Search Results (626)

The physical characteristics of a heated non-Newtonian Eyring–Powell fluid in a conduit with sinusoidally moving ciliated walls are highlighted in this analytical study. The impact of mass transmission is considered in this model. The dimensional form of the governing equations is simplified using the long-wavelength estimation and suitable transformations to produce a set of dimensionless partial differential equations with pertinent boundary conditions. To solve it, the perturbation technique is utilized applying polynomial solutions. The solutions of temperature, concentrations, and velocity profiles are obtained, and then are further analyzed through graphical results. An accurate mathematical solution for the pressure gradient is achieved by integrating the velocity profile over the elliptic cross-section. The non-Newtonian Eyring–Powell fluid flows quicker through this vertical ciliated elliptic duct than the Newtonian fluid. Moreover, the cilia elliptic movement eccentricity and the wave number for metachronal wave have a dual effect on the velocity profile. Increasing the dimensionless flow rate and occlusion leads to an increase in closed contour size, as seen in the streamline description. Full article

Carcinoma showing thymus-like differentiation (CASTLE) is a rare malignancy arising in the thyroid or neck, with an uncertain cellular origin that complicates both diagnosis and treatment. To better understand its molecular underpinnings and identify potential therapeutic avenues, we conducted integrated whole-exome and transcriptome sequencing on six CASTLE and six thymic carcinoma samples. Whole-exome sequencing (WES) was performed on all 12 samples, while RNA sequencing was successful for 1 CASTLE and 6 thymic carcinoma samples. Our analysis included somatic mutation profiling, mutational signature deconvolution, differential gene expression, and characterization of tumor microenvironment for the cases with available data, with comparisons to genomic data from other thyroid cancers. CASTLE tumors demonstrated a higher median tumor mutational burden than thymic carcinoma and lacked the common BRAF and RAS mutations typically found in thyroid cancers. They harbored alterations in genes such as TRHDE, cilia-associated genes (ANKS6, CFAP46, DNAH6), and Wnt signaling components (TRRAP, BCL9L), as well as mutational signatures suggestive of mismatch repair deficiency and oxidative damage. MSIsensor-pro analysis of the WES data provided support for the potential for mismatch repair deficiency in a subset of CASTLE samples. Exploratory transcriptomic analysis from a single CASTLE case showed downregulation of thyroid follicular markers and an “immune-hot”, lymphocyte-rich microenvironment, closely resembling that of thymic carcinoma. While these findings require validation in larger cohorts, they support a thymic origin for CASTLE and establish its molecular distinction from follicular-derived thyroid cancers. The immunogenic tumor landscape suggests that immune checkpoint inhibitors, particularly those targeting PD-1/PD-L1, may be a promising therapeutic strategy, alongside emerging targets for precision oncology. Full article

Parkinson’s disease (PD) is a common neurodegenerative disorder marked by progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies, intracellular inclusions enriched in α-synuclein. Synphilin-1 interacts with α-synuclein, localizes to Lewy bodies, and has been implicated in inclusion formation and neuroprotection in cellular and animal models; however, its physiological function in vivo remains poorly defined. Here, we generated and characterized a synphilin-1 knockout (Sph-1 KO) mouse by targeted genetic deletion of the Sph-1 locus and performed a comprehensive phenotyping battery including behavioral testing as well as biochemical, histological, structural, and ultrastructural analyses. Sph-1 KO mice survived to nearly two years of age and showed normal body weight, lifespan, motor performance, learning and memory, anxiety-like behavior, attention, and gross brain morphology. Western blot analyses indicated that levels of α-synuclein and synaptic proteins were largely unchanged. While outer mitochondrial membrane proteins were unaffected, the mitochondrial matrix protein HSP60 was reduced, consistent with altered mitochondrial proteostasis in the absence of synphilin-1. Strikingly, histochemical analyses, magnetic resonance imaging, and electron microscopy revealed early-onset hydrocephalus in Sph-1 KO mice associated with severe loss and disorganization of motile ependymal cilia in the ventricular lining, a cell type that normally expresses high levels of synphilin-1. Ultrastructural and immunohistochemical analyses revealed disrupted ependymal architecture, mislocalization of acetylated α-tubulin to the cytoplasm, cellular swelling, and enlarged, aberrant mitochondria, whereas cortical neurons appeared largely structurally unaffected. Together, these findings identify synphilin-1 as a key regulator of microtubule organization and cytoskeletal/organelle homeostasis in ependymal cells, required to maintain motile ciliogenesis, cerebrospinal fluid flow, and ventricular integrity. This unexpected role for synphilin-1 in ciliated brain epithelia, along with a reduction in the critical mitochondrial chaperone HSP60, broadens our understanding of synphilin-1 biology and provides a new framework for its potential relevance to PD-associated pathology. Full article

Ciliopathies, initially known as fibrocystic liver diseases, encompass a group of inherited disorders characterized by cystic dilatation of intrahepatic bile ducts and portal fibrosis, frequently associated with renal anomalies. These disorders are now recognized as resulting from defects in primary cilia. The hepatic manifestations, such as congenital hepatic fibrosis (CHF), Caroli syndrome, and polycystic liver disease, arise from ductal plate malformation. Recent studies have implicated variants in the TULP3 (Tubby related protein variant 3) gene in a novel monogenic ciliopathy affecting the liver, kidneys, and heart. We report an 8-year-old boy who presented with variceal bleeding and evolved to a progressive phenotype of CHF. Whole exome sequencing revealed a homozygous novel TULP3 mutation. The patient was managed by endotherapy and propranolol prophylaxis. Due to repeated episodes of variceal bleeding and progressive worsening of hepatic synthetic functions, he underwent a living donor liver transplantation at the age of 12 years. Full article

Bronchial thermoplasty (BT) is a non-pharmacological treatment for severe asthma. The working mechanism and response determinants of BT remain partly unknown. This study aims to investigate whether a systemic transcriptomic response to BT can be detected and contextualized against a control cohort. Whole blood was collected at baseline and six months after BT from severe asthma patients (n = 31) and a control cohort (n = 126). RNA was isolated and sequenced. The following comparisons were made: before and after BT, responders and non-responders, and severe asthma (at baseline) versus controls. Differentially expressed genes were identified across 179 samples using DESeq2. Pathway enrichment was investigated using gene set enrichment and overrepresentation analyses. Following BT, pathways related to nervous system development, ion channel activity, muscle tissue development, and cilia function were downregulated. In responders specifically, gene sets involved in nervous system and muscle development were downregulated. Compared with the control cohort, pathways related to nervous system development and ion channel activity were upregulated in the severe asthma cohort at baseline. In conclusion, systemic blood-derived transcriptomic changes can be detected in severe asthma patients six months after BT and may provide insight into BT mechanisms and its responder profile. Full article

Deoxynivalenol (DON) is a common mycotoxin linked to ovarian oxidative stress, toxicity, and reduced reproductive performance. Fermented Chinese chive is known for its antioxidant properties and potential reproductive benefits, but their individual and combined effects on ovarian function remain unclear in post-pubertal mice. In this study, a 21-day oral gavage model in female Kunming mice was used to evaluate the effects of DON (2 mg/kg/day), fermented Chinese chive extract (LEEK; 0.2 mL/day), and their combined exposure (LKDON) on ovarian physiology, oocyte quality, and ovarian transcriptomic responses. The results showed that DON exposure significantly reduced the zygote cleavage rate, increased intracellular reactive oxygen species levels, and disrupted oocyte mitochondrial membrane potential. While histological examination revealed disturbed follicular architecture. Transcriptomic hub gene analysis showed that DON exposure down-regulate the key associated with innate immune responses and motile cilia/axonemal structure, including Rsph4a, Drc1, Zmynd10, Hydin, and Tmem212. In contrast, LEEK alone was associated with immunomodulatory upregulated genes, including Il5, Cd27, and Crp. Interestingly, LKDON and DON comparison revealed upregulation of a motile cilia/axoneme gene network (Dnah5, Dnah11, Tekt1, Zmynd10, Cfap44, and Spag6l), rather than a global reversal of DON-induced changes. Overall, finding suggest that DON disrupts ovarian immune and structural pathways, while fermented Chinese chive provides partial protection by modulating specific biological processes. Further studies are needed to confirm the underlying mechanisms. Full article

Primary ciliary dyskinesia (PCD) is a rare ciliopathy resulting in chronic oto-sino-pulmonary disease. PCD diagnosis can be achieved by a combination of different diagnostic and adjuvant tools, including high-speed video-microscopy analysis (HSVA). A founder variant has been described in Puerto Rico as the most common cause of PCD in the island. Background/Objectives: In HSVA, objective parameters such as ciliary beat frequency (CBF) and subjective parameters such as ciliary beat pattern (CBP) shed light on the biophysical properties of cilia. However, the subjective nature of CBP creates a gap in knowledge; characteristics such as the length, angle, and bending index of cilia are poorly described. Our goal is to quantify cilia dynamics of the RSPH4A (c.921+3_921+6delAAGT (intronic)) founder variant in Puerto Rico through biophysical properties of cilia. This approach enhances longitudinal patient care by understanding treatment progress through biophysical ciliary function. Methods: We analyzed images from HSVA of six patients with PCD homozygous for the founder variant and six healthy controls (HC) (n = 12). Results: We found that ciliary length (PCD = 7.62 ± 0.95 μm, HC = 8.12 ± 1.36 μm, p = 0.204 ns), orientation vector (PCD = 7.20 ± 0.93 μm, HC = 7.25 ± 1.01 μm, p = 0.883 ns), straight angle (PCD = 1.67 ± 0.27 rad, HC = 1.76 ± 0.29 rad, p = 0.380 ns), and area (PCD = 2.35 ± 0.52 μm², HC = 2.10 ± 0.53 μm², p = 0.264 ns) did not have statistically significant differences between PCD and HC. In contrast, bending index (PCD = 1.06 ± 0.04, HC = 1.12 ± 0.09, p = 0.01), bent angle (PCD = 1.11 ± 0.30 rad, HC = 0.67 ± 0.21 rad, p < 0.0001), net angle (PCD = 0.56 ± 0.26 rad, HC = 1.09 ± 0.35 rad, p < 0.0001), amplitude (PCD = 5.77 ± 1.25 μm, HC = 7.99 ± 1.65 μm, p < 0.0001), and amplitude per second (PCD = 48.83 ± 13.23 A(s), HC = 91.66 ± 27.96 A(s), p < 0.0001) showed significant differences between both groups. Conclusions: Reduced angular excursion and amplitude in PCD demonstrate that the beating pattern of the RSPH4A founder variant is dysfunctional as compared with healthy controls. Our study provides an objective framework to understand the biophysical properties of the RSPH4A founder variant. Full article

Background/Objectives: Heterotopic ossification (HO), the aberrant formation of bone within soft tissues, arises either from rare genetic mutations or more commonly from traumatic insults. It is a major cause of morbidity not only in individuals harboring causative mutations, but also in those undergoing musculoskeletal surgery or trauma and in soldiers sustaining blast or burn injuries. Bone morphogenetic protein (BMP) signaling is a central driver of both hereditary and acquired forms of HO. Primary cilia are nonmotile, antenna-like organelles that extend from the cell surface and serve as crucial sensory and signaling hubs by concentrating key pathway components within a confined volume at the ciliary tip. However, their functional role in the pathogenesis of traumatic HO remains poorly understood. Methods: We investigate the role of primary cilia in traumatic HO using a genetically modified mouse model and cellular model. Results: We demonstrate that BMP signaling is attenuated when primary cilia function is disrupted. Both ciliation frequency and ciliary length were reduced in Scleraxis-CreERT2; Intraflagellar transport 88 ^{floxed/floxed} (Scx-CreERT2;Ift88^fl/fl) tenocytes. Deletion of Ift88 effectively suppressed pathological BMP signaling and inhibited HO formation. Conclusions: These findings establish that functional primary cilia are required for traumatic HO development and highlight ciliary regulation as a potential therapeutic avenue for preventing or mitigating post-traumatic HO. Full article

Background/Objectives: Primary ciliary dyskinesia (PCD) is a rare inherited disorder caused by dysfunction of motile cilia, leading to chronic respiratory disease. Diagnosis is challenging due to heterogeneous and non-specific clinical manifestations and the absence of a single definitive diagnostic test. Current diagnostic strategies rely on a combination of functional, ultrastructural, and genetic analyses. The objective of this study was to evaluate whether ciliary beat frequency (CBF), combined with ciliary beat pattern (CBP) assessment using digital high-speed video microscopy (DHSV), could serve as an effective first-line screening tool to identify patients requiring further diagnostic investigations. Methods: This single-center retrospective study included 65 patients (52 children and 13 adults) with clinical suspicion of PCD. Ciliary beat analysis was performed on nasal or bronchial samples using DHSV and Sisson–Ammons Video Analysis software. CBF and CBP were assessed and compared between patients with confirmed PCD and those in whom PCD was excluded based on transmission electron microscopy (TEM) and/or molecular genetic analysis. Results: Fifteen patients were diagnosed with PCD. Mean CBF was significantly lower in the PCD group compared with the non-PCD group (3.3 Hz vs. 8.1 Hz; p < 0.001). A CBF cut-off value of 5.25 Hz yielded a sensitivity of 78.6% and a specificity of 95.7%. Three patients with PCD had CBF values above this threshold; however, two of them exhibited abnormal CBP. Sample type, patient age, and the presence of airway pathogens did not significantly influence CBF measurements. Conclusions: CBF and CBP analysis using DHSV represents a useful first-line screening tool within a multifaceted diagnostic approach for PCD, allowing rapid identification of patients who should undergo further confirmatory testing. Full article

Recent studies have demonstrated that primary cilia not only play a role in cardiovascular development, but also in the progression of acquired heart disease. Their role in atrial fibrillation (AF) is incompletely understood. We hypothesize that there is a causal link between primary cilia genes and the occurrence of AF. We integrated AF GWAS data with various multi-omic datasets—including data on gene expression, DNA methylation, and protein expression quantitative trait loci (eQTL, mQTL, and pQTL)—from human left atrial appendage (LAA) tissues and blood. Genetic variants linked to primary cilia-related genes were used as instrumental variables to explore their causal links to AF, through summary-data-based Mendelian randomization (SMR) and Bayesian colocalization. Single-cell sequencing data were used to analyze the expression of the selected genes across different cell types. The mechanisms by which the selected genes exert their effects were explored using RNA sequencing data, clinical indicators, and immunohistochemical markers from 22 patients without AF from the PREDICT-AF cohort, and 21 patients with paroxysmal AF and 19 patients with persistent AF from the MARK-AF cohort. Through SMR analyses, we established significant associations between predicted CEP68 expression and AF in both blood (OR 1.25; 95% CI 1.18–1.33; false discovery rate (FDR) = 1.81 × 10⁻⁹) and LAA tissue (OR 1.12; 95% CI 1.08–1.16; FDR = 6.18 × 10⁻⁹). Moreover, predicted methylation of CEP68 showed an inverse relationship with AF risk (OR 0.87; 95% CI 0.84–0.90; FDR = 2.55 × 10⁻¹⁵). Colocalization results for CEP68 in both blood and the LAA indicated strong evidence of a shared causal variant. Within single-cell data, compared to the control group, AF patients had higher levels of CEP68 in fibroblasts (p = 0.046). In bulk RNA-seq data, CEP68 expression showed no significant differences among the no AF, paroxysmal AF, and persistent AF groups. CEP68 was positively correlated with the cardiac remodeling marker Thrombospondin-2 in 22 patients without AF from the PREDICT-AF cohort (r = 0.45, p = 0.03). In AF patients from the MARK-AF study, CEP68 was also positively associated with LAVI (r = 0.34, p = 0.03). Collectively, our results support a model in which genetically predicted CEP68 regulation is linked to AF liability and is consistent with fibroblast activation and remodeling-related pathways as potential mediators. Full article

Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disorder of motile cilia that leads to impaired mucociliary clearance and recurrent airway infections. Children with PCD often present with ear and sinus disease resembling common pediatric conditions, yet the true burden and management remain incompletely defined. To address this gap, a systematic search for pediatric cohort studies published between 2020 and 2025 reporting otologic and sinonasal features of PCD was performed. Searches of PubMed, Embase, Scopus, and Web of Science identified 12 eligible studies, encompassing 524 children with confirmed PCD. Data extracted focused on demographics, otologic and sinonasal manifestations, vestibular findings, radiographic imaging, and interventions. Across studies, 60.3% had a history of otitis media and 39.1% had hearing loss, predominantly conductive. Tympanostomy tubes were utilized in more than half of patients, with many requiring multiple sets over time due to recurrent effusions or tube occlusion. Sinonasal disease was nearly universal, with 78.5% demonstrating chronic rhinosinusitis and most reporting nasal congestion and rhinorrhea; nasal polyps were uncommonly noted. Vestibular symptoms were also infrequently assessed but present in some patient cohorts. In conclusion, otologic and sinonasal disease are highly co-prevalent in pediatric PCD, highlighting the need for early recognition, regular surveillance, and standardized outcome reporting to guide long-term management of this complex chronic disease. Full article

The minimum size of particles being efficiently captured in the gills of filter-feeding bivalves differs between mussels with well-developed laterofrontal cirri (lfc) and scallops having only simple pro-laterofrontal cilia (pro-lfc). The presence of branching compound lfc increases the particle retention efficiency below the lower limit of about 4 µm for 100% retention, whereas the simple pro-lfc cilia in scallops are less efficient with decreasing retention efficiency for particles smaller than about 7 µm. To understand the particle capture mechanisms in bivalves, attention must be paid to the ciliary structures and water flow in flat gills (mussels) versus plicate gills (scallops, oysters). Here, we briefly review the literature on particle capture mechanisms in filter-feeding marine bivalves with large lfc (mussels, clams), short lfc (oysters), and with only pro-lfc (scallops), and then we describe our present understanding of these processes. This is carried out along with comments on a long-lasting and current controversy on particle-capture mechanisms in filter-feeding bivalves. We rebut the hypothesis of “hydrosol filtering” proposed by Ward et al. (1998), where the approach angle of a particle towards the gill is 30° and the particle is captured by direct interception with a gill filament, whereas lfc generate “zones of blocked through-flow”. No further test of the hydrosol hypothesis has so far been made, but nevertheless, it has been cited in many publications over the last 25 years. Full article

Background/Objective: The primary cilium is the sensory organelle of a cell and a dynamic membrane protrusion during the cell cycle. It originates from the centriole at G₀/G₁ and undergoes disassembly to release centrioles for spindle formation before a cell enters mitosis, thereby serving as a cell cycle checkpoint. Cancer cells that undergo rapid cell cycle and replication have a low ciliation rate. In this study, we aimed to identify cilia-promoting drugs that can accelerate ciliation and decelerate replication of cancer cells. Methods: To perform a comprehensive and efficient literature search on drugs that can promote ciliation, we developed an intelligent process that integrates either the GPT 4 Turbo, Gemini 1.5 Pro, or Claude 3.5 Haiku application programming interfaces (APIs) into a PubMed scraper that we coded, enabling the large language models (LLMs) to directly query articles for predefined user questions. We evaluated the performance of this intelligent literature search based on metrics and tested the effect of two candidate drugs on ciliation and proliferation of medulloblastoma cells. Results: Gemini was the best model overall, as it balanced high accuracy with solid precision and recall scores. Among the top candidate drugs identified are Alvocidib and Alisertib, small-molecule inhibitors of CILK1 and AURKA, respectively. Here, we show that both kinase inhibitors can effectively increase cilia frequency and significantly decrease the replication of medulloblastoma cells. Conclusions: The results demonstrated the potential of using cilia-promoting drugs, such as Alvocidib and Alisertib, to suppress cancer cell replication. Additionally, it shows the massive benefits of integrating accessible large language models to conduct sweeping, rapid, and accurate literature searches. Full article

The “Neuroimaging and Pathology Biomarkers in Parkinson’s Disease” course held on 12–13 September 2025 in Milan, Italy, convened an international faculty to review state-of-the-art biomarkers spanning neurotransmitter dysfunction, protein pathology and clinical translation. Here, we synthesize the four themed sessions and highlights convergent messages for diagnosis, stratification and trial design. The first session focused on neuroimaging markers of neurotransmitter dysfunction, highlighting how positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) provided complementary insights into dopaminergic, noradrenergic, cholinergic and serotonergic dysfunction. The second session addressed in vivo imaging of protein pathology, presenting recent advances in PET ligands targeting α-synuclein, progress in four-repeat tau imaging for progressive supranuclear palsy and corticobasal syndromes, and the prognostic relevance of amyloid imaging in the context of mixed pathologies. Imaging of neuroinflammation captures inflammatory processes in vivo and helps study pathophysiological effects. The third session bridged pathology and disease mechanisms, covering the biology of α-synuclein and emerging therapeutic strategies, the clinical potential of seed amplification assays and skin biopsy, the impact of co-pathologies on disease expression, and the “brain-first” versus “body-first” model of pathological spread. Finally, the fourth session addressed disease progression and clinical translation, focusing on imaging predictors of phenoconversion from prodromal to clinically overt stages of synucleinopathies, concepts of neural reserve and compensation, imaging correlates of cognitive impairment, and MRI approaches for atypical parkinsonism. Biomarker-informed pharmacological, infusion-based, and surgical strategies, including network-guided and adaptive deep brain stimulation, were discussed as examples of how multimodal biomarkers may inform personalized management. Across all sessions, the need for harmonization, longitudinal validation, and pathology-confirmed outcome measures was consistently emphasized as essential for advancing biomarker qualification in multicentre research and clinical practice. Full article

Kidney cells are exposed to a wide range of physiological and pathological stresses, including hormonal changes, mechanical forces, hypoxia, hyperglycemia, and inflammation. These insults can trigger adaptive responses, but when they persist, they can lead to organelle stress. Organelles such as mitochondria, the endoplasmic reticulum, and primary cilia sustain cellular metabolism and tissue homeostasis. When organelle stress occurs, it disrupts cellular processes and organelle communication, leading to metabolic dysfunction, inflammation, fibrosis, and progression of kidney disease. Sex and hormonal factors play a significant role in the development of renal disorders. Many glomerular diseases show distinct differences between the sexes. Chronic Kidney Disease is more common in women, while men often experience a faster decline in kidney function, partly due to the influence of androgens. Additionally, the loss of female hormonal protection after menopause highlights the importance of sex as a factor in renal susceptibility. This narrative review synthesizes preclinical evidence on how sexual dimorphism and sex hormones affect organelle stress in mitochondria, the endoplasmic reticulum, and primary cilia, from 33 studies identified through a non-systematic literature search of the PubMed database, to provide an overview of how these mechanisms contribute to sex-specific differences in kidney disease pathophysiology. Full article