Search Results (492)

Proteostasis is essential for maintaining the proper function of the proteome and diverse cellular processes. The ubiquitin system plays a central role in proteostasis by regulating protein stability, trafficking, and termination. Under cellular stress, rapid proteome remodeling is required to maintain proteostasis and support adaptive cellular stress-response pathways, including the DNA damage response (DDR). Proper DDR function relies on precise control of protein abundance and signaling dynamics, primarily achieved through ubiquitin-mediated proteostatic regulation involving both proteolytic degradation and non-proteolytic scaffolding function. Dysregulation of the ubiquitin system alters the dynamic control of the DDR cascade, leading to genomic instability and disease progression. Therefore, targeting key components of the ubiquitin system may restore proper DDR signaling regulation and offer novel therapeutic opportunities for disease treatment. In this review, we summarize the role of the ubiquitin system in proteostasis-mediated DDR regulation and explore the potential of targeting ubiquitin system components as therapeutic strategies in cancer treatment. Full article

Recognition and binding to β-galactose-containing carbohydrates and lipids are crucial for several fundamental biological processes that are mediated primarily by a family of proteins known as galectins (S-type lectins). Galectins in the human placenta regulate critical processes such as maternal–fetal immune tolerance, trophoblast invasion, vascular remodeling and angiogenesis, ensuring proper fetal development and preventing pregnancy complications such as preeclampsia and miscarriage. Gestational diabetes mellitus (GDM) is a widespread complication of pregnancy, affecting approximately 1 in 7 pregnancies, and its incidence is increasing globally, indicating a particularly strong association with the obesity pandemic. Profiles of placental expression and distribution of individual galectins significantly change during the course of GDM. This is accompanied by placental dysfunction, which is especially severe with poor glycemic control. The aim of this review is to present the current state of knowledge on the involvement of abnormal galectin signaling in the pathomechanisms of GDM-associated placental dysfunction. Further research is needed to determine whether changes in placental galectins occur secondary to metabolic abnormalities in GDM or are involved as a primary cause. Galectins present in placental tissue and serum should be validated as potential biomarkers of GDM. Full article

The proper regulation of signaling pathways, including WNT signaling, during early embryonic development is critical for whole-organism development. In particular, maternally enriched WNTs play critical roles in cell cleavage and axis formation through non-canonical and canonical pathways during early embryogenesis. However, early developmental processes related to maternal WNTs and their underlying mechanisms have remained unstudied in avian species. In this study, we investigated WNT signaling-mediated early development in the chicken embryo. We found that WNT4 and WNT6, different ligands from other species, exhibited expression patterns consistent with maternal enrichment in chicken. The chemical inhibition of maternal WNT signaling in intrauterine embryos led to aberrant zygotic expression of WNT8C, which is important for primitive streak formation. Combined with in vitro functional studies, we demonstrated that WNT4 increased WNT8C expression through the non-canonical JNK pathway and that WNT8C subsequently promoted the canonical β-catenin pathway. Our results indicate that maternal WNT4 activates zygotic WNT8C and potentially regulates embryonic polarity in chicken. Full article

Fiber-reinforced laminates composed of a thermoset matrix have seen widespread use in industries such as the aerospace, wind power, and automotive industries, due to their strength-to-weight ratios and ease of formability. For optimal performance, the instantaneous cure state must be sufficient such that the component will not deform during or after molding, a state that can vary based on many manufacturing-related factors. Thus, monitoring the cure process non-destructively in situ is key to manufacturing composite laminates to achieve the as-designed properties while balancing the cycle time reduction. The current work presents a pulse-echo ultrasound method to correlate the acoustic waveform to the thermoset resin cure state and the instantaneous structural properties, specifically the resin storage and loss moduli. This latter information provides a fabricator knowledge of when a part can be successfully demolded, allowing for optimizing part cycle times. The present paper provides the results for the neat resin specimen and fiberglass specimen impregnated with the same resin system. The results provide a direct correlation between the acoustic and the viscoelastic properties. Interestingly, it is noted that there is a direct correlation between the peak signal attenuation and the peak gelation of the material, thus providing a means to predictively schedule the demolding time while maintaining proper curing cycles. Full article

Lactobacilli strains are one of the major groups belonging to probiotics. Lactobacilli strains are known to be beneficial microbes widely studied and utilized for their health benefits and applications in various fields. Recently, Lactobacilli strains have emerged as promising agents in cancer management due to their ability to influence various physiological processes. Lactobacilli strains have shown potential in producing tumor-suppressive compounds, enhancing immune responses, and reshaping gut microbiota balance for the management of various cancer types. Lactobacilli strains demonstrated tumor-suppressive activity through mechanisms including induction of apoptosis, inhibition of migration, and regulation of key oncogenic signaling pathways. However, the effects of Lactobacilli strains appear to be strain- and cancer-type-dependent, necessitating further research to identify the most effective strains for the proper cancer type with the optimal treatment regimens. In this review article, we focus on Lactobacilli strains studied between 2021 and 2025 that have demonstrated tumor-suppressive properties in various experimental models. In addition, this article explores the current limitations in research methodologies and proposes potential avenues for future investigations in this area of study. Full article

This paper presents the design of a fuzzy PID controller with a parallel structure for controlling an electro-hydraulic servo system. The main factors affecting control performance in electro-hydraulic systems are discussed in detail. The proposed fuzzy controller features a specific structure obtained through a coefficient transfer approach from a classical PID controller, enabling seamless integration of the fuzzy logic component and simplifying the tuning process. Relevant mathematical equations and dependencies are provided. The closed-loop system’s stability is analyzed using the BIBO (Bounded Input, Bounded Output) criterion. The designed controller is implemented in the MATLAB/Simulink 2019 environment and tested using a real-time measurement and control system. Graphical results are presented, illustrating the performance of the closed-loop system under step and sinusoidal reference signals. The obtained results confirm the qualities and proper tuning of the implemented controller. Full article

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are among the most common congenital malformations and the leading cause of chronic kidney disease in children. They arise when key steps in kidney development are disrupted, including ureteric bud induction, branching morphogenesis and nephron progenitor differentiation. These processes depend on coordinated transcriptional programs, signaling pathways, ciliary function and proper extracellular matrix (ECM) organization. Advances in whole exome and whole genome sequencing, as well as copy number variation analysis, have expanded the spectrum of known monogenic causes. Pathogenic variants have now been identified in major transcriptional regulators and multiple ciliopathy-related genes. Evidence also points to defects in central signaling pathways and changes in ECM composition as contributors to CAKUT pathogenesis. Clinical presentations vary widely, shaped by modifying effects of genetic background, epigenetic regulation and environmental influences such as maternal diabetes and fetal hypoxia. Emerging tools, including human kidney organoids, gene-editing approaches and single-cell or spatial transcriptomics, allow detailed exploration of developmental mechanisms and validation of candidate pathways. Overall, CAKUT reflects a multifactorial condition shaped by interacting genetic, epigenetic and environmental determinants. Integrating genomic data with experimental models is essential for improving diagnosis, deepening biological insight and supporting the development of targeted therapeutic strategies. Full article

Astrocytes and microglia constitute nearly half of all central nervous system cells and are indispensable for its proper function. Both exhibit striking morphological and functional heterogeneity, adopting either neuroprotective (A2, M2) or proinflammatory (A1, M1) phenotypes in response to cytokines, pathogen-associated molecular patterns (PAMPs)/damage-associated molecular patterns (DAMPs), toll-like receptor 4 (TLR4) activation, and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling. Crucially, many of these phenotypic transitions arise during the earliest stages of neurodegeneration, when glial dysfunction precedes overt neuronal loss and may act as a primary driver of disease onset. This review critically examines glial-centered hypotheses of neurodegeneration, with emphasis on their roles in early disease phases: (i) microglial polarization from an M2 neuroprotective state to an M1 proinflammatory state; (ii) NLRP3 inflammasome assembly via P2X purinergic receptor 7 (P2X7R)-mediated K⁺ efflux; (iii) a self-amplifying astrocyte–microglia–neuron inflammatory feedback loop; (iv) impaired microglial phagocytosis and extracellular-vesicle–mediated propagation of β-amyloid (Aβ) and tau; (v) astrocytic scar formation driven by aquaporin-4 (AQP4), matrix metalloproteinase-9 (MMP-9), glial fibrillary acidic protein (GFAP)/vimentin, connexins, and janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling; (vi) cellular reprogramming of astrocytes and NG2 glia into functional neurons; and (vii) mitochondrial dysfunction in glia, including Dynamin-related protein 1/Mitochondrial fission protein 1 (Drp1/Fis1) fission imbalance and dysregulation of the sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Sirt1/PGC-1α) axis. Promising therapeutic strategies target pattern-recognition receptors (TLR4, NLRP3/caspase-1), cytokine modulators (interleukin-4 (IL-4), interleukin-10 (IL-10)), signaling cascades (JAK2–STAT, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositide 3-kinase–protein kinase B (PI3K–AKT), adenosine monophosphate-activated protein kinase (AMPK)), microglial receptors (triggering receptor expressed on myeloid cells 2 (TREM2)/spleen tyrosine kinase (SYK)/ DNAX-activating protein 10 (DAP10), siglec-3 (CD33), chemokine C-X3-C motif ligand 1/ CX3C motif chemokine receptor 1 (CX3CL1/CX3CR1), Cluster of Differentiation 200/ Cluster of Differentiation 200 receptor 1 (CD200/CD200R), P2X7R), and mitochondrial biogenesis pathways, with a focus on normalizing glial phenotypes rather than simply suppressing pathology. Interventions that restore neuroglial homeostasis at the earliest stages of disease may hold the greatest potential to delay or prevent progression. Given the complexity of glial phenotypes and molecular isoform diversity, a comprehensive, multitargeted approach is essential for mitigating Alzheimer’s disease and related neurodegenerative disorders. This review not only synthesizes pathogenesis but also highlights therapeutic opportunities, offering what we believe to be the first concise overview of the principal hypotheses implicating glial cells in neurodegeneration. Rather than focusing on isolated mechanisms, our goal is a holistic perspective—integrating diverse glial processes to enable comparison across interconnected pathological conditions. Full article

White-matter development during fetal life represents one of the most vulnerable processes to environmental disruption, as it relies on the precisely timed proliferation, migration, and differentiation of oligodendrocyte lineage cells. Among environmental threats, exposure to toxic compounds contained in tobacco smoke and vaping aerosols represents a major yet preventable risk during pregnancy. Despite growing awareness, tobacco smoking remains widespread, and a substantial proportion of the population—including pregnant women—continues to perceive electronic nicotine delivery systems (ENDS) as less harmful, a misconception that contributes to persistent prenatal exposure. These products expose the fetus to numerous substances that readily cross the placenta and reach the developing brain, including compounds with endocrine-disrupting activity, where they interfere with white-matter development. Epidemiological and neuroimaging studies consistently reveal microstructural alterations in white matter that correlate with long-term cognitive and behavioral impairments in offspring exposed in utero. These alterations may arise from both nicotine-specific pathways and the actions of other toxicants in cigarette smoke and ENDS aerosols that cross the placenta and disrupt white-matter emergence and maturation. Preclinical research provides mechanistic insight: nicotine acts directly on nicotinic acetylcholine receptors (nAChRs) in oligodendrocyte precursor cells, disrupting calcium signaling and differentiation, while additional constituents of smoke and vaping aerosols also affect astrocyte and microglial function and disturb the extracellular milieu required for proper myelination. Full article

Heat hardening induces complex biochemical reprogramming that enhances thermal resilience in marine bivalves. Despite this technique’s promising results in marine animals, the molecular basis of heat hardening is far from understood. This study elucidates the molecular mechanisms underlying the hardening process in Mytilus galloprovincialis exposed to a 4-day sublethal heat treatment. Induction of hsf-1, hsp70, and hsp90 genes revealed the activation of the heat shock response and proteostasis machinery, ensuring proper protein folding and preventing oxidative and proteotoxic stress. Simultaneous upregulation of mitochondrial (atpase6, cox1, nadh) and glycolytic (pk, cs) genes reflects enhanced oxidative phosphorylation and glycolytic flux, maintaining ATP supply and metabolic flexibility under elevated temperatures. Increased hif-1α expression suggests transient hypoxia signaling, coordinating oxygen utilization with redox control. Reinforcement of antioxidant defenses, together with elevated autophagy-related transcription, denotes a shift toward oxidative stress mitigation and damaged organelle clearance. Balanced expression of pro- (bax) and anti-apoptotic (bcl-2) factors, along with nf-κb modulation, supports tight regulation of cell survival and inflammatory responses. These findings underscore a highly integrated biochemical network linking proteostasis, intermediary metabolism, redox balance, and antioxidant defense with cellular quality control, which together underpin the physiological plasticity of heat-hardened M. galloprovincialis, enhancing survival under transient thermal stress. Full article

Oral health is a critical factor in maintaining overall health, and its association with systemic diseases, including cardiovascular disease and diabetes mellitus, has been extensively investigated. Effective plaque removal through proper toothbrushing techniques is fundamental for preventing dental caries and periodontal diseases. Despite standardized guidelines, many individuals fail to adhere to correct brushing techniques, thereby increasing the risk of oral diseases. To address this issue, this study proposes a fine-grained toothbrushing region recognition approach incorporating six machine learning classifiers and two inertial measurement units (IMUs), which are embedded in the toothbrush holder and mounted on the right wrist of the participant, respectively. By analyzing the continuous motion signals, the proposed hierarchical approach is capable of identifying brushing and transition activities and subsequently recognizing specific toothbrushing regions based on the predicted brushing activities. To further improve recognition reliability, post-processing strategies such as contextual smoothing and majority voting are applied. Experimental results demonstrate that random forest achieves the highest recognition accuracy of 96.13%, sensitivity of 96.10%, precision of 95.51%, and F1-score of 95.60%. The results indicate that the proposed approach is both effective and feasible for providing fine-grained toothbrushing region recognition in toothbrushing monitoring. Full article

It has been more than a century since the day the first commercial generator was put into operation. Since then, our technical civilization has been dependent on the reliability of electric generators for electrical supply. The reliable and uninterruptible operation of power generators depends heavily on a proper maintenance strategy, and faults occurring during operation should be detected in a timely manner. In this work, a review of state-of-the-art fault diagnosis strategies is presented. Faults occurring in electric generators are presented and categorized, and the quantities utilized for their detection are provided. Traditional signal processing methods and machine learning (ML) approaches for their reliable detection are analyzed. Trends and challenges are discussed, and future directions are highlighted. Full article

The economic value of goose down is attributed to its extensive application in the production of down-based clothing and related products. The primordium formation stage governs the proper morphogenesis of the feather follicle, while the Wnt signaling pathway serves a positive regulatory function during this stage. To identify critical miRNAs and molecular mechanisms regulating the development of goose feather follicle primordium, we performed transcriptomic sequencing of skin tissues collected from six geese at pre- and post-feather follicle primordium developmental stages. Bioinformatics analysis identified 350 differentially expressed miRNAs (DE miRNAs), which were functionally enriched in processes related to system development and multicellular organismal development, etc. As demonstrated by dual-luciferase reporter experiments, miR-200a binds directly to PITX2’s 3′ untranslated region (3′UTR). Furthermore, overexpression of miR-200a decreased the expression levels of genes linked to the Wnt pathway and suppressed the proliferation of GEDFs, as validated by RT-qPCR, CCK8, and EdU assays. Notably, co-transfection experiments demonstrated that miR-200a-mediated regulation of GEDF proliferation through the Wnt pathway is functionally dependent on PITX2. Collectively, this work expands the regulatory network underlying feather follicle development and provides a genetic foundation aimed at breeding geese with enhanced down production quality. Full article

Molecular chaperones are crucial for maintaining protein homeostasis by assisting in the proper folding, stabilization, and function of proteins. Among them, Heat shock protein 90 (Hsp90), represents a highly conserved protein family of molecular chaperones that plays an essential role in diverse biological processes and is fundamental to cellular health and survival. As a highly abundant molecular chaperone, Hsp90 comprises 1–2% of cellular proteins, increasing to 4–6% under stress conditions. It interacts with client proteins, assisting them in proper folding and stability. Unlike classical chaperonins, Hsp90 operates through a highly regulated, ATP-dependent cycle that involves multiple co-chaperones. This process allows Hsp90 to selectively engage with numerous client proteins, including signaling proteins, kinases, hormone receptors, and transcription factors. Recent discoveries have revealed its involvement in processes beyond protein folding, demonstrating its role in diverse cellular functions such as epigenetic regulation, immune signaling, and oncogenic transformation. This current review highlighted the specific characteristics of cytoplasmic and endoplasmic reticulum (ER) as well as mitochondrial paralogs and functions, focusing on its contribution to buffering genetic variation, facilitating oncogene addiction, and modulating disease phenotypes in conditions such as cancer, neurodegeneration, cardiovascular diseases (CVD), and diabetes. We also discuss the therapeutic potential of targeting Hsp90 and its co-chaperones, outlining the challenges and prospects in drug development. These insights not only reshape our understanding of chaperone biology but also present opportunities for precision medicine in various human diseases. Full article

Background: Ectopic bone formation models provide useful insights into bone tissue formation and remodeling processes. The use of a subcutaneous site emphasizes the focus on cytokine signaling and cell migration and proliferation while minimizing the effect of mechanical loading and direct interaction with surrounding stem cells. Methods: To study the effect of BMP3 on bone formation and remodeling, Bmp3^-/- mice were subcutaneously implanted with an autologous blood coagulum device containing BMP6, and bone formation was examined at days 7 and 14 post-implantation. Bone marrow cell composition was assessed using FACS. Formation of ectopic bone was analyzed using micro-CT, immunohistochemistry, and RNAseq to obtain transcriptomic data. Results: Bone marrow from Bmp3^-/- mice showed reduced lymphoid-lineage subsets, expanded myeloid lineage, and altered proportions of several osteochondroprogenitor subsets. A limited amount of newly formed bone tissue was seen in the implants after 7 days, while ectopic bone was more evident after 14 days, with significantly more bone in the Bmp3^-/- mice compared to WT mice. Localization of Sox9 and Runx2 showed a more advanced stage of bone tissue remodeling in Bmp3^-/- mice. Transcriptomic analysis showed upregulation of approximately 1700 genes on day 7 and 190 genes on day 14. Conclusions: These results suggest that BMP3 regulates the composition of bone and cartilage progenitor populations in bone marrow and consequently bone formation by arresting the remodeling of cartilage to bone tissue. The lack of BMP3 in ectopic bone accelerates the transition from the cartilaginous template to proper bone tissue. Full article