Search Results (134)

Background/Objectives: Accessory mandibular foramina (AMaFs) are small osseous openings of the mandible that are clinically relevant anatomical variations. This study aimed to characterize the morphology and spatial distribution of AMaFs in dry mandibles and to integrate the existing anatomical evidence through a systematic review and meta-analysis, with the goal of clarifying their potential clinical relevance. Methods: A series of dry mandibles from human adults of unknown age and sex from our laboratory collection was examined to document AMaFs using direct osteological inspection. Stainless steel wire threads and digimatic caliper measurements were utilized by two separate raters. Cluster analysis was employed for the classification of foramina into distinct spatial groups. Furthermore, in accordance with the PRISMA guidelines, an unrestricted literature search was conducted across PubMed, Scopus, SciELO, and Google Scholar using appropriate database-specific combinations of the terms “accessory mandibular” and “foramen/foramina” to search for studies on the prevalence and morphology of AMaFs in dry mandibles or cadaveric material. Radiological studies were excluded. The search was completed on 13 July 2025. Study quality was evaluated using the appropriate AQUA tool. Data synthesis was carried out using STATA 19. No external funding was received. Results: A total of 96 dry mandibles (50 dentate and 46 edentulous) were analyzed. AMaFs were detected in 8/96 mandibles (8.3%). In these mandibles, a total of 25 accessory mandibular foramina, all superior to the mandibular foramen, were identified (mean: 3.13 foramina/mandible), with a mean diameter (SD) of 0.56 ± 0.10 mm and a mean distance from the mandibular foramen of 11.34 ± 1.29 mm (mean vertical distance: 10.32 ± 1.35 mm; mean absolute horizontal distance: 3.78 ± 0.49 mm). Of these foramina, 21/25 (84%) had a diameter ≥0.5 mm; the number, diameters, and distances from the mandibular foramen were comparable between left and right hemimandibles. Based on their positioning relative to the mandibular foramen, the AMaFs were classified into two distinct groups (clusters). In the meta-analysis, a total of 36 studies were included. In most of the mandibles (65.1%; 95% CI: 57.7–72.2%; I²: 94.9%), no AMaFs were detected. The unilateral presence of one or more AMaFs was observed in 20.9% of the mandibles (95% CI: 16.3–25.9%; I²: 91.3%), while bilateral occurrence was identified in 10.6% (95% CI: 6.9–15.0%; I²: 93.0%). Additionally, 2.4% of the mandibles (95% CI: 1.0–4.2%; I²: 86.3%) exhibited multiple AMaFs (≥2) on at least one side. On average, each hemimandible contained 0.253 AMaFs (95% CI: 0.198–0.312; I²: 96.9%). The overall mean diameter of AMaFs was estimated to be 0.65 ± 0.33 mm. The substantial heterogeneity observed was not explained by geographic origin, sample size, publication period, or publication bias. Conclusions: AMaFs were detected in approximately one-third of the mandibles in the studies included in the meta-analysis. AMaFs are typically located superior to the mandibular foramen and may represent additional anatomical pathways associated with inferior alveolar nerve branching. Awareness of these features could help clinicians to anticipate anatomical variability during mandibular surgery and when applying local anesthesia. In addition, it should be acknowledged that inferior alveolar nerve block failure is multifactorial and not solely determined by the presence of AMaFs. Full article

Low back pain (LBP) remains a leading cause of disability worldwide, imposing substantial socioeconomic burdens. Among its many causes, facetogenic pain accounts for a significant proportion of cases and is generally attributed to irritation of the richly innervated facet joint capsule, mediated by the medial branches of the dorsal rami. This narrative, hypothesis-driven review synthesises the current anatomical, biomechanical, neurophysiological, and clinical literature and advances a conceptual framework proposing a novel anatomical mechanism that may contribute to LBP. We hypothesise that ossification of the mamillo-accessory ligament (MAL) may be a plausible but under-recognised anatomical variant that may influence lumbar biomechanics and neural interfaces. The MAL connects the mammillary and accessory processes of lumbar vertebrae, serving as a stabilising anchor for deep paraspinal muscles and forming a conduit for the medial branch of the dorsal ramus (MBDR). Ossification of the MAL, resulting in a mamillo-accessory foramen, may theoretically impair spinal biomechanics via three principal mechanistic domains: (1) disruption of muscle attachment and segmental stabilisation, (2) potential compression of the MBDR causing denervation and muscle atrophy, and (3) chronic nerve entrapment leading to asymmetrical postural adaptations and persistent pain. Collectively, these pathways may contribute to spinal instability, facet degeneration, and variable response to standard interventional treatments such as radiofrequency ablation. Recognition of MAL ossification may have potential implications for clinical assessment, targeted imaging strategies, and treatment stratification in patients with chronic, non-specific LBP. Full article

Background: PRKAG2 cardiac syndrome is a rare autosomal dominant glycogen-storage cardiomyopathy that mimics sarcomeric hypertrophic cardiomyopathy (HCM) but features ventricular pre-excitation, progressive conduction disease and concentric hypertrophy due to intracellular glycogen accumulation. The c.905G>A (p.Arg302Gln) variant is one of the most frequently reported pathogenic substitutions. Case summary: We describe a three-generation family carrying the heterozygous PRKAG2 p.Arg302Gln variant. The proband, a 41-year-old man, presented with paroxysmal atrial fibrillation, short PR interval and abnormal intraventricular conduction associated with concentric left ventricular hypertrophy and preserved ejection fraction. Holter monitoring disclosed episodes of high-grade atrioventricular block, prompting implantation of a primary-prevention dual-chamber ICD. Two gene-positive brothers exhibited milder hypertrophy but shared sinus bradycardia, ventricular pre-excitation and supraventricular arrhythmias; one underwent catheter ablation of a posteroseptal accessory pathway. The affected mother displayed a hypertrophic phenotype complicated by sick sinus syndrome and permanent atypical atrial flutter requiring pacemaker implantation. No relevant extracardiac involvement was detected in any family member. Review and novelty: Using this family as a starting point, we provide a concise narrative review of PRKAG2 syndrome with emphasis on the Arg302Gln genotype, molecular mechanisms and emerging treatment strategies. We highlight key multimodality imaging and tissue-characterization features that help distinguish diffuse, concentric glycogen-storage hypertrophy from the often-asymmetric pattern of sarcomeric HCM. Integration of our findings with published Arg302Gln cohorts illustrates the broad phenotypic variability in conduction disease, pre-excitation and atrial arrhythmias. Conclusions: PRKAG2 p.Arg302Gln-related cardiomyopathy should be suspected in patients with otherwise unexplained left ventricular hypertrophy associated with short PR interval, pre-excitation or early brady–tachy arrhythmias. Early recognition of red-flag features, systematic genetic testing, family screening and tailored arrhythmia/device management are crucial, while emerging gene- and pathway-targeted therapies may offer future disease-modifying potential. Full article

The recruitment and polarization of tumor-associated macrophages (TAMs) play a pivotal role in shaping the immunosuppressive tumor microenvironment in breast cancer. Interleukin-1 receptor accessory protein (IL1RAP), a critical co-receptor for IL-1 family cytokines, is emerging as a potential regulator of macrophage function, though its specific role in TAM biology remains to be explained. In this study, we investigated the impact of IL1RAP on macrophage recruitment and M2-like polarization. Initial bioinformatics analysis of public databases revealed a significant correlation between elevated IL1RAP expression in macrophages and signatures of immune suppression and poor prognosis in breast cancer. To functionally validate these findings, we performed IL1RAP knockdown in a murine macrophage cell line. Our results demonstrated that IL1RAP deficiency markedly impaired the migratory capacity of macrophages towards classic chemotactic stimuli. Furthermore, under M2-polarizing conditions, IL1RAP-knockdown macrophages exhibited a significantly attenuated M2 phenotype, as evidenced by the decreased expression of canonical M2 markers (e.g., Arg1, Mrc1) and reduced functional outputs. Collectively, our integrated approach combining bioinformatics and in vitro experimentation identifies IL1RAP as a novel regulator that potentiates both the recruitment and the M2 polarization of macrophages. These findings suggest that targeting the IL1RAP pathway could represent a promising therapeutic strategy for reprogramming the tumor-immune microenvironment by limiting pro-tumoral macrophage infiltration and polarization. Full article

Background/Objectives: Patients with WPW syndrome have a risk of sudden cardiac death that can be assessed using an electrophysiological study. In symptomatic patients, the preferred route is intracardiac, whereas in asymptomatic children, transesophageal. Our study aimed to evaluate the risk using a transesophageal study, considering a threshold age of 12 years for sedation. Methods: We investigated 41 asymptomatic WPW children with a mean age of 12.5 ± 4.4 years (range 1 to 18 years old), with 48.8% being male. We determined three values: (1) the accessory pathway effective refractory period (APERP), (2) the minimal cycle length demonstrating 1:1 conduction through the accessory pathway, and (3) the shortest RR interval between two consecutive pre-excited beats during atrial fibrillation. Results: Children under 12 years had a mean age of 7.5 ± 2.5 years, while those over 12 years had a mean age of 15.5 ± 1.9 years. Sedation was administered exclusively to children under 12 years of age. Orthodromic reentrant tachycardia was induced in four children, and atrial fibrillation was induced in 14 children. Comparing the group under 12 with the group over 12, the mean APERP was 296 ± 38 ms vs. 286 ± 45 ms (p = 0.48), the average 1:1 conduction over the accessory pathway was 287.3 ± 41 ms vs. 282 ± 46 ms (p = 0.71), and the average shortest pre-excited RR interval during atrial fibrillation was 280 ms vs. 262 ms years (p = 0.75). Conclusions: Asymptomatic children under 12 years of age showed a lower incidence of inducible atrial fibrillation. They had accessory pathways with reduced risk, except one, and no children under 12 years underwent catheter ablation. Full article

The oncogene KRAS drives tumor growth by activating pathways such as MAPK and PI3K-AKT in a constitutive manner. Although direct KRAS inhibitors exist, they are often limited in clinical use due to therapeutic resistance and toxicity. Therefore, alternative combinatorial therapeutic strategies are urgently needed. This study examined the knockout of five KRAS-related proteins—galectin-3 (GAL3), phosphodiesterase delta (PDEδ), nucleophosmin (NPM1), IQ motif-containing GTPase-activating protein 1 (IQGAP1), and SHOC2—using CRISPR-Cas9 in adenocarcinoma cell lines harboring the KRAS(G12V) oncogenic mutation, as well as in the noncancerous HEK-293 cell line. These proteins act as critical modulators that regulate KRAS activity, cellular localization, and that of its downstream signaling components. We analyzed the downstream activation of ERK and AKT kinases and evaluated subsequent cancer cell proliferation. Knockout of GAL3 and PDEδ was highly effective, significantly reducing MAPK and PI3K-AKT pathway activity and substantially impairing cell proliferation. SHOC2 knockout selectively and potently disrupted MAPK activation, while NPM1 knockout resulted in the complex, reciprocal modulation of the two major pathways. Notably, knocking out IQGAP1 enhanced PI3K–AKT and mTORC2–AKT signaling without affecting the MAPK pathway. These distinct modulatory roles highlight the non-redundant functions of the accessory proteins. In conclusion, our findings establish GAL3 and PDEδ, two KRAS-associated proteins, as promising combinatorial drug targets. Targeting these modulators provides an effective alternative strategy to overcome resistance mechanisms and enhance the clinical utility of existing KRAS inhibitors. Full article

Background: Endolichenic fungi represent an emerging source of bioactive secondary metabolites; however, the genomic basis of their chemical diversity remains largely poorly characterized. Specifically, the metabolic capabilities of Cladosporium limoniforme have not been explored at the genomic level. Objectives: This study aimed to characterize the biosynthetic potential of C. limoniforme by presenting its first whole-genome sequence and conducting a comparative analysis of its biosynthetic gene clusters (BGCs), with a specific focus on the evolutionary conservation of the DHN-melanin pathway. Methods: Genome mining was performed using antiSMASH and fungiSMASH tools. Comparative genomics involved heatmap-based distribution analysis across the Cladosporium genus, synteny profiling using Clinker to assess gene order conservation, and Maximum Likelihood phylogenetic analysis of the polyketide synthase (T1PKS) domain. Results: We identified 26 putative BGCs, revealing a largely untapped metabolic repertoire. Comparative analysis demonstrated a high degree of conservation for the metachelin C (siderophore) and 1,3,6,8-tetrahydroxynaphthalene (T4HN) clusters across the genus. Notably, synteny and phylogenetic analyses showed that while C. limoniforme retains a conserved, ancestral T1PKS core essential for stress survival, it exhibits a significant reduction in accessory genes compared to plant-pathogenic congeners. Conclusions: These findings support a “metabolic streamlining” hypothesis driven by the endolichenic lifestyle, where the fungus retains essential protective machinery while shedding costly accessory genes unnecessary in the buffered lichen niche. This study establishes C. limoniforme as a valuable genomic resource for future biotechnological research. Full article

Background/Objectives: The stellate ganglion (SG), formed by the fusion of the inferior cervical and first thoracic sympathetic ganglia in approximately 80% of individuals, plays crucial roles in cardiac innervation, pain management, and autonomic regulation. This review examines the anatomical variations, histological structure, clinical applications, and therapeutic implications of the SG and stellate ganglion block (SGB), presenting original high-resolution magnetic resonance imaging (MRI) evidence of SG visualization, an underutilized approach in autonomic nervous system research. Methods: We conducted a comprehensive literature review of anatomical, physiological, and clinical studies on the SG, incorporating original anatomical dissections and high-resolution MRI. Contemporary research on SGB applications, complications, and mechanisms of action was analysed and correlated with imaging characteristics. Results: The SG demonstrates significant anatomical variability, including the presence of intermediate ganglia, accessory nerve pathways, and variable relationships with surrounding vascular structures. Our original MRI imaging consistently identified the SG at the thoracic inlet, anterior to the neck of the first rib, lateral to the longus colli muscle, and posterior to the vertebral artery, demonstrating that advanced imaging can reliably visualize this critical autonomic structure and its anatomical variants. Histologically, it contains typical sympathetic architecture, comprising postganglionic neurons, satellite glial cells, and specialized SIF cells that modulate ganglionic transmission. SGB shows therapeutic efficacy across diverse conditions, including cardiac arrhythmias, chronic pain syndromes, post-traumatic stress disorder, sleep disorders, and immune dysfunction. The procedure’s mechanisms involve both direct sympathetic blockade and complex neuroimmune pathways that affect central autonomic centers and lymphoid organs. Complications include vascular injury, pneumothorax, and nerve blocks affecting the recurrent laryngeal and phrenic nerves. Conclusions: The SG represents a critical autonomic structure with expanding clinical applications. This work advances the field by demonstrating that high-resolution MRI can consistently and non-invasively visualize the SG and its anatomical variations, knowledge previously mostly limited to cadaveric studies. Understanding these imaging-defined anatomical variations is essential for optimizing therapeutic interventions. Advanced imaging guidance integrated with comprehensive anatomical knowledge is crucial for maximizing efficacy while minimizing complications in stellate ganglion block procedures. Full article

Carcinogenesis is driven by aberrant activation of molecular signaling pathways governing cell proliferation, apoptosis, and differentiation. Among these, the RAS/RAF/MEK/ERK (RAS/MAPK) cascade is one of the most frequently dysregulated oncogenic pathways, driving tumor initiation and progression across diverse cancer types. Although inhibitors of BRAF and MEK have achieved clinical success in selected malignancies, adaptive resistance often undermines therapeutic durability. This has spurred interest in alternative nodes within the pathway. The kinase suppressor of Ras (KSR) is a scaffold protein that organizes RAF, MEK, and ERK into functional complexes, ensuring efficient and sustained signal transmission. Once regarded as a passive structural component, KSR1 is now recognized as an active regulator of pathway dynamics. Emerging evidence indicates that KSR1 overexpression promotes cancer cell proliferation and survival, while genetic or pharmacologic inhibition of KSR1 attenuates RAS/MAPK signaling and suppresses tumor growth in preclinical models. In this review, we provide a comprehensive overview of accessory and scaffold proteins modulating the RAS/MAPK pathway, with a particular focus on KSR1. We highlight its structural and functional properties, summarize preclinical evidence for KSR1-targeted interventions, and discuss its therapeutic potential in cancer, with emphasis on hepatocellular carcinoma (HCC). Full article

Dongxiang wild rice (DXWR, Oryza rufipogon Griff.), the northernmost known wild rice species, exhibits exceptional tolerance to combined low-temperature and anaerobic stress during seed germination, providing a unique model for understanding plant adaptation to complex environmental constraints. Here, we employed an integrated multi-omics approach combining genomic, transcriptomic, and metabolomic analyses to unravel the synergistic regulatory mechanisms underlying this tolerance. Genomic comparative analysis categorized DXWR genes into three evolutionary groups: 18,480 core genes, 15,880 accessory genes, and 6822 unique genes. Transcriptomic profiling identified 10,593 differentially expressed genes (DEGs) relative to the control, with combined stress triggering the most profound changes, specifically inducing the upregulation of 5573 genes and downregulation of 5809 genes. Functional characterization revealed that core genes, including DREB transcription factors, coordinate energy metabolism and antioxidant pathways; accessory genes, such as glycoside hydrolase GH18 family members, optimize energy supply via adaptive evolution; and unique genes, including specific UDP-glycosyltransferases (UDPGTs), confer specialized stress resilience. Widely targeted metabolomics identified 889 differentially accumulated metabolites (DAMs), highlighting significant accumulations of oligosaccharides (e.g., raffinose) to support glycolytic energy production and a marked increase in flavonoids (153 compounds identified, e.g., procyanidins) enhancing antioxidant defense. Hormonal signals, including jasmonic acid and auxin, were reconfigured to balance growth and defense responses. We propose a multi-level regulatory network based on a “core-unique-adaptive” genetic framework, centered on ERF family transcriptional hubs and coordinated through a metabolic adaptation strategy of “energy optimization, redox homeostasis, and growth inhibition relief”. These findings offer innovative strategies for improving rice stress tolerance, particularly for enhancing germination of direct-seeded rice under early spring low-temperature and anaerobic conditions, by utilizing key genes such as GH18s and UDPGTs, thereby providing crucial theoretical and technological support for addressing food security challenges under climate change. Full article

Background: Fetal tachyarrhythmias occur in less than 0.1% pregnancies, with atrial flutter accounting for one-third of cases. Atrial flutter results from a reentrant circuit within the atrium with atrial rates in fetal atrial flutter ranging from 300 to 540 beats per minute. The fetal atrial flutter is most often an isolated finding; however, it may also be associated with maternal diabetes, neonatal macrosomia, cardiac rhabdomyoma, maternal substance use, Turner syndrome, congenital heart disease, and the presence of accessory pathways. The majority of cases of atrial flutter in the neonatal period are isolated; however, only a few cases of recurrent atrial flutter have been described. Methods: This is a single-institution, retrospective chart review of neonates with recurrent atrial flutter. Results: Four neonates with recurrent atrial flutter were identified, each linked either to a correctable trigger or to an underlying substrate, guiding individualized therapy. When no clear trigger was present, antiarrhythmic medication was required. Conclusions: These cases highlight the importance of the recognition of potential triggers of recurrent neonatal atrial flutter, tailoring therapy accordingly and considering antiarrhythmic agents when necessary. Full article

Background: Right free wall (RFW) accessory pathways (APs) represent a relatively rare form of AP, and transcatheter (TC) ablation of these APs carries high procedural failure rates, both with radiofrequency (RF) and cryoenergy. The aim of this study was to report the outcomes of a minimally invasive approach in non-fluoroscopic 3D TC ablation of RFW APs, comparing cryoenergy and RF. Methods: Between March 2010 and March 2024, 62 consecutive patients with RFW APs underwent transcatheter ablation at our institution with a minimally invasive approach. The ablation results were analyzed and compared. Results: The overall acute success rate was 83.9% [52/62 patients; 25/28 (89.3%) for right lateral (RL) APs, 18/19 (94.7%) for right anterior–lateral (RAL) APs, and 9/15 (60.0%) for right posterior–lateral (RPL) APs, p = 0.014], with very limited fluoroscopy use and no complications. There were no significant differences in the acute success rates between the RF and cryoablation groups (32/37 vs. 20/25, p = 0.506). The median follow-up was 24.8 months (IQR 12.5–49.8), and 16 recurrences (30.8%) were observed (3 in the cryoablation group and 13 in the RF group, p = 0.068). The RAL localization of the AP and age > 12 years were predictors of ablation success in multivariate regression analysis. Conclusions: In children, a minimally invasive 3D TC ablation of RFW APs is a completely safe and quite effective approach, with better results for RAL and RL APs, poorer results for RPL APs, and no significant differences between cryoenergy and RF. Full article

Background/Objectives: Heart disease affects 0.1% to 4% of pregnant women, with congenital heart defects being the leading cause in developed countries. While maternal mortality is generally low, pre-existing cardiac conditions substantially increase adverse outcome risks. This report describes the multidisciplinary management of a pregnant patient with a bicuspid aortic valve, severe aortic stenosis, and ascending aortic ectasia. Case Presentation: A 34-year-old pregnant woman, asymptomatic but at high risk (World Health Organization Class III) for hemodynamic decompensation, was closely monitored throughout gestation. At 36 weeks, intrauterine growth restriction was detected, prompting an elective cesarean delivery at 38 weeks. Postpartum, the patient developed pre-eclampsia, which was managed successfully. Imaging revealed progressive aortic dilation, leading to surgical aortic valve replacement and ascending aorta reduction plasty. Post-operatively, atrioventricular reentrant tachycardia from an unrecognized accessory pathway developed; medical therapy effectively controlled the arrhythmia after failed catheter ablation. One year later, both mother and child remained in good health. Discussion: This case illustrates the complexity of managing pregnancy in women with congenital heart disease and significant aortic pathology. The physiological changes of pregnancy can exacerbate underlying lesions, necessitating individualized risk assessment, vigilant monitoring, and timely intervention. Conclusions: A multidisciplinary approach involving cardiology, obstetrics, anesthesiology, and genetics is essential to optimize outcomes for pregnant women with significant heart disease. As advances in care allow more women with congenital heart defects to reach childbearing age, structured care pathways remain vital for ensuring safe pregnancies and long-term cardiovascular health. Full article

Human leukocyte antigen class I (HLA-I) molecules present intracellular peptides on the cell surface to enable CD8+ T cells to effectively control viral infections. Many viruses disrupt this antigen presentation pathway to evade immune detection. In this study, we demonstrate that SARS-CoV-2 Nsp1 impairs both the constitutive and interferon-γ (IFN-γ)-induced upregulation of HLA-I. Moreover, Nsp1 also blocks IFN-γ-induced expression of HLA-II. We found that, contrary to previously published work, the early SARS-CoV-2 B 1.1.7 Alpha variant lacking the accessory protein ORF8 retained full capacity to downregulate HLA-I, comparable to an ORF8-expressing wild-type isolate. While ectopic overexpression of ORF8 could reduce HLA-I surface levels, this effect was only observed at high expression levels. In contrast, moderate expression of the viral protein Nsp1 was sufficient to potently suppress both basal and IFN-γ-induced HLA-I, as well as HLA-II expression. To probe the underlying mechanism, we analyzed HLA-I-associated genes in previously published RNA-sequencing datasets and confirmed that Nsp1 reduces expression of components required for HLA-I biosynthesis and antigen processing. These findings identify Nsp1 as a key factor that impairs antigen presentation pathways, potentially contributing to the ability of SARS-CoV-2 to modulate immune recognition. Full article

Grapholita molesta is a globally significant fruit pest. Females achieve maximal reproductive output through efficient sperm utilization following a single copulation. Post-mating maturation of eupyrene sperm is a critical step in reproductive success. Here, we report that a male accessory gland-derived serine protease (named GmAGSP1) is essential for this process. GmAGSP1 was only distantly related to other identified sperm-activating SPs, and its transcript was highly expressed in the AG at 48 h after emergence. RNAi-mediated knockdown of GmAGSP1 in males did not affect courtship rate, copulation duration, or mating frequency, whereas male fertility decreased significantly. Mating with GmAGSP1-knockdown males markedly impaired eupyrene sperm maturation in the spermatophores, with phenotypes including failure of eupyrene sperm bundles to dissociate normally and marked reduction in viability of the dissociated eupyrene sperm. Finally, untargeted metabolomic analysis preliminarily demonstrated marked alterations in multiple metabolic pathways within the spermatophore following mating with GmAGSP1-knockdown males. This study advances our understanding of the regulatory mechanism of “sperm activation in the spermatophore’s metabolic microenvironment mediated by male AG-derived SP” while providing critical insights for the development of novel genetic control strategies targeting G. molesta. Full article