Search Results (1,266)

Background: Signaling pathways like those depending on cAMP/PKA, calcium/calmodulin/CaMK, MEK-1/MAPK or PI3K/Akt have been described to modulate suprachiasmatic nucleus (SCN) neuronal signaling via influencing transcription factors like CREB. Here, we analyzed the effect of cyclic nucleotide phosphodiesterase inhibitors and structurally similar substances commonly used as autophagy modulators on a cell line stably expressing a cyclic nucleotide element-driven luciferase reporter. Methods: We used an SCN cell line stably transfected with a CRE-luciferase reporter (SCNCRE) to evaluate signaling and vitality responses to various isoform-selective PDE inhibitors and autophagy modulators to evaluate the mechanism of action of the latter. Results: In this study the different impacts of common PDE inhibitors and autophagy modulators on CRE-luciferase activity applied alone and in combination with known CRE-luciferase activating agents showed that (1) PDE3, 4 and 5 are present in SCNCRE cells, with (2) PDE3 being the most active and (3) the autophagy inhibitor 3-Methyladenin (3-MA) displaying PDE inhibitor-like behavior. Conclusions: Experiments provide evidence that, in addition to the extracellular signaling pathways components shown before to be involved in CRE-luciferase activity regulation like cAMP analogs, adenylate cyclase activators and beta-adrenoceptor agonists, cyclic nucleotide metabolism as realized by phosphodiesterase activity, or molecule/agents influencing processes like autophagy or inflammation, modulate transcriptional CRE-dependent activity in these cells. Specifically, we provide evidence that the autophagy inhibitor 3-MA, given that PDEs are expressed, may also act as a PDE inhibitor and inducer of CRE-mediated transcriptional activity. Full article

The Kekeya oilfield is located at the southwestern edge of the Tarim Basin, in the southern margin of the Yecheng depression, at the western end of the second structural belt of the northern foothills of the Kunlun Mountains. It is one of the important oil and gas fields in western China, with significant oil and gas resource potential in the X4-X5 section of the Xihepu Formation. This study focuses on the edge of the alluvial fan depositional system, employing various techniques, including core data and well logging data, to precisely characterize the sand body architecture and comprehensively analyze the reservoir architecture in the study area. First, the regional geological background of the area is analyzed, clarifying the sedimentary environment and evolutionary process of the Xihepu Formation. Based on the sedimentary environment and microfacies classification, the sedimentary features of the region are revealed. On this basis, using reservoir architecture element analysis, the interfaces of the reservoir architecture are finely subdivided. The spatial distribution characteristics of the planar architecture are discussed, and the spatial distribution and internal architecture of individual sand body units are analyzed. The study focuses on the spatial combination of microfacies units along the profile and their internal distribution patterns. Additionally, a quantitative analysis of the sizes of various types of sand bodies is conducted, constructing the sedimentary model for the region and revealing the control mechanisms of different sedimentary architectures on reservoir properties and oil and gas accumulation patterns. This study pioneers a quantitative model for alluvial fan fringe in gentle-slope basins, featuring the following: (1) lobe width-thickness ratios (avg. 128), (2) four base-level-sensitive boundary markers, and (3) a retrogradational stacking mechanism. The findings directly inform reservoir development in analogous arid-climate systems. This research not only provides a scientific basis for the exploration and development of the Kekeya oilfield but also serves as an important reference for reservoir architecture studies in similar geological contexts. Full article

To advance the development of protein-rich plant-based foods, a novel binder system for vegan sausage alternatives without the requirement of heat application was investigated. This enables long-term ripening of plant-based analogs similar to traditional fermented meat or dairy products, allowing for refined flavor and texture development. This was achieved by using a poorly water-soluble calcium source (calcium carbonate) to introduce calcium ions into a low-ester pectin—gluten matrix susceptible to crosslinking via divalent ions. The gelling reaction of pectin–gluten dispersions with Ca²⁺ ions was time-delayed due to the gradual production of lactic acid during fermentation. Firm, sliceable matrices were formed, in which particulate substances such as texturized proteins and solid vegetable fat could be integrated, hence forming an unheated raw-fermented plant-based salami-type sausage model matrix which remained safe for consumption over 21 days of ripening. Gluten as well as pectin had a significant influence on the functional properties of the matrices, especially water holding capacity (increasing with higher pectin or gluten content), hardness (increasing with higher pectin or gluten content), tensile strength (increasing with higher pectin or gluten content) and cohesiveness (decreasing with higher pectin or gluten content). A combination of three simultaneously occurring effects was observed, modulating the properties of the matrices, namely, (a) an increase in gel strength due to increased pectin concentration forming more brittle gels, (b) an increase in gel strength with increasing gluten content forming more elastic gels and (c) interactions of low-ester pectin with the gluten network, with pectin addition causing increased aggregation of gluten, leading to strengthened networks. Full article

In a previous study, eight chronically HBV-infected nucleos (t)ide analog (NA)-naïve patients began receiving entecavir (ETV) concomitant with a single ARC-520 HBV siRNA injection. This single dose of ARC-520 (SD) was followed by 6–8 months of ETV alone before the patients received 4–9 monthly doses of ARC-520, the multi-dose (MD) period, while continuing ETV. Quantities of HBV DNA, RNA, and antigens were measured from serum and a liver biopsy collected ~30 months after the last MD from five patients. All full-length HBV transcripts from the livers were characterized. Viral parameters and HBV transcripts from patients were compared to these measurements collected at multiple points in ARC-520 + ETV-treated chronically HBV-infected chimpanzees. Multiple forms of HBx mRNA were observed, and these differed between chimpanzees and patients. Products of cccDNA were greatly decreased in patients who were previously highly viremic and HBeAg+, although a biopsied patient had similar amounts of cccDNA to the highly viremic HBeAg+ chimpanzees. The comparison of all HBV transcripts and cccDNA levels between patients and chimpanzees demonstrate the transcriptional silencing of cccDNA following the siRNA treatment of patients but not the chimpanzees that received a different treatment regimen. Results from this small study suggest that continued NA treatment during and between periods of HBV antigen re-expression post-siRNA treatment enhanced viral parameter reductions. Full article

Ant venoms are rich sources of bioactive molecules, including peptide toxins with potent and selective activity on ion channels, which makes them valuable for pharmacological research and therapeutic development. Voltage-dependent potassium (Kv) channels, critical for regulating cellular excitability or cell cycle progression control, are targeted by a diverse array of venom-derived peptides. This study focuses on MYRTX_A4-Tb11a, a peptide from Tetramorium bicarinatum venom, which was previously shown to have a strong paralytic effect on dipteran species without cytotoxicity on insect cells. In the present study, we show that Tb11a exhibited no or low cytotoxicity toward mammalian cells either, even at high concentrations, while electrophysiological studies revealed a blockade of hKv1.3 activity. Additionally, Ta11a, an analog of Tb11a from the ant Tetramorium africanum, demonstrated similar Kv1.3 inhibitory properties. Structural analysis supports that the peptide acts on Kv1.3 channels through the functional dyad Y21-K25 and that the disulfide bridge is essential for biological activity, as reduction seems to disrupt the peptide conformation and impair the dyad. These findings highlight the importance of three-dimensional structure in channel modulation and establish Tb11a and Ta11a as promising Kv1.3 inhibitors. Future research should investigate their selectivity across additional ion channels and employ structure-function studies to further enhance their pharmacological potential. Full article

This paper deals with a standard cell-based analog-in-concept pW-power building block as a comparator and a wake-up oscillator. Both topologies, traditionally conceived as an analog building block made by a custom process and supply voltage-dependent design flow, are designed only by using digital gates, enabling them to be automated and fully synthesizable. This further results in supply voltage scalability and regulator-less operation, allowing direct powering by an energy harvester without additional ancillary circuit blocks (such as current and voltage sources). In particular, the circuit similarities in implementing a rail-to-rail dynamic voltage comparator and a relaxation oscillator using only digital gates are discussed. The building blocks previously reported in the literature by the author will be described, and the common root of their design will be highlighted. Full article

The increasing complexity and scale of electronic health records (EHRs) demand advanced tools for efficient data retrieval, summarization, and comparative analysis in clinical practice. MERA (Medical Electronic Records Assistant) is a Retrieval-Augmented Generation (RAG)-based AI system that addresses these needs by integrating domain-specific retrieval with large language models (LLMs) to deliver robust question answering, similarity search, and report summarization functionalities. MERA is designed to overcome key limitations of conventional LLMs in healthcare, such as hallucinations, outdated knowledge, and limited explainability. To ensure both privacy compliance and model robustness, we constructed a large synthetic dataset using state-of-the-art LLMs, including Mistral v0.3, Qwen 2.5, and Llama 3, and further validated MERA on de-identified real-world EHRs from the MIMIC-IV-Note dataset. Comprehensive evaluation demonstrates MERA’s high accuracy in medical question answering (correctness: 0.91; relevance: 0.98; groundedness: 0.89; retrieval relevance: 0.92), strong summarization performance (ROUGE-1 F1-score: 0.70; Jaccard similarity: 0.73), and effective similarity search (METEOR: 0.7–1.0 across diagnoses), with consistent results on real EHRs. The similarity search module empowers clinicians to efficiently identify and compare analogous patient cases, supporting differential diagnosis and personalized treatment planning. By generating concise, contextually relevant, and explainable insights, MERA reduces clinician workload and enhances decision-making. To our knowledge, this is the first system to integrate clinical question answering, summarization, and similarity search within a unified RAG-based framework. Full article

Background/Objectives: Total knee arthroplasty (TKA) is an effective surgical intervention for end stage knee osteoarthritis in elderly patients, with emerging robotically assisted techniques aiming to enhance surgical precision and patient outcomes. This study aimed to compare medium-term balance and functional outcomes between robotically assisted and conventional manual TKA in community-dwelling elderly patients. Methods: This cross-sectional study included 50 elderly patients undergoing TKA, who were divided into robotically assisted (n = 25) and conventional manual (n = 25) groups. Demographic and clinical data, balance performance, and functional outcomes were compared at nearly 1.5 years postoperatively. Outcome measures included balance performance assessed by the Berg Balance Scale (BBS), pain via the Visual Analog Scale (VAS), knee function as measured by the Lysholm Knee Scoring Scale, quality of life using the Short Form-12 (SF-12), joint awareness as evaluated by the Forgotten Joint Score-12 (FJS-12), and surgical satisfaction. Results: The groups had similar demographic and clinical data regarding age, gender, follow-up duration, surgical time, and anesthesia type (p > 0.05). The robotically assisted group demonstrated better balance performance on the BBS (p = 0.043) and had a statistically shorter length of hospital stay (1.22 vs. 1.42 days; p = 0.005). However, no statistically significant differences were observed in VAS activity pain (p = 0.053), Lysholm Knee Scoring Scale (p = 0.117), SF-12 physical and mental scores (p = 0.174 and p = 0.879), FJS-12 (p = 0.760), and surgical satisfaction (p = 0.218). Conclusions: Robotically assisted TKA is associated with advantageous postoperative recovery, particularly in terms of balance performance, showing no clinical difference in other functional outcomes compared to the conventional manual technique. From a physical therapy perspective, these findings emphasize the importance of developing tailored and effective rehabilitation strategies in the medium term for functional recovery in the elderly population. Full article

The global impact of the COVID-19 crisis has underscored the need for novel therapeutic candidates capable of efficiently targeting essential viral proteins. Existing therapeutic strategies continue to encounter limitations such as reduced efficacy against emerging variants, safety concerns, and suboptimal pharmacodynamics, which emphasize the potential of natural-origin compounds as supportive agents with immunomodulatory, anti-inflammatory, and antioxidant benefits. The present study significantly advances prior molecular docking research through comprehensive virtual screening of structurally related analogs derived from antiviral phytochemicals. These compounds were evaluated specifically against the SARS-CoV-2 main protease (3CLpro) and papain-like protease (PLpro). Utilizing chemical similarity algorithms via the ChEMBL database, over 600 candidate molecules were retrieved and subjected to automated docking, interaction pattern analysis, and comprehensive ADMET profiling. Several analogs showed enhanced binding scores relative to their parent scaffolds, with CHEMBL1720210 (a shogaol-derived analog) demonstrating strong interaction with PLpro (−9.34 kcal/mol), and CHEMBL1495225 (a 6-gingerol derivative) showing high affinity for 3CLpro (−8.04 kcal/mol). Molecular interaction analysis revealed that CHEMBL1720210 forms hydrogen bonds with key PLpro residues including GLY163, LEU162, GLN269, TYR265, and TYR273, complemented by hydrophobic interactions with TYR268 and PRO248. CHEMBL1495225 establishes multiple hydrogen bonds with the 3CLpro residues ASP197, ARG131, TYR239, LEU272, and GLY195, along with hydrophobic contacts with LEU287. Gene expression predictions via DIGEP-Pred indicated that the top-ranked compounds could influence biological pathways linked to inflammation and oxidative stress, processes implicated in COVID-19’s pathology. Notably, CHEMBL4069090 emerged as a lead compound with favorable drug-likeness and predicted binding to PLpro. Overall, the applied in silico framework facilitated the rational prioritization of bioactive analogs with promising pharmacological profiles, supporting their advancement toward experimental validation and therapeutic exploration against SARS-CoV-2. Full article

Post-traumatic stress disorder (PTSD) has traditionally been viewed as a psychiatric disorder of fear, memory, and emotional regulation. However, growing evidence implicates systemic and neuroinflammation as key contributors. Individuals with PTSD often exhibit elevated blood levels of pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, and C-reactive protein, indicating immune dysregulation. Dysfunctions in the hypothalamic–pituitary–adrenal (HPA) axis marked by reduced cortisol levels impair the body’s ability to regulate inflammation, allowing persistent immune activation. Circulating cytokines cross a weakened blood–brain barrier and activate microglia, which release additional inflammatory mediators. This neuroinflammatory loop can damage brain circuits critical to emotion processing including the hippocampus, amygdala, and prefrontal cortex, and disrupt neurotransmitter systems like serotonin and glutamate, potentially explaining PTSD symptoms such as hyperarousal and persistent fear memories. Rodent models of PTSD show similar inflammatory profiles, reinforcing the role of neuroinflammation in disease pathology. Bromo-epi-androsterone (BEA), a synthetic analog of dehydroepiandrosterone (DHEA), has shown potent anti-inflammatory effects in clinical trials, significantly reducing IL-1β, IL-6, and TNF-α. By modulating immune activity, BEA represents a promising candidate for mitigating neuroinflammation and its downstream effects in PTSD. These findings support the rationale for initiating clinical trials of BEA as a novel therapeutic intervention for PTSD. Full article

The robotic exploration of space began only five decades ago, and yet in the intervening years, a wide and diverse ecosystem of robotic explorers has been developed for this purpose. Such devices have greatly benefited from miniaturization trends and the increased availability of high-quality commercial off-the-shelf (COTS) components. This review outlines the specific taxonomic distinction between planetary surface rovers and other robotic space exploration vehicles, such as orbiters and landers. Additionally, arguments are made to standardize the classification of planetary rovers by mass into categories similar to those used for orbital satellites. Discussions about recent noteworthy trends toward the miniaturization of planetary rovers are also included, as well as a compilation of previous planetary rovers. This analysis compiles relevant metrics such as the mass, the distance traveled, and the locomotion or actuation technique for previous planetary rovers. Additional details are also examined about archetypal rovers that were chosen as representatives of specific small-scale rover classes. Finally, potential future trends for miniature planetary surface rovers are examined by way of comparison to similar miniaturized orbital robotic explorers known as CubeSats. Based on the existing relationship between CubeSats and their Earth-based simulation equivalents, CanSats, the importance of a potential Earth-based analog for miniature rovers is identified. This research establishes such a device, coining the new term ‘CanBot’ to refer to pathfinding systems that are deployed terrestrially to help develop future planetary surface exploration robots. Establishing this explicit genre of robotic vehicle is intended to provide a unified means for categorizing and encouraging the development of future small-scale rovers. Full article

Background: Snoring is a common symptom within the spectrum of sleep-disordered breathing, often occurring independently or in association with obstructive sleep apnea syndrome (OSAS). Despite its prevalence, treatment strategies remain variable and lack standardization, particularly regarding surgical interventions. This review aims to evaluate and summarize the outcomes of soft palate and pharyngeal surgeries for adult snoring based on recent literature. Methods: A systematic review was conducted using the PubMed database, identifying studies published between 2014 and 2024 that involved adult patients undergoing upper airway surgery for snoring. Inclusion criteria required pre- and postoperative snoring assessment using the Visual Analog Scale (VAS). Studies were categorized by surgical technique (anterior vs. lateral/circumferential), anesthesia type, presence of tonsillectomy, BMI, OSAS severity (based on AHI), and use of Drug-Induced Sleep Endoscopy (DISE). Descriptive analysis was performed on the changes in VAS scores. Results: A total of 43 studies involving 2713 patients were included, with 18 eligible for quantitative analysis (716 patients). Across all patients, mean VAS scores improved from 7.29 to 3.50 (ΔVAS 3.79). Both anterior and lateral/circumferential techniques yielded significant symptom reduction (ΔVAS 4.12 and 3.68, respectively). General anesthesia showed slightly better outcomes than local anesthesia. Notably, tonsillectomy was associated with greater symptom improvement (ΔVAS 5.17 vs. 4.49). Patients with lower BMI and milder OSAS showed higher baseline VAS but similar improvements. Limited objective measures and heterogeneity in surgical protocols were key limitations. Conclusions: Surgical interventions for snoring provide subjective symptom relief regardless of surgical approach or OSAS severity. Tonsillectomy may enhance outcomes. Future efforts should prioritize standardized, objective outcome measures and personalized treatment planning, potentially incorporating DISE and wearable acoustic technologies. Full article

Background/Objectives: Patellar instability in adolescents is a significant cause of short- and long-term morbidity and disability. Traditionally, patients with first-time patellar dislocation are managed nonoperatively, although most studies are not focusing on the adolescent athletic population. The primary objective of the current study was to compare patient-reported outcomes and complications in adolescent athletes who underwent surgery either after the first patellar dislocation or after the recurrence of the dislocation with a minimum postoperative follow-up of 48 months (48–75 months). Methods: A total of 39 adolescent athletes who underwent medial patellofemoral ligament (MPFL) reconstruction (Group A, after the first dislocation, and Group B, recurrent patella dislocation) were included in this study. In all the patients, the same MPFL reconstruction technique was applied using a semitendinosus autograft. The graft was fixed on the patella using a transverse tunnel and adjustable loop button fixation and, in the femur, using a tunnel and absorbable screw fixation. The tunnel was drilled obliquely to prevent penetration of the distal femoral physis. The preoperative and postoperative clinical and functional evaluations of the patients were conducted via the visual analog scale (VAS), the Lysholm Knee Scoring System, the Kujala Anterior Knee Pain Scale, and the Pediatric International Knee Documentation Committee (Pedi-IKDC), and the return to sports score was assessed via the Tegner Activity Scale (TAS). Results: At the latest follow-up, both groups demonstrated significant improvement in the Lysholm scores, with Group A achieving a mean of 92.57 ± 6.21 and Group B achieving a mean of 90.53 ± 8.21 (p = 0.062). Postoperatively, Group A achieved a mean Kujala score of 94.21 ± 9.23, whereas Group B reached 92.76 ± 12.39, with no statistically significant difference (p = 0.08). The Pedi-IKDC score improved postoperatively in both groups. In Group A, it increased from 67.98 ± 12.29 to 93.65 ± 4.1, and in Group B, from 56.21 ± 13.6 to 91.67 ± 6.21 (p = 0.067). The preoperative visual analog scale (VAS) score for pain was significantly lower in Group A (3.1 ± 1.13) than in Group B (4.2 ± 3.01, p < 0.01). At the latest follow-up, the VAS scores improved in both groups, with Group A reporting a mean score of 0.47 ± 1.01 and Group B 0.97 ± 1.32 (p = 0.083). The Tegner activity scores were similar between the groups preoperatively, with Group A at 7.72 ± 1.65 and Group B at 7.45 ± 2.09 (p = 0.076). Postoperatively, Group A had a mean score of 7.28 ± 2.15, whereas Group B had a mean score of 6.79 ± 3.70 (p = 0.065). The mean time to return to sports was significantly shorter in Group A (5.1 ± 1.3 months) than in Group B (7.6 ± 2.1 months) (p < 0.01). Overall, 84.61% of the patients returned to their previous activity level. Specifically, 95.2% (20/21) of patients in Group A achieved this outcome, whereas 72.22% (13/18) achieved it in Group B. Patient satisfaction was generally high, with 76% (16/21) of patients in Group A reporting being satisfied or very satisfied, compared with 77% (14/18) in Group B. Conclusions: MPFL reconstruction is a safe and effective procedure for both acute and recurrent patellar dislocation in adolescent athletes. While patients who underwent acute reconstruction returned to sport more quickly and showed higher absolute postoperative scores, the greatest overall improvement from preoperative to final follow-up was observed in those treated for recurrent instability. Both surgical approaches demonstrated high satisfaction rates and minimal complications, supporting MPFL reconstruction as a reliable option in both acute and recurrent cases. Full article

In this paper, we introduce a new class of sequences of integers called t-dimensional Gersenne sequences, with $2\le t<\infty$, which extends the classical Mersenne-type sequences into higher dimensions by incorporating complex and hyper-complex structures. One of our main goals is to establish analogous or symmetrical properties for the t-dimensional Gersenne sequences that are similar to those we know for the classical Gersenne sequence. We investigate some algebraic properties of this new sequences, and the Binet formula is given so as to allow us to study several identities, such as the Tagiuri–Vajda identity, among others. Furthermore, some results concerning the partial sums involving terms of these new sequences are presented. Full article

Background: Surfactants can be added into polymer–amorphous drug systems to further enhance solubility. However, this may cause amorphous drugs to become physically unstable, and the inherent mechanism at play here is not fully understood. Methods: We explored the effects of poloxamer, a poly (ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide) (PEO-PPO-PEO) triblock copolymer surfactant, and its segments on the nucleation and growth kinetics of amorphous nitrendipine (NTP) from the melt through polarized light microscopy. The effects of poloxamer and structural analogs on the melting point and glass transition temperature were also investigated using differential scanning calorimetry. Results: The poloxamer and its structural analogs enhanced nucleation and growth kinetics in supercooled liquid. Poloxamer and its structural analogs exhibited similar effects on the nucleation and growth kinetics of amorphous NTP, suggesting minimal dependence on structural variation. The overall crystallization rate of the NTP increased when increasing the poloxamer content and ultimately reached a maximum value; after that, the crystallization rates of NTP decreased when increasing the poloxamer content. Conclusions: Poloxamer and its structural analogs achieve similar effects on crystallization due to their comparable plasticizing effects. The nucleation and growth rates show different trends as a function of the poloxamer content. This effect is a result of both kinetic and thermodynamic factors. This study is relevant to understanding the impacts of the surfactant on the physical instability of amorphous drugs. Full article