the Eastern Tropical Pacific Ocean off Mexico (ETPOM) and the Southern Gulf of California (SGC) during the strong El Niño event of 2023/24. A multidisciplinary research cruise was conducted in the winter of 2024, during which high-resolution hydrographic data and water samples for phytoplankton cell determinations were collected at 33 sites. Additionally, satellite data were obtained to evaluate sea surface temperature and chlorophyll-a levels. A total of 269 phytoplankton species were identified, comprising one hundred and fifty diatoms, one hundred and twelve dinoflagellates, five silicoflagellates, one ciliate and one cyanobacteria. The dominant species included the diatom Pseudo-nitzschia pseudodelicatissima, the dinoflagellate Gyrodinium fusiforme, the silicoflagellate Octactis octonaria, and the ciliate Mesodinium rubrum. The cyanobacterium Trichodesmium hildebrandtii was also identified. In terms of total abundances, diatoms were the most prevalent, with 224,900 cells L⁻¹, followed by dinoflagellates at 104,520 cells L⁻¹, ciliates at 20,980 cells L⁻¹, cyanobacteria at 1760 cells L⁻¹, and silicoflagellates at 1500 cells L⁻¹. Notably, interesting differences emerged in species richness and abundance when comparing both regions. These results enhance our understanding of phytoplankton dynamics associated with strong El Niño events. The ETPOM remains a region that requires further monitoring through in situ observations. Full article

In unmanned aerial vehicle (UAV) aerial imagery scenarios, challenges such as small target size, compact distribution, and mutual occlusion often result in missed detections and false alarms. To address these challenges, this paper introduces YOLO-MARS, a small target recognition model that incorporates a multi-level attention residual mechanism. Firstly, an ERAC module is designed to enhance the ability to capture small targets by expanding the feature perception range, incorporating channel attention weight allocation strategies to strengthen the extraction capability for small targets and introducing a residual connection mechanism to improve gradient propagation stability. Secondly, a PD-ASPP structure is proposed, utilizing parallel paths for differentiated feature extraction and incorporating depthwise separable convolutions to reduce computational redundancy, thereby enabling the effective identification of targets at various scales under complex backgrounds. Thirdly, a multi-scale SGCS-FPN fusion architecture is proposed, adding a shallow feature guidance branch to establish cross-level semantic associations, thereby effectively addressing the issue of small target loss in deep networks. Finally, a dynamic WIoU evaluation function is implemented, constructing adaptive penalty terms based on the spatial distribution characteristics of predicted and ground-truth bounding boxes, thereby optimizing the boundary localization accuracy of densely packed small targets from the UAV viewpoint. Experiments conducted on the VisDrone2019 dataset demonstrate that the YOLO-MARS method achieves 40.9% and 23.4% in the mAP50 and mAP50:95 metrics, respectively, representing improvements of 8.1% and 4.3% in detection accuracy compared to the benchmark model YOLOv8n, thus demonstrating its advantages in UAV aerial target detection. Full article

Salivary gland carcinomas (SGCs) represent a rare and heterogeneous group of malignancies accounting for 3–6% of all head and neck cancers. While surgical resection and radiotherapy remain the standard for locoregional control, systemic treatment is indicated for recurrent or metastatic disease. Advances in molecular profiling have identified actionable targets such as NTRK gene fusions, HER2, immune checkpoint regulators, androgen receptors, and RET receptors. These have facilitated the development of targeted therapies, including TRK inhibitors, HER2-directed agents, and androgen receptor modulators, as well as emerging combinations of immunotherapy and chemotherapy. Despite these advancements, challenges such as resistance mechanisms and limited therapeutic efficacy persist. Overall response rates remain relatively low across most systemic therapies, reflecting a persistent unmet clinical need. This review discusses the current landscape of treatment options and explores promising clinical trials and future directions to enhance outcomes for patients with SGCs. Full article

Martensitic stainless steel (MSS) is widely used in several parts of automobiles where high strength, hardness, and corrosion resistance are required. However, the metastability of retained austenite can transform into martensite under severe deformation, adversely affecting material properties. Cryogenic treatments (CTs) have been extensively employed in iron-based alloys for fastener application due to their advantageous effect. This study explores the heat treatment processes applied to 13Cr-2Ni-2Mo martensitic stainless steel (MSS), including austenitizing, cryogenic treatment, and tempering cycles. Cryogenic treatment at (−150 °C) for varying durations, followed by tempering at 200 °C for 2 h, and the impact of post-cryogenic tempering at 200 °C for different tempering duration on the microstructure and mechanical properties were evaluated. Experimental results indicate that the sample quenched at 1040 °C for 2 h (CHT) contains lath martensite, retained austenite, δ-ferrite, and undissolved carbide precipitation. Compared to as-quenched samples, hardness decreased by 5.04%, 7.24%, and 7.32% after tempering for 2 h, 5 h, and 10 h, respectively. Extending cryogenic durations to 2 h, 12 h, and 20 h promoted nucleation of a mixture of M₃C and M₂₃C₆ small globular carbides (SGCs) and grain refinement but resulted in hardness reductions of 5.04%, 5.32%, and 8.36%, respectively. The reduction in hardness is primarily attributed to a decrease in solid solution strengthening and promoted carbide coarsening. Full article

In this paper, we present recent advancements in transmitter and receiver technologies for Optical Wireless Communication (OWC). OWC offers very wide license-free optical spectrum which enables very high capacity transmission. Additionally, beam-steered OWC is more power-efficient and more secure due to low divergence of light. One of the main challenges of OWC is wide angle transmission and reception because law of conservation of etendue restricts maximization of both aperture and field of view (FoV). On the transmitter side, we use Micro Electro-Mechanical System cantilevers activated by piezoelectric actuators together with silicon micro-lenses for narrow laser beam steering. Such design allowed us to experimentally demonstrate at least 10 Gbps transmission over 100° full angle FoV. On the receiver side, we show the use of photodiode array, and Indium-Phosphide Membrane on Silicon (IMOS) Photonic Integrated Circuit (PIC) with surface grating coupler (SGC) and array of SGC. We demonstrate FoV greater than 32° and 16 Gbps reception with photodiode array. PIC receiver allowed to receive 100 Gbps WDM with single SGC, and 10 Gbps with an array of SGC which had 8° FoV in the vertical angle and full FoV in the horizontal angle. Our results suggest that solutions presented here are scalable in throughputs and can be adopted for future indoor high-capacity OWC systems. Full article

Background/Objectives: Pulmonary hypertension is a progressive disease leading to right heart failure. One treatment strategy is to induce vasodilation via the nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate (NO–sGC–cGMP) signaling pathway. There are currently two soluble guanylate cyclase stimulators on the market: Riociguat and vericiguat, with vericiguat having a longer half-life and needing to be taken only once a day. This study investigated whether the pharmacological differences between the drugs affect pulmonary vessels and airways. Methods: The effects of vericiguat and riociguat on pulmonary arteries, veins, and airways were studied using rat precision-cut lung slices (PCLS). Vessels were pretreated with endothelin-1 and airways with serotonin. In isolated perfused lungs (IPL), the effects of sGC stimulation on pulmonary artery pressure (PAP), airway resistance, inflammatory cytokine, and chemokine release were quantified. Results: Riociguat and vericiguat caused pulmonary artery dilation in PCLS. During IPL, riociguat was more effective than vericiguat in reducing PAP with a statistically significant reduction of 10%. Both drugs were potent bronchodilators in preconstricted airways (p < 0.001). Only vericiguat reduced airway resistance during IPL, as shown here for the first time. Both drugs significantly reduced IL-6 and IL-1ß levels, while riociguat also reduced VEGF-A and KC-GRO levels. Conclusions: Riociguat and vericiguat had three main effects in the two rat ex-vivo models: They dilated the pulmonary arteries, induced bronchodilation, and reduced inflammation. These properties could make sGC stimulators useful for treating diseases associated with endothelial dysfunction. In the future, vericiguat may provide an alternative treatment to induce bronchodilation in respiratory diseases. Full article

The dried root of Sanguisorba officinalis L. (commonly known as Diyu) has been studied for its various pharmacological effects, including its antibacterial, antitumor, antioxidant, and anti-inflammatory activities. In the present study, primary cultured vascular endothelial cells (HUVECs) and isolated phenylephrine-precontracted rat thoracic aortic rings were examined to investigate the possible mechanism of a butanol extract of Diyu (BSO) in its vascular relaxant effect. HUVECs treated with BSO produced a significantly higher amount of nitric oxide (NO) compared to the control. However, its production was inhibited by pretreatment with N^G-nitro-L-arginine methylester (L-NAME) or wortmannin. BSO also increased the phosphorylation levels of endothelial nitric oxide synthase (eNOS) and Akt. In the aortic ring, BSO relaxed PE-precontracted rat thoracic aortic rings in a concentration-dependent manner. The absence of the vascular endothelium significantly attenuated BSO-induced vasorelaxation. The non-selective NOS inhibitor, L-NAME, and the selective inhibitor of soluble guanylyl cyclase (sGC), 1H-[1,2,4]-oxadiazolo-[4,3-α]-quinoxalin-1-one (ODQ), dramatically inhibited the BSO-induced relaxation effect of the endothelium-intact aortic ring. Ca²⁺-free buffer and intracellular Ca²⁺ homeostasis regulators (TG, Gd³⁺, and 2–APB) inhibited BSO-induced vasorelaxation. In Ca²⁺-free Krebs solution, BSO markedly reduced PE-induced contraction. Vasodilation induced by BSO was significantly inhibited by wortmannin, an inhibitor of Akt. Pretreatment with the non-selective inhibitor of Ca²⁺-activated K⁺ channels (K_Ca), tetraethylammonium (TEA), significantly attenuated the BSO-induced vasorelaxant effect. Furthermore, BSO decreased the systolic blood pressure and heart rate in a concentration-dependent manner in rats. In conclusion, BSO induces vasorelaxation via endothelium-dependent signaling, primarily through the activation of the PI3K-Akt-eNOS-NO signaling pathway in endothelial cells, and the activation of the NO-sGC-cGMP-K⁺ channels pathway in vascular smooth muscle cells. Additionally, store-operated Ca²⁺ entry (SOCE)-eNOS pathways and the inhibition of Ca²⁺ mobilization from intracellular stores contribute to BSO-induced vasorelaxation. Full article