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Hearing loss (HL) affects more than 1.5 billion people worldwide and remains a leading cause of disability across the lifespan. While genetic predispositions, otitis media (OM), and cholesteatoma are well-recognized contributors, Eustachian tube dysfunction (ETD) is an underappreciated but pivotal determinant of auditory morbidity. By impairing middle ear pressure (MEP) regulation, ETD drives conductive hearing loss (CHL) through stiffness and mass-loading effects, contributes to sensorineural hearing loss (SNHL) via altered window mechanics and vascular stress, and produces mixed hearing loss (MHL) when these pathways converge. A characteristic clinical trajectory emerges in which conductive deficits often resolve quickly with restored ventilation, whereas sensorineural impairment requires prolonged, physiology-restoring intervention, resulting in transient or persistent MHL. This review integrates mechanistic insights with clinical manifestations, diagnostic approaches, and therapeutic options. Diagnostic frameworks that combine patient-reported outcomes with objective biomarkers such as wideband absorbance, tympanometry, and advanced imaging enable reproducible identification of ETD-related morbidity. Conventional treatments, including tympanostomy tubes and balloon dilation, offer short-term benefit but rarely normalize tubal physiology. In contrast, Eustachian tube catheterization (ETC) has emerged as a promising, mechanism-based intervention capable of reestablishing dynamic tubal opening and MEP regulation. Looking forward, integration of physiology-based frameworks with personalized diagnostics and advanced tools such as artificial intelligence (AI) may help prevent progression from reversible conductive deficits to irreversible SNHL or MHL.

Railway point devices act as actuators that provide different routes to trains by driving switchblades from the current position to the opposite one. Point failure can significantly affect railway operations, with potentially disastrous consequences. Therefore, early detection of anomalies is critical for monitoring and managing the condition of rail infrastructure. We present a data mining solution that utilizes audio data to efficiently detect and diagnose faults in railway condition monitoring systems. The system enables extracting mel-frequency cepstrum coefficients (MFCCs) from audio data with reduced feature dimensions using attribute subset selection, and employs support vector machines (SVMs) for early detection and classification of anomalies. Experimental results show that the system enables cost-effective detection and diagnosis of faults using a cheap microphone, with accuracy exceeding 94.1% whether used alone or in combination with other known methods.

Traditionally, Thunb. (GJ) extract has been used to treat headaches and dizziness. We hypothesize that GJ exhibits anti-platelet activity that may prevent ischemic events to alleviate these symptoms. In this study, we investigated the anti-platelet activity of GJ as a potential mechanism for enhancing blood flow and preventing vessel occlusion. Platelets were stimulated with collagen, adenosine diphosphate (ADP) or thrombin. Platelet aggregation was carried out using a platelet aggregometer with washed platelets from Sprague-Dawley rats. We observed the mobilization of calcium ions using Fura-2AM and adenosine triphosphate (ATP) release via a luminometer. The activation of integrin αIIbβ3 and population of platelet-neutrophil aggregates (PNAs) were investigated using flow cytometry. Platelet shape change was observed using scanning electron microscopy and transmission electron microscopy. GJ extract inhibited collagen, ADP and thrombin-induced platelet aggregation. It effectively prevented the mobilization of calcium ions, ATP secretion, and serotonin release while thromboxane B2 levels did not change. Moreover, GJ inhibited the inside-out and outside-in signaling of integrin αIIbβ3. Notably, GJ treatment led to elevated expression of cyclic guanine monophosphate (GMP) (but not cyclic adenosine monophosphate). The protein expressions in the PI3K/Akt pathway were inhibited and platelet shape change was prevented. Finally, GJ treatment resulted in a decreased population of PNAs . GJ exhibits potent anti-platelet activity acting by upregulating cGMP. It holds promise as a potential candidate for supplementation in patients with cardiovascular disease and thrombosis.

The immune system has traditionally been divided into innate and adaptive branches, with immunological memory considered a hallmark of adaptive immunity. However, recent studies reveal that innate immune cells can also exhibit memory-like properties, known as trained immunity. This phenomenon involves the long-term functional reprogramming of innate immune cells following exposure to exogenous or endogenous stimuli, mediated by epigenetic and metabolic changes. Trained immunity enhances responses to subsequent unrelated challenges and serves as a protective mechanism against reinfection. Nonetheless, it may also contribute to the development of chronic inflammatory diseases such as autoimmune disorders, allergies and atherosclerosis. Whereas much of the research has focused on pathogen-associated molecular patterns as inducers of trained immunity, emerging evidence highlights that sterile inflammation, driven by damage-associated molecular patterns and lifestyle-associated molecular patterns, can similarly induce this immune adaptation. Here we examine the molecular mechanisms underlying damage-associated molecular pattern- and lifestyle-associated molecular pattern-induced trained immunity and their roles in chronic inflammation. This Review also discusses central trained immunity, characterized by the durable reprogramming of hematopoietic stem and progenitor cells, and its implications in disease progression. Finally, potential therapeutic strategies targeting metabolic and epigenetic pathways are considered. Understanding noninfectious stimuli-induced trained immunity offers new insights into chronic inflammatory disease management. trained immunity reveals innate cells can remember challenges The immune system has two parts: innate and adaptive immunity. Scientists used to think only adaptive immunity had memory, but recent studies show innate immunity can also remember. Trained immunity involves long-term changes in innate immune cells, such as macrophages, due to vaccines or other stimuli, leading to better responses to future infections. Researchers have found that not just infections but also noninfectious factors such as diet and stress can trigger trained immunity. This Review reviews recent findings on how certain molecules, called damage-associated molecular patterns and lifestyle-associated molecular patterns, can induce trained immunity. These molecules are released from damaged cells or accumulated owing to poor clearance and can cause chronic inflammation, contributing to diseases such as atherosclerosis and chronic kidney disease. The Review concludes that understanding trained immunity could lead to new treatments for chronic inflammatory diseases by targeting these pathways. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Various combination treatments have been considered to attain the effective therapy threshold by combining independent antitumor mechanisms against the heterogeneous characteristics of tumor cells in malignant brain tumors. In this study, the natural killer (NK) cells associated with bevacizumab (Bev) plus irinotecan (Iri) against glioblastoma multiforme (GBM) were investigated. For the experimental design, NK cells were expanded and activated by K562 cells expressing the OX40 ligand and membrane-bound IL-18 and IL-21. The effects of Bev and Iri on the proliferation and NK ligand expression of GBM cells were evaluated through MTT assay and flow cytometry. The cytotoxic effects of NK cells against Bev plus Iri-treated GBM cells were also predicted via the LDH assay in vitro . The therapeutic effect of different injected NK cell routes and numbers combined with the different doses of Bev and Iri was confirmed according to tumor size and survival in the subcutaneous (s.c) and intracranial (i.c) U87 xenograft NOD/SCID IL-12Rγ null mouse model. The presence of injected-NK cells in tumors was detected using flow cytometry and immunohistochemistry ex vivo . As a result, Iri was found to affect the proliferation and NK ligand expression of GBM cells, while Bev did not cause differences in these cellular processes. However, the administration of Bev modulated Iri efficacy in the i.c U87 mouse model. NK cells significantly enhanced the cytotoxic effects against Bev plus Iri-treated GBM cells in vitro. Although the intravenous (IV) injection of NK cells in combination with Bev plus Iri significantly reduced the tumor volume in the s.c U87 mouse model, only the direct intratumorally (IT) injection of NK cells in combination with Bev plus Iri elicited delayed tumor growth in the i.c U87 mouse model. Tumor-infiltrating NK cells were detected after IV injection of NK cells in both s.c and i.c U87 mouse models. In conclusion, the potential therapeutic effect of NK cells combined with Bev plus Iri against GBM cells was limited in this study. Accordingly, further research is required to improve the accessibility and strength of NK cell function in this combination treatment.

Neuromodulation is frequently used to modulate neuronal activity and influence brain function [...].Neuromodulation is frequently used to modulate neuronal activity and influence brain function [...].

Emerging data have suggested that single short peptides have limited success as a cancer vaccine; however, extending the short peptides into longer multi-epitope peptides overcame the immune tolerance and induced an immune response. Moreover, the combination of adjuvants such as lenalidomide and anti-programmed cell death protein 1 (PD1) with a peptide vaccine showed potential vaccine effects in previous studies. Therefore, the effects of a long multi-epitope peptide vaccine in combination with lenalidomide and anti-PD1 were analyzed in this study. Long multi-epitope peptides from two MHCI peptides (BIRC5 97-104 and EphA2 682-689 ) and the pan-human leukocyte antigen-DR isotype (HLA-DR) binding epitope (PADRE) were synthesized. The therapeutic effects of long multi-epitope peptides in combination with lenalidomide and anti-PD1 were confirmed in the murine GL261 intracranial glioma model. Immune cells’ distribution and responses to the long multi-epitope peptides in combination with these adjuvants were also estimated in the spleens, lymph nodes, and tumor tissues. The difference between long multi-epitope peptides and a cocktail of multi-epitope peptides combined with lenalidomide and anti-PD1 was also clarified. As a result, long multi-epitope peptides combined with lenalidomide and anti-PD1 prolonged the survival of mice according to the suppression of tumor growth in an intracranial mouse model. While long multi-epitope peptides combined with these adjuvants enhanced the percentages of activated and memory effector CD8 + T cells, the increase in percentages of regulatory T cells (Tregs) was observed in a cocktail of multi-epitope peptides combined with lenalidomide and anti-PD1 group in the tumors. Long multi-epitope peptides combined with these adjuvants also enhanced the function of immune cells according to the enhanced pro-inflammatory cytokines and cytotoxicity against GL261 cells in ex vivo . In conclusion, long multi-epitope peptides composed of MHCI peptides, BIRC5 and EphA2, and the MHCII peptide, PADRE, in combination with lenalidomide and anti-PD1 has the potential to improve the therapeutic effects of a vaccine against GBM.

Branched-chain amino acids (BCAAs), particularly leucine, are indispensable AAs for immune regulation through metabolic rewiring. However, the molecular mechanism underlying this phenomenon remains unclear. Our investigation revealed that T-cell receptor (TCR)-activated human CD4 + T cells increase the expression of BCAT1, a cytosolic enzyme responsible for BCAA catabolism, and SLC7A5, a major BCAA transporter. This upregulation facilitates increased leucine influx and catabolism, which are particularly crucial for Th17 responses. Activated CD4 + T cells induce an alternative pathway of cytosolic leucine catabolism, generating a pivotal metabolite, β-hydroxy β-methylbutyric acid (HMB), by acting on BCAT1 and 4-hydroxyphenylpyruvate dioxygenase (HPD)/HPD-like protein (HPDL). Inhibition of BCAT1-mediated cytosolic leucine metabolism, either with BCAT1 inhibitor 2 (Bi2) or through BCAT1, HPD, or HPDL silencing using shRNA, attenuates IL-17 production, whereas HMB supplementation abrogates this effect. Mechanistically, HMB contributes to the regulation of the mTORC1-HIF1α pathway, a major signaling pathway for IL-17 production, by increasing the mRNA expression of HIF1α. This finding was corroborated by the observation that treatment with L-β-homoleucine (LβhL), a leucine analog and competitive inhibitor of BCAT1, decreased IL-17 production by TCR-activated CD4 + T cells. In an in vivo experimental autoimmune encephalomyelitis (EAE) model, blockade of BCAT1-mediated leucine catabolism, either through a BCAT1 inhibitor or LβhL treatment, mitigated EAE severity by decreasing HIF1α expression and IL-17 production in spinal cord mononuclear cells. Our findings elucidate the role of BCAT1-mediated cytoplasmic leucine catabolism in modulating IL-17 production via HMB-mediated regulation of mTORC1-HIF1α, providing insights into its relevance to inflammatory conditions. Immune regulation: leucine’s role in Th17 response modulation T-cell, a type of infection-fighting white blood cell, alter their metabolic process, relying heavily on amino acids, the building blocks of proteins. This study investigates how T cells use the amino acid leucine to power their response. Researchers conducted experiments with human T-cell and a mouse model of autoimmune disease, a condition where the body attacks its own cells. They studied how leucine’s metabolic process affects T-cell function. The study discovered that a specific process involving leucine’s metabolic pathway in T cells is vital for their ability to produce IL-17. Blocking a crucial enzyme reduced IL-17 production and eased symptoms in a mouse model of autoimmune disease. These findings underline the importance of leucine’s metabolic process in T-cell function and suggest a potential target for treating autoimmune diseases more effectively, offering hope for new treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.