Effects of Dietary Yeast ß-1,3/1,6-D-Glucan on Immunomodulation in RAW 264.7 Cells and Methotrexate-Treated Rat Models.

A new subclass of nutraceuticals, called immunoceuticals, is dedicated to immunological regulation. Although yeast-derived ß-1,3/1,6-D-glucan shows promise as an immunoceutical candidate, further studies are needed to define its precise immune-enhancing processes and to standardize its use. Following methotrexate (MTX)-induced immunosuppression in rats, we evaluated the immunomodulatory efficacy of a highly pure and standardized ß-1,3/1,6-D-glucan sample (YBG) in RAW 264.7 macrophages. In in vitro and in vivo models, YBG demonstrated remarkable immunomodulatory effects, such as repair of immune organ damage, elevation of blood cytokine levels, and enhanced phagocytosis and nitric oxide production in RAW 264.7 cells. These results are consistent with the established immunostimulatory properties of ß-glucan. It is noteworthy that this research indicates the potential of YBG as an immunomodulatory nutraceutical, as it is among the first to demonstrate immunological augmentation in an immunosuppression setting produced by MTX. Based on these observations, further investigation of YBG is warranted, particularly given its potential to emerge as a combination immunoceutical to mitigate immunosuppression and reduce the risk of infection in rheumatoid arthritis (RA) patients receiving long-term MTX therapy.

Mechanistic Exploration of Smilax glabra Roxb. in Osteoarthritis: Insights from Network Pharmacology, Molecular Docking, and In Vitro Validation.

Background: Arthritis, a debilitating joint disease, remains a significant global health burden. This study uncovers the therapeutic potential of the medicinal plant Smilax glabra Roxb. (SGR) in attenuating progression of disease by modulating immune responses. Methods: Through computational approaches, key bioactive compounds in SGR were identified by using freely available databases: TCMSP, TCMID, HIT2.0, HERB, and INPUT in order to elucidate their underlying mechanisms of action. Therapeutic targets for the disease have been retrieved by TTD, GeneCard, and OMIM databases. The STRING database was used to analyze the protein-protein interactions (PPI) of intersecting genes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to reveal the functional roles of genes. Mcule was used for molecular docking and binding affinity of compounds and targets were evaluated by DeepPurpose model. ALP activity, cell viability assay, TRAP staining were also performed. Results: A total of 14 active SGR compounds with 59 common targets for arthritis have been identified. These targets have a major role in controlling biological processes such as wound healing, oxygen responses, and chemical stimuli. Molecular docking by Mcule platform demonstrated that quercetin and ß-sitosterol showed higher binding energy affinities with TNF, TP53, PTGS2, and JUN as compared to other targets. To explore the complex relationship between compounds and targets, pre-trained Davis and KIBA models were used to predict the affinity values of selected compounds. In MC3T3-E1 cells, ALP activity was significantly increased and bone marrow macrophages (BMM) showed a low number of TRAP-positive cells in SGR-treated cells. Conclusions: Our findings demonstrate that SGR effectively inhibits/regulates inflammatory responses, prevents cartilage degradation, promotes bone regeneration, and can be used as a promising candidate for the development of novel arthritis treatment.

Inhibitory Effects of Reynoutria japonica Houtt. on Pain and Cartilage Breakdown in Osteoarthritis Based on Its Multifaceted Anti-Inflammatory Activity: An In Vivo and In Vitro Approach.

In the past 30 years, the number of years lived with disability due to osteoarthritis (OA) has doubled, making it an increasing global health burden. To address this issue, interventions that inhibit the progressive pathology driven by age-related low-grade inflammation, the primary mechanism of OA, are being actively pursued. Recent investigations have focused on modulating the age-related low-grade inflammatory pathology of this disease as a therapeutic target. However, no agent has successfully halted the disease's progression or reversed its irreversible course. Reynoutria japonica Houtt. (RJ), a promising East Asian herbal medicine, has been utilized for several diseases due to its potent anti-inflammatory activity. This study aims to determine RJ's capacity to inhibit OA symptoms and associated inflammation, exploring its potential for further development. In vivo and in vitro experiments demonstrated RJ's anti-OA activity and modulation of multifaceted inflammatory targets. RJ significantly inhibited pain, gait deterioration, and cartilage destruction in a monosodium iodoacetate-induced OA rat model, with its analgesic effect further confirmed in an acetic acid-induced writhing model. RJ exhibited consistent anti-inflammatory activity against multiple targets in serum and cartilage of the OA rat model and lipopolysaccharide-induced RAW 264.7 cells. The inhibition of inflammatory cytokines, including interleukin-1ß, interleukin-6, matrix metalloproteinase-13, tumor necrosis factor-α, and nitric oxide synthase 2, suggests that RJ's alleviation of OA manifestations relates to its multifaceted anti-inflammatory activity. These results indicate that RJ merits further investigation as a disease-modifying drug candidate targeting OA's inflammatory pathology. To further characterize the pharmacological properties of RJ, future studies with expanded designs are warranted.

Direct Multi-Target Teaching Interface for Autonomous Handling of Multi-Stack Logistics in a Warehouse.

This study presents a framework for enabling autonomous pick-place operations, addressing the need for efficiency in complex logistics environments using a direct multi-target teaching interface. First, tag and segmentation information were combined to recognize products in a complex warehouse, and a camera was installed on the rack to allow workers to remotely see the work environment, allowing workers to view the work environment in real time through a tablet. Workers can access the camera view showing the rack containing the target product through a swiping action and select the target product through direct teaching action. When the target product is finally selected, an optimal path is created through task planning, and an autonomous pick-place operation is performed based on the generated path. As a result of conducting a usability evaluation using the SUS (System Usability Scale) with six users on the interface that enables these tasks, it was confirmed that high user satisfaction was achieved with an average of 77.5 points. In conclusion, the proposed interface enhances operational efficiency and provides a user-friendly solution for complex warehouse tasks.

Investigating the Anti-Inflammatory, Analgesic, and Chondroprotective Effects of Gynostemma pentaphyllum (Thunb.) Makino in Osteoarthritis: An In Vitro and In Vivo Study.

Osteoarthritis (OA) is an age-related disease characterized by inflammation, pain, articular cartilage damage, synovitis, and irreversible disability. Gynostemma pentaphyllum (Thunb.) Makino (GP), a herbal medicine traditionally used in East Asia for its anti-inflammatory properties, was investigated for its potential to modulate OA pathology and symptoms. This study evaluated GP's efficacy in inhibiting pain, functional decline, and cartilage destruction in monosodium iodoacetate-induced OA and acetic acid-induced writhing models. Additionally, the effects of GP on OA-related inflammatory targets were assessed via mRNA and protein expression in rat knee cartilage and lipopolysaccharide-induced RAW 264.7 cells. The GP group demonstrated significant pain relief, functional improvement, and cartilage protection. Notably, GP inhibited key inflammatory mediators, including interleukin (IL)-1ß, IL-6, matrix metalloproteinases (MMP)-3 and MMP-13, cyclooxygenase-2, and prostaglandin E receptor 2, surpassing the effects of active controls. These findings suggest that GP is a promising candidate for disease-modifying OA drugs and warrants further comprehensive studies.

Simple methods to determine the dissociation constant, Kd.

The determination of the dissociation constant (Kd) is pivotal in biochemistry and pharmacology for understanding binding affinities in chemical reactions, which is crucial for drug development and comprehending biological systems. Here, we introduce a single-molecule fluorescence resonance energy transfer-based method for determining Kd, alongside the conventional electrophoretic mobility shift assay method of Kd, offering insights into thermodynamic interactions between proteins and substrates. The single-molecule fluorescence resonance energy transfer approach is highlighted for its ability to accurately measure binding and dissociation kinetics through fluorescence labeling and the intrinsic nature of protein-DNA interactions, representing a significant advancement in the fields of molecular biology and pharmacology.

Changes in Smartphone Usage among Adolescents and Associated Subjective Health Concerns: A Secondary Analysis of the Korea Youth Risk Behavior Survey.

BACKGROUND: We evaluated changes in the smartphone use rate and time among Korean adolescents and their awareness of associated health problems. METHODS: This study was a secondary analysis of the Korea Youth Risk Behavior Survey (2020-2023) conducted by the Korean Disease Control and Prevention Agency. The total number of enrolled adolescents aged 12-18 years was 214,526. RESULTS: The weekly smartphone usage rate increased from 96.4% to 97.1% (p = 0.03), with no significant changes observed in weekend usage. The average smartphone use time was 4.7 h on weekdays (p = 0.17) and 6.6 h on weekends (p = 0.37). Middle school adolescents had a higher weekday use rate than high school adolescents, but the average smartphone use time was significantly less. By 2023, the proportion of adolescents with overdependence was 28% (n = 14,672). Additionally, 11.8% (n = 6255) responded that they had experienced health problems due to smartphone use. CONCLUSIONS: The longer they used their smartphones for on the weekends, the more likely they considered their health to be worse. In conclusion, our youth population needs to be educated on the proper use of smartphones.

Efficacy and Safety of Orally Administered East Asian Herbal Medicine Combined with Narrowband Ultraviolet B against Psoriasis: A Bayesian Network Meta-Analysis and Network Analysis.

Psoriasis is a chronic, immune-mediated inflammatory skin disease with many complications and a poor prognosis that imposes a significant burden on individuals and society. Narrowband ultraviolet B (NB-UVB) represents a cost-effective non-drug therapeutic intervention for psoriasis. East Asian herbal medicine (EAHM) is currently being investigated for its potential as a safe and effective psoriasis treatment. Consequently, it has the potential to be employed as a combination therapy with NB-UVB. The objective was to ascertain the efficacy and safety of the EAHM with NB-UVB combination therapy and to identify important drugs for further research. In this study, randomized controlled trials (RCTs) were retrieved from ten databases in Korea, China, and Japan. All statistical analyses were conducted using R software version 4.3.0. The primary outcomes were the Psoriasis Area and Severity Index (PASI) and the incidence rate of adverse events (AEs), while the secondary outcomes were hematologic markers and the Dermatology Life Quality Index (DLQI), which reflect the immune-mediated inflammatory pathology of psoriasis. The analysis of 40 RCTs, including 3521 participants, demonstrated that EAHM with NB-UVB combination therapy exhibited a statistically significant superiority over NB-UVB monotherapy with respect to primary and secondary outcomes. The Bayesian network meta-analysis revealed that Investigator Presciption 3 and Ziyin Liangxue Decoction exhibited a consistent relative advantage with respect to each PASI-based efficacy metric. The network analysis estimated the potential influence ranking for all individual herbs according to PageRank centrality. The findings of this study suggest that EAHMs co-administered with NB-UVB may provide additional efficacy and safety-related benefits for patients with psoriasis. However, the quality of evidence is still low, and further high-quality trials are needed to reach more definitive conclusions.

Pain Relief, Functional Recovery, and Chondroprotective Effects of Angelica gigas Nakai in Osteoarthritis Due to Its Anti-Inflammatory Property: An In Vitro and In Vivo Study.

Osteoarthritis (OA), characterized by chronic pain and joint degradation, is a progressive joint disease primarily induced by age-related systemic inflammation. Angelica gigas Nakai (AG), a medicinal plant widely used in East Asia, exhibits promising results for such conditions. This study aimed to evaluate the potential of AG as a drug candidate for modulating the multifaceted pathology of OA based on its anti-inflammatory properties. We evaluated the efficacy of AG in pain relief, functional improvement, and cartilage erosion delay using monosodium iodoacetate-induced OA rats and acetic acid-induced writhing mice, along with its anti-inflammatory effects on multiple targets in the serum and cartilage of in vivo models and lipopolysaccharide-stimulated RAW 264.7 cells. In vivo experiments demonstrated significant analgesic and chondroprotective effects of AG, along with functional recovery, in model animals compared with the active controls. AG dose-dependently modulated inflammatory OA pathology-related targets, including interleukin-1ß, tumor necrosis factor-α, matrix metalloproteinase-13, and cyclooxygenase-2, both in vitro and in vivo. In conclusion, AG could be a potential drug candidate for modulating the multifaceted pathology of OA. Nevertheless, further comprehensive investigations, involving a broader range of compounds, pathologies, and mechanisms, are warranted to validate these findings.

Importance of Autophagy Regulation in Glioblastoma with Temozolomide Resistance.

Glioblastoma (GBM) is the most aggressive and common malignant and CNS tumor, accounting for 47.7% of total cases. Glioblastoma has an incidence rate of 3.21 cases per 100,000 people. The regulation of autophagy, a conserved cellular process involved in the degradation and recycling of cellular components, has been found to play an important role in GBM pathogenesis and response to therapy. Autophagy plays a dual role in promoting tumor survival and apoptosis, and here we discuss the complex interplay between autophagy and GBM. We summarize the mechanisms underlying autophagy dysregulation in GBM, including PI3K/AKT/mTOR signaling, which is most active in brain tumors, and EGFR and mutant EGFRvIII. We also review potential therapeutic strategies that target autophagy for the treatment of GBM, such as autophagy inhibitors used in combination with the standard of care, TMZ. We discuss our current understanding of how autophagy is involved in TMZ resistance and its role in glioblastoma development and survival.

Emerging Roles of Natural Compounds in Osteoporosis: Regulation, Molecular Mechanisms and Bone Regeneration.

Bone health is a critical aspect of overall well-being, and disorders such as osteoporosis pose significant challenges worldwide. East Asian Herbal Medicine (EAHM), with its rich history and holistic approach, offers promising avenues for enhancing bone regeneration. In this critical review article, we analyze the intricate mechanisms through which EAHM compounds modulate bone health. We explore the interplay between osteogenesis and osteoclastogenesis, dissect signaling pathways crucial for bone remodeling and highlight EAHM anti-inflammatory effects within the bone microenvironment. Additionally, we emphasize the promotion of osteoblast viability and regulation of bone turnover markers by EAHM compounds. Epigenetic modifications emerge as a fascinating frontier where EAHM influences DNA methylation and histone modifications to orchestrate bone regeneration. Furthermore, we highlight EAHM effects on osteocytes, mesenchymal stem cells and immune cells, unraveling the holistic impact in bone tissue. Finally, we discuss future directions, including personalized medicine, combinatorial approaches with modern therapies and the integration of EAHM into evidence-based practice.

Pathogenesis of Cerebral Small Vessel Disease: Role of the Glymphatic System Dysfunction.

Cerebral small vessel disease (CSVD) is a group of pathologies that affect the cerebral blood vessels. CSVD accounts for 25% of strokes and contributes to 45% of dementia. However, the pathogenesis of CSVD remains unclear, involving a variety of complex mechanisms. CSVD may result from dysfunction in the glymphatic system (GS). The GS contains aquaporin-4 (AQP-4), which is in the perivascular space, at the endfeet of the astrocyte. The GS contributes to the removal of waste products from the central nervous system, occupying perivascular spaces and regulating the exchange and movement of cerebrospinal fluid and interstitial fluid. The GS involves astrocytes and aquaporin channels, which are components of the blood-brain barrier, and problems with them may constitute the pathogenesis of CSVD. Vascular risk factors, including diabetes, dilate the perivascular space, disrupting the glymphatic system and the active regulation of AQP-4. CSVD exacerbation due to disorders of the GS is associated with multiple vasculopathies. Dysfunction of the glymphatic system and AQP-4 interferes with the functioning of the blood-brain barrier, which exacerbates CSVD. In a long-term follow-up of CSVD patients with microbleeds, lacunar infarcts, and white matter hyperintensity, several vascular risk factors, including hypertension, increased the risk of ischemic stroke. Dysfunction of the GS may be the cause of CSVD; however, the underlying treatment needs to be studied further.

A foundation model for clinical-grade computational pathology and rare cancers detection.

The analysis of histopathology images with artificial intelligence aims to enable clinical decision support systems and precision medicine. The success of such applications depends on the ability to model the diverse patterns observed in pathology images. To this end, we present Virchow, the largest foundation model for computational pathology to date. In addition to the evaluation of biomarker prediction and cell identification, we demonstrate that a large foundation model enables pan-cancer detection, achieving 0.95 specimen-level area under the (receiver operating characteristic) curve across nine common and seven rare cancers. Furthermore, we show that with less training data, the pan-cancer detector built on Virchow can achieve similar performance to tissue-specific clinical-grade models in production and outperform them on some rare variants of cancer. Virchow's performance gains highlight the value of a foundation model and open possibilities for many high-impact applications with limited amounts of labeled training data.

Astragalus Extract Mixture HT042 Alleviates Dexamethasone-Induced Bone Growth Retardation in Rat Metatarsal Bones.

The most widely used synthetic glucocorticoid, dexamethasone (DEX), causes stunted growth in children when used excessively or for long periods of time; however, there are still plenty of pediatric patients require long-term treatment with DEX. As an alternative, growth hormone is used in combination, but it has side effects, a high cost, and psychological factors, and it is not satisfactory in terms of effectiveness. It is necessary to develop a safe and affordable treatment that can replace it. The Korean Food and Drug Administration approved HT042, a standardized functional food ingredient, with the claim that it can help height growth of children. In this study, it was found that HT042 activated the Indian hedgehog/parathyroid hormone-related protein signaling pathway and enhanced the number of growth hormone receptors and insulin-like growth factor-1 receptors on the growth plate surface, which were reduced by DEX treatment, and restored growth retardation. In metatarsal bone and primary chondrocyte models, it was found that HT042 can promote the length of growth plate and recover DEX-induced growth retardation. It was also found that HT042 promotes cell proliferation using bromodeoxyuridine and terminal deoxynucleotidyl transferase dUTP nick end labeling assays; moreover, we verified increased expression of GHR/IGF-1R and Ihh/PTHrP pathway activity using qRT-PCR, western blotting, and siRNA analyses to verify its direct action on the growth plate. The anti-apoptotic effect of HT042 was identified by regulating the expression of apoptotic factors such as caspase-3, Bcl2, Bclx, and Bax. These results were identified using both ex vivo and in vitro models. Our study verified that co-administration of HT042 could recover the DEX induced growth retardation.

Mortality in sea lions is associated with the introduction of the H5N1 clade 2.3.4.4b virus in Brazil October 2023: whole genome sequencing and phylogenetic analysis.

Clade 2.3.4.4b highly pathogenic avian influenza (HPAI) H5N1 virus was detected in the South American sea lions found dead in Santa Catarina, Brazil, in October 2023. Whole genome sequencing and comparative phylogenetic analysis were conducted to investigate the origin, genetic diversity, and zoonotic potentials of the H5N1 viruses. The H5N1 viruses belonged to the genotype B3.2 of clade 2.3.4.4b H5N1 virus, which was identified in North America and disseminated to South America. They have acquired new amino acid substitutions related to mammalian host affinity. Our study provides insights into the genetic landscape of HPAI H5N1 viruses in Brazil, highlighting the continuous evolutionary processes contributing to their possible adaptation to mammalian hosts.

The association between serum free fatty acid levels and neurological outcomes in out-of-hospital cardiac arrest patients: A prospective observational study.

Free fatty acids (FFA) are a known risk factor in the development of sudden cardiac death. However, the relationship between FFA and the outcome of out-of-hospital cardiac arrest (OHCA) patients remains unclear. We aimed to examine the association between FFA and neurological outcomes in OHCA patients. This prospective observational study included adult (≥18 years) OHCA patients between February 2016 and December 2022. We measured serial FFA levels within 1 hour after ROSC and at 6, 12, 24, 48, and 72 hours after the return of spontaneous circulation (ROSC). The primary outcome was neurological outcome at 6 months. A poor neurological outcome was defined by cerebral performance categories 3, 4, and 5. A total of 147 patients were included. Of them, 104 (70.7%) had poor neurological outcomes, whereby the median FFA levels within 1 hour after ROSC (0.72 vs 1.01 mol/L), at 6 hours (1.19 vs 1.90 mol/L), 12 hours (1.20 vs 1.66 mol/L), and 24 hours (1.20 vs 1.95 mol/L) after ROSC were significantly lower than in good outcome group. The FFA levels at 6 hours (odds ratio, 0.583; 95% confidence interval, 0.370-0.919; P = .020), and 12 hours (odds ratio, 0.509; 95% confidence interval, 0.303-0.854; P = .011) after ROSC were independently associated with poor neurological outcomes. The lower FFA levels at 6 hours and 12 hours after ROSC were associated with poor neurological outcomes in patients with OHCA. FFA may reflect oxidative metabolism as well as oxidative stress.

Bypassing Stationary Points in Training Deep Learning Models.

Gradient-descent-based optimizers are prone to slowdowns in training deep learning models, as stationary points are ubiquitous in the loss landscape of most neural networks. We present an intuitive concept of bypassing the stationary points and realize the concept into a novel method designed to actively rescue optimizers from slowdowns encountered in neural network training. The method, bypass pipeline, revitalizes the optimizer by extending the model space and later contracts the model back to its original space with function-preserving algebraic constraints. We implement the method into the bypass algorithm, verify that the algorithm shows theoretically expected behaviors of bypassing, and demonstrate its empirical benefit in regression and classification benchmarks. Bypass algorithm is highly practical, as it is computationally efficient and compatible with other improvements of first-order optimizers. In addition, bypassing for neural networks leads to new theoretical research such as model-specific bypassing and neural architecture search (NAS).

Neuronal Cell Differentiation of iPSCs for the Clinical Treatment of Neurological Diseases.

Current chemical treatments for cerebrovascular disease and neurological disorders have limited efficacy in tissue repair and functional restoration. Induced pluripotent stem cells (iPSCs) present a promising avenue in regenerative medicine for addressing neurological conditions. iPSCs, which are capable of reprogramming adult cells to regain pluripotency, offer the potential for patient-specific, personalized therapies. The modulation of molecular mechanisms through specific growth factor inhibition and signaling pathways can direct iPSCs' differentiation into neural stem cells (NSCs). These include employing bone morphogenetic protein-4 (BMP-4), transforming growth factor-beta (TGFß), and Sma-and Mad-related protein (SMAD) signaling. iPSC-derived NSCs can subsequently differentiate into various neuron types, each performing distinct functions. Cell transplantation underscores the potential of iPSC-derived NSCs to treat neurodegenerative diseases such as Parkinson's disease and points to future research directions for optimizing differentiation protocols and enhancing clinical applications.

Virus-like particles expressing microneme-associated antigen of Plasmodium berghei confer better protection than those expressing apical membrane antigen 1.

Malaria is a global disease affecting a large portion of the world's population. Although vaccines have recently become available, their efficacies are suboptimal. We generated virus-like particles (VLPs) that expressed either apical membrane antigen 1 (AMA1) or microneme-associated antigen (MIC) of Plasmodium berghei and compared their efficacy in BALB/c mice. We found that immune sera acquired from AMA1 VLP- or MIC VLP-immunized mice specifically interacted with the antigen of choice and the whole P. berghei lysate antigen, indicating that the antibodies were highly parasite-specific. Both VLP vaccines significantly enhanced germinal center B cell frequencies in the inguinal lymph nodes of mice compared with the control, but only the mice that received MIC VLPs showed significantly enhanced CD4+ T cell responses in the blood following P. berghei challenge infection. AMA1 and MIC VLPs significantly suppressed TNF-α and interleukin-10 production but had a negligible effect on interferon-γ. Both VLPs prevented excessive parasitemia buildup in immunized mice, although parasite burden reduction induced by MIC VLPs was slightly more effective than that induced by AMA1. Both VLPs were equally effective at preventing body weight loss. Our findings demonstrated that the MIC VLP was an effective inducer of protection against murine experimental malaria and should be the focus of further development.

Whole genome sequencing of low pathogenicity avian influenza virus (H6N2) detected from a Brazilian teal (Amazonnetta brasiliensis) in Brazil, 2023.

The whole genome sequence of a low pathogenicity avian influenza virus (H6N2) was sequenced from a Brazilian teal (Amazonetta brasiliensis) in Brazil, 2023. Phylogenetic analysis of the whole genome revealed a distinct genome pertaining to South American LPAIV from 2014 to 2016, indicating extensive circulation among South American wild birds.